For more information, contact: HIV/AIDS Programme World ...Antiretroviral therapyfor HIV infection...

AntiretrovirAl therApy for hiv infection in Adults

And Adolescents

Recommendations for a public health approach

2010 revision

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Strengthening health services to fight HIV/AIDS

HIV/AIDS ProgrammeFor more information, contact:

World Health Organization Department of HIV/AIDS

20, avenue Appia 1211 Geneva 27 Switzerland

E-mail: [email protected]

www.who.int/hiv

ISBN 978 92 4 159976 4

WHO Library Cataloguing-in-Publication Data

Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. – 2010 rev.

1.Anti-retroviral agents - therapeutic use. 2.Anti-retroviral agents - pharmacology. 3.HIV infections – drug therapy. 4.Adult. 5.Adolescent. 6.Guidelines. 7.Developing countries. I.World Health Organization.

ISBN 978 92 4 159976 4 (NLM classification: WC 503.2)

© World Health Organization 2010

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And AdolescentsRecommendations for a public

health approach

2010 revision

iii

1. Acronymsandabbreviations.............................................................................................. 1

2. Acknowledgements............................................................................................................ 5

3. Executivesummary............................................................................................................ 7

4. Background........................................................................................................................ 8

5. Fundinganddeclarationsofinterest.................................................................................. 9

6. Guidingprinciples............................................................................................................ 10

7. Objectivesoftheguidelinesandtargetaudience.............................................................11

8. Methodologyandprocess............................................................................................... 12

9. Fromevidencetorecommendation................................................................................. 14

10. Adaptingtheguidelines................................................................................................... 17

11. Summaryofchanges....................................................................................................... 19

12. Recommendationsataglance........................................................................................ 20

13. Whentostart.................................................................................................................... 2413.1. Recommendations............................................................................................... 2413.2. Evidence............................................................................................................... 2413.3. Summaryoffindings............................................................................................. 2513.4. Benefitsandrisks................................................................................................. 2613.5. Acceptabilityandfeasibility.................................................................................. 2613.6. Clinicalconsiderations......................................................................................... 27

14. Whattostart..................................................................................................................... 3114.1. Recommendations............................................................................................... 3114.2. Evidence............................................................................................................... 3114.3. Summaryofmainfindings.................................................................................... 3214.4. Benefitsandrisks................................................................................................. 3314.5. Acceptabilityandfeasibility.................................................................................. 3314.6. ThechoicebetweenNVPandEFV....................................................................... 3414.7. AZT+3TC+EFVoption..................................................................................... 3514.8. AZT+3TC+NVPoption..................................................................................... 3614.9. TDF+3TC(orFTC)+EFVoption....................................................................... 3714.10. TDF+3TC(orFTC)+NVPoption....................................................................... 3814.11. TripleNRTIoption................................................................................................. 3914.12. Stavudine(d4T).................................................................................................... 3914.13. NRTIsnottobeusedtogether.............................................................................. 40

contents

ivAntiretrovirAl therApy for hiv infection in Adults And Adolescents

recommendAtions for A public heAlth ApproAch

15. Specificpopulations–whenandwhattostart................................................................ 4115.1. RecommendationsforHIV-infectedpregnantwomen.......................................... 4115.2. RecommendationsforwomenwithpriorexposuretoantiretroviralsforPMTCT.. 4215.3. RecommendationsforHIV/HBVcoinfection......................................................... 4415.4. RecommendationsforHIV/tuberculosiscoinfection............................................ 4515.5. Rifabutin............................................................................................................... 46

16. WhentoswitchART......................................................................................................... 4816.1. Recommendations............................................................................................... 4816.2. Evidence............................................................................................................... 4816.3. Summaryoffindings............................................................................................. 4816.4. Benefitsandrisks................................................................................................. 4916.5. Clinicalconsiderations......................................................................................... 50

17. Second-lineregimens...................................................................................................... 5317.1.Recommendations................................................................................................... 5317.2. Evidence............................................................................................................... 5317.3. Summaryoffindings............................................................................................. 5317.4. Benefitsandrisks................................................................................................. 5417.5. Acceptabilityandfeasibility.................................................................................. 5417.6. Clinicalconsiderations......................................................................................... 5517.7. Selectionofsecond-lineNRTIs............................................................................ 5617.8. Maintaining3TCinthesecond-lineregimen........................................................ 5617.9. NRTIsforHIV/HBVcoinfection............................................................................. 5717.10. Selectionofboostedproteaseinhibitor................................................................ 57

18. Third-lineregimens.......................................................................................................... 5818.1.Recommendations................................................................................................... 5818.2. Evidence............................................................................................................... 5818.3. Summaryoffindings............................................................................................. 5818.4. Benefitsandrisks................................................................................................. 5918.5. Acceptabilityandfeasibility.................................................................................. 5918.6. Clinicalconsiderations......................................................................................... 60

19. Packageofcareinterventions.......................................................................................... 6119.1. Guidingprinciples................................................................................................ 6119.2. Voluntarycounsellingandtestingandprovider-initiatedtestingandcounselling.... 6119.3. PreventingfurthertransmissionofHIV................................................................. 6119.4. TheThreeI'sforHIV/TB........................................................................................ 6219.5. Cotrimoxazoleprophylaxis................................................................................... 6219.6. Sexuallytransmittedinfections............................................................................. 6219.7. Treatmentpreparedness...................................................................................... 6319.8. EarlyinitiationofART............................................................................................ 6319.9. ARTasprevention................................................................................................ 63

v

20. Laboratorymonitoring...................................................................................................... 6420.1. Guidingprinciples................................................................................................ 6420.2. LaboratorymonitoringonART............................................................................. 65

21. Annexes............................................................................................................................ 6721.1. SpecialnoteoncoinfectionwithHIVandhepatitisC........................................... 6721.2. Dosagesofrecommendedantiretrovirals............................................................ 6721.3. Toxicitiesandrecommendeddrugsubstitutions.................................................. 6921.4. ARV-relatedadverseeventsandrecommendations............................................ 7121.5. DiagnosticcriteriaforHIV-relatedclinicalevents................................................. 7321.6. Gradingofselectedclinicalandlaboratorytoxicities........................................... 8121.7. PreventionandassessmentofHIVdrugresistance............................................. 8621.8. Specialnoteonantiretroviralpharmacovigilance................................................. 8721.9. GRADEevidencetables....................................................................................... 89

22. References..................................................................................................................... 126

1

3TC lamivudine

AB antibody

ABC abacavir

ACTG AIDSClinicalTrialsGroup

AIDS acquiredimmunodeficiencysyndrome

ALT alanineaminotransferase

ANC antenatalclinic

ART antiretroviraltherapy

ARV antiretroviral

AST aspartateaminotransferase

ATV atazanavir

AZT zidovudine(alsoknownasZDV)

BID twicedaily

BMI bodymassindex

bPI boostedproteaseinhibitor

CD4cell T-lymphocytebearingCD4receptor

CEM cohorteventmonitoring

CMV cytomegalovirus

CNS centralnervoussystem

CXR chestX-ray

d4T stavudine

DART DevelopmentofAntiretroviralTherapy(inAfrica)

DBS driedbloodspot

ddI didanosine

DNA deoxyribonucleicacid

DRV darunavir

EC enteric-coated

EFV efavirenz

EIA enzymeimmunoassay

ETV etravirine

EPTB extrapulmonarytuberculosis

FBC fullbloodcount

FDC fixed-dosecombination

FPV fos-amprenavir

FTC emtricitabine

1. Acronyms And AbbreviAtions

2AntiretrovirAl therApy for hiv infection in Adults And Adolescents


GDG GuidelinesDevelopmentGroup

GI gastrointestinal

GNP+ GlobalNetworkofPeopleLivingwithHIV

GRADE GradingofRecommendationsAssessment,DevelopmentandEvaluation

Hb haemoglobin

HBV hepatitisBvirus

HCV hepatitisCvirus

HDL high-densitylipoprotein

HIV humanimmunodeficiencyvirus

HIVDR HIVdrugresistance

HIVRNA humanimmunodeficiencyvirusribonucleicacid

HSV herpessimplexvirus

ICW InternationalCommunityofWomenLivingwithHIV/AIDS

IDU injectingdruguser

IDV indinavir

INH isoniazid

IRIS immunereconstitutioninflammatorysyndrome

ITCP InternationalTreatmentPreparednesscoalition

LPV lopinavir

LPV/r lopinavir/ritonavir

MTCT mother-to-childtransmission(ofHIV)

NAM nucleoside/nucleotideanaloguemutation

NFV nelfinavir

NNRTI non-nucleosidereversetranscriptaseinhibitor

NRTI nucleosidereversetranscriptaseinhibitor

NVP nevirapine

OBR optimizedbackgroundregimen

OI opportunisticinfection

OST opioidsubstitutiontreatment

PCP Pneumocystis jirovecipneumonia

PEPFAR President’sEmergencyPlanforAIDSRelief

PETRA PerinatalTransmissionStudy

PGL persistentgeneralizedlymphadenopathy

PI proteaseinhibitor

PLHIV peoplelivingwithHIV

3

PML progressivemultifocalleukoencephalopathy

PMTCT preventionofmother-to-childtransmission(ofHIV)

/r low-doseritonavir

RAL raltegravir

RBV ribavirin

RCT randomizedclinicaltrial

RNA ribonucleicacid

RT reversetranscriptase

RTI reversetranscriptaseinhibitor

RTV ritonavir

Sd-NVP single-dosenevirapine

SJS Stevens-Johnsonsyndrome

SQV saquinavir

STI structuredtreatmentinterruption

TB tuberculosis

TDF tenofovirdisoproxilfumarate

TEN toxicepidermalnecrolysis

TLC totallymphocytecount

VL viralload

ULN upperlimitofnormal

UNAIDS JointUnitedNationsProgrammeonHIV/AIDS

WBC whitebloodcellcount

WHO WorldHealthOrganization

5

The World Health Organization wishes to express its gratitude to the following institutions,technicalcommitteesandconsultantsfortheircontributionstotherevisionoftheantiretroviraltreatmentrecommendationsforHIV-infectedadultsandadolescents.

University of California, San Francisco, USAJamalHarris,TaraHorvath,ElizaHumphreys,GailKennedy,GeorgeRutherford,KarenSchlein,SarahWan,GavrilahWells,RoseWhitmore

South African Cochrane Centre, Medical Research Council of South Africa, Cape Town, South AfricaJoyOliver,ElizabethPienaar,NandiSiegfried

University of California, Berkeley, USAAndrewAnglemyer

University of Minnesota, USAAlicenSpaulding

Johns Hopkins University, USALarryChang

University of North Carolina, USAAmitabhSuthar

University of Birmingham, UKOlalekanUthman

McMaster University, CanadaNancySantesso,HolgerSchünemann,

University of Alberta, CanadaAmeetaSingh,ThomasWong

University of Liverpool, UKDavidBack,SaraGibbons,SayeKhoo,KaySeden

Griffith University, AustraliaPatriciaWhyte

University of Bern, SwitzerlandMartinBrinkhof,MathiasEgger,OliviaKeiser

Global Network of People Living with HIV/AIDS (GNP+)

International Community of Women Living with HIV/AIDS Southern Africa (ICW)

Members of the WHO ART Guidelines CommitteeCarlos Avila (UNAIDS, Switzerland), Lori Bollinger (Futures Institute, USA), Alexandra Calmy(UniversityofGeneva,Switzerland),ZenganiChirwa(MinistryofHealth,Malawi),FrancoisDabis(ISPED,France),ShaffiqEssajee(ClintonFoundation,USA),LoonGangte(GNP+,India),JulianGold (University of New South Wales, Australia), James Hakim (University of Zimbabwe,

2. Acknowledgements



Zimbabwe), Charles Holmes (PEPFAR, USA), Robert Josiah (NACP, Tanzania), Ayesha Khan(MinistryofHealth,Pakistan),StephenLawn(UniversityofCapeTown,SouthAfrica),FrankLule(WHOAFRO,Congo),Jean-PaulMoatti(INSERM,France),LynneMofenson(NIH,USA), IreneMukui(MinistryofPublicHealthandSanitation,Kenya),PaulaMunderi(UgandaVirusResearchInstitute,Uganda),MutintaNalubamba(MinistryofHealth,Zambia),PortiaNgcaba(TAC,SouthAfrica), Megan O’Brien (Clinton Foundation, USA), Sylvia Ojoo (Institute of Human Virology,Kenya), Vladimir Osin (ITPC, Russia), Praphan Phanuphak (Thai Red Cross, Thailand), BBRewari (National AIDS Control Organization, India), Papa Salif Sow (University of Dakar,Senegal), Omar Sued (WHO AMRO, USA), Tengiz Tsertsvadze (National AIDS Programme,Georgia),RochelleWalensky(HarvardCenterforAIDSResearch,USA),RobinWood(Universityof Cape Town, South Africa), Augustin Yuma (National HIV/AIDS Programme, DemocraticRepublicofCongo),OlegYurin(CentralInstituteofEpidemiology,Russia).

External peer reviewersXavier Anglaret (University of Bordeaux, France), Stefano Lazzari (Global Fund for AIDS,TuberculosisandMalaria,Switzerland),VeroniqueBortolotti(WHOEMRO,Egypt),PedroCahn(FundaciónHuesped,Argentina),SergeEholie (ANEPA,Côted'Ivoire), JeanBaptisteGuiard-Schmid(WHOAFRO,BurkinaFaso),ScottHammer(ColumbiaUniversity,USA),MarkHarrington(TAG,USA),EllyKatabira (MakerereUniversity,Uganda),RicardoKuchembecker (MinistryofHealth,Brazil),NagalingeswaranKumarasamy(YRGCare,India),BarbaraMarston(CDC,USA),ElliotRaizes(CDC,USA),PadminiSrikantiah(WHOSEARO,India).

WHOalsowishestoacknowledgecommentsandcontributionsmadebyJacquelineBataringaya(InternationalAIDSSociety,Switzerland),SilviaBertagnolio(WHO/HTM/HIV),JoseMariaGarciaCalleja (WHO/HTM/HIV),HelenChun(DepartmentofDefense,USA),SuzanneCrowe(BurnetInstitute, Australia), Micheline Diepart (WHO/HTM/HIV), Boniface Dongmo (WHO/HTM/HIV),Andrew Doupe (WHO/HTM/HIV), Ted Ellenbrook (CDC, USA), Robert Ferris (PEPFAR, USA),HaileyesusGetahun(WHO/HTM/STB),SarahGlover(LSHTM,UnitedKingdom),ReubenGranich(WHO/HTM/HIV), Catherine Godfrey (NIH, USA), Alexandre Hamilton (St. Vincent's Hospital,Australia),JohnKaplan(CDC,USA),JohnLiddy(independentconsultant,Thailand),MaryLouLudgren(CDC,USA),BrianMcMahon(CDC,USA),ThomasMinior(PEPFAR,USA),NeilParkin(WHO/HTM/HIV), FrancoiseRenaud-Thery (WHO/HIV/SIR), Erik Schouten (Ministry ofHealth,Malawi),DelphineSculier(WHO/HTM/STB),NathanShaffer(WHO/HTM/HIV),TinTinSint(WHO/HTM/HIV),YvesSouteyrand(WHO/HTM/HIV),StevenWiersma(WHO/FCH/IVB)andPaulWeidle(CDC,USA).

Special thanks go to Victoria Anagbo, Sally Girvin and Nadia Hilal of WHO/HTM/HIV, whoprovided administrative support, and to Chris Duncombe of HIVNAT Research Network(Thailand)andtheUniversityofNewSouthWales(Australia),whowasthemajorwriterof theARTguidelinesdocument.

TheworkwascoordinatedbySiobhanCrowleyandMarcoVitoriaofWHO/HTM/HIV,Geneva,Switzerland.

7

Sincethepublicationin2006ofAntiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach,newevidencehasemergedonwhentoinitiateART,optimalARTregimens,themanagementofHIVcoinfectionwithtuberculosisandchronicviral hepatitis and the management of ART failure. This evidence formed the basis for therecommendationscontainedinthe2010update,whichoutlinesapublichealthapproachtothedeliveryofARTforadultsandadolescentsinsettingswithlimitedhealthsystemscapacityandresources. The recommendations were based on the preparation GRADE evidence profiles,systematic and targeted reviews, risk-benefit analyses, consultations with PLHIV, technicalreports,andassessmentsofimpact,feasibilityandcost.

This guideline revision was conducted in accordance with procedures outlined by the WHO Guidelines Review Committee and isbasedontheGRADEapproachtoevidencereview.Theprocessinvolvedfourseparateworkinggroups:theInternal WHO ART Guideline Working Group,theART Guideline Drafting Group,theexternalART Peer Review PanelandthefullART Guideline Review Committee.

Theconsensus recommendations,whichemerged fromconsultationsof theworkinggroups,encourageearlierHIVdiagnosisandearlierantiretroviraltreatment,andpromotetheuseoflesstoxic regimens and more strategic laboratory monitoring. The guidelines identify the mostpotent, effective and feasible first-line, second-line and subsequent treatment regimens,applicable to the majority of populations, the optimal timing of ART initiation and improvedcriteriaforARTswitching,andintroducetheconceptofthird-lineantiretroviralregimens.

Theprimaryaudiencesarenationaltreatmentadvisoryboards,partnersimplementingHIVcareand treatment, and organizations providing technical and financial support to HIV care andtreatmentprogrammesinresource-limitedsettings.

It is critical that national ART programme and public health leaders consider theserecommendationsinthecontextofcountries’HIVepidemics,thestrengthsandweaknessesofhealthsystems,andtheavailabilityoffinancial,humanandotheressentialresources.Inadaptingtheseguidelines,caremustbeexercisedtoavoidunderminingcurrenttreatmentprogrammes,toprotectaccessforthemostat-riskpopulations,toachievethegreatestimpactforthegreatestnumber of people and to ensure sustainability. It is similarly important to ensure that theadaptation of these guidelines do not stifle ongoing or planned research, since the newrecommendationsreflectthecurrentstateofknowledgeandnewinformationforsustainabilityandfuturemodificationsofexistingguidelineswillbeneeded.

3. executive summAry



WHOguidelinesforARTforHIVinfectioninadultsandadolescentswereoriginallypublishedin2002,andwererevisedin2003and2006.NewevidencehasemergedonwhentoinitiateART,optimalARTregimens,themanagementofHIVcoinfectionwithtuberculosisandchronicviralhepatitis, and the management of ART failure. This evidence formed the basis for the newrecommendations contained in the 2010 guidelines and summarized in the Rapid advice: Antiretroviral therapy for HIV infection in adults and adolescents(http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf).Considerationwasgiventotherisksandbenefitsofimplementingeachrecommendation,inadditiontoitsacceptability,costandfeasibility.TheguidelinesincorporatethebestavailableevidencewithinaframeworkthatemphasizesthepublichealthapproachtothescalingupofqualityHIVcareandtreatment.(1)

The consensus recommendations encourage earlier diagnosis and earlier treatment, andpromotetheuseoflesstoxicregimensandmorestrategiclaboratorymonitoring.Itiscriticalthatnational ART programme and public health leaders consider these recommendations in thecontextofcountries’HIVepidemics,thestrengthsandweaknessesofhealthsystems,andtheavailabilityoffinancial,humanandotheressentialresources.(1)Caremustbeexercisedtoavoidunderminingcurrenttreatmentprogrammes,toprotectaccessforthemostat-riskpopulations,toachievethegreatestimpactforthegreatestnumberofpeopleandtoensuresustainability.

4. bAckground

9

Funding tosupport thisworkcomes fromtheUSPresident’sEmergencyPlan forAIDSRelief(PEPFAR), The United Nations Joint Programme on HIV/AIDS Unified Budget and Workplan(UNAIDSUBW),andspecificfundsthroughstafftime.

Declaration of interest forms were collected from everymember of each guidelines workinggroup. Two declarations of interest were made. Dr Charles Holmes declared previousemployment,whichceasedinJanuary2008,byGileadSciences,largelyforphase1studiesofexperimental ARVs. This interest was assessed by the WHO Secretariat as not sufficient toprecludeDrHolmes’participationinthismeeting.DrPedroCahnactedasamemberofthePeerReviewGroupanddeclaredthatheservesasadvisoryboardmemberforAbbott,BristolMyersSquibb, Tibotec, Merck, Avexa, Pfizer and Gilead. This interest was assessed by the WHOSecretariatasnotsufficienttoprecludeDrCahn’sparticipationinthismeeting.

5. funding And declArAtions of interest



Theprinciplesguidingthedevelopmentoftheserecommendationswereasfollows:

• toprioritizethebestoptionsfortreatmentofHIVinfectionandproposealternativesifthebestoptionwasnotavailable;

• tobeclearwhenhigh-qualityevidencesupportsastrongrecommendation;

• tobeclearwhenlow-qualityevidenceoranuncertainbalancebetweenrisksandbenefitsupportsaconditionalrecommendation;

• to be both realistic and aspirational, recognizing the possibility for progressiveimplementationoftherecommendationsoverthelifetimeoftheseguidelinesuntil2012.

6. guiding principles

11

• Toprovideevidence-basedrecommendationsoutliningapublichealthapproachtothedeliveryofARTforadultsandadolescents,withafocusonsettingswithlimitedhealthsystemscapacityandresources.

• Toidentifythemostpotent,effectiveandfeasiblefirst-line,second-lineandsubsequenttreatmentregimensascomponentsofexpandednationalresponsesforHIVcare.

• To develop recommendations applicable to themajority of populations regarding theoptimal timingofART initiation,preferred first-lineandsecond-lineARV regimensandimproved criteria for ART switching, and to introduce the concept of third-line ARTregimens.

Thetarget audiencesarenationaltreatmentadvisoryboards,partnersimplementingHIVcareand treatment, and organizations providing technical and financial support to HIV care andtreatmentprogrammesinresource-limitedsettings.

7. objectives of the guidelines And tArget Audience



Throughout2009,WHOworkedtoupdatetheguidelinesforAntiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach throughaseriesofcoordinatedeffortstoreviewandsynthesizenewandemergingevidenceontheoptimaluseofART within a public health approach. This process was based on the preparation GRADEprofiles, systematic and targeted reviews, risk-benefit analyses, technical reports andassessmentsofimpact,feasibilityandcost.

All evidencedocumentationprepared for theseguidelines isavailableon the2009-2010 ART guidelines for adults and adolescents evidence map webpage (http://www.who.int/hiv/topics/treatment/evidence3/en/index.html).

Preparatoryworkincludedthefollowing:

• GRADEprofilesonwhentostartART,whattouseinfirst-lineandsecond-lineregimensandwhentoswitchtosecond-linetherapy.

• Systematicandtargetedreviewson:

− themanagementofHIV/hepatitisandHIV/TBcoinfection;

− ARTsafety,toxicityandteratogenicity;

− theutilityofCD4countandviralloadinmonitoringART;

− ARTfailurecriteria;

− third-lineART;

− interactions between ARVs and opioids, and drugs used for the treatment oftuberculosis(TB),viralhepatitisandmalaria.

• ConsultationswithPLHIV.

• AreportonARTadherence.

• AreviewofcurrentARTguidelinesfrom26countries.

• CostinginformationbasedonstudiesofprocurementandproductionofARVs.

• An impact assessment of the number of patients in need of treatment according tovariousCD4countthresholds.

• AfeasibilityanalysisfortheintroductionoftheproposedguidelinesinMalawi.

Search strategies employed in the systematic reviews, meta-analyses and GRADE profileswhichwereconductedbytheCochraneHIV/AIDSgroupfollowedmethodologydescribedinThe Cochrane handbook for systematic reviews of interventions (Version 5.0.2; last updatedSeptember2009,availableathttp://www.cochrane-handbook.org/.

Inreviewswheredatawerenotamenabletometa-analysisand/orGRADEprofiles,systematicsearches,usingrelevantkeywordsandsearchstrings,wereconductedofelectronicdatabases(Medline/Pubmed, Embase, CENTRAL), conference databases (Aegis, AIDSearch, NLMGatewayandhandsearches)andclinicaltrialregisters(http://clinicaltrials.gov/www.controlled-trials.comwww.pactr.org).

ThisguidelinerevisionisinaccordancewithproceduresoutlinedbytheWHO Guidelines Review Committee andisbasedontheGRADEapproachtoevidencereview.Theprocessinvolvedfour

8. methodology And process

13

separateworkinggroups: the Internal WHO ART Guideline Working Group, theART Guideline Drafting Group,theexternalART Peer Review PanelandthefullART Guideline Review Committee. The composition of the groups was in accordance with WHO procedures for guidelinedevelopment and included HIV experts, civil society representatives, programmemanagers,costing experts, guideline methodologists, epidemiologists, health economists, PEPFARtechnicalworkinggrouprepresentatives,PLHIVcommunityrepresentatives,andWHOregionalandcountryofficers.DeclarationsofInterestsweresubmittedbygroupparticipants.

The work was coordinated by the Antiretroviral, Treatment and HIV Care team of the WHODepartmentofHIV/AIDS.

TheacademicinstitutionsthatcontributedtowritingtheguidelinesweretheLiverpoolMedicalSchool (UK), the South African Medical Research Council / South African Cochrane Centre(South Africa), the University of California, San Francisco / Cochrane Collaborative ReviewgrouponHIV/AIDS(USA), theUniversityofNewSouthWales(Australia)andtheUniversityofBern(Switzerland).ContributionswerealsoreceivedfromtheUSCentersforDiseaseControlandPrevention(CDC),UNAIDSandtheGlobalFundtoFightAIDS,TuberculosisandMalaria.Consultations were held with civil society networks including the Global Network of PeopleLiving with HIV (GNP+), the International Treatment Preparedness Coalition (ITCP) and theInternationalCommunityofWomenwithHIV/AIDS(ICW).

Groupprocessesweremanagedasfollows.TheproposedrecommendationswereconsideredseparatelybytheARTGuidelineWorkingandDraftingGroupsusingarisk-benefitanalysistoolconsistingofatableexploringthefollowingdomains:existingandproposedrecommendations,evidencefortheoutcomesdeemedcritical(mortality,diseaseprogressionandseriousadverseevents),risksandbenefitsofimplementingtherecommendations,acceptability,costs,feasibility,suggestedrankingofrecommendations(strongorconditional),gapsandresearchneeds.ThegroupsplacedemphasisonconcernsandimportantoutcomesasvoicedbyPLHIVandonthecriticalneedtomaintainequity,accessandcoverage.

Thedraftrecommendations,GRADEprofiles,risk-benefitanalysistablesandsupportingdatawerecirculatedtotheART Peer Review PanelforcommentbeforeconveningthemultidisciplinaryART Guideline Review Committee in October 2009. Following the release ofRapid advice inNovember2009,successivedraftsofthefullguidelineswerepreparedandcirculatedtotheART Guideline Drafting GroupandtheexternalART Peer Review Panelforcomments.Allresponseswereconsideredandaddressedinthefinaldraft.Disagreementswereresolvedindiscussions.

Theguidelineswillbedisseminatedasapaper-basedhandbookandelectronicallyontheWHOwebsite.

Regional and subregional meetings are planned to adapt these global recommendations tolocalneedsandfacilitateimplementation.

Aplanwillbedevelopedtoevaluatetheimplementationoftheguidelinesbyusers.

A reviewof theguidelines isplanned for2012.Therewillbe interim reviewsasnewevidencebecomesavailable.



Recommendations contained in the 2006 guidelines were based on levels of evidence fromrandomized clinical trials (RCTs), scientific studies, observational cohort data and, whereinsufficientevidencewasavailable,expertopinion.Eachrecommendationwasratedusingthecriteria described in Table 1, the letters A, B, and C representing the strengths of therecommendationsandthenumeralsI,II,IIIandIVrepresentingthequalityoftheevidence.Cost-effectiveness,acceptabilityandfeasibilitywerenotexplicitlyconsidered.

Table 1. Assessment of evidence as used in the 2006 guidelines

Strength of recommendation Level of evidence to make for recommendation

A.Recommended−shouldbefollowed

B.Consider−applicableinmostsituations

C.Optional

I. Atleastonerandomizedcontrolledtrialwithclinical,laboratoryorprogrammaticend-points

II. Atleastonehigh-qualitystudyorseveraladequatestudieswithclinical,laboratoryorprogrammaticend-points

III. Observationalcohortdata,oneormorecase-controlledoranalyticalstudiesadequatelyconducted

IV. Expertopinionbasedonevaluationofotherevidence

Inthe2010guidelinesthedevelopmentofarecommendationremainsguidedprimarilybythequalityofevidenceusingGRADEmethodology.However, theGRADEapproach includes theadditional domains of the balance between risks and benefits, acceptability (values andpreferences), cost and feasibility. Values and preferences may differ in regard to desiredoutcomesortheremaybeuncertaintyaboutwhetheraninterventionrepresentsawiseuseofresources.Furthermore,despiteclearbenefits,itmaynotbefeasibletoimplementaproposedrecommendationinsomesettings.

Table 2. Assessment of strengths of recommendations as used in the 2010 guidelines

Strength of recommendation Rationale

StrongThepanelisconfidentthatthedesirableeffectsofadherencetotherecommendationoutweightheundesirableeffects.

9. from evidence to recommendAtion

15

Strength of recommendation Rationale

Conditional

Thepanelconcludesthatthedesirableeffectsofadherencetoarecommendationprobablyoutweightheundesirableeffects.

However:

therecommendationisonlyapplicabletoaspecificgroup,populationorsettingOR

newevidencemayresultinchangingthebalanceofrisktobenefitOR

thebenefitsmaynotwarrantthecostorresourcerequirementsinallsettings.

No recommendation possibleFurtherresearchisrequiredbeforeanyrecommendationcanbemade.

IntheGRADEapproach,thequalityofabodyofevidenceisdefinedastheextenttowhichonecanbeconfidentthatthereportedestimatesofeffect(desirableorundesirable)availablefromtheevidenceareclosetotheactualeffectsofinterest.Theusefulnessofanestimateoftheeffectofaninterventiondependsonthelevelofconfidenceinthatestimate.Thehigherthequalityofevidence, themore likelyastrongrecommendationcanbemade. It isnotalwayspossible toprepareGRADEprofilesforallinterventions.

Table 3. Assessment of strength of evidence as used in the 2010 guidelines

Evidence level Rationale

HighFurtherresearchisveryunlikelytochangeconfidenceintheestimateofeffect.

Moderate Furtherresearchislikelytohaveanimportantimpactonconfidenceintheeffect.

Low Furtherresearchisverylikelytohaveanestimateofeffectandislikelytochangetheestimate.

Very low Anyestimateofeffectisveryuncertain.



Table 4. Additional domains considered in developing strengths of recommendations

Domain Rationale

Benefits and risks

Whendevelopinganewrecommendation,desirableeffects(benefits)needtobeweighedagainstundesirableeffects(risks),consideringanypreviousrecommendationoranalternative.Thelargerthegaporgradientinfavourofthebenefitscomparedtotherisks,themorelikelyastrongrecommendationwillbemade.

Values and preferences (acceptability)

Iftherecommendationislikelytobewidelyacceptedorvaluedmorehighly,astrongrecommendationwillprobablybemade.Ifthereisagreatdealofvariabilityoriftherearestrongreasonsthattherecommendedcourseofactionisunlikelytobeaccepted,itismoreprobablethataconditionalrecommendationwillbemade.

Costs / financial implications (resource use)

Lowercosts(monetary,infrastructure,equipmentorhumanresources),orgreatercost-effectivenesswillmoreprobablyresultinastrongrecommendation.

Feasibility

Ifaninterventionisachievableinasettingwherethegreatestimpactisexpectedtobeattained,astrongrecommendationismoreprobable.ToolshavebeendevelopedtoassistnationalARTadvisorycommitteeswhenassessingthefeasibilityofimplementinganewrecommendation.Theseareavailableat:http://www.who.int/hiv/topics/treatment/evidence3/en/index.html

17

WHOnormativeguidelinesaredeveloped foraglobalaudienceand it isexpected thateachcountrywilladapttherecommendationstosuititsowncircumstances.WHOendorsestheuseofanationaltechnicaloradvisorytreatmentworkinggrouptodirecttheadaptationprocess.Itisrecognizedthattheimplementationofsomerecommendationsmaybechallenginginsomesettings in view of the differing prevalence of HIV and of limited available and promisedresources. It is recognized that the new recommendations have the potential to increasesubstantiallythenumberofpeopleeligibleforARTandtoincreasethecostofdeliveringARTaspartofcomprehensivecare.Immediateandfullimplementationoftheserecommendationsmaynotbepracticable,feasibleoraffordable.However,country-levelstrategicplanningshouldbedirected towards eventually implementing these recommendations and achieving nationaluniversal access to HIV care and treatment. It is recommended that national ART advisorycommittees consider the following six guiding principles to direct decision-making whenintroducingtherevisedrecommendations.

1. Do no harm

SeektomaintaincurrentprogressoftreatmentprogrammeswithoutdisruptingthecareofthoseontreatmentorcompromisingPLHIVathighestriskforpooroutcomes.

2. Accessibility

EnsurethatallclinicallyeligiblepeopleinfectedwithHIVareabletoentertreatmentservices.

3. Quality of care

Ensurethatcareachievesthehigheststandardspossible.

4. Equity of access

Ensurefairnessandjusticeinaccesstotreatmentservices.

5. Efficiency in resource use

Aimtoachievethegreatesthealthimpactwiththeoptimaluseofavailablehumanandfinancialresources.

6. Sustainability

Understandthelong-termconsequencesofchangesandhavethevisiontoprovidecontinued,lifelongaccesstoARTforthoseinneed.

While the six guidingprinciples shouldbe used to direct decision-making, contextual issuesmust also be taken into consideration, and it is not expected that all national ART advisorycommitteeswillcometothesamedecisions.Itisimportanttoengagestakeholders,includingPLHIV,civilsocietyandhealth-careworkers, inopendiscussionsabouthowtomakechoicesandimplementchanges.

Inaddition,thefollowingpointsshouldbeconsidered.

10. AdApting the guidelines



1. Strengthen health systems

In making decisions, priority should be given to interventions that will directly or indirectlystrengthenhealthsystems.

2. Implement in phases

Itmay not be possible to implement every new recommendation in every setting. A phasedapproachmaybenecessaryifonlysomerecommendationscanbeimplemented.

3. Understand the perspectives of PLHIV

Thetoxicityofd4TisofconcerntothemajorityofPLHIVanditscontinuingusemayundermineconfidenceinART.Ifd4Thastobeincludedinongoingregimens,strategiesshouldbedevisedto allow for substituting an alternative drug in cases of toxicity. There should be a plan toeventuallyavoidtheroutineuseofthisdrug.

4. Be forward-looking

TheWHOguidelineAntiretroviral therapy for HIV infection in adults and adolescents will nextbeupdated in2012.MemberStatesshouldstrivetoadoptthe2010recommendationsbeforethatdate.

Anadaptationguidehasbeenwrittentoaccompanytheseguidelines.WHOrecognizesthatthenewrecommendationswillpromotesignificantbenefitstoHIV-infectedindividuals,andalsothattheyhavethepotentialtosubstantiallyincreasethenumberofpeopleinneedofARTandthecostofdeliveringit.Dependingonhowthenewguidelinesareimplementedorinterpreted,theycouldalsoleadtounintendedconsequences,suchasreducedaccesstothosemostinneedorthe undermining of existing ART coverage or impending ongoing or planned research. Thepurpose of the adaptation guide is to assist Member States and programme managers tochooseandprioritizetherecommendations,especiallywhereresourcesarelimited.Inaddition,theguideisintendedtoserveasanadvocacytoolforpolicy-makersandtoprovideabasisfordifficult choices and decisions in Member States. The adaptation guide is available at:http://www.who.int/hiv/topics/treatment/guide_for_adaptation.pdf.

To further assist countries, programme managers, academic institutions and national ARTadvisory committees to adapt these new recommendations to their local circumstances, thefollowingmaterialsareavailableontheWHOmainevidencemapwebpage.http://www.who.int/hiv/topics/treatment/evidence3/en/index.html.

19

Earlier initiation of ART

OnthebasisoftheavailableevidencethepanelrecommendedARTinitiationforallPLHIVwithaCD4countof≤350cells/mm3andforthosewithWHOclinicalstage3or4ifCD4testingisnotavailable.

Simplified, less toxic antiretroviral drugs for use in first-line and second-line therapy

WhilecurrentoptionshavepermittedrapidARTscale-up,thecostintermsofside-effectshasbeen considerable. There is a clear demand both from PLHIV and health-care providers tophase in less toxicARVswhilemaintainingsimplified fixed-dosecombinations.TheavailableevidenceindicatesthatinitialARTshouldcontainanNNRTI(eitherNVPorEFV)plustwoNRTIs,oneofwhichshouldbe3TCorFTCandtheotherAZTorTDF.Countriesareadvisedtochooseonesecond-lineregimenforindividualswithfirst-linefailure.

Promoting the initiation of ART for all those with HIV/TB coinfection

While recognizing that this recommendation will be challenging for many countries with asignificantHIVandTBburden, thepanelplacedhighvalueon reducing the impactofTBonsocietiesandon thedatademonstratinga reduction inall-causemortalityamong individualsprovidedwithTBtherapyandART.

Promoting improved HBV diagnosis and more effective treatment of HIV/HBV coinfection

EvidencesupportstheinitiationofART,irrespectiveofWHOdiseasestageorCD4cellcount,forallthosewithHIV/HBVcoinfectionandchronicactivehepatitisBwhentreatmentisindicatedforhepatitisB.However,thereisnoagreeddefinitionofchronicactivehepatitisinresource-limitedsettings.Despitethis,thepanelfeltthatitwasnecessarytoincludetheprinciplesofoptimumcareforthosewithHIV/HBVcoinfectionandbringtheseintoalignmentwithrecommendationsinwell-resourced settings. There is an urgent need to develop diagnostic criteria to identifyindividualswithHIV/HBVcoinfectionwhoneedtreatmentinsituationswhereHBVDNAandliverbiopsyarenotroutinelyavailable.

More strategic monitoring for antiretroviral efficacy and toxicity

While laboratorymonitoringshouldnotbeabarrier to initiatingART,thenewlyrecommendedARV regimens may require more laboratory monitoring than current regimens, especially inindividuals at higher risk for adverse events. A phased-in approach to the use of viral loadtesting,iffeasible,willimprovetheidentificationoftreatmentfailure.

11. summAry of chAnges



When to start

AlladolescentsandadultsincludingpregnantwomenwithHIVinfectionandCD4countsof≤350cells/mm3,shouldstartART,regardlessofthepresenceorabsenceofclinicalsymptoms.Thosewithsevereoradvancedclinicaldisease(WHOclinicalstage3or4)shouldstartARTirrespectiveoftheirCD4cellcount.

What to use in first- line therapy

First-linetherapyshouldconsistofanNNRTI+twoNRTIs,oneofwhichshouldbezidovudine(AZT)ortenofovir(TDF).Countriesshouldtakestepstoprogressivelyreducetheuseofstavudine(d4T)infirst-lineregimensbecauseofitswell-recognizedtoxicities.

What to use in second-line therapy

Second-lineARTshouldconsistofaritonavir-boostedproteaseinhibitor(PI)plustwoNRTIs,oneofwhichshouldbeAZTorTDF,basedonwhatwasusedinfirst-linetherapy.Ritonavir-boostedatazanavir(ATV/r)orlopinavir/ritonavir(LPV/r)arethepreferredPIs.

Laboratory monitoring

AllpatientsshouldhaveaccesstoCD4cell–counttestingtooptimizepre-ARTcareandARTmanagement.HIVRNA(viral-load)testingisrecommendedtoconfirmsuspectedtreatmentfailure.Drugtoxicitymonitoringshouldbesymptom-directed.

HIV/TB coinfectionIrrespectiveofCD4cellcounts,patientscoinfectedwithHIVandTBshouldbestartedonARTassoonaspossibleafterstartingTBtreatment.

HIV/HBV coinfection

IrrespectiveofCD4cellcountsorWHOclinicalstage,patientswhorequiretreatmentforHBVinfectionshouldstartART.First-lineandsecond-lineregimensfortheseindividualsshouldcontainTDFandeitheremtricitabine(FTC)orlamivudine(3TC).

12. recommendAtions At A glAnce

21

Table 5. When to start antiretroviral therapy

Target population 2010 ART guideline 2006 ART guideline

HIV+ asymptomatic ARV-naive individuals

CD4≤350cells/mm3 CD4≤200cells/mm3

HIV+ symptomatic ARV-naive individuals

WHOclinicalstage2ifCD4≤350cells/mm3OR

WHOclinicalstage3or4irrespectiveofCD4cellcount

WHOstage2or3andCD4≤200cells/mm3

WHOstage3ifCD4notavailable

WHOstage4irrespectiveofCD4cellcount

ConsidertreatmentforWHOclinicalstage3andCD4cellcountbetween200and350cells/mm3

HIV+ pregnant women

CD4≤350cells/mm3irrespectiveofclinicalsymptomsOR

WHOclinicalstage3or4irrespectiveofCD4cellcount

WHOstage1or2andCD4≤200cells/mm3

WHOstage3andCD4≤350cells/mm3

WHOstage4irrespectiveofCD4count

HIV/TB coinfection ARV-naive individuals

PresenceofactiveTBdisease,irrespectiveofCD4cellcount

PresenceofactiveTBdiseaseandCD4≤350cells/mm3

ARTInitiationcanbedelayedifCD4≥200cells/mm3

HIV/HBV coinfection ARV-naive individuals

IndividualswhorequiretreatmentfortheirHBVinfection*,irrespectiveofCD4cellcount

Nospecificrecommendation

* Thecurrentdiagnosisofchronicactivehepatitisinwell-resourcedsettingsisbasedonhistologicalparametersobtained by liver biopsy and/or the availability of HBV DNA testing, neither of which is usually available inresource-limitedsettings.Aglobaldefinitionofchronicactivehepatitisinthecontextofresource-limitedsettingsbasedonclinicalsignsandsimplerlaboratoryparametersisunderdiscussion.



Table 6. What antiretroviral therapy to start

Target population 2010 ART guideline 2006 ART

guideline

HIV+ ARV-naive adults and adolescents

Nochange,butinsettingswhered4TregimensareusedastheprincipaloptionforstartingARTaprogressiveplantomovetowardsAZT-basedorTDF-basedfirst-lineregimensshouldbedeveloped,basedonanassessmentofcostandfeasibility

AZTorTDF+3TC(orFTC)+EFVorNVP

HIV+ pregnant women

AZTpreferredbutTDFacceptable

EFVincludedasaNNRTIoption(butdonotinitiateEFVduringfirsttrimester)

BenefitsofNVPoutweighriskswhereCD4countis250−350cells/mm3

InHIV+womenwithpriorexposuretoMTCTregimens,seeARTrecommendationsinsection13.2

AZT+3TC+NVP

HIV/TB

coinfection

Nochange

ARTshouldbeinitiatedassoonaspossibleinallHIV/TB-coinfectedpatientswithactiveTB(within8weeksafterthestartofTBtreatment)

AZTorTDF+3TC(orFTC)+EFV

HIV/HBV

coinfection

NNRTIregimensthatcontainbothTDF+3TC(orFTC)arerequired

TDF+3TC(orFTC)+EFV

Table7. Recommended second-line antiretroviral therapy

Target population 2010 ART guideline* 2006 ART

guideline

HIV+ adults and adolescents

Ifd4TorAZTusedinfirst-linetherapy

TDF+3TC(orFTC)+ATV/rorLPV/r

ABC+ddIorTDF+ABCorddI+3TCorTDF+3TC(±AZT)plusATV/rorFPV/rorIDV/rorLPV/rorSQV/r

IfTDFusedinfirst-linetherapy

AZT+3TC(orFTC)+ATV/rorLPV/r

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Target population 2010 ART guideline* 2006 ART

guideline

HIV+ pregnant women

Sameregimensasrecommendedforadultsandadolescents

ABC+ddIorTDF+ABCorddI+3TCorTDF+3TC(±AZT)plusLPV/rorNFVorSQV/r

HIV/TB

coinfection

Ifrifabutinavailable(150mg3times/week)

Sameregimensasrecommendedforadults

ABC+ddIorTDF+ABCorddI+3TCorTDF+3TC(±AZT)plusLPV/rorSQV/rwithadjusteddoseofRTV

(LPV/r400mg/400mgtwiceadayorLPV/r800mg/200mgtwiceadayorSQV/r400mg/400mgtwiceaday)

Ifrifabutinnotavailable

SameNRTIbackbonesrecommendedforadultsplusLPV/rorSQV/rwithadjusteddoseofRTV

(LPV/r400mg/400mgtwiceadayorLPV/r800mg/200mgtwiceadayorSQV/r400mg/400mgtwiceaday)

HIV/HBV

coinfectionAZT+TDF+3TC(orFTC)+ATV/rorLPV/r

3TC-and/orTDF-containingregimens

* ABC and ddI can be considered as backup options in case of AZT or TDF toxicity or if AZT or TDF arecontraindicated.



13.1. Recommendations

1. ItisrecommendedtotreatallpatientswithCD4countsof≤350cells/mm3irrespectiveoftheWHOclinicalstage.(Strong recommendation, moderate quality of evidence)

2. ItisrecommendedthatallpatientswithWHOclinicalstage1and2shouldhaveaccesstoCD4testingtodecidewhentoinitiatetreatment.(Strong recommendation, low quality of evidence)

3. It is recommendedto treatallpatientswithWHOclinicalstage3and4 irrespectiveofCD4count.(Strong recommendation, low quality of evidence)

Inmakingtheserecommendations,theART Guideline Review Committee(the“panel”)placedhighvalueonavoidingdeath,diseaseprogressionandthelikelyriskofHIVtransmissionoverandabovecostandfeasibility.

13.2. Evidence

The evidence used in formulating recommendations on when to start ART comes from asystematic review: Optimal time of initiation of antiretroviral therapy for asymptomatic, HIV-infected, treatment-naive adults.(2) The review included randomized controlled clinical trials(RCTs)andcohortstudies,inwhichARTinitiationwasstratifiedaccordingtoCD4cellcount.OnthebasisofGRADEmethodology,theevidencewasratedforeachofthecriticalandimportantoutcomestodeterminewhetherornottochangethecurrentWHOguideline.

TherecommendationsaresupportedbymoderatequalityevidenceforcriticalpatientandpublichealthoutcomesfromoneunpublishedRCTandoneposthocanalysisnestedinanRCT.IntheGRADEevidenceprofile,pooleddatafromthesetwostudiesprovidemoderateevidencethatstarting ART at CD4 levels higher than 200 or 250 cells/mm3 reduces mortality rates inasymptomatic, ART-naive, HIV-infected people. The panel also reviewed large observationaldatasetsfrombothresource-limitedandwell-resourcedsettingsthatwereconsistentwithdatafromtheRCT,butthesedidnotaddtotheoverallqualityofevidence.Thepanelconsideredtherecommendations to be feasible if introduced in a phased manner, with the speed andcompleteness determined by health-system capacity, HIV burden, ART coverage, equity ofaccessandfunding.

Recentmodellingandobservationaldatasuggestthatmorethan50%ofHIV-infectedpatientswithWHOclinicalstage2mayhaveaCD4countof≤350cells/mm3.However,consideringtheuncertainprognosticvalueofsomeWHOclinicalstage2conditions,thepanelrecommendedthatHIV-infectedindividualswithWHOclinicalstage1and2shouldhaveaccesstoCD4testingtodecideiftreatmentshouldbeinitiated.

13. when to stArt

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13.3. Summary of findings

Moderate-qualityevidencesupportsstrongrecommendationsforthetimingofARTinitiationforthecriticaloutcomesofabsoluteriskofdeath,diseaseprogression(includingtuberculosis),andtheoccurrenceofseriousadverseevents.

One RCT specifically aimed to determine the optimal time to initiate ART in asymptomatic,treatment-naive, HIV-infected adults. TheCIPRA HT-001 (2009) study, a single-centre trial inHaiti,randomized816ART-naiveparticipantswithaCD4countof200−350cells/mm3,toreceiveearlytreatment(startARTwithin2weeksofenrolment)versusstandard-of-caretreatment(startARTwhentheCD4countis<200cells/mm3orfollowingthedevelopmentofanAIDS-definingillness).(3)ThemedianCD4countatstudyentrywas280cells/mm3intheearlytreatmentgroupand282cells/mm3inthestandard-of-caregroup.Theprimarystudyend-pointwassurvivalandthe secondary end-point was incident TB. The Data Safety and Monitoring Board (DSMB)recommendedcessationof the studyafter amedian followupof 21months (1−44months).DeathsandincidentTBoccurredin6and18patientsrespectivelyintheearlygroupcomparedto23and36patients inthedelayedgroup(mortalityHR4.0,p=0.0011; incidentTBHR2.0,p=0.0125).Oftheparticipantsinthestandard-of-caregroup,40%reachedaCD4cellcountof<200cells/mm3,developedanAIDS-definingillnessordied.

EarlyARTinitiationwasexaminedfurtherinonesubgroupposthocanalysis(249participants)nested in a larger RCT. The SMART trial was a multicentre study conducted at 318 sites in33 high-income and low/middle-income countries, which randomized 5472 participants withCD4cellcountsof>350cells/mm3toeitheraviralsuppressionstrategy(goalofmaximalandcontinuousviralsuppression)versusadrugconservationstrategy(ARTdeferreduntilCD4was<250 cells/mm3).(4) In a subset analysis of 477 patientswhowere ART-naive at study entry(n=249)orwhohadnotreceivedARTfor>6monthsbeforerandomization(n=228)andwhowererandomizedtostartARTimmediately(withCD4of>350cells/mm3)ordelayeduntilafterCD4dropped to<250 cells/mm3, therewasa reductionof diseaseprogression and seriousnon-AIDSeventswhenARTwasinitiatedbeforetheCD4cellcountdroppedto≤350cells/mm3comparedwithdelayinguntiltheCD4countwas<250cells/mm3.

IntheGRADEprofile,pooleddatafromthisRCTandthesubgroupposthocanalysisprovidedmoderateevidencethatstartingARTatCD4levelshigherthan200or250cells/mm3reducedmortalityratesinasymptomatic,ART-naiveHIV-infectedpeople.Evidenceregardingareductioninmorbiditywas lessstrongbecause therewere fewevents.Thenumbersofadverseeventswerealsosmall.

AstheCIPRA-HT001 2009trialwasconductedinaresource-limitedsetting,theapplicabilityoftheseresultsindeterminingachangeinWHOguidelinesishigh.

TheGRADEprofilenotesthatthequalityofthesedatawaslimitedbyimprecision(therewasonlyoneRCT),indirectness(theSMARTdatacomefromaposthocsubsetanalysis)andreportingbias (theremaybeother trialswhichdidnotconductorpublishsimilaranalysesofpotentialsubsetswithintheoriginaltrials).



The results from theCIPRA HT-001 and SMART trials are consistent with four observationalcohort studies from resource-limited and well-resourced countries, which showed that earlyinitiationofARTwasassociatedwithreducedmorbidityandmortality.(5−8)GRADEtableswerenotproducedforthefourobservationalstudiesidentifiedinthesystematicreviewastheywouldnothaveincreasedtheoverallqualityofevidence.NotrialswereidentifiedwhichevaluatedtheoptimaltimingofinitiationofARTinpeoplecoinfectedwithhepatitisB,hepatitisCorboth.

13.4. Benefits and risks

Benefits

ModellingestimatespredictthattheinitiationofARTforindividualswithaCD4cellcountof≤350cells/mm3orwithWHOclinicalstage3or4willresultinthenumbersofpeopleonARTincreasingby49%andareductioninHIV-relatedmortalityof20%by2010−2015.(9)FurthermodellingdatasuggestadditionaltransmissionbenefitfromearlierinitiationofARTforbothsexualtransmissionandMTCTofHIVprovidingthatthereishightreatmentcoverageandhighadherence.(10)EarlierinitiationandmoretimespentonARTmayprovideimpetustoshifttolesstoxicfirst-lineregimensandreducedpricesfornewerfixed-dosecombinations(FDCs).

ObservationalandRCTdataconfirmthatthereisanincreasedriskofTBandinvasivebacterialdiseasesasCD4cellcountsdecline.(11,12)Conversely,thereisa54%to92%reductioninTBinindividualsreceivingART.(13)

Risks

ItisestimatedthatincreasingthethresholdforARTinitiationcanincreaseARTcostupto57%by2010−2015.(9)Broadening thecriteria for treatmentmay result in somepersons inurgentneedoftreatmentbeingdisplacedbypersonsforwhomtreatmentwouldbebeneficialbutnotasurgent. InrecommendingahigherCD4count threshold for initiation,aguidingprinciple isthatthosemostinneedoftreatmentshouldretainpriorityaccess.

EarlierinitiationwillmeanlongerexposuretoART(estimatedtobe1to2yearsmore)andthepossibility of more ART-related side-effects and ARV resistance. It remains unclear ifasymptomatic individuals will accept HIV testing or ART. Additionally, the impact of earlierinitiationonadherenceisuncertain.

13.5. Acceptability and feasibility

In consultations with PLHIV, the benefits of starting ART earlier were recognized and stronglysupported.However,concernwasvoicedabouttheincreasedriskofadverseevents,resistancetofirst-lineARVs,drugstock-outs,andunavailabilityofsecond-lineregimens.WhileearlierARTinitiationwillreducethecurrentdisparitybetweentreatmentrecommendationsinresource-limitedandwell-resourcedsettings,itwillappeartodecreasetreatmentcoverage.Ministriesanddonorsmay feel underpressure toaddress immediate increasedcosts.Feasibilitywill beenhanced ifthere is a phased introduction of the higher thresholds, with the speed and completenessdeterminedbythehealthsystem’scapacity,HIVburden,ARTcoverageandfunding.

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13.6. Clinical considerations

Table 8. WHO clinical staging of HIV disease in adults and adolescents

Clinical stage 1

Asymptomatic

Persistentgeneralizedlymphadenopathy

Clinical stage 2

Moderateunexplainedweightloss(under10%ofpresumedormeasuredbodyweight)

Recurrentrespiratorytractinfections(sinusitis,tonsillitis,otitismedia,pharyngitis)

Herpeszoster

Angularcheilitis

Recurrentoralulcerations

Papularpruriticeruptions

Seborrhoeicdermatitis

Fungalnailinfections

Clinical stage 3

Unexplainedsevereweightloss(over10%ofpresumedormeasuredbodyweight)

Unexplainedchronicdiarrhoeaforlongerthan1month

Unexplainedpersistentfever(intermittentorconstantforlongerthan1month)

Persistentoralcandidiasis

Oralhairyleukoplakia

Pulmonarytuberculosis

Severebacterialinfections(e.g.pneumonia,empyema,meningitis,pyomyositis,boneorjointinfection,bacteraemia,severepelvicinflammatorydisease)

Acutenecrotizingulcerativestomatitis,gingivitisorperiodontitis

Unexplainedanaemia(below8g/dl),neutropenia(below0.5x109/l)and/orchronicthrombocytopenia(below50x109/l)



Clinical stage 4

HIVwastingsyndrome

Pneumocystis jirovecipneumonia

Recurrentseverebacterialpneumonia

Chronicherpessimplexinfection(orolabial,genitaloranorectalofmorethan1month’sdurationorvisceralatanysite)

Oesophagealcandidiasis(orcandidiasisoftrachea,bronchiorlungs)

Extrapulmonarytuberculosis

Kaposisarcoma

Cytomegalovirusdisease(retinitisorinfectionofotherorgans,excludingliver,spleenandlymphnodes)

Centralnervoussystemtoxoplasmosis

HIVencephalopathy

Extrapulmonarycryptococcosisincludingmeningitis

Disseminatednontuberculousmycobacteriainfection

Progressivemultifocalleukoencephalopathy

Chroniccryptosporidiosis

Chronicisosporiasis

Disseminatedmycosis(histoplasmosis,coccidiomycosis)

Recurrentsepticaemia(includingnontyphoidalSalmonella)

Lymphoma(cerebralorBcellnon-Hodgkin)

Invasivecervicalcarcinoma

Atypicaldisseminatedleishmaniasis

SymptomaticHIV-associatednephropathyorHIV-associatedcardiomyopathy

Source: Revised WHO clinical staging and immunological classification of HIV and case definition of HIV forsurveillance.2006.

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Table 9. Criteria for ART Initiation in specific populations

Target population Clinical condition Recommendation

Asymptomatic individuals (including pregnant women)

WHOclinicalstage1 StartARTifCD4≤350

Symptomatic individuals (including pregnant women)

WHOclinicalstage2 StartARTifCD4≤350

WHOclinicalstage3or4StartARTirrespectiveofCD4cellcount

TB and hepatitis B coinfections

ActiveTBdiseaseStartARTirrespectiveofCD4cellcount

HBVinfectionrequiringtreatment*

StartARTirrespectiveofCD4cellcount

* The current standard definition of chronic active hepatitis in industrialized countries is mainly based onhistological parameters obtained by liver biopsy, a procedure not usually available in the large majority ofresource-limitedsettings.Aglobaldefinitionofchronicactivehepatitis for resource-limitedsettingsbasedonclinicalandmoresimplelaboratoryparametersisunderdiscussion.

WhileincreasedaccesstoCD4testingisapriority,thelackofaCD4cellcountshouldnotbeabarrier to the initiation of ART. For ART programmes inmany countrieswith the highest HIVburden, clinical criteria remain the basis for decidingwhen to initiate ART. In both resource-limitedandwell-resourcedsettings,thereisamovetowardsearlierinitiationofART.However,manypeoplestillpresentforthefirsttimewithadvancedHIVdisease,withaCD4countof<200cells/mm3orwithanopportunisticinfection.(14,15)

Clinical assessment

Clinical staging is intended for usewhereHIV infectionhasbeenconfirmedbyHIVantibodytesting. It isusedtoguidedecisionsonwhentostartcotrimoxazoleprophylaxisandwhentostartART.Table8(WHO clinical staging of HIV disease in adults and adolescents)andAnnex21.5(Diagnostic criteria for HIV-related clinical events in adults and adolescents)providedetailsofspecificstagingconditionsandthecriteriaforrecognizingthem.

ForindividualswithadvancedHIVdisease(WHOclinicalstage3or4),ARTshouldbeinitiatedirrespective of theCD4cell count.Both stages 3 and 4 are independently predictive ofHIV-relatedmortality.(16−19)AssessingtheneedforARTinthosewithWHOclinicalstage2presentschallenges. Some stage 2 conditions may be considered more indicative of HIV diseaseprogressionthanothers.Forexample,papularpruriticeruptions(PPEs)typicallyoccurwithCD4countsof<200cells/mm3,andmostphysicianswouldrecommendtheinitiationofARTinthepresenceofPPEsandtheabsenceofaCD4count.(20,21)Conversely,recurrentoralulcerationor a fungal nail infection generally would not be considered triggers to start ART.Given theuncertainty with which stage 2 conditions predict mortality and disease progression, HIV-



infected individualswithWHO clinical stage 2 should have priority access toCD4 testing todecide if treatment should be initiated. The same recommendation to promote CD4 testingappliestoasymptomaticindividuals(WHOstage1).TheobjectiveistoidentifythosewithalowCD4count,arestillwell,butneedtostartART.

Immunological assessment

Expandedprovider-initiatedtestingandcounselling(PITC)andvoluntarycounsellingandtesting(VCT),togetherwithimmunologicalassessment(CD4testing),arecriticaltoachievingthegoalsof earlierdiagnosis andstartingARTbeforepeoplebecomeunwell orpresentwith their firstopportunisticinfection.(22)ACD4cellcountperformedatentryintocareorpriortoARTinitiationwillguidethedecisiononwhentostartARTandservesasthebaselineifCD4testingisusedforARTmonitoring.ARTshouldbecommencedinindividualswithaCD4countof≤350cells/mm3.

AbsoluteCD4cellcountsfluctuatewithinindividualsandwithintercurrentillnesses.Iffeasible,CD4testingshouldberepeatedifamajormanagementdecisionrestsonthevalue,ratherthanusing a single value. Serial CD4 measurements are more informative than individual valuesbecause they reflect trends over time. The total lymphocyte count (TLC) is no longerrecommendedtoguidetreatmentdecisionsinadultsandadolescents.

Virological assessment

Inresource-limitedsettings,plasmaviralload(HIVRNA)measurementisnotrequiredbeforetheinitiationofART.However,expandedaccesstoviralloadtestingisneededtoimprovetheaccuracyof diagnosing treatment failure. Earlier detection of virological failure allows both targetedadherenceinterventionsandbetterpreservationoftheefficacyofsecond-lineregimens.(23)

31


StartoneofthefollowingregimensinART-naiveindividualseligiblefortreatment.

• AZT+3TC+EFV

• AZT+3TC+NVP

• TDF+3TC(orFTC)+EFV

• TDF+3TC(orFTC)+NVP

(Strong recommendation, moderate quality of evidence)

Because stavudine (d4T) is relatively inexpensive and is currently a component of first-linetherapyinmanycountries,thepanelspecificallyconsideredstudiesofd4T-basedregimens.Inmaking these recommendations, the panel placed high value on avoiding the disfiguring,unpleasantandpotentiallylife-threateningtoxicityofd4T,inadditiontotheselectionofregimenssuitableforuseinmostpatientgroups,treatmentdurabilityandthebenefitsofusingfixed-dosecombinations. The available information suggests that abacavir (ABC) and didanosine (ddI)haveseriousconstraintsforuseinfirst-lineregimens(toxicitiesandcost)andthepanelfocusedoncomparisonsbetweenAZT,TDFandd4T-basedregimens.

14.2. Evidence

UsingCochranesystematicreviewmethodology,triple-drugARVsfortheinitialtreatmentofHIVinfectionwereexaminedinRCTS,othercontrolledtrials,andcohortandcase-controlstudies.Thecomparisonsof interestweremortality,diseaseprogression,virological response toART(theproportionofindividualswhosuppressedviralreplicationtoundetectablelevels,definedas<40,<400or<500copies/ml),seriousadverseevents(Division of AIDS adverse event toxicity scale,NationalInstituteofAllergyandInfectiousDiseases,USA,2004),adherence,tolerabilityandretention,andimmunologicalresponsetoART(medianormeanchangeinCD4cellcountfrombaseline).ThequalityofevidencewasassessedusingGRADEevidenceprofiles.

Thefollowingspecificinterventionswerecompared:

• dualNRTIbackbonewithd4TversusdualNRTIbackbonewithAZT;

• dualNRTIbackbonewithTDFversusdualNRTIbackbonewithAZTord4T;

• 2NRTIs+NVPversus2NRTIs+EFV.

Currentevidencesuggests that thenew recommended regimensarecomparable in termsofefficacy,withabetteroveralltoxicityprofilethand4T-basedregimens.Thepanelwasreassuredby theGRADE evidence profile fromRCTs, non-randomized trials and observational studiesfromlow-incomeandmiddle-incomecountries,whichindicatenosuperiorityfortheoutcomesofinterestofAZToverTDF,orofNVPoverEFVaspartofcombinationARTfortreatment-naiveindividuals.

14. whAt to stArt



14.3. Summary of main findings

This systematic review did not find any evidence from RCTs, non-randomized trials orobservational studies from resource-limited settings that clearly indicated the superiority ofregimens based on AZT, d4T or TDF or the superiority of either EFV or NVP, in triple-drugantiretroviralregimensfortreatment-naivepatients.

Studies which compared or are comparing AZT and d4T in different combinations providereasonably robustevidence thatAZT-containingandd4T-containingregimensareequivalent.(24−33) These studies have a variety of limitations and the overall GRADE evidence profileratingwasvery low.Fiveofthesixstudieswereopen-label,severalstudiescomparedAZT+3TC to d4T+ddI, potentially obscuring the head-to-head comparison of AZT and d4T, andothersusedproteaseinhibitorsasathirddrug.TheAdult Antiretroviral Treatment and Resistance Study(TSHEPOstudy)inBotswanaisdirectlycomparingcombinationsofAZT+3TC+NVPorEFVandd4T+3TC+NVPorEFV.(34)

ThreeRCTshavecomparedregimenscontainingTDFtod4TorAZT.Twoofthesestudiesused3TCasthesecondNRTIandallowedfordirectcomparisons(35,36);thethirdcomparedAZT+3TCwithTDF+FTC.(37)Twoofthesestudieshadequivalentfindings;thatefficacyandsafetyweresimilarforAZT+3TC+EFVandd4T+3TC+EFV,andforTDF+FTC+EFVandTDF+3TC+EFV.(35,36)

The third study compared TDF + 3TC to AZT +3TC, both with once-daily NVP, and wasprematurelydiscontinuedafterfailureoftheTDF+3TC+NVParmtosuppressviralreplicationin8of35participants(35,36).Intwoothersmallstudies,similarratesoffailuretosuppressviralreplicationhavealsobeen found inpatients receivingNVPoncedaily.(38,39)However, in thelarge ARTEN study, (atazanavir/ritonavir on a background of tenofovir and emtricitabine vs.nevirapine)inwhich569patientswererandomizedtoreceiveNVP200mgBID,NVP400mgODorATV/r300/100mgODeachgivenwithTDF/FTCOD,non-inferiorityoftheprimaryend-point(undetectableVLatweek48)wasestablishedbetweenthecombinedNVParmsandATV/rarm.(40)

Data fromAIDS therapy evaluation in the Netherlands (ATHENA) andSwiss HIV cohort study(4471onNVPtwice-dailyand629onNVPonce-dailyregimens)suggestthatNVPoncedailyisatleastasefficientasNVPprescribedtwicedaily.(41)

AdditionalevidencecomesfromobservationalstudieswhichwerenotincludedintheGRADEprofile.Nonewereconductedinlow-incomeandmiddle-incomesettings.Thesestudiesshowedthat TDF-containing backbones were associated with a higher proportion of non-detectableviraemia,(42)a lowerratechangeduetotoxicity,(43)overallgreaterdurability(44)andslowerratesofCD4-cellincrease.(45,46)TwoobservationalstudiesreportedthatTDF/FTCor3TCwascost-savingcomparedtoAZT+3TC.(47,48)

SixRCTswhichhavecomparedNVPtoEFVfoundnodifferencesinefficacy.(49−54)OneRCTreportedthatEFVwaslesslikelythanNVPtobeassociatedwiththedevelopmentofantiretroviralresistance.(53) TheGRADE evidence profile ismoderate to high, with the exception of drug

33

resistance,whichwasexaminedinonlyasinglestudy.Ongoingstudieswilladdsubstantiallytothisliterature.(55−57)

Thesystematic reviewofd4Tsafetyand toxicityprepared for thisguideline revision reporteddata fromthreeRCTsand24observationalstudies,demonstrating theconsistentassociationbetweend4Tandperipheralneuropathy,lipoatrophyandlacticacidosis.


Benefits

PhasinginAZTandTDFwillreducetheriskofacuted4T-relatedlacticacidosisandoflong-termmitochondrial toxicities (particularly lipoatrophy and peripheral neuropathy), and has thepotentialforimprovedadherenceandreducedlosttofollow-up.TDFcanbeincludedinaonce-dailyFDC.ThecombinationofTDF+3TCorFTCistherecommendedNRTIbackboneinthepresence of HBV coinfection. AZT + 3TC is a preferred NRTI backbone option in pregnantwoman.Therewillbefewerwithin-classchangeswithmoredurableandsaferregimens.

Risks

AZTandTDFmayrequiremorelaboratorymonitoringthand4T-basedregimens.TheremaybeconcernfromPLHIVandcareprovidersaboutanaemia(AZT)andrenaltoxicity(TDF).Thereisuncertaintywhether TDF requires renal screening andmonitoring in all individuals or only inselectedpopulations(elderly,thosewithlowbodyweight,thosetakingconcomitantrenaltoxicdrugs or with diseases such as diabetes and hypertension). TDF has been reported asassociatedwithbonemineral loss.(58)Recently,safetyandeffectiveness inadolescentswasreviewed;individualsaged≥12yearsandweighing≥35kgshouldusethedoserecommendedin adults.(58) In addition to anaemia, AZT is associated with initial gastrointestinal adverseevents,proximalmyopathyandskinhyperpigmentation.Notallof theseoptionsarecurrentlyavailableasafullFDC(AZT+3TC+EFV;TDF+3TC+NVP;TDF+FTC+NVP).

While progressive reduction in the use of d4T is occurring, itmay be retained as an interimmeasureifplansareinitiatedtomonitorandmanagetoxicity.Incertainsituations,d4Tmayberetainedasabackupdrug,suchaswhenTDFandAZTarecontraindicated.


As current evidence suggests that the recommended regimens are comparable in terms ofefficacy,countriesshouldselectoneofthemasthepreferredoptionformostpatientsinitiatingART,onthebasisoffactorsrelatedtoacceptabilityandfeasibility,suchas:

• numbersofindividualsneedingtostartARTaccordingto2010and2015targets;

• numbers of individuals starting ART who have HIV/TB coinfection or chronic activeHIV/HBVcoinfection;

• anaemia(duetomalaria,malnutrition,intestinalparasites,repeatedpregnanciesorothercauses);

• pregnantwomenorwomenofreproductiveage;



• predictedexpenditureperpersonneedingART(basedonselectednationalstartcriteria);

• availabilityofFDC;

• in-countrycostofthedrugregimens;

• decisionsbycountriesonlaboratoryrequirementstomonitortoxicities;

• trainingneedsfortheintroductionandmanagementoftheregimens;

• countriesmayneedtousemodellingtoassistindecision-making.

Table 10. Preferred first-line ART in treatment-naive adults and adolescents

Target population Preferred options Comments

Adults and adolescents

AZTorTDF+3TCorFTC+EFVorNVP

SelectthepreferredregimensapplicabletothemajorityofPLHIV

Usefixed-dosecombinations

Pregnant women

AZT+3TC+EFVorNVP

DonotinitiateEFVduringfirsttrimester

TDFacceptableoption

InHIVwomenwithpriorexposuretoPMTCTregimens,seeARTrecommendationsinTable11

HIV/TB coinfection

AZTorTDF+3TCorFTC+EFV

InitiateARTassoonaspossible(withinthefirst8weeks)afterstartingTBtreatment

NVPortripleNRTIsareacceptableoptionsifEFVcannotbeused

HIV/HBV coinfection

TDF+3TCorFTC+EFVorNVP

ConsiderHBsAgscreeningbeforestartingART,especiallywhenTDFisnotthepreferredfirst-lineNRTI

UseoftwoARVswithanti-HBVactivityrequired

14.6. The choice between NVP and EFV

NVPandEFVhavecomparableclinicalefficacywhenadministered incombination regimens.However,differencesintoxicityprofiles,thepotentialforinteractionwithothertreatments,andcostshouldbeconsideredwhenanNNRTIisbeingchosen.(54,59)

NVPisassociatedwithahigherincidenceofrash,Stevens-Johnsonsyndrome,andhepatotoxicitycompared toEFV.(54) The simultaneous initiationofNVPandother newdrugs that canalsocauserash(e.g.cotrimoxazole)shouldbeavoidedwherepossible.Inthecaseofseverehepaticor skin reactions, NVP should be permanently discontinued and not restarted. NVP is the

35

preferredNNRTI for women if there is potential for pregnancy or during the first trimester ofpregnancy.While there are conflicting data regarding an increased risk of hepatic toxicity inwomenwithCD4countsbetween250and350cells/mm3,thepanelfoundthattherewaslimitedevidencetocauseconcernbutstillurgedcautionintheuseofNVPinwomenwithCD4countsof>250cells/mm3or in thosewith unknownCD4cell counts.Closeclinicalmonitoring (andlaboratorymonitoringiffeasible)duringthefirst12weeksoftherapyisrecommendedwhenNVPisinitiatedinwomenwithaCD4cellcountof250−350cells/mm3.

EFVcanbeusedoncedaily, isgenerallywell toleratedbut ismorecostly andcurrently lesswidelyavailablethanNVP.Itsprimarytoxicitiesarerelatedtothecentralnervoussystem(CNS)andpossible,butnotproven teratogenicity, if receivedduring the first trimesterofpregnancy(butnotinthesecondandthirdtrimesters),andrash.Rashisgenerallymildandself-resolvingandusuallydoesnotrequirethediscontinuationoftherapy.TheCNSsymptomsarecommon.While they typically resolve after 2−4 weeks, they can persist for months, resulting indiscontinuationofthedrug.EFVshouldbeavoidedinpatientswithahistoryofseverepsychiatricillness,whenthereisapotentialforpregnancy(unlesseffectivecontraceptioncanbeassured)andduringthefirsttrimesterofpregnancy.EFVistheNNRTIofchoiceinindividualswithTB/HIVcoinfectionwhoarereceivingrifampicin-basedTBtherapy.

ThereareclinicalsituationswhenindividualsneedtoreplaceEFVwithNVP.Themostcommonscenariosarewhenpatients temporarilychange fromNVPtoEFVbecause theyneed to takerifampicin-containingTBtreatmentandsubsequentlyswitchbacktoNVPoncompletionofTBtreatment,andindividualswithpersistentEFVCNSintolerance.Inthiscase,EFVcanbestoppedandfull-doseNVP(200mgtwicedaily)canbestartedimmediately.Thereisnoneedforlead-inNVPdosing.(60,61)

14.7. AZT + 3TC + EFV option

Inrecommendingthisasapreferredfirst-lineregimen,thepanelplacedhighvalueontheutilityofEFVinthetreatmentofHIV/TBcoinfection.

Efficacy and safety

Low (for AZT) to moderate (for EFV) GRADE evidence profiles for the critical outcomes ofmortality,clinicalprogressionandseriousadverseeventssupportthisoption.

InthesystematicreviewofAZTtoxicity,lowbodymassandlowCD4cellcountwereindependentpredicators of developing AZT-induced anaemia.(62,63) Background rates of anaemia varyconsiderably.Malaria,pregnancy,malnutritionandadvancedHIVdiseasearewell-recognizedriskfactorsforanaemia.Theprevalence,incidenceandpredictorsofsevereanaemiawithAZT-containingregimensinAfricanadultswereassessedinthe Development of antiretroviral therapy in Africa(DART)trial.(63)Morethan6%ofindividualsreceivingAZTdevelopedgrade4(ACTGtoxicitygradingscale)anaemiaby12months.IndatafromninePEPFARfocuscountries,12%stoppedAZTbecauseofanaemiaorgastrointestinal intolerance.(64) InUganda,25%of1029patientswhoinitiatedad4T-containingARTwereswitchedtoAZTbecauseofd4Ttoxicity,(65)and5%subsequentlyswitchedtoanotherdrugbecauseofAZTtoxicity.



The EFV toxicity review showed consistent reports of self-limiting or tolerable CNS adverseeventsanduncertaintiesaboutteratogenicriskinhumans.Intheimportantoutcome(asdistinctfromthepredeterminedcriticaloutcomesofmortality,diseaseprogressionandadverseevents)ofARVresistance,EFVmaybesuperiortoNVP.(66)

EFVshouldnotbeinitiatedinthefirsttrimesterofpregnancybutmaybeinitiatedinthesecondandthirdtrimesters.ThereisconflictingevidenceofverylowqualityontherisksofEFVcausingneuraltubedefects.TheoverallratesofbirthdefectsreportedinassociationwithEFV,NVP,LPV/rorTDFappearsimilarandareconsistentwithratesreportedincongenitaldefectsregistriesfromgeneralpopulations.However,neural tubebirthdefectsare rare,withan incidence0.1% in thegeneralpopulation.Prospectivedataarecurrentlyinsufficienttoprovideanassessmentofneuraltubedefectriskwithfirst-trimesterexposure,excepttoruleoutapotentialtenfoldorhigherincreaseinrisk(i.e.anincreaseinriskfrom0.1%to>1%).Sinceneuraltubeclosureoccursbyapproximately28daysofgestationandveryfewpregnanciesarerecognizedbythistime,thepotentialriskwiththe use of EFV inwomenwhomight conceivewhile receiving the drug is difficult to estimate.Women who are planning to become pregnant or who may become pregnant should use aregimenthatdoesnotincludeEFV,inordertoavoidthehighestriskperiodofexposure in utero(conception to day 28 of gestation). If a woman is diagnosed as pregnant before 28 days ofgestation,EFVshouldbestoppedandsubstitutedwithNVPoraPI.Ifawomanisdiagnosedaspregnantafter28daysofgestation,EFVshouldbecontinued.ThereisnoindicationforterminationofpregnancyinwomenexposedtoEFVinthefirsttrimesterofpregnancy.

Risk, benefits and acceptability

AZTrequirestwicedailydosingandcurrentlythereisnoAZT-containingtriple-drugFDC(adualFDCcontainingAZT+3TCisavailable).

PotentiallytroublesomeAZTtoxicities,suchasproximalmyopathy,gastrointestinalintolerance,skinhyperpigmentationandlipodystrophy,arenotuncommon.

EFVispreferredinindividualstakingrifampicin-containingTBtreatment.EFVisnotapprovedinchildrenunder3yearsofage(andthereareinsufficientdataonappropriatedosingforthatagegroup). Recent single-dose NVP for the prevention ofmother-to-child transmission (PMTCT)maycompromise response toEFVbecauseofcross-resistance.EFV isassociatedwithCNSadverseevents,whicharecommon.

14.8. AZT + 3TC + NVP option

Inrecommendingthisasapreferredfirst-lineregimen,thepanelplacedhighvalueonitasthepreferredoptioninpregnancy.Itiswidelyavailable,thereisextensiveexperienceinitsuseandthecostislowerthananEFV-containingregimen.

Efficacy and safety

NVPmaybe inferior toEFV in the important,noncriticaloutcomeofARVresistance(asdistinctfromthepredeterminedcriticaloutcomesofmortality,diseaseprogressionandseriousadverseevents).(53)Basedonsafetyconcernsraisedinsomeofthesestudies,theUSFDAhascautioned

37

againsttheuseofNVPinwomenwithhighCD4cellcounts.ThiscurrentreviewofNVPsafetyinwomen with CD4 counts of 250−350 cells/mm3 did not confirm an increased risk of seriousadverseevents.Availableevidenceisbasedlargelyonretrospectivereviewsoropen-labelstudies,withoneRCTandtwoposthocanalyseswithinanRCT(2NNstudy)informingtheevidenceprofile.(54,67) The data are conflicting, with increased rates of hepatotoxicity and hypersensitivityreportedinsomestudies(54,67−72)andnotinothers.(73−80)Twoofthesetrialswereinpregnantwomen.OtherstudiesreportednodifferenceinadverseeventsbetweenthosewithlowandhighCD4cell counts in virologically suppressedpatients switching toNVP.(76,81,82) These studiessupport the concept that a suppressed viral load is a protective factor for NVP-relatedhypersensitivity inthesituationwherepatientsneedtoswitchfromanEFV-based(orPI-based)regimentoNVP.Whilethereisagoodrepresentationofstudiesinresource-limitedsettings,thekeyrecommendationregardingcautioususeofNVPinthepresenceofhigherCD4cellcountsisfrom high-income and middle-income settings.(54) An increased risk of hypersensitivity andhepatoxicityhasbeenreportedinmenwithaCD4countof>400cells/mm3.(83)

The panel found that there was limited evidence to cause concern about the use of NVP inwomenwithCD4countsof250−350cells/mm3buturgedcautionintheuseofNVPinwomenwith CD4 counts of >250 cells/mm3 or in those with unknown CD4 cell counts. The panelconcludedthatthebenefitsofusingNVPinthissituationoutweightherisksofnotinitiatingARTbutstillurgedcloseclinicalmonitoring(andlaboratorymonitoringiffeasible)duringthefirst12weeksoftherapywhenNVPisinitiatedinwomenwithaCD4cellcountof250−350cells/mm3orwithanunknownCD4cellcountandinmenwithaCD4cellcountof>400cells/mm3orwithanunknownCD4cellcount.


Theregimeniswidelyavailable,applicabletopaediatricandadultpopulationsandapreferredoptioninpregnancy,andthereis largeprogrammaticexperience.TripleFDCformulationsareavailable for adults and children. Some countries have moved to or are considering thiscombinationalready.PLHIVwantlowpill-burdenandFDCoptions,butAZTandNVPadverseeventsmaybeunacceptable.NVP-associatedhepatotoxicity/skinrashcanbelife-threatening(but there is an unclear relationship with CD4 and gender). Rifampicin and NVP drug-druginteractionsaresuchthatthecombinationshouldnotbeusedunlessnoalternativeisavailable.TheNVPlead-indoseaddscomplexity.Recentsingle-doseNVP(sdNVP)useforPMTCTmaycompromisevirologicalresponse.(84)

14.9. TDF + 3TC (or FTC) + EFV option

Inrecommendingthisasapreferredregimen,thepanelplacedhighvalueonthesimplicityofuse(potentialforonepilloncedaily)andthetreatmentofHIV/HBVcoinfection.

Efficacy and safety

TheGRADE evidence profiles summarize evidence of low (for TDF) andmoderate (for EFV)qualitysupportingtheuseofTDF+3TC(orFTC)+EFVforthecriticaloutcomesofmortality,clinicalprogressionandseriousadverseevents.ExistingTDFtoxicitydatasuggestlowratesof



renaltoxicityinprescreenedpatients.However,baselineratesofrenaldiseaseinAfricanpatientsseemtobehigherthaninnon-Africanpopulations.

TheGRADEevidenceprofileproducedforthisguidelinerevisiondemonstratednodifferenceintheoccurrenceofadverseevents(changes increatinine,proteinuria,allgrade3or4adverseevents or treatment discontinuation) in patients using TDF-containing regimens compared toother regimens. Imprecision (onepharmacokineticstudy)andstudy limitations (smallsamplesize)werereportedintheprofile.ThecumulativeincidenceofnephrotoxicityinTDF-containingregimenshasbeenreportedas1%to4%,andtherateofFanconi’ssyndromeas0.5%to2.0%,with no association between renal disease and gender, age or race.(85,86) Only one study(open-label, 86 participants) reported data from resource-limited settings (Argentina, Brazil,DominicanRepublic),withnodiscontinuationsattributabletorenaladverseevents.(87)A2007report of all postmarketing adverse drug reactions up to April 2005 for 10 343 patients indevelopedcountriesusingTDFreportedobservationsofrenalseriousadverseeventsin0.5%ofindividualsandgradedelevationsofserumcreatininein2.2%.Riskfactorsforincreasedserumcreatinine were concomitant nephrotoxic medications, elevated serum creatinine, low bodyweight,advancedageandlowerCD4cellcount.Onestudyof15pregnantwomenwithlimitedtreatmentoptionsreportedcreatinineclearanceof>90ml/mininallbutone,whohadatransientdecline.(88)


A triple FDC is available with low pill-burden (one pill once daily) which is well accepted byPLHIV.

Two drugs in the regimen are active against HBV, no lead-in dosing is required, and thecombination canbeused in patients receiving rifampicin-containing TB treatment. There arelimiteddataontheuseofTDFwithoutrenalscreeningormonitoringinresource-limitedsettings.TDFisnotapprovedinchildrenandadolescentsandtherearelimiteddataonthesafetyofTDFinpregnancy.

CliniciansmayhaveconcernsaboutTDFusewithoutrenalmonitoring,especiallyinindividualsathigher risk for renalcomplications.Therewillbeadditionalcost if laboratorymonitoringofcreatinineisrequired.Theregimenmayonlybefeasiblewhererenalscreeningisavailableornotaprerequisite.

An alternative non-EFV-containing regimen is required in the context of the first trimester ofpregnancyorforwomenseekingtobecomepregnant.

14.10. TDF + 3TC (or FTC) + NVP option

Inrecommendingthisasapreferredfirst-lineregimen,thepanelplacedhighvalueonlowercostcomparedtoEFV-containingregimensandthetreatmentofHIV/HBVcoinfection.

Efficacy and safety

TDFandNVParediscussedinprevioussections.

39


Twodrugs in theregimenareactiveagainstHBV.There isarelatively lowpillburdenandthepotential for a once-daily regimen. There is limited programmatic experience with thiscombinationandtherehavebeenreportsofhigherratesofvirologicalfailurewhencomparedtoTDF+3TCorFTC+EFV.(53)

14.11. Triple NRTI option

ItisrecommendedthatthetriplenucleosideregimensAZT+3TC+ABCorAZT+3TC+TDFshouldbeusedfor individualswhoareunabletotolerateorhavecontraindicationstoNNRTI-basedregimens,particularlyinthefollowingsituations:

• HIV/TBcoinfection;

• pregnantwomen;

• chronicviralhepatitisB;

• HIV-2infection.

(Conditional recommendation, low quality of evidence)

ThesetwotripleNRTIregimensmaybeconsideredasalternativefirst-linetreatmentsinsituationssuchasintolerancetobothNNRTIs,orwhereanNVP-containingregimeniscontraindicatedandEFVisnotavailable,incoinfectionwithTBorchronichepatitisB,orinHIV-2infection.Recentdata from theDART trial,where the largemajority of patients are takingAZT+3TC+TDF,showedgoodclinicalresponseandsurvivalratesofaround90%over5yearsoffollow-up.(63)However,somespecifictripleNRTIcombinations,suchasABC+3TC+TDFandTDF+ddI+3TC,showedhighratesofvirologicalfailureandshouldnotbeused.InHIV-2infection,somestudiessuggestahigherriskofvirologicalfailurewiththetriplenucleosideregimenofAZT+3TC+ABCwhencomparedwithboostedPIregimens.

14.12. Stavudine (d4T)

Inresource-limitedsettings,d4TcontinuestoplayacriticalroleinthescalingupofART,whereapproximately56%ofHIVregimensstillcontaind4T.(89)Alternativeoptions(AZTandTDF)aremore expensive, require more laboratory monitoring and have higher initial discontinuationrates.(35,90)Cumulativeexposuretod4Thasthepotentialtocausedisfiguring,painfulandlife-threatening side-effects, such as lipodystrophy, peripheral neuropathy and lactic acidosis.(91,92)

Studieshaveidentifiedseveralriskfactorsassociatedwithd4T-relatedadverseevents.Peripheralneuropathy was significantly associated with older age (over 35 or 40 years).(93−95)Lipodystrophy and hyperlactataemia were significantly associated with BMI>25 and femalegender.(93,96,97) Female gender and high baselineweightwere also significantly related tosymptomatichyperlactataemia/lacticacidosisandlipodystrophyinSouthAfrica.(98)



Ontheissueofprogressivereductionintheuseofd4Tinsettingswhered4TregimensareusedastheprincipaloptionforstartingART,countriesshoulddevelopaplantomovetowardsAZT-basedorTDF-basedfirst-lineregimens,onthebasisofanassessmentofcostandfeasibility.Systemstoprevent,monitorandmanaged4T-relatedtoxicitiesshouldbe implemented.Saferbutcurrentlymoreexpensivefirst-lineARTsshouldbeprogressivelyintroducedascurrentlytheymay not be feasible or affordable in many high-burden settings with low coverage, lessdeveloped health systems, limited laboratory capacity, finite budgets and competing healthpriorities.Incountrieswithhighcoverageandmoredevelopedhealthsystems,transitiontonewtreatmentregimensshouldoccursooner.Ifd4Tuseiscontinued,itshouldbedosedat30mgBIDforallindividuals,irrespectiveofbodyweight.(99)

14.13. NRTIs not to be used together

CertaindualNRTIbackbonecombinationsshouldnotbeusedinthree-drugtherapy.Theseared4T + AZT (proven antagonism), d4T + ddI (overlapping toxicities) and 3TC + FTC(interchangeable,butshouldnotbeusedtogether).ThecombinationsofTDF+3TC+ABCandTDF+3TC+ddIselectfortheK65Rmutationandareassociatedwithhighincidencesofearlyvirologicalfailure.ThecombinationsofTDF+ddI+anyNNRTIarealsoassociatedwithhighratesofearlyvirologicalfailureandshouldbeavoided.

41

15.1. Recommendations for HIV-infected pregnant women

1. StartARTinallpregnantwomenwithHIVandaCD4countof≤350cells/mm3,irrespectiveofclinicalsymptoms.(Strong recommendation, moderate quality of evidence)

2. CD4testingisrequiredtodetermineifpregnantwomenwithHIVandWHOclinicalstage1or2diseaseneedtostartARVtreatmentorARVprophylaxisforPMTCT.(Strong recommendation, low quality of evidence)

3. StartARTinallpregnantwomenwithHIVandWHOclinicalstage3or4,irrespectiveofCD4count.(Strong recommendation, low quality of evidence)

4. StartonethefollowingregimensinART-naivepregnantwomeneligiblefortreatment:

• AZT+3TC+EFV;

• AZT+3TC+NVP;

• TDF+3TC(orFTC)+EFV;

• TDF+3TC(orFTC)+NVP.


5. DonotinitiateEFVduringthefirsttrimesterofpregnancy.(Strong recommendation, low quality of evidence)

Inmakingtheserecommendations,theARTandPMTCTpanelsplacedhighvalueonensuringthattreatmentbeginsearlyforpregnantwomenwithHIV,improvingmaternalandchild-healthoutcomesandavoidingMTCT,overandaboveconcernsaboutcostorfeasibility.

When to start

Onthequestionofwhentostart,nostudiesspecifictopregnantwomenwereidentifiedinthesystematic review prepared for this guideline revision. Evidence from the general populationsupportsstrongrecommendationsforthetimingofinitiationintermsofreductionofmortality,diseaseprogression, serious adverse events, the risk of TBand the risk ofHIV transmission(sexual and mother to child). As with the recommendation on when to start in the generalpopulation, thepanel recognized the uncertainty around theprognostic valueof someWHOclinicalstage2conditions,anddatafrommodellingandobservationalstudies indicatingthatmorethan50%ofHIV-infectedpatientswithWHOclinicalstage2haveaCD4countof≤350cells/mm3.ThepanelthereforerecommendedthatallpregnantwomenwithWHOclinicalstages1and2shouldhaveaccesstoCD4testinginordertodecidewhentostarttreatment.

What to start

Onthequestionofwhattostart,noGRADEevidenceprofileswerepreparedasnoRCTswereidentifiedthatcomparedtheuseofdifferentARVregimensinpregnantwomen.Cohortstudiesreport a reduction of HIV transmission and death.(100) There is no evidence to suggest anincrease inmaternal serious adverse events and there are no studies specifically evaluating

15. specific populAtions – when And whAt to stArt



maternal response toART.Registrydataon theuseofTDF inpregnancyshownosignals toraiseconcern,andthereisnoevidencetosuggestthatTDF+3TC(orFTC)isnotanacceptablealternativetoAZT+3TC.(101,102)

AsdiscussedinthesectiononEFV,thereisverylowqualityconflictingevidenceontherisksofEFVcausingneuraltubedefects,withtheoverallratesofbirthdefectsreportedinassociationwith EFV, NVP and TDF similar to rates reported in congenital defects registries of generalpopulations.However,dataarecurrentlyinsufficienttodeterminewhetherthereisanincreasedriskofrareanomaliessuchasneuraltubedefectswithfirst-trimesterEFVexposure.

ThereviewofNVPsafetyinpregnantwomenwithCD4countsbetween250and350cells/mm3

did not confirm an increased risk of serious adverse events. However, while data from twoprospectivecohortsindicatenoassociationbetweenNVPandliverenzymeelevation,pregnancyitselfwasassociatedwithanincreasedriskofanyliverenzymeelevationandthatthisassociationwaspresent,regardlessofpriorARTandNVPexposurehistory.(103)ThepanelconcludedthatthebenefitsofusingNVPinpregnancyoutweighedtherisks.Thepanelwasunabletoconcludefrom the evidence reviewed whether there were benefits associated with the use of EFVcomparedtoNVPinpregnantwomenafterthefirsttrimesterandwithhigherorunknownCD4cellcounts,althoughmorethanhalfofthepanelmemberspreferredEFVinthesesituations.

15.2. Recommendations for women with prior exposure to antiretrovirals for PMTCT

1. Initiate a non-NNRTI-basedART inwomenwhohave received single-dose nevirapine(sdNVP)aloneorincombinationwithotherdrugswithoutanNRTItailwithin12monthsofinitiatingchronicART.IfanNNRTI-basedregimenisstarted,performviralloadtestingat6monthsand,ifthereare>5000copies/ml,switchtoabPI-basedregimen.

2. InitiateastandardNNRTI-basedARTregimeninwomenwhohavereceivedsdNVPaloneorincombinationwithotherdrugswithanNRTItailwithin12monthsofinitiatingchronicART and perform viral load-testing at 6months. If the viral load is>5000 copies/ml,changingtoabPIisrecommended.

3. Initiate a standard NNRTI-based ART regimen in women who have received sdNVP(aloneorincombinationwithotherdrugs)morethan12monthsbeforestartingtherapy(withorwithoutaNRTItail) ifpossible.Theviral loadshouldbeevaluatedat6monthsandifitis>5000copies/mlachangeinthebPI-basedregimenisrequired.

InitiateastandardNNRTIregimeninwomenwhohavereceivedARVdrugssuchasAZTalone,withoutsdNVP,forPMTCT.

43

Table 11. ART regimens recommended for women with prior exposure to PMTCT regimen

Previous ARV exposure for PMTCT Recommendations for initiation of ART when needed for treatment of HIV for maternal health

sdNVP1(+/-antepartumAZT)withnoAZT/3TCtail2inlast12months

Initiateanon-NNRTIregimen

PIpreferredover3NRTI

sdNVP(+/-antepartumAZT)withanAZT/3TCtailinlast12months

InitiateanNNRTIregimen

Ifpossible,checkviralload3at6monthsandif>5000copies/ml,switchtosecond-lineARTwithPI

sdNVP(+/-antepartumAZT)withorwithoutanAZT/3TCtailover12monthsago



Option A4

AntepartumAZT(fromasearlyas14weeksofgestation)

sdNVPatonsetoflabour*

AZT+3TCduringlabouranddelivery*

AZT+3TCtailfor7dayspostpartum*

*sd-NVPandAZT+3TCcanbeomittedifmotherreceives>4weeksofAZTantepartum



IfnosdNVPwasgiven,startstandardNNRTI(viralloaddoesnotneedtobecheckedunlessclinicallyindicatedasnosdNVPreceived)

AlltripleARVregimens(includingOption B),irrespectiveofdurationofexposureandtimesinceexposure

Option B4

TripleARVfrom14weeksgestationuntilafterallexposuretobreastmilkhasendedAZT+3TC+LPV/rAZT+3TC+ABCAZT+3TC+EFVTDF+[3TCorFTC]+EFV

InitiatestandardNNRTIregimen

IfEFV-basedtripleARVwasusedforprophylaxisandnotail(AZT+3TC;orTDF+3TC;orTDF+FTC)wasgivenwhentripleARVwasdiscontinuedaftercessationofbreastfeeding(ordeliveryifformulafeeding),checkviralload3at6monthsandif>5000copies/ml,switchtosecond-lineARTwithPI

1Single-dosenevirapine(sdNVP)isone200-mgtabletofNVP.2AtailistheprovisionoftwoNRTIs,typicallyAZT/3TC,foraminimumof7daysfollowingsdNVPorthecessationofanyNNRTI-basedregimenwiththeobjectiveofminimizingNNRTIresistance.3IfVLisnotavailable,continueNNRTIregimenandmonitorclinically(andimmunologicallyifavailable).4OptionsAorBareviewedasequallyeffectiveforPMTCTinwomenwhodonotrequiretherapyfortheirownhealthandarerecommendedoptions in the2010updateof Use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants.



Evidence

The longhalf-lifeofNVPand its lowgeneticbarrier to resistancemeans thatdetectabledruglevelspersistfor2−3weeksinthepresenceofactiveviralreplicationfollowingasinglematernaldose.(104−106)EFValsohasalonghalf-life,withdetectabledruglevelsformorethan21daysfollowingdiscontinuation.(107)ThishasclinicalrelevanceinpregnancywhenARVsareprovidedsolely for prophylaxis against perinatal transmission and discontinued after delivery or afterbreastfeeding.Inameta-analysisof10studies,theprevalenceofNVPresistance4to8weeksfollowing sdNVP was 35.7% and the prevalence of NVP resistance in infants who becameinfecteddespiteprophylaxiswas52.6%.(108)Inmostwomen,resistantviruscannolongerbedetected6to12monthsafterexposure.However, lowlevelsofviralresistancecanpersistforlongerperiodsandinsomecasescanremainpresentinlatentlyinfectedcells.(109−111)

DatasuggestthatwomenstartingNNRTI-basedtherapywithin6−24monthsofsdNVPexposurehave higher rates of viral failure than those without sdNVP exposure. A definite relationshipbetween time fromsdNVPexposure tostartingNNRTI-basedtherapyhasbeenobservedbutvariedbetweenstudiesfrom6monthsto24months,withadefiniteimprovementinresponseif>12monthssincesdNVPexposureandstartoftherapy.(112−119)Atailregimenforaminimumof7daysisrecommendedfollowingsdNVPorifNNRTI-basedtripletherapyARTisusedforthepreventionofperinataltransmissionandsubsequentlystopped.NNRTIresistanceratesof0%to7% at 2 to 6 weeks postpartum have been reported with the use of various tail regimens.(120−125)

15.3. Recommendations for HIV/HBV coinfection

1. Start ART in all HIV/HBV-coinfected individuals who require treatment for their HBVinfection,(chronicactivehepatitis),irrespectiveoftheCD4cellcountortheWHOclinicalstage.(Strong recommendation, low quality of evidence)

2. StartTDFand3TC(orFTC)-containingantiretroviralregimensinallHIV/HBVcoinfectedindividualsneedingtreatment.(Strong recommendation, moderate quality of evidence)

Indevelopingtheserecommendations,thepanelplacedhighvalueonpromotingHBVdiagnosisandmoreeffectivetreatmentofHIV/HBVcoinfection.ThesystematicreviewofthistopicdidnotfindRCTswhichaddressedcriticalHIVoutcomes(death,diseaseprogression,seriousadverseevents)andtheGRADEprofilereportedonlyonoutcomesrelatedtoHBV(HBVviral loadandHBVdrugresistance).

Liver biopsy and HBVDNA are not usually available in the largemajority of resource-limitedsettings.Aglobaldefinitionof chronicactivehepatitis for resource-limitedsettingsbasedonclinicalandavailablelaboratoryparametersisunderdiscussion.

45

When to start

OnthequestionofwhentostartARTinHIV/HBVcoinfection,therearenoRCTscomparingearlyversus late initiation of ART. However, observational data demonstrate that individuals withHIV/HBVcoinfectionhaveathreefoldtosixfoldincreasedriskofdevelopingchronicHBVinfection,anincreasedriskoffibrosisandcirrhosisanda17-foldincreasedriskofdeathcomparedtoHBV-infectedindividualswithoutHIVinfection.(126,127)Similarly,observationaldatasupportareductioninliver-relateddiseasewithearlierandHBV-activecombinationART.(128)

What to start

On the question of what ART to start in HIV/HBV coinfection, there are data from one RCTsupporting theuseofat least twoagentswithactivityagainstHBV(TDFplus3TCorFTC) intermsofimprovedHBVviralloadresponseandreduceddevelopmentofHBVdrugresistance.(129,130)

15.4. Recommendations for HIV/tuberculosis coinfection

1. StartARTinallHIV-infectedindividualswithactiveTB,irrespectiveoftheCD4cellcount.(Strong recommendation, low quality of evidence)

2. StartTBtreatmentfirst,followedbyARTassoonaspossibleafterwards(andwithinthefirsteightweeks).(Strong recommendation, moderate quality of evidence)

3. Useefavirenz(EFV)asthepreferredNNRTIinpatientsstartingARTwhileonTBtreatment.(Strong recommendation, high quality of evidence)

In making these recommendations, the panel placed high value on the reduction of earlymortality from HIV/TB coinfection, the potential for reduction of TB transmission when allindividualswithHIVarestartedonARTearlier,andimprovedmorbidity/mortality,reductionofTBrecurrenceandimprovedmanagementofTBforcoinfectedHIV/TBpatients.

When to start

OnthequestionofwhentoinitiateARTinTBinfection,oneRCT(SAPITstudy)providesmoderateevidencefortheearlyinitiationofARTintermsofreducedall-causemortalityandimprovedTBoutcomes.(131)Trialparticipantsweregroupedinto“integrated”(immediateandendofTBdruginitiationphasescombined)and “sequential” treatmentarms.Mortalitywas55% lower in theintegrated treatment arm (5.1/100 person-years) compared to the sequential treatment arm(11.6 per 100 person-years), which was terminated. The trial is continuing to examine theoutcomesofstartingARTimmediatelyorstartingatthecompletionoftheinitiationphaseofTBtreatment.Untilfurtherdataareavailable,itisrecommendedthatARTbeinitiatedassoonasTBtherapyistolerated.Ideally,thismaybeasearlyas2weeksandnotlaterthan8weeks.

TherearelimiteddataontheinitiationofARTinpatientswithTBandCD4countsof>350cells/mm3.



Impact on TB transmission and incidence

ART has been reported to reduce TB rates by up to 90% at the individual level and byapproximately60%atthepopulationlevel,andtoreduceTBrecurrenceratesby50%.(13,132,133)ModellingsuggeststhattheinitiationofARTforallthosewithHIV/TBcoinfection,ifaccompaniedbyhighlevelsofcoverageandARTadherence,reducesthenumberofTBcases,TBmortalityratesandTBtransmissionatthepopulationlevel.(134)

What to start

The recommendations from the 2006 ART guidelines are maintained. Specifically, EFV isrecommendedbecauseoflessinteractionwithrifampicincomparedtoNVP.ForthoseHIV/TBcoinfectedindividualswhoareunabletotolerateEFV,anNVP-basedregimenoratripleNNRTI(AZT+3TC+ABCorAZT+3TC+TDF)arealternativeoptions.Inthepresenceofrifampicin,nolead-indoseofNVPisrequired.(50,135−138).Similarly,ifpatientstemporarilychangefromNVP to EFV because they need to take rifampicin-containing TB therapy and subsequentlyswitchbacktoNVPoncompletionofTBtreatment,nolead-indosingofNVPisrequired.(60,61)

15.5. Rifabutin

Background

Drug interactions between rifampicin and boosted protease inhibitors (bPIs) prohibit theconcomitantuseofstandardtherapiesforbothHIVandTB.RifampicininducesthecytochromeP450enzymesystem,loweringstandard-dosebPIplasmaconcentrationsby75−90%.AllbPIs(at standarddoses) are contraindicatedwith rifampicin. LPV/r orSQV/rmaybeusedwith anadjusted,superboosteddoseofRTV(LPV/r400mg/400mgBIDorSQV/r400mg/400mgBID)ordoublingthestandardLPV/rdailydose(LPV/r800mg/200mgBID)butthisisassociatedwithhighlevelsoftoxicity,andrequirescloseclinicalandlaboratorymonitoring.TherecommendationtouseLPV/r 800mg/200mgBID isbasedon low-quality evidenceand is associatedwithasimilarleveloftoxicitytoLPV/r400mg/400mgBID.However,thisoptionmaybemorefeasibleinRLS,asLPV/riswidelyavailablebutRTVasasoleformulationisnot.(139−142)

ThereisnocomparablerecommendationforATV/r,aWHO-preferredbPI(143).Unlikerifampicin,rifabutinhasminimaleffectonbPIplasmaconcentrations.

Evidence

Inasystematicreviewconductedforthisguidelineupdate,tenclinicaltrials(fiveRCTsandfivecohortstudies)wereidentified,whichassessedtheefficacyandsafetyofrifabutininTBinfectionwithorwithoutHIVinfection.ThefiveRCTswereincludedinaCochranereview,whichfoundnodifferencesinTBcureorrelapseratesbetweenrifampicinandrifabutin.(28)

Inthefivecohortstudies,313individualsreceivedrifabutinandART,ofwhom125receivedaPI.Duetomethodologicalissues,norigorousefficacyassessmentfromthesestudieswaspossible,buttherewasnosignofrifabutininferiorityincomparisonwithrifampicin.

47

Takentogether,thesestudiesreportcomparablesafetyandefficacyofrifabutinandrifampicin.However,evidencefromRCTscomeslargelyfromHIV-uninfectedindividuals,anddataontheuseofrifabutinwithARTarelimitedtofirst-generation,usuallyunboosted,PIs.AfurtherlimitationisthattheevidenceinHIV-infectedindividualsreceivingabPIandrifabutinisbasedononly125patients. In addition, the clinical experience with rifabutin for TB disease in resource-limitedsettingsislimited,especiallyinthecontextofthebPIscurrentlyrecommendedbyWHO.

Clinical considerations

Dosing

Therecommendeddoseofrifabutin inthepresenceofabPI is150mgthreetimesperweek.(144) However, it should be noted that this dose has been reported to result in inadequaterifabutinlevelsandacquiredrifabutinresistance.(145)RifabutiniscontraindicatedifadministeredwiththenewNNRTIetravirineplusabPI(37%reductionofetravirinelevels).

Adverse events

The most common adverse events associated with rifabutin are neutropenia, leucopenia,elevationsof hepaticenzymes, rashanduppergastrointestinal complaints, and,more rarely,uveitis.Inthesystematicreview,discontinuationattributabletoadverseeventswasuncommon.ThisreviewrevealedonecasereportofuveitisincombinationwithabPI.(146)

Monitoring and programmatic implications

ThissystematicreviewindicatesthatabPIandrifabutincoadministrationwillnotrequireintensivemonitoringandcanbeused inprimarycare settings.However, theDOTSstrategypromotesdailyadministrationofTBtherapy,preferably inFDCs.(147) Intermittentdosingofrifabutinwillcomplicatetheprogrammaticroll-outofTBtherapyandprecludesthedevelopmentofrifabutin-containingFDCs.Furtherresearchisneededintothepharmacokineticsofrifabutin75mgonce-daily inthepresenceofbPIs.Meanwhile, theability tousestandardbPIdosesoutweighstheinconvenienceofintermittentdosing.




1. Whereavailable,useviralload(VL)toconfirmtreatmentfailure.(Strong recommendation, low quality of evidence)

2. Whereroutinelyavailable,useVLevery6monthstodetectviralreplication.(Conditional recommendation, low quality of evidence)

3. ApersistentVLof>5000copies/mlconfirmstreatmentfailure.(Conditional recommendation, low quality of evidence)

4. WhenVLisnotavailable,useimmunologicalcriteriatoconfirmclinicalfailure.(Strong recommendation, moderate quality of evidence)

Inmakingtheserecommendations,thepanelwasconcernedbythelimitationsofclinicalandimmunologicalmonitoringfordiagnosingtreatmentfailure,andplacedhighvalueonavoidingprematureorunnecessaryswitchingtoexpensivesecond-lineART.Thepanelalsovaluedtheneedtooptimizetheuseofvirologicalmonitoringandensureadherence.

16.2. Evidence

Asystematicreviewwasconductedtoassessdifferentstrategiesfordeterminingwhentoswitchantiretroviral therapy regimens for first-line treatment failure among PLHIV in low-resourcesettings. Standard Cochrane systematic review methodology was employed. Outcomes ofinterestinorderofpriorityweremortality,morbidity,viralloadresponse,CD4responseandthedevelopmentofantiretroviralresistance.


Basedonthepooledanalysisoftheside-effectsfromtworandomizedtrials(Home-based AIDS care [HBAC] andDevelopment of antiretroviral therapy in Africa [DART]), clinical monitoringalone(comparedtocombinedimmunologicalandclinicalmonitoringortocombinedvirological,immunologicalandclinicalmonitoring) resulted in increases inmortality,diseaseprogressionandunnecessaryswitches,but therewerenodifferences inseriousadverseevents.(148,149)However,intheHBACtrial,combinedimmunologicalandclinicalmonitoringwascomparedtocombinedvirological, immunologicalandclinicalmonitoring,andtherewerenodifferencesinmortality,diseaseprogression,unnecessaryswitchesorvirologicaltreatmentfailures.(148)

Viralloadmeasurementisconsideredamoresensitiveindicatoroftreatmentfailurecomparedtoclinicalor immunological indicators.VLmaybeused ina targetedor routinestrategy.Theobjective of the targeted strategy is to confirm suspected clinical or immunological failure,maximizing the clinical benefits of first-line therapy and reducing unnecessary switching tosecond-linetherapy.TargetedVLmayalsobeusedearlier in thecourseofART(within4to6monthsofARTinitiation)toassessadherenceandintroduceanadherenceinterventioninat-riskpatientsbeforeviralmutationsstarttoaccumulate.(150)

16. when to switch Art

49

TheobjectiveoftheroutineVLstrategyistodetectvirologicalfailureearly,leadingtoadherenceinterventionsorchanges in therapy thatwill limitongoingviral replications, reduce the riskofaccumulation of resistancemutations and protect the drug susceptibility of second-line andsubsequenttherapies.

Whilestayingonafailingfirst-linetherapyisassociatedwithanincreasedmortalityrisk,(151)itisuncertainifVLmonitoring,comparedtoclinicalorimmunologicalmonitoring,affectscriticaloutcomes.Immunologicalcriteriaappeartobemoreappropriateforrulingoutthanforrulinginvirological failure.(152) Mathematical modelling that compared these three ART monitoringstrategiesdidnot findsignificantlydifferentoutcomes.(153) Theuseof virologicalmonitoringstrategieshasbeenassociatedwithearlierandmorefrequentswitchingtosecond-lineregimensthan the use of clinical/immunological monitoring strategies. However, data from ARTprogrammes and global procurement systems also suggests that treatment switching hasoccurredatlowerthanexpectedratesinresource-limitedsettings.Lowaccesstosecond-linedrugs,difficultiesindefiningtreatmentfailureandthelimitedavailabilityofvirologicalmonitoringhavebeenidentifiedasimportantreasonsforlateswitching.ThereisevidencetosupportaVLthresholdof5000−10000copies/mltodefinefailureinanadherentpatientwithnootherreasonsforanelevatedVL(e.g.drug-druginteractions,poorabsorption,intercurrentillness):thisrangeofvaluesisassociatedwithhigherratesofclinicalprogressionandimmunologicaldeteriorationinsomecohortstudies.(154,155)

Immunologicalfailureisnotagoodpredictorofvirologicalfailure.Dependingonthestudy,8%to 40% of individuals who present with evidence of immunological failure have virologicalsuppressionandriskbeingunnecessarilyswitchedtosecond-lineART.(156)

While no consensus onARTmonitoring and the diagnosis of failurewas reached, the panelsupportedmovestoreducerelianceonclinicalfailuredefinitions,expandtheuseimmunologicalcriteriaanduseviral load testing forconfirmationofclinical/immunological failure indecidingwhentoswitchtosecond-linetherapy.


Benefits

Moreaccurateassessmentoftreatmentfailurewillreducethedelayinswitchingtosecond-linedrugs.TargeteduseofVLcanlimitunnecessaryswitchingandroutineuseofVLcanreducetheriskofresistance.Whileexpensive,VLhasthepotentialtosavethecostofexpensivesecond-linedrugsbyconfirmingthattheyareneeded.

Risks

TheoptimumthresholdfordefiningVLfailureinapublichealthapproachisstillunknown,andtherearelimiteddataonthediagnosticaccuracyofVLinresource-limitedsettings.ThereisariskthatresourcesusedtoexpandlaboratorycapacityorconductVLtestingwoulddivertfundsawayfromexpandingaccesstotreatment.



Acceptability and feasibility

ARTswitchinghasoccurredatlowerthanexpectedratesinresource-limitedsettings,andthelimiteduseofvirologicalmonitoringhasbeenidentifiedasanimportantfactor.ManycountriesareconsideringemployingVL tooptimize theuseofexpensivesecond-linedrugs.Thesamerationaleapplieswhenthird-linedrugsareavailable.PhysiciansandPLHIVconsiderclinicalandimmunologicalmonitoringinsufficienttopromoteatimelyswitchandwantVLmonitoring.Theinitialandongoingcostishigh.TheuseofVLtoconfirmclinical-immunologicalswitch(targetedapproach)willcostlessthantheroutineuseofVLmonitoring.Qualityassuranceprogrammesshould be implemented at VL facilities irrespective of the VL strategy adopted. Central VLfacilities with adequate specimen transportation from clinic to laboratory are feasible, as ispoint-of-careVLcapacityinurbansettings.Point-of-careVLcapacityinruralsettingsislikelytoremainunfeasiblewith current technologies.Feasibilitywasnot systematically assessed,buttargeteduseofVLseemedmorefeasibletothepanelthanroutineuse.


OneofthecriticaldecisionsinARTmanagementiswhentoswitchfromoneregimentoanotherfor treatment failure. The 2006 recommendations onAntiretroviral therapy for HIV infection in adults and adolescents recognizedthatdefinitions for treatment failurewerenotstandardizedandoutlinedasetofdefinitionsforARTfailurebasedonavailableevidenceatthattime.TheseremainbasicallyunchangedexceptthattheVLthresholdforfailurehaschangedfrom10000copies/mlin2006recommendationsto5000copies/mlinthecurrentguidelines.AnindividualmustbetakingARTforatleast6monthsbeforeitcanbedeterminedthataregimenhasfailed.

Table 12. ART switching criteria

Failure Definition Comments

Clinical failureNeworrecurrentWHOstage4condition

Conditionmustbedifferentiatedfromimmunereconstitutioninflammatorysyndrome(IRIS)

CertainWHOclinicalstage3conditions(e.g.pulmonaryTB,severebacterialinfections),maybeanindicationoftreatmentfailure

51

Failure Definition Comments

Immunological failure

FallofCD4counttobaseline(orbelow)OR

50%fallfromon-treatmentpeakvalueOR

PersistentCD4levelsbelow100cells/mm3

WithoutconcomitantinfectiontocausetransientCD4celldecrease

Virological failure

Plasmaviralloadabove5000copies/ml

Theoptimalviralloadthresholdfordefiningvirologicalfailurehasnotbeendetermined.Valuesof>5000copies/mlareassociatedwithclinicalprogressionandadeclineintheCD4cellcount

Fig. 1. Targeted viral load strategy for failure and switching

Suspected clinical orimmunological failure

VL ≤ 5,000 copies/ml VL > 5,000 copies/ml

Test viral load

VL>5,000 copies/ml

Adherence intervention

Repeat VL

Do not switch to second line Switch to second line



Fig. 2. Routine viral load strategy for failure and switching

NOTE:Thisalgorithmalsoapplies to the recommendation tocheckviral load6monthsafter initiationofART inwomenwhohavebeenexposedtosd-NVPforPMTCT.

Routine Viral Load Testing(not a prerequisite for initiating ART)

VL ≤ 5,000 copies/ml VL > 5,000 copies/ml

Adherence intervention

VL>5,000 copies/ml

Repeat VL

Do not switch to second line Switch to second line

53


1. A boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs) arerecommendedforsecond-lineART.(Strong recommendation, moderate quality of evidence)

2. ATV/randLPV/rarethepreferredbPIsforsecond-lineART.(Strong recommendation, moderate quality of evidence)

3. SimplificationofsecondNRTIoptionsisrecommended.

• Ifd4TorAZThasbeenusedinfirst-linetherapy,useTDF+(3TCorFTC)astheNRTIbackboneinsecond-linetherapy.

• If TDF has been used in first-line therapy, use AZT+ 3TC as the NRTI backbone insecond-linetheapy.


Inmakingtheserecommendations, thepanelplacedhighvalueonusingsimplersecond-lineregimensandtheavailabilityofheat-stableformulationsandfixed-dosecombinations.

17.2. Evidence

Asystematic reviewwasconductedwith theobjectiveofassessing theoptimumsecond-lineARTregimeninPLHIVfailingfirst-linetherapyinresource-limitedsettings.StandardCochranesystematic reviewmethodologywasemployed.Outcomesof interest inorderofpriorityweremortality, morbidity (combined disease progression and serious adverse events), viral loadresponse,CD4responseanddevelopmentofantiretroviralresistance.


Second-line NRTIs

Despiteacomprehensivesearch,fewstudiesofrelevancewereidentified.Onestudyreportednodifference in virological outcomesamong thosemaintaining3TC in second-line regimenscomparedtothosewhodidnot(lowqualityofevidence).(157)Observationaldatasupportedthisfinding.(158)

Boosted PI comparisons

bPIsprovidemostoftheantiviralactivityinsecond-lineregimens.Thereisinsufficientevidenceoncritical patient outcomes to distinguish between bPIs in the context of second-line therapy.RandomizedtrialscomparingLPV/rwithDRV/r,ATV/rorFPV/rinART-naivepatientsshowednon-inferiorityat48weeksofallthreebPIs(evidenceoflowtomoderatequality).(159−163)DRV/rwassuperiortoLPV/rat96weeks.(161)ThereisevidenceofmoderatequalitythatATV/risnon-inferiorto LPV/r (in combination with TDF and an optimized second NRTI) in treatment-experiencedpatients.(164) Non-serious adverse events varied by boosted PI and there were no significantdifferencesinseriousadverseevents.(165,166).AllunboostedPIsareconsideredinferiortobPIs.

17. second-line regimens



PI monotherapy

On the question of whether PI monotherapy could be used as second-line ART, there is amoderatequalityofevidencefromatargetedreview(asopposedtoaformalsystematicreview)ofnineRCTsandindividualstudyreportsshowinglessvirologicalsuppressionandhigherratesofviralreboundforPImonotherapycomparedtostandardtripleARTregimens.(167−173)Therewerenoothersignificantdifferencesinthecriticaloutcomesofmortality,diseaseprogressionorserious adverse events, or the important outcomes of immunological response and drugresistance(bothvery lowtomoderatequalityevidence).Non-criticaloutcomes,suchasnon-seriousadverseeventsandlipoatrophy,werenotcapturedintheGRADEevidenceprofile.ThepanelconcludedthatanNRTIbackboneshouldbemaintainedinasecond-linebPI-containingregimen.


Benefits

These recommendations will facilitate the simplification of therapeutic options and drugprocurement as the NRTIs recommended in second-line therapy are also used in first-linetherapy (in different combinations), and shouldbepurchasedby all programmes. There is apotentialforsimplifieddrugregimens.

Risks

TheremaybeconfusionbecauseAZT,TDFand3TC,theonlyNRTIsrecommendedinsecond-line regimens, also are recommended in first-line regimens. Some countries have alreadychosen alternative bPIs (IDV/r, SQV/r, FPV/r) in preference to the recommended ones (ATV/r,LPV/r).


PLHIVwantbettersecond-lineoptionswithfewerside-effects.ThepreferredbPIsareavailableinmostcountries.Genericheat-stableLPV/risonthemarketalready.Agenericheat-stableFDCofATV/r(co-blisterpackedwithTDF/3TC)isindevelopment.AlternativebPIs(SQV,IDV,FPVandDRV)arenotavailableasFDCsandaremoreexpensivethanthepreferredoptions.Saquinavirhasahighpill-burden,IDVhasahighriskoftoxicityandFPVisexpensive.Cliniciansmaynotbecomfortable with not replacing both first-line NRTIs with two new NRTIs in the second-lineregimen.

55

17.6 Clinical considerations

Table 13. Preferred second-line ART options

Target population Preferred options Comments

Adults and adolescents (including pregnant women)

If d4T or AZT used in first-line therapy

TDF+3TCorFTC+ATV/rorLPVr

NRTIsequencingbasedonavailabilityofFDCsandpotentialforretainedantiviralactivity,consideringearlyandlateswitchscenarios

ATV/randLPVrarecomparableandavailableasheat-stableFDCsorco-packageformulations

If TDF used in first-line therapy

AZT+3TC+ATV/rorLPVr

TB/HIV coinfection

If rifabutin available

Sameregimensasrecommendedaboveforadultsandadolescents

Nodifferenceinefficacybetweenrifabutinandrifampicin

RifabutinhassignificantlylessdruginteractionwithbPIs,permittingstandardbPIdosing

If rifabutin not available

SameNRTIbackbonesasrecommendedforadultsandadolescentsplusLPVrorSQV/rwithsuperboosteddosingofRTV

(LPV/r400mg/400mgtwicedailyor

LPV/r800mg/200mgtwicedailyor

SQV/r400mg/400mgtwicedaily)

RifampicinsignificantlyreducesthelevelsofbPIs,limitingtheeffectiveoptions.UseofextradosesofritonavirwithselectedbPIs(LPVandSQV)canovercomethiseffectbutwithincreasedratesoftoxicity

Hepatitis B coinfectionAZT+TDF+3TCorFTC+ATV/rorLPVr

IncaseofARTfailure,TDF+3TCorFTCshouldbemaintainedforanti-HBVactivityandthesecond-lineregimenshouldincludeotherdrugswithanti-HIVactivity



17.7. Selection of second-line NRTIs

TherationalefortheselectionoftheNRTIsinsecond-linetherapyistochoosethemostlogicalcombinationdependingonwhatwasusedinthefirst-lineregimen.Residualactivityoffirst-lineNRTIs(withthepossibleexceptionof3TCandFTC)ismorelikelytheearlierfailureisdetectedandswitchingisimplemented.Conversely,anynewNRTIsmaybecompromisedinthesecond-line regimen if there is late detection of failure and late switching. The recommended NRTIsequencingisbasedonlikelyresistancemutationsandthepotentialforretainedantiviralactivity.

Therearetwoclinicalscenarios:

• earlyswitchingbasedonsensitivemonitoringforfailure,usingviralload;

• lateswitchingbasedoninsensitivemonitoring,usingclinicalorimmunologicalcriteriafordefiningfailure.

IfAZT+3TCareusedinthefirst-lineregimenwithsensitivemonitoringandearlyswitching,theNRTIswithmostlikelyactivityareTDFandddI.Inthescenarioofinsensitivemonitoringandlateswitching,TDFandddIactivityarelesslikely.

IfTDF+3TCareuseinfirst-linetherapy,withearlyorlateswitching,theNRTIswithremainingactivityareAZTandd4T(bothverylikely).Retainedactivityof3TCislikelyintheearlyswitchingscenarioandlesslikelyinthecaseoflateswitching.(174)

ABCandddIareno longer recommendedasprefferedoptions insecond-line regimens.ThepanelconcludedthattherewasnospecificadvantageinusingABCorddIandtheiruseaddedcomplexityandcost,butnewdatawillbegeneratedfromongoingtrials.(175)Onestudyinthereviewreportednodifferenceinviralsuppressionfollowingmainlyd4T-basedfirst-lineART,withand without a ddI-containing NRTI backbone in an LPV/r-based second-line regimen.(176)Anotherstudyreportedsimilarvirologicaloutcomesin individualswithandwithouttheM184Vmutationandtakingasecond-lineregimenwithorwithoutddI.(158)Nostudiesreportingfailurefollowingafirst-lineABC-containing(orTDF-containing)regimenwereidentified.

17.8. Maintaining 3TC in the second-line regimen

Thereisuncertaintyaboutwhether3TCshouldbeaddedasafourthdrugintheNRTIcomponentofsecond-lineregimensifddIorABCareusedasthebackboneNRTIs.OnlyoneRCThasbeenconductedtoexaminethisissue;itfoundnosignificantdifferenceinthereductionofHIVRNAinindividualswhomaintained3TCin theirsecond-lineregimencomparedto thosewhodidnot.(157)OneobservationalstudyreportedsimilarvirologicalresponseamongindividualswiththeM184Vmutation (indicating resistance to3TCandFTC)whosubsequently took3TC-orFTC-containingregimencomparedtothosewhotooka3TC-orFTC-sparingregimen.(177)

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17.9. NRTIs for HIV/HBV coinfection

In individuals with HIV/HBV coinfection who require treatment for their HBV infection and inwhomTDF+(3TCorFTC)failinthefirst-lineregimen,theseNRTIsshouldbecontinuedinthesecond-lineregimenforanti-HBVactivityandtoreducetheriskofhepaticflares,irrespectiveoftheselectedsecond-lineregimen,whichshouldbeAZT+TDF+(3TCorFTC)+bPI.

17.10. Selection of boosted protease inhibitor

The recommend bPIs are equivalent in terms of efficacy. In studies of populations with PIresistance,thereisgrowingsupportfortheuseofonce-dailybPIregimensinwhichtheritonavircomponentisonly100mgperday.Suchregimenshavefewergastrointestinalside-effectsandlessmetabolictoxicitythanregimensthatuseritonavirboostingatadoseof200mgperday.(178,179) Large head-to-head trials have demonstrated non-inferiority or superiority of ATV/rcomparedwithLPV/r,withlessgastrointestinalandlipidtoxicity.(159)




1. Nationalprogrammesshoulddeveloppoliciesforthird-linetherapythatconsiderfunding,sustainabilityandtheprovisionofequitableaccesstoART.(Conditional recommendation, low quality of evidence)

2. Third-line regimens should include newdrugs likely to have anti-HIV activity, such asintegraseinhibitorsandsecond-generationNNRTIsandPIs.(Conditional recommendation, low quality of evidence)

3. Patientsonafailingsecond-lineregimenwithnonewARVoptionsshouldcontinuewithatoleratedregimen.(Conditional recommendation, very low quality of evidence)

Thepanelwasconcernedbyunpublishedcohortreportsofhighmortalityamongpatientsfailingsecond-linetherapy,butplacedhighvalueonbalancingtheneedtodeveloppoliciesforthird-linetherapywhileexpandingaccesstofirst-linetherapy.Itwasrecognizedthatmanycountrieshavefinancialconstraintsthatmightlimittheadoptionofthird-lineregimens.

18.2. Evidence

A targeted literature review of relevant studies provides limited evidence to guide third-linestrategiesinresource-limitedsettings,withfewstudiesofneweragentsinthesesettings.DatafromRCTs,predominantlyindevelopedcountries,areavailableforboosteddarunavir(DRV/r),etravirine and raltegravir. Taken together, these data support the efficacy of these agents inhighlyART-experiencedpatients. Therewas no uncertainty among thepanel concerning theneed for third-line regimens. However, there was uncertainty about how making third-lineregimensavailablewouldaffecttheprovisionoffirst-lineandsecond-lineART.Therewasalsouncertaintyaboutwhatthird-linedrugsshouldbeprovided,asmanystudiesarestillinprogress.


The evidence is very limited, particularly in resource-limited settings.However, as access tomonitoring improves and the scale-up of initial ART continues, demand for second-line andthird-lineregimenswillincrease.Thecriteriafordiagnosingsecond-linefailurearethesameasthoseusedfordiagnosingfirst-linefailure.

Inapooledsubgroupanalysis,DRV/rplusanoptimizedbackgroundregimen(OBR)chosenbygenotyping andphenotypingwas shown to be superior to the control group (bPI plusOBR,where the bPI was selected by the investigator) in highly treatment-experienced individuals.(180,181) Thesestudieswereconducted inhigh-middle incomecountries (Argentina,Brazil)andsomewell-resourcedsettings.Inafurtheranalysis,DRV/rwaswelltoleratedintreatment-experienced, HBV- or HCV-coinfected patients, with no differences in liver-related adverseeventsbetweenDRV/randthecontrolbPIgroup.(182)Indevelopedcountrysettings,DRV/rhasbeenreportedtobecost-effectivecomparedtoLPV/r.(183)Inindividualswithlimitedtreatment

18. third-line regimens

59

options,raltegravir(RAL)plusOBRprovidedbetterviralsuppressionthanOBRaloneforatleast48weeks.(184,185)Similarly,etravirine (ETV)plusOBRprovidedbetterviralsuppressionandimproved immunological response than OBR alone.(186) In patients with multidrug-resistantviruswhohavefewremainingtreatmentoptions,thecombinationofRAL,ETV,andDRV/rwaswelltolerated,andwasassociatedwitharateofvirologicalsuppressionsimilartothatexpectedintreatment-naivepatients.(187)


Benefits

Therapy with newer agents is associated with a reduction in clinical progression andimmunologicaldeterioration.DRV/rhasahighergeneticbarriertoresistancecomparedtoearly-generationPIsandisactiveagainstmultidrug-resistantHIVisolates.Whilehigh-levelresistanceto ETV following NVP or EFV failure appears uncommon, low-level resistance is common.(188−190)

Risks

Thereare fewstudiesofneweragents in third-line regimens in resource-limitedsettings.(191)Most studies have been conducted in well-resourced or high-income to middle-incomecountries,andhavedemonstratedbenefit fornon-criticaloutcomes(viral loadsuppressionorimmunological improvement).There isevidencefrompostmarketingreportsofhigherratesofhypersensitivitytoETVthanpreviouslyreported.(192)Etravirineandraltegravirarenotapprovedforuseinindividualslessthan16yearsofage.Therearelimiteddataontheuseofnewerdrugsinpregnancy,includingverylimitedpharmacokineticandsafetydata.


PhysiciansandPLHIVwanta third-line regimen tobeavailable. Instudiesconducted inwell-resourcedsettingsandinmodelledcost-effectivenessanalysis,DRV/rhasbeendemonstratedtobecost-effectivecomparedtootherbPIsinheavilypretreatedpatients.TheacquisitioncostforETVisonetotwotimeshigherthanthatofEFVandNVP.TheacquisitioncostofDRVandRAL has not been established in resource-limited settings but is expected to be high. Theavailabilityofthesedrugsinresource-limitedsettingsnowandinthenearfutureisuncertain.




Table 14. Toxicities of third-line ARVs

Toxicities of third-line ARVs

Darunavir (DRV) Skinrash(10%)–DRVhasasulfonamidemoiety;Stevens-Johnsonsyndromeanderythremamultiformehavebeenreported

Hepatotoxicity

Diarrhoea,nausea

Headache

Hyperlipidaemia

Transaminaseelevation

Hyperglycaemia

Fatmaldistribution

Possibleincreasedbleedingepisodesinpatientswithhaemophilia

Ritonavir (RTV)

(as pharmacokinetic booster)

GIintolerance,nausea,vomiting,diarrhoea

Paresthesias—circumoralandextremities

Hyperlipidaemia(especiallyhypertriglyceridaemia)

Hepatitis

Asthenia

Tasteperversion

Hyperglycaemia

Fatmaldistribution


Raltegravir (RAL)

Nausea

Headache

Diarrhoea

Pyrexia

CPKelevation

Etravirine (ETV)

Rash(2%discontinuationbecauseofrashduringclinicaltrials)

Hypersensitivityreactionshavebeenreported,characterizedbyrash,constitutionalfindings,andsometimesorgandysfunction,includinghepaticfailure

Nausea

61

19.1. Guiding principles

1. Countriesshouldestablishapackageofcareinterventions,inadditiontoART,toreduceHIVtransmission,preventillnessandimprovethequalityoflife.

2. A key component of the package of care interventions is the promotion of early HIVdiagnosisandearlyassessmentofARTeligibilitybyCD4 testing, inorder tominimizelateinitiationofARTandmaximizeHIVprevention.

3. WHOcontinuestoadvocateforwideraccesstomonitoringtools,includingCD4andviralloadtesting.

4. ThepackageofcareinterventionsshouldbealignedwiththeWHOEssential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings.(193)

NotallPLHIVareeligibleforART.However,itisimperativethatasmanyPLHIVaspossibleentercarebefore theybecome illwith their first opportunistic infection (OI) orbefore theydevelopadvancedimmunosuppression(CD4cellcount<200cells/mm3),whichputsthemathigherriskofdevelopingopportunisticdisease.ExpandedaccesstoHIVtestingandcounselling,especiallyprovider-initiatedbutalsoclient-initiated,iscriticaltoidentifyingpeoplewhoneedtoentercare.Thepre-ARTperiodincareprovidesasettingforinterventionstopreventfurthertransmissionofHIV,totreatandpreventotherillnesses,toprepareforthetimewhenARTwillbenecessaryandtomaximizelong-termretentionincare.

19.2. Voluntary counselling and testing and provider-initiated testing and counselling

Client-initiatedvoluntarycounsellingandtesting(VCT)istheprocesswherebytheclientrequestsatest.However,attendanceatanyhealthfacilityoffersanopportunitytointegratediscussionofHIVandHIVtestingintoroutinemedicalcarethroughprovider-initiatedtestingandcounselling(PITC).(22)PITCfacilitatesearlyHIVdiagnosis,partnerdiagnosisandenrolment intopre-ARTcare,andminimizeslateinitiationofART.

19.3. Preventing further transmission of HIV

Fromapublichealthperspective,PLHIVmakeupthemostimportantgrouptoaddresswithHIVpreventionstrategies.(194)Achange in the riskbehaviourofapersonwithHIVhasagreaterimpactonthetransmissionofHIVthanthesamebehaviouralchangeinapersonwithoutHIV.(195)EnrolmentintocarefacilitatestheidentificationofPLHIVwithbehaviouralriskfactorsandinterventions to reduce risk, and facilitates the identification of clinical risk factors, such assexually transmitted infections and treatment, and interventions to reduce unplannedpregnanciesandmother-to-childtransmissionofHIV.(196)

19. pAckAge of cAre interventions



Pre-ART care includes harm reduction for peoplewho inject drugs (supportive environment,opioid substitution therapy and the provision of clean needles and syringes). This not onlyreducesHIV transmission but has the potential to stabilize the persons’ lifestyles by limitingactivedruguseinpreparationforARTinitiation.

Positivepreventionstrategies,atgroupandindividuallevels,havedemonstratedareductioninHIVriskbehavioursamongpeoplewithHIV.Theyincludesupporttoimprovetheconsistencyofcondom use, a reduction of needle-sharing and unprotected sex among people who injectdrugs,andareductioninthenumberofsexualpartners.(197−199)

19.4. The Three I's for HIV/TB

Amongpeople livingwithHIV,TB is themost frequent life-threateningopportunistic infectionandaleadingcauseofdeath.Pre-ARTcareprovidesasettingforimplementationoftheWHOThree I 'sstrategy:isoniazidpreventivetreatment(IPT)whereindicated,intensifiedcasefinding(ICF)foractiveTB,andTBinfectioncontrol(IC)atallclinicalencounters,whicharekeypublichealthstrategiestodecreasetheimpactofTBamongindividualsandthecommunity.TheThree I 'sshouldbeacentralpartofHIVcareandtreatmentandarecriticalforthecontinuedsuccessofARTscale-up.(200)TBinfectioncontrolisessentialtokeepvulnerablepatients,health-careworkersandtheircommunitiessafefrombecominginfectedwithTB.(200)InformationaboutTBshouldbeprovidedtoallpeoplewithHIV.CounsellingshouldincludeinformationabouttheriskofacquiringTB,strategiesforreducingexposure,clinicalmanifestationsofTBdisease,andtheriskoftransmittingTBtoothers.

19.5. Cotrimoxazole prophylaxis

Cotrimoxazole prophylaxis is recommended for all symptomatic individuals (WHO clinicalstages 2, 3 or 4) including pregnant women. Where CD4 testing is available, cotrimoxazoleprophylaxisisrecommendedforindividualswithaCD4cellcountof<350cells/mm3,particularlyinresource-limitedsettingswherebacterialinfectionandmalariaareprevalentamongPLHIV.Ifthe main targets for cotrimoxazole prophylaxis are Pneumocystis jiroveci pneumonia andtoxoplasmosis infection, a CD4 threshold of <200 cells/mm3may be chosen. Data from anobservational analysis in the DART trial showed that the use of cotrimoxazole prophylaxisreducedmortality by 50% in severely immune-suppressedHIV-infected adults initiating ART,withbenefitscontinuingforatleast72weeks.Furthermore,cotrimoxazoleprophylaxisreducedmalariaincidenceinthesepatients.(201)

19.6. Sexually transmitted infections

Pre-ART (and on-ART) care is an opportunity to provide comprehensive STI services, whichshouldincludecorrectdiagnosisbysyndromeorlaboratorytest,provisionofeffectivetreatmentatthefirstencounter,notificationandtreatmentofpartners,reductionoffurtherriskbehaviourand transmission through education, counselling and the provision of condoms. Laboratory

63

screeningshouldincludeaserologicaltestforsyphilis,especiallyinpregnantwomen,andHIVtestingforallindividualsdiagnosedwithanSTI.(196)

19.7. Treatment preparedness

ThereisevidencethatsomePLHIVdonothaveaccesstoaccurateknowledgeaboutHIV,theeffectivenessofARTandthechallengesofadherence.(202)Inresource-limitedsettings,majorfactorscontributingtogoodadherencearefreeARVS,easeofuse,andpreparednessforuse.(203)ModellingstudiessuggestthattreatmentreadinessisassociatedwithimprovedadherenceonceARThascommenced.(204)EnrolmentintocarebeforethetimeofinitiationofARTprovidesanopportunityforPLHIVtolearn,understandandprepareforsuccessfullifelongART.

19.8. Early initiation of ART

Enrolment into pre-ART care is critical for the early initiation of ART, maximizing treatmentresponseandminimizingtreatmentcomplicationsuchas immunereconstitution inflammatorysyndrome(IRIS).(205,206)Inreality,mostpeopledonotreceiveanypre-ARTcare,presentingwithadvancedHIVdisease,andthisresults indelayedinitiationofART.Mortalityratesduringthe firstyearofARTarehigh (3−26%),mostdeathsoccurring in the first fewmonths, largelybecauseoflatepresentation.(207)ThefundamentalneedisforearlierHIVdiagnosis,enrolmentintocare,ideallywithCD4countmonitoringtodetermineeligibilityforART,andtheinitiationofARTbeforesicknessoccurs.(208)

19.9. ART as prevention

Studies continue to support the benefits of ART for prevention.(209) There is evidence thatindividualsonfullysuppressiveARTwhoareadherenttothetherapyarelesslikelytotransmitHIVtosexualpartners.Conversely,thosewithunrecognizedHIVinfectioncontributesignificantlytoonwardsexualtransmission.Atanindividuallevel,ARTreducesviralloadandinfectiousness.(210)TheuseofARVdrugshasbeenprovedtoreduceMTCTofHIV.



20.1. Guiding principles

1. LaboratorymonitoringisnotaprerequisitefortheinitiationofART.

2. CD4andviralloadtestingarenotessentialformonitoringpatientsonART.

3. Symptom-directed laboratory monitoring for safety and toxicity is recommended forthoseonART.

4. Ifresourcespermit,useviralloadinatargetedapproachtoconfirmsuspectedtreatmentfailurebasedonimmunologicaland/orclinicalcriteria.

5. Ifresourcespermit,useviralloadinaroutineapproach,measuredevery6months,withtheobjectiveofdetectingfailureearlierthanwouldbethecaseifimmunologicaland/orclinicalcriteriawereusedtodefinefailure.

Table 15. Laboratory monitoring before, during and after initiating ART

Phase of HIV management Recommended test Desirable test

AtHIVdiagnosis CD4 HBsAg

Pre-ART CD4

AtstartofART CD4

HbforAZT1

CreatinineclearanceforTDF2

ALTforNVP3

OnART CD4

HbforAZT1

CreatinineclearanceforTDF2

ALTforNVP3

Atclinicalfailure CD4 Viralload

Atimmunologicalfailure Viralload

WomenexposedtoPMCTinterventionswithsd-NVPwithatailwithin12monthsandwithoutatailwithin6monthsofinitiatingART

Viralload6monthsafterinitiationofART

1RecommendedtestinpatientswithhighriskofadverseeventsassociatedwithAZT(lowCD4orlowBMI).2Recommendedtest inpatientswithhighriskofadverseeventsassociatedwithTDF(underlyingrenaldisease,olderagegroup,lowBMI,diabetes,hypertensionandconcomitantuseofaboostedPIornephrotoxicdrugs).3RecommendedtestinpatientswithhighriskofadverseeventsassociatedwithNVP(ART-naiveHIV+womenwithCD4of>250cells/mm3,HCVcoinfection).

PatientswhoarenotyeteligibleforARTshouldhaveCD4countmeasurementeverysixmonthsandmorefrequentlyastheyapproachthethresholdtoinitiateART.Iffeasible,HBsAgshouldbeperformedinordertoidentifypeoplewithHIV/HBVcoinfectionandwho,therefore,shouldinitiateTDF-containingART.

20. lAborAtory monitoring

65

20.2. Laboratory monitoring on ART

TwoRCTs(DARTandHBAC)andtwoobservationalstudieshaveassessedlaboratorymonitoringstrategies.TheDARTstudycomparedalaboratory-drivenmonitoringstrategy(CD4cellcountevery3months)toaclinically-drivenmonitoringstrategy.(211)Therewasasmallbutstatisticallysignificantdifference inmortalityanddiseaseprogression in favourof the laboratorystrategybut only from the third year on ART. HBAC compared clinical monitoring alone to clinicalmonitoringandtheadditionofCD4cellcountorCD4cellcountandviralload,bothperformedevery3months.Inthisstudy,clinicalmonitoringalonewasassociatedwithanincreasedrateofAIDS-definingeventsandatrendtowardsincreasedmortality.NoadditionalbenefitwasseenfromaddingquarterlyviralloadmeasurementstoCD4cellcountinthefirst3yearsofART.(148)

The twoobservationalstudieswhichcompared immunologicalandclinicalversusvirological,immunological and clinical monitoring reported that, in programmes with virological,immunologicalandclinicalmonitoringaswitch tosecond-line therapyoccurredearlier,morefrequently and at higher CD4 counts.(212) Three further monitoring trials, all of which areassessingviralloadmonitoringindifferentstrategies,areprogressinginCameroon,Thailand,andZambia.(213−215)

ForNNRTI-containing regimens, symptom-directed laboratorymonitoring of liver enzymes isrecommended.Symptom-directedmonitoringmeansorderingtestsonlywhenthecareproviderrecognizessignsandsymptomsofpotentialART-relatedtoxicity.ForwomeninitiatingNVPwithaCD4countof250−350cells/mm3,iffeasible,itisrecommended(butnotrequired)tomonitorhepaticenzymesatweeks2,4and12afterinitiation.

For AZT-containing regimens, haemoglobin (Hb) measurement is recommended before theinitiationofAZTand thenas indicatedbysigns/symptoms.Patients receivingAZT-containingregimensandwithlowbodyweightand/orlowCD4cellcountsareatgreaterriskofanaemia.ThesepatientsshouldhaveroutineHbmonitoring1monthafterinitiatingAZTandthenatleastevery3months.AZTshouldnotbegivenifHbis<7g/dl.

For TDF-containing regimens, creatinine clearance calculation is recommended, if feasible,beforeinitiationandevery6months.Theinabilitytoperformcreatinineclearanceisnotabarrierto TDF use. Creatinine clearancemonitoring is recommended in thosewith underlying renaldisease, of older age groups, and with low body weight or other renal risk factors such asdiabetesorhypertension.

ThereisevidencethatindividualstakingTDFandaPI/rmayexperiencegreatermediandeclinein creatinine clearance than those takingTDFandanNNRTI-based regimen.(216)CreatinineclearanceshouldbemonitoredmorecloselywhenTDFisusedwithaPI/r.

For individuals with HIV/HBV or HIV/HCV coinfection it is recommended to monitor hepaticenzymesatweeks4and12followingARTinitiationiffeasible.



Table 16. Monitoring ART in those at higher risk of adverse events

ARV drug Major toxicity High-risk situations*

d4T

Lipodystrophy

Neuropathy

Lacticacidosis

Age>40years

CD4countof<200cells/mm3

BMI>25(orbodyweight>75kg)

ConcomitantusewithINHorddI

AZTAnaemia

Neutropaenia

CD4countof<200cells/mm3

BMI<18.5(orbodyweight<50kg)

Anaemiaatbaseline

TDF Renaldysfunction

Underlyingrenaldisease

Age>40years

BMI<18.5(orbodyweight<50kg)

Diabetesmellitus

Hypertension

ConcomitantuseofabPIornephrotoxicdrugs

EFV

Teratogenicity firsttrimesterofpregnancy(donotuseEFV)

PsychiatricillnessDepressionorpsychiatricdisease(previousoratbaseline)

NVP Hepatotoxicity HCVandHBVcoinfection

67

21.1. Special note on coinfection with HIV and hepatitis C

Hepatitis C (HCV) coinfection is significantly associated with increased risk of death andadvancedliverdiseaseinHIV-positiveindividuals.HIVinfectionacceleratesHCV-relateddiseaseprogressionandmortality(217−219)butthereciprocaleffectofHCVontherateofHIVdiseaseprogressionremainsdifficulttoquantifybecauseoftheheterogeneityofstudyresults.Arecentmeta-analysis showedan increase in theoverall riskofmortalitybutdidnotdemonstrateanincreasedriskofAIDS-definingeventsamongcoinfectedpatients.(220)

AmajorobservationalcohortstudyontheleveloftoxicitiesofspecificARTregimensusedforHIV/HCVcoinfectiondidnotfindsignificantdifferences.(221)However,thesystematicreviewondrug-drug interactions prepared for these guidelines found important pharmacologicalinteractionsbetweenribavirinandABC,ATV,AZT,d4TandddIthatcanincreasethetoxicityriskifthesedrugsareusedconcomitantly.(222−226)

Many studies also suggest that the sustained viral response rates of HCV therapy in HIV-coinfectedindividualsaresignificantlylowerthaninHCV-monoinfectedpatients(227−230)butothershaveachievedhigherratesinthispopulation.(231)

ConsideringthesignificantlevelofuncertaintyonthesetopicsandtheimportanceofhepatitisCmanagementinthecontextofHIVcoinfection(animportantgaphighlightedbytheguidelinespanelgroup,particularlytherepresentativesfromthepeoplelivingwithHIVcommunity),WHOisplanningtorevisetherecommendationsforthepreventionandtreatmentofmajorHIV-relatedopportunistic infections and comorbidities, including hepatitis C. Furthermore, it is expectedthat the 2010 World Health Assembly will establish global policy recommendations for themanagement of viral hepatitis,whichwill increase support for an integrated approach to theprevention,treatmentandcareofHIV/HCVcoinfection.

Meanwhile,theinitiationofARTinHIV/HCVcoinfectedpeopleshouldfollowthesameprinciplesand recommendations as for its initiation inHIV-monoinfected individuals.However, patientsshouldbecloselymonitoredbecauseoftheincreasedriskofdrugtoxicitiesanddruginteractionsbetweensomeARVsandanti-HCVdrugs.

21.2. Dosages of recommended antiretrovirals

Generic name Dose

Nucleoside reverse transcriptase inhibitors (NRTIs)

Abacavir(ABC)300mgtwicedailyor600mgoncedaily

Didanosine(ddI)400mgoncedaily(>60kg)250mgoncedaily(≤60kg)

Emtricitabine(FTC) 200mgoncedaily

21. Annexes



Generic name Dose

Lamivudine(3TC)150mgtwicedailyor300mgoncedaily

Stavudine(d4T) 30mgtwicedaily

Zidovudine(AZT) 250−300mgtwicedaily

Nucleotide reverse transcriptase inhibitors (NtRTIs)

Tenofovir 300mgoncedaily1

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz(EFV) 600mgoncedaily

Etravirine(ETV) 200mgtwicedaily

Nevirapine(NVP) 200mgoncedailyfor14days,followedby200mgtwicedaily2

Proteases inhibitors (PIs)

Atazanavir+ritonavir(ATV/r) 300mg+100mgoncedaily

Darunavir+ritonavir(DRV/r) 600mg+100mgtwicedaily

Fos-amprenavir+ritonavir(FPV/r)

700mg+100mgtwicedaily

Indinavir+ritonavir(IDV/r) 800mg+100mgtwicedaily

Lopinavir/ritonavir(LPV/r)

FixedDoseCombinationtablets(LPV200mg/RTV50mg)

Twotablets(400mg/200mg)twicedaily3

Considerations for individuals on TB therapy

Inthepresenceofrifabutin,nodoseadjustmentrequired

Inthepresenceofrifampicin;useritonavirsuperboosting

(LPV400mg+RTV400mgtwicedaily)orLPV800mg+RTV200mgtwicedaily,withcloseclinicalandhepaticenzymemonitoring

69

Generic name Dose

Saquinavir+ritonavir(SQV/r)

1000mg+100mgtwicedaily

Considerations for individuals on TB therapy

Inthepresenceofrifabutin,nodoseadjustmentrequired

Inthepresenceofrifampicin;useritonavirsuperboosting

(SQV400mg+RTV400mgtwicedaily)withcloseclinicalandhepaticenzymemonitoring

Integrase strand transfer inhibitors (INSTIs)

Raltegravir(RAL) 400mgtwicedaily

1TDFdosageadjustmentforindividualwithalteredcreatinineclearancecanbeconsidered(usingCockcroft-Gaultformula).

Creatinineclearance≥50ml/min,300mgoncedaily.

Creatinineclearance30−49ml/min,300mgevery48hours.

Creatinineclearance≥10−29ml/min(ordialysis),300mgonceevery72−96hours.

Cockcroft-Gaultformula:GFR = (140-age) x (Wt in kg) x (0.85 if female) / (72 x Cr)

2Inthepresenceofrifampicin,orwhenpatientsswitchfromEFVtoNVP,noneedforlead-indoseofNVP.

3LPV/rcanbeadministeredas4tabletsoncedaily(i.e.LPV800mg+RTV200mgoncedaily)inpatientswithlessthanthreeLPVresistance-associatedmutationsongenotypictesting.Once-dailydosingisnotrecommendedinpregnantwomenorpatientswithmorethanthreeLPVresistance-associatedmutations.

21.3. Toxicities and recommended drug substitutions

ARV drug Common associated toxicity Suggested substitute

TDF

Asthenia,headache,diarrhoea,nausea,vomiting,flatulence

Renalinsufficiency,Fanconisyndrome

Osteomalacia

Decreaseinbonemineraldensity

SevereacuteexacerbationofhepatitismayoccurinHBV-coinfectedpatientswhodiscontinueTDF

Ifusedinfirst-linetherapy

AZT(ord4Tifnootherchoice)

Ifusedinsecond-linetherapy

Withinapublichealthapproach,thereisnooptionIfpatienthasfailedAZT/d4Tinfirst-linetherapy.Iffeasible,considerreferraltoahigherlevelofcarewhereindividualizedtherapymaybeavailable




AZT

Bonemarrowsuppression:macrocyticanaemiaorneutropaenia

Gastrointestinalintolerance,headache,insomnia,asthenia

Skinandnailpigmentation

Lacticacidosiswithhepaticsteatosis

Ifusedinfirst-linetherapy

TDF(ord4Tifnootherchoice)

Ifusedinsecond-linetherapy

d4T

EFV

Hypersensitivityreaction

Stevens-Johnsonsyndrome

Rash

Hepatictoxicity

PersistentandsevereCNStoxicity(depression,confusion)

Hyperlipidaemia

Malegynaecomastia

Potentialteratogenicity(firsttrimesterofpregnancyorwomennotusingadequatecontraception)

NVP

bPIifintoleranttobothNNRTIs

TripleNRTIifnootherchoice

NVP

Hypersensitivityreaction

Stevens-Johnsonsyndrome

Rash

Hepatictoxicity

Hyperlipidaemia

EFV

bPIifintoleranttobothNNRTIs

TripleNRTIifnootherchoice

ATV/r

Indirecthyperbilirubinaemia

Clinicaljaundice

ProlongedPRinterval—firstdegreesymptomaticAVblockinsomepatients

Hyperglycaemia

Fatmaldistribution

Possibleincreasedbleedingepisodesinindividualswithhaemophilia

Nephrolithiasis

LPV/r

71


LPV/r

GIintolerance,nausea,vomiting,diarrhoea

Asthenia

Hyperlipidaemia(especiallyhypertriglyceridaemia)

Elevatedserumtransaminases

Hyperglycaemia

Fatmaldistribution


PRintervalprolongation

QTintervalprolongationandtorsadedepointes

ATV/r

21.4. ARV-related adverse events and recommendations

Table 17. Symptom-directed toxicity management table

Adverse events Major first-line ARVs

Recommendations

Acutepancreatitis d4T

DiscontinueART.Givesupportivetreatmentwithlaboratorymonitoring.ResumeARTwithanNRTIwithlowpancreatictoxicityrisk,suchasAZTorTDF.

Drugeruptions(mildtosevere,includingStevens-Johnsonsyndromeortoxicepidermalnecrolysis)

NVP,EFV(lesscommonly)

Inmildcases,symptomaticcare.EFVrashoftenstopsspontaneouslyafter3−5dayswithoutneedtochangeART.Ifmoderaterash,non-progressingandwithoutmucosalinvolvementorsystemicsigns,considerasingleNNRTIsubstitution(i.e.fromNVPtoEFV).Inmoderateandseverecases,discontinueARTandgivesupportivetreatment.Afterresolution,resumeARTwithabPI-basedregimenortripleNRTIifnootherchoice.



Adverse events Major first-line ARVs

Recommendations

Dyslipidaemia

AllNRTIs(particularlyd4T)

EFV

ConsiderreplacingthesuspectedARV

Anaemiaandneutropaenia

AZT

Ifsevere(Hb<7.0g/dland/orANC<750cells/mm3),replacewithanARVwithminimalornobonemarrowtoxicity(e.g.d4TorTDF)andconsiderbloodtransfusion

HepatitisAllARVs(particularlyNVP)

IfALTisatmorethanfivetimesthebasallevel,discontinueARTandmonitor.Afterresolution,restartART,replacingthecausativedrug(e.g.EFVreplacesNVP).

Lacticacidosis

AllNRTIs

(particularlyd4T)

DiscontinueARTandgivesupportivetreatment.Afterresolution,resumeARTwithTDF.

Lipoatrophyandlipodystrophy

AllNRTIs(particularlyd4T)

EarlyreplacementofthesuspectedARVdrug(e.g.d4TforTDForAZT)

Neuropsychiatricchanges

EFV

Usuallyself-limited,withouttheneedtodiscontinueART.

Ifintolerabletothepatient,replaceNVPwithEFVorbPI.SinglesubstitutionrecommendedwithoutcessationofART.

Renaltoxicity(renaltubulardysfunction)

TDFConsidersubstitutionwithAZT

Peripheralneuropathy d4T

Replacementofd4TwithAZT,TDF.

Symptomatictreatment(amitriptyline,vitaminB6).

73

21.5. Diagnostic criteria for HIV-related clinical events

Clinical event Clinical diagnosis Definitive diagnosis

Clinical stage 1

AsymptomaticNoHIV-relatedsymptomsreportedandnosignsonexamination

Notapplicable

Persistentgeneralizedlymphadenopathy

Painlessenlargedlymphnodes>1cm,intwoormorenoncontiguoussites(excludinginguinal),inabsenceofknowncauseandpersistingfor3monthsorlonger

Histology

Clinical stage 2

Moderateunexplainedweightloss(under10%ofbodyweight)

Reportedunexplainedweightloss.Inpregnancy,failuretogainweight

Documentedweightloss(under10%ofbodyweight)

Recurrentbacterialupperrespiratorytractinfections(currenteventplusoneormoreinlast6months)

Symptomscomplex,e.g.unilateralfacepainwithnasaldischarge(sinusitis),painfulinflamedeardrum(otitismedia),ortonsillopharyngitiswithoutfeaturesofviralinfection(e.g.coryza,cough)

Laboratorystudiesifavailable,e.g.cultureofsuitablebodyfluid

HerpeszosterPainfulvesicularrashindermatomaldistributionofanervesupplydoesnotcrossmidline

Clinicaldiagnosis

Angularcheilitis

Splitsorcracksattheangleofthemouthnotattributabletoironorvitamindeficiency,andusuallyrespondingtoantifungaltreatment

Clinicaldiagnosis

Recurrentoralulcerations(twoormoreepisodesinlast6months)

Aphthousulceration,typicallypainfulwithahaloofinflammationandayellow-greypseudomembrane

Clinicaldiagnosis




PapularpruriticeruptionPapularpruriticlesions,oftenwithmarkedpostinflammatorypigmentation

Clinicaldiagnosis

Seborrhoeicdermatitis

Itchyscalyskincondition,particularlyaffectinghairyareas(scalp,axillae,uppertrunkandgroin)

Clinicaldiagnosis

Fungalnailinfections

Paronychia(painfulredandswollennailbed)oronycholysis(separationofnailfromnailbed)ofthefingernails(whitediscolouration,especiallyinvolvingproximalpartofnailplate,withthickeningandseparationofnailfromnailbed)

Fungalcultureofnail/nailplatematerial

Clinical stage 3

Severeunexplainedweightloss(morethan10%ofbodyweight)

Reportedunexplainedweightloss(over10%ofbodyweight)andvisiblethinningofface,waistandextremitieswithobviouswastingorbodymassindexbelow18.5.Inpregnancy,weightlossmaybemasked.

Documentedlossofmorethan10%ofbodyweight

Unexplainedchronicdiarrhoeaforlongerthan1month

Chronicdiarrhoea(looseorwaterystoolsthreeormoretimesdaily)reportedforlongerthan1month

Notrequiredbutconfirmedifthreeormorestoolsobservedanddocumentedasunformed,andtwoormorestooltestsrevealnopathogens

Unexplainedpersistentfever

(intermittentorconstantandlastingforlongerthan1month)

Reportsoffeverornightsweatsformorethan1month,eitherintermittentorconstantwithreportedlackofresponsetoantibioticsorantimalarials,withoutotherobviousfociofdiseasereportedorfoundonexamination.Malariamustbeexcludedinmalariousareas.

Documentedfeverexceeding37.6oCwithnegativebloodculture,negativeZiehl-Nielsenstain,negativemalariaslide,normalorunchangedchestX-rayandnootherobviousfocusofinfection

75


Oralcandidiasis

Persistentorrecurringcreamywhitecurd-likeplaqueswhichcanbescrapedoff(pseudomembranous),orredpatchesontongue,palateorliningofmouth,usuallypainfulortender(erythematousform)

Clinicaldiagnosis

Oralhairyleukoplakia

Finewhitesmalllinearorcorrugatedlesionsonlateralbordersofthetongue,whichdonotscrapeoff

Clinicaldiagnosis

PulmonaryTB

Chronicsymptoms(lastingatleast2to3weeks):cough,haemoptysis,shortnessofbreath,chestpain,weightloss,fever,nightsweats,plus

EITHERpositivesputumsmear

ORnegativesputumsmearANDcompatiblechestradiograph(includingbutnotrestrictedtoupperlobeinfiltrates,cavitation,pulmonaryfibrosisandshrinkage).Noevidenceofextrapulmonarydisease.

IsolationofM. tuberculosisonsputumcultureorhistologyoflungbiopsy(togetherwithcompatiblesymptoms)

Severebacterialinfection(e.g.pneumonia,meningitis,empyema,pyomyositis,boneorjointinfection,bacteraemia,severepelvicinflammatorydisease)

Feveraccompaniedbyspecificsymptomsorsignsthatlocalizeinfection,andresponsetoappropriateantibiotic

Isolationofbacteriafromappropriateclinicalspecimens(usuallysterilesites)

Acutenecrotizingulcerativestomatitis,gingivitisorperiodontitis

Severepain,ulceratedgingivalpapillae,looseningofteeth,spontaneousbleeding,badodour,rapidlossofboneand/orsofttissue

Clinicaldiagnosis




Unexplainedanaemia(below8g/dl),neutropenia(below0.5x109/l)and/orchronic(morethan1month)thrombocytopenia(under50x109/l)

Nopresumptiveclinicaldiagnosis

Diagnosedonlaboratorytestingandnotexplainedbyothernon-HIVconditions.Notrespondingtostandardtherapywithhaematinics,antimalarialsoranthelminticsasoutlinedinrelevantnationaltreatmentguidelines,WHOIMCIguidelinesorotherrelevantguidelines.

Clinical stage 4

HIVwastingsyndrome

Reportedunexplainedweightloss(over10%ofbodyweight)withobviouswastingorbodymassindexbelow18.5,plus

EITHER

unexplainedchronicdiarrhoea(looseorwaterystoolsthreeormoretimesdaily)reportedforlongerthan1month

OR

reportsoffeverornightsweatsformorethan1monthwithoutothercauseandlackofresponsetoantibioticsorantimalarials.Malariamustbeexcludedinmalariousareas.

Documentedweightloss(over10%ofbodyweight)

plus

twoormoreunformedstoolsnegativeforpathogens

OR

documentedtemperatureexceeding37.6oCwithnoothercauseofdisease,negativebloodculture,negativemalariaslideandnormalorunchangedCXR

Pneumocystispneumonia

Dyspnoeaonexertionornonproductivecoughofrecentonset(withinthepast3months),tachypnoeaandfever;ANDCXRevidenceofdiffusebilateralinterstitialinfiltrates,ANDnoevidenceofbacterialpneumonia.Bilateralcrepitationsonauscultationwithorwithoutreducedairentry.

Cytologyorimmunofluorescentmicroscopyofinducedsputumorbronchoalveolarlavage(BAL),orhistologyoflungtissue

77


Recurrentbacterialpneumonia

(thisepisodeplusoneormoreepisodesinlast6months)

Currentepisodeplusoneormoreepisodesinlast6months.Acuteonset(under2weeks)ofsymptoms(e.g.fever,cough,dyspnoea,andchestpain)PLUSnewconsolidationonclinicalexaminationorCXR.Responsetoantibiotics.

Positivecultureorantigentestofacompatibleorganism

Chronicherpessimplexvirus(HSV)infection(orolabial,genitaloranorectal)ofmorethan1month,orvisceralatanysiteoranyduration

Painful,progressiveanogenitalororolabialulceration;lesionscausedbyrecurrentHSVinfectionandreportedformorethanonemonth.Historyofpreviousepisodes.VisceralHSVrequiresdefinitivediagnosis.

PositivecultureorDNA(byPCR)ofHSVorcompatiblecytology/histology

Oesophagealcandidiasis

Recentonsetofretrosternalpainordifficultyinswallowing(foodandfluids)togetherwithoralcandidiasis

Macroscopicappearanceatendoscopyorbronchoscopy,orbymicroscopy/histology

ExtrapulmonaryTB

Systemicillness(e.g.fever,nightsweats,weaknessandweightloss).OtherevidenceforextrapulmonaryordisseminatedTBvariesbysite:pleural,pericardial,peritonealinvolvement,meningitis,mediastinalorabdominallymphadenopathy,osteitis.

MiliaryTB:diffuseuniformlydistributedsmallmiliaryshadowsormicronodulesonCXR.

DiscretecervicallymphnodeM. tuberculosisinfectionisusuallyconsideredalesssevereformofextrapulmonarytuberculosis.

M. tuberculosisisolationorcompatiblehistologyfromappropriatesite,togetherwithcompatiblesymptoms/signs(ifculture/histologyisfromrespiratoryspecimentheremustbeotherevidenceofextrapulmonarydisease)




Kaposisarcoma

Typicalappearanceinskinororopharynxofpersistent,initiallyflatpatcheswithapinkorblood-bruisecolour,skinlesionsthatusuallydevelopintoviolaceousplaquesornodules

Macroscopicappearanceatendoscopyorbronchoscopy,orbyhistology

Cytomegalovirusdisease(retinitisorinfectionofotherorgans,excludingliver,spleenandlymphnodes)

Retinitisonly:maybediagnosedbyexperiencedclinicians.Typicaleyelesionsonfundoscopicexamination:discretepatchesofretinalwhiteningwithdistinctborders,spreadingcentrifugally,oftenfollowingbloodvessels,associatedwithretinalvasculitis,haemorrhageandnecrosis.

CompatiblehistologyorCMVdemonstratedinCSFbycultureorDNA(byPCR)

CNStoxoplasmosis

RecentonsetofafocalneurologicalabnormalityorreducedlevelofconsciousnessANDresponsewithin10daystospecifictherapy.

PositiveserumtoxoplasmaantibodyAND(ifavailable)single/multipleintracranialmasslesiononneuroimaging(CTorMRI)

HIVencephalopathy

Clinicalfindingofdisablingcognitiveand/ormotordysfunctioninterferingwithactivitiesofdailyliving,progressingoverweeksormonthsintheabsenceofaconcurrentillnessorcondition,otherthanHIVinfection,whichmightexplainthefindings

Diagnosisofexclusion,and,ifavailable,neuroimaging(CTorMRI)

Extrapulmonarycryptococcosis(includingmeningitis)

Meningitis:usuallysubacute,feverwithincreasinglysevereheadache,meningism,confusion,behaviouralchangesthatrespondtocryptococcaltherapy

IsolationofCryptococcus neoformansfromextrapulmonarysiteorpositivecryptococcalantigentest(CRAG)onCSF/blood

79


Disseminatednon-tuberculousmycobacteriainfection


Diagnosedbyfindingatypicalmycobacterialspeciesfromstool,blood,bodyfluidorotherbodytissue,excludinglung

Progressivemultifocalleukoencephalopathy(PML)


Progressiveneurologicaldisorder(cognitivedysfunction,gait/speechdisorder,visualloss,limbweaknessandcranialnervepalsies)togetherwithhypodensewhitematterlesionsonneuroimagingorpositivepolyomavirusJC(JCV)PCRonCSF

Cryptosporidiosis(withdiarrhoealastingmorethan1month)


CystsidentifiedonmodifiedZNmicroscopicexaminationofunformedstool

Chronicisosporiasis Nopresumptiveclinicaldiagnosis IdentificationofIsospora

Disseminatedmycosis(coccidiomycosis,histoplasmosis)


Histology,antigendetectionorculturefromclinicalspecimenorbloodculture

Recurrentsepticemia(includingnon-typhoidsalmonella)

Nopresumptiveclinicaldiagnosis Bloodculture

Lymphoma(cerebralorBcellnon-Hodgkin)orothersolidHIV-associatedtumours


Histologyofrelevantspecimenor,forCNStumours,neuroimagingtechniques

Invasivecervicalcarcinoma

Nopresumptiveclinicaldiagnosis Histologyorcytology




Atypicaldisseminatedleishmaniasis


Histology(amastigotesvisualized)orculturefromanyappropriateclinicalspecimen

HIV-associatednephropathy

Nopresumptiveclinicaldiagnosis Renalbiopsy

HIV-associatedcardiomyopathy


Cardiomegalyandevidenceofpoorleftventricularfunctionconfirmedbyechocardiography

Source: Revised WHO Clinical staging and immunological classification of HIV and case definition of HIV for surveillance.2006.

81

21.6

. G

rad

ing

of

sele

cted

clin

ical

an

d la

bo

rato

ry t

oxi

citie

s

Est

imat

ing

seve

rity

gra

de

Mild

Gra

de

1

Mo

der

ate

Gra

de

2

Sev

ere

Gra

de

3

Po

ten

tial

ly

life

- th

reat

enin

g

Gra

de

4

Clinicaladverse

event NOT

identified

elsewhereinthe

table

Symptomscausing

noorminimal

interferencewith

usualsocialand

functional activities

Symptoms causinggreaterthan

minimalinterferencewithusualsocial

andfunctionalactivities

Symptomscausing

inabilitytoperform

usualsocialand

f unctionalactivities

Symptomscausing

inabilitytoperform

basicself-careOR

medicalor

operative

intervention

indicatedtoprevent

permanent

i mpairment,

persistentdisability

ordeath

Haemoglobin

8.0−9.4g/dl OR

80−94g/l OR

4.93−5.83mmol/l

7.0−7.9g/dlOR

70−79g/lOR

4.31−4.92mmol/l

6.5−6.9g/dlOR

65−69g/lOR

4.03−4.30mmol/l

<6.5g/dlOR

<65g/lOR

<4.03mmol/l

Absoluteneutrophil

count

1000−1500/mm3

OR1.0−1.5/G/l*

750−999/mm3 OR

0.75−0.99/G/l*

500−749/mm3 OR

0.5−0.749/G/l*

<500/mm3 OR

<0.5/G/l*

Platelets

75000-99000/mm3

OR75−99/G/l*

50000−74999/mm3 OR50−74.9/G/l*

20000−49999/

mm3 OR20−49.9/

G/l*

<20000/mm3 OR

<20/G/l*



Ch

emis

trie

sM

ild

Gra

de

1

Mo

der

ate

Gra

de

2

Sev

ere

Gra

de

3

Po

ten

tial

ly

life

-th

reat

enin

g

Gra

de

4

Hyperbilirubinaemia

>1.0−1.5xULN

>1.5−2.5xULN

>2.5−5xULN

>5xULN

Glucose(fasting)

110−125mg/dl

126−250mg/dl

251−500mg/dl

>500mg/dl

Hypoglycaemia

55−64mg/dlOR

3.01−3.55mmol/l

40−54mg/dlOR

2.19−3.00mmol/l

30−39mg/dlOR

1.67−2.18mmol/l

<30mg/dlOR

<1.67mmol/l

Hyperglycaemia

(nonfastingandno

prior diabetes)

116−160 mg/dlOR

6.44−8.90mmol/l

161−250mg/dlOR

8.91−13.88mmol/l

251−500mg/dlOR

13.89−27.76

mmol/l

>500 mg/dlOR

>27.76mmol/l

Triglycerides

−400−750mg/dlOR

4.52−8.47mmol/l

751−1200mg/dl

OR

8.48−13.55mmol/l

>1200mg/dlOR

>13.55 mmol/l

Creatinine

>1.0−1.5xULN

>1.5−3.0xULN

>3.0−6.0xULN

>6.0xULN

AST(SGOT)

1.25−2.5 xULN

>2.5−5.0 xULN

>5.0−10.0xULN

>10.0xULN

ALT(SGPT)

1.25−2.5xULN

>2.5−5.0xULN

>5.0−10.0xULN

>10.0xULN

GGT

1.25−2.5xULN

>2.5−5.0xULN

>5.0−10.0xULN

>10.0xULN

Alkaline

phosphatase

1.25−2.5 xULN

>2.5−5.0 xULN

>5.0−10.0xULN

>10.0xULN

Bilirubin

1.1−1.5XULN

1.6−2.5xULN

2.6−5.0xULN

>5xULN

Amylase

>1.0−1.5xULN

>1.5−2.0 xULN

>2.0−5.0 xULN

>5.0 xULN

Pancreaticamylase

>1.0−1.5xULN

>1.5−2.0xULN

>2.0−5.0xULN

>5.0xULN

83

Lipase

>1.0−1.5xULN

>1.5−2.0xULN

>2.0−5.0xULN

>5.0xULN

Lactate

<2.0xULNwithout

acidosis

>2.0xULN

withoutacidosis

IncreasedlactatewithpH<7.3without

life-threateningconsequences

Increasedlactate

withpH<7.3with

life-threatening

consequences

Gas

tro

inte

stin

alM

ild

Gra

de

1

Mo

der

ate

Gra

de

2

Sev

ere

Gra

de

3

Po

ten

tial

ly

life

-th

reat

enin

g

Gra

de

4

Nausea

MildORtransient;

reasonableintake

maintained

Moderate

discomfortOR

i ntakedecreased

for<3days

SeverediscomfortORminimalintakefor

>3days

Hospitalization

required

Vomiting

MildORtransient;

2 −3e pisodesper

dayORmild

vomitinglasting<1

week

ModerateOR

persistent;4−5

episodesperday

ORvomiting

lasting>1week

Severevomitingofallfoods/fluidsin24

hoursORorthostatichypotensionOR

intravenousRxrequired

Hypotensiveshock

ORhospitalization

forintravenousRx

required

Diarrhoea

MildORtransient;

3−4loosestools

perdayORmild

diarrhoealasting

<1week

ModerateOR

persistent;5−7

loose stoolsper

dayORdiarrhoea

lasting>1week

Bloody diarrhoeaORorthostatic

hypotensionOR>7 loose stools/dayOR

intravenousRxrequired

Hypotensiveshock

ORhospitalization

required



Res

pir

ato

ryM

ild

Gra

de

1

Mo

der

ate

Gra

de

2

Sev

ere

Gra

de

3

Po

ten

tial

ly

life

-th

reat

enin

g

Gra

de

4

Dyspnoea

Dyspnoeaon

exertion

Dyspnoeawith

normalactivity

Dyspnoeaatrest

Dyspnoearequiring

O2therapy

Uri

nal

ysis

Mild

Gra

de

1

Mo

der

ate

Gra

de

2

Sev

ere

Gra

de

3

Po

ten

tial

ly

life

-th

reat

enin

g

Gra

de

4

Proteinuria

Spoturine

1+2+or3+

4+Nephrotic

s yndrome

24-hoururine

200mgto1gloss/

dayOR<0.3%OR

<3 g/l

1gto2gloss/

dayOR0.3%to

1.0%OR3gto10

g/l

2gto3.5gloss/dayOR>1.0%OR

>10g/l

Nephrotic

syndrome OR

>3.5gloss/day

Grosshaematuria

Microscopiconly

Gross,noclots

Grossplusclots

Obstructive

Mis

cella

neo

us

Mild

Gra

de

1

Mo

der

ate

Gra

de

2

Sev

ere

Gra

de

3

Po

ten

tial

ly

life

-th

reat

enin

g

Gra

de

4

Fever(oral,>12

hours)

37.7−38.50COR

100.0−101.50 F

38.6−39.50COR

101.6−102.90 F

39.6−40.50COR

103−1050 F

>40.50COR

>1050 Ffor≥12

c ontinuoushours

85

Headache

Mild;noRx

required

ModerateOR

non-narcotic

analgesiaRx

SevereORrespondstoinitialnarcotic

Rx

Intractable

Allergicreaction

Prurituswithout

rash

Localized

urticaria

Generalizedurticaria,angioedema

Anaphylaxis

Rash

hypersesnitivity

Erythema,pruritus

Diffuse

maculopapular

rashORdry

desquamation

VesiculationORmoistdesquamation

ORulceration

ANYONEOF:

mucousmembrane

involvement,

suspected

Stevens-Johnson

(TEN),erythema

multiforme,

exfoliative

dermatitis

Fatigue

Normalactivity

r educedby<25%

Normalactivity

r educedby

25−50%

Normalactivityreducedby>50%;

c annotwork

Unabletocarefor

s elf

Sou

rce:DivisionofAIDS,NationalInstituteofAllergyandInfectiousDiseases,version1.0December2004,clarificationAugust2009.

NO

TE:ThisclarificationincludestheadditionofGrade5toxicity,whichisdeath.

Forabnormalitiesnotfoundelsewhereinthetoxicitytable,usetheinformationonE

stim

atin

g se

verit

y g

rad

einthefirstcolumn.



21.7. Prevention and Assessment of HIV Drug Resistance

TheemergenceofHIVdrugresistance(HIVDR)isofincreasingconcernincountrieswhereARTandARVprophylaxisiswidelyused,andrepresentsapotentialimpedimenttotheachievementof long-termsuccess in treatmentoutcomes.The rapidoruncontrolledemergenceofHIVDRcouldleadtoanincreaseintherapeuticfailures,transmissionofresistantvirus,andadecreasein therapeutic options, treatment programme effectiveness and survival. Implementingprogrammeelements thatminimize theemergenceofHIVDR, includingoptimizingaccess toART, supporting appropriate ART prescribing and adherence, and ensuring adequate andcontinuousdrugsupplies,isessentialforpreservingtheefficacyofthelimitednumberofARVdrugsavailableinmanycountries.iTransmissionofresistantvirusisminimizedthroughsupportforpreventionprogrammesforHIVpositiveindividuals.

Toguidetheseinterventions,WHO,togetherwithitspartnersinTheGlobalHIVDrugResistanceNetwork(HIVResNet),developedandencouragescountriestoadoptanHIVDRpreventionandassessmentstrategy.Thegoalofthestrategy,coordinatedatcountrylevelbyanationalHIVDRworkinggroup,istosupportdevelopmentofevidencetoinformprogrammeactionsthatmaintaintheeffectivenessofARTregimensandlimitHIVDRtransmission.Theelements,whichcomprisean importantpublichealth tool tosupportnational, regionalandglobalARTscale-upefforts,include:

Regularmonitoringofkeyearlywarning indicators inARTsitesthatmaybeprogrammaticallyimprovedtominimizetheemergenceofHIVDR;

Monitoringsurveys toassess theemergenceofHIVDRandassociated factors incohort(s)oftreatedpatients12monthsafterARTinitiationinsentinelARTsites;and

Surveillancefortransmitteddrug-resistantHIV-1amongindividualsnewlyinfected.

Further informationonandresourcestosupporttheWHOHIVDRpreventionandassessmentstrategyareavailableathttp://www.who.int/hiv/drugresistance/.

i NotethatWHOdoesnotrecommendroutineHIVdrugresistancetestingforindividualpatientmanagementinsettingswhereotherbasiclaboratorymeasurementssuchasCD4andHIVVLarenotyetavailable.

87

21.8. Special Note on Antiretroviral Pharmacovigilance

Background

Pharmacovigilance is the science and activities relating to the detection, assessment,understandingandpreventionofadverseeffectsoranyotherpossibledrug-relatedproblems.ii

It incorporatesandprovidestrainingintheidentificationofadversereactions,datacollection,processing,analysisandreporting.Pharmacovigilanceisakeycomponentofcomprehensivepatientcareandthesafeuseofmedicines.Adverseeventsandsevereadverseevents,bothpreandpostmarketing,havebeenreportedwithallantiretrovirals.Notmonitoring,understandingand managing these events can result in poor adherence, treatment failure and reduceconfidenceinARTbybothPLHIVandcareproviders.

Objectives of pharmacovigilance

Themain objectives of pharmacovigilance in antiretroviral programs are tomaximize patientsafety and the outcomes of public health programs, identify early warning signs (signals) ofadverse reactions to drugs used in the management of HIV infection, monitor the safety ofantiretroviralsinspecificgroupsincludingpregnantwomenandinchildren,identifydrug-druginteractions and quantify the rates of these events and report them to health authorities/clinicians. Pharmacovigilance programs also provide methodological training and addressissuesrelatedtounregulatedprescribing,drugqualitycontrolandcounterfeitdrugs.

Pharmacovigilance in resource limited settings

Inresourcelimitedsettings,antiretroviralpharmacovigilanceispoorlydevelopedbutiscriticalbecauseoffactorsuniquetothesesettings.Therehasbeenrapidscale-upof largelygenericantiretroviral therapy drug combinations not commonly used in well-resource settings.Pharmacovigilance is required not only for chronic antiretroviral therapy but also for theantiretroviralsusedforthepreventionofmothertochildtransmissionofHIV.Therearedistinctco-comorbidities(tuberculosis,malaria)anddrug-druginteractions.

Methodology

Thereare twomainmethodsofmonitoring,cohorteventmonitoring (CEM)andspontaneousreporting.Athirdmethodisconsumerreporting,wherebyareportofasuspectedadversedrugreactionisinitiatedbythedrugconsumer.

Inspontaneousreportingsystems,suspectedadversedrugeventsarevoluntarilysubmittedbyhealth professionals and pharmaceutical manufacturers to the national regulatory authority.Spontaneousreportingisthemostcommonformofpharmacovigilanceandisthecoreactivityofnationalpharmacovigilancecentresparticipating in theWHO internationaldrugmonitoringprogram. It requires fewer human and financial resources than CEM, and is likely to be themethod used in most resource limited settings in the foreseeable future. The system haslimitations. The successor failureof a spontaneous reporting systemdependson theactiveparticipation of reporters. Under reporting is common in all counties, irrespective of their

ii Thesafetyofmedicinesinpublichealthprogrammes:Pharmacovigilanceanessentialtool(WHO,2006).



resources.Without informationonutilizationandon theextentof consumption, spontaneousreports do not make it possible to determine the frequency of an adverse drug reactionattributabletoaproduct,oritssafetyinrelationtoacomparator.iii

CEMisaprospectiveobservationalcohortstudyofadverseeventsassociatedwithoneormoremedicines. InCEM,alladverseeventsoccurringinapatienttakingantiretroviralarecollectedirrespectiveofcausalityorrelationshiptheantiretrovirals.AdvantagesofCEM(overspontaneousreporting) include the ability to produce rates, rapid results, early detection of signals, fewermissingdataandlessreportingbias.However,CEMisrequiresmoreresourcesthanspontaneousreporting.

WHOandpartnersarepreparingatoolkitforcountrieswishingincorporatepharmacovigilanceintotheirantiretroviralprograms.Inthemeantime,thefollowingresourcesareavailable:

• Pharmacovigilanceforantiretroviralshomepage

http://www.who.int/hiv/topics/pharmacovigilance/en/index.html

• Apracticalhandbookonthepharmacovigilanceofantiretroviralmedicines(WHO2009)

http://www.who.int/hiv/topics/pharmacovigilance/arv_pharmacovigilance_handbook.pdf

• Pharmacovigilanceforantiretroviralinresourcelimitedsettings(WHO2007)

http://www.who.int/medicines/publications/PhV_for_antiretrovirals.pdf

• Thesafetyofmedicinesinpublichealthprogrammes:Pharmacovigilanceanessentialtool(WHO2006)

www.who.int/medicines/areas/quality_safety/safety_efficacy/Pharmacovigilance_B.pdf

• Theimportanceofpharmacovigilance:SafetyMonitoringofmedicinalproducts

http://apps.who.int/medicinedocs/pdf/s4893e/s4893e.pdf

iii MeyboomRHB,EgbertsACG,GribnauFWJ,HeksterYA.Pharmacovigilanceinperspective.Drug Safety1999;21(6):429-447.

89

21.9 GRADE evidence tables

Thefollowingtablespresentprofilesoftheevidenceconsideredfortherecommendationsmadeintheseguidelines.

ForfurtherinformationonthemethodologyoftheGRADEprocessseeThe Conchrane handbook for systematic reviews of interventions,availableathttp://cochrane-handbook.org.



Wh

en t

o s

tart

AR

T

Au

tho

rs:

NandiLSiegfried,OlolakenUthman,GeorgeWRutherford

Dat

e:

11Sep2009

Qu

esti

on:

EarlyARTversusstandardordeferredART(CD4≤200orCD4≤250cells/µl)forasymptomatic,HIV-infected,

treatment-naiveadults.

Bib

liog

rap

hy:SiegfriedNL,UthmanO, RutherfordGW. Optimaltime ofinitiation for asymptomatic, HIV-infected, treatment-naive

adults. Cochrane Database

ofSystematicReviews.

Qua

lity

asse

ssm

ent

Sum

mar

y o

f fin

din

gs

Imp

ort

ance

No.

of p

atie

nts

Eff

ect

Qua

lity

No.

of

stud

ies

Des

ign

Lim

itatio

ns

Inco

nsi

s-te

ncy

Ind

irec

t-ne

ssIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

Ear

ly A

RT

vers

us

stan

dar

d o

r d

efer

red

A

RT

(CD

4

≤20

0 o

r C

D4

≤25

0 el

ls/µ

l)

Co

ntr

ol

Rel

ativ

e (9

5% C

I)A

bso

lute

Dea

th2

Random-

izedtrials

Noserious

limitations1

Noserious

inconsis-

tency

Noserious

indirectness

Noserious

imprecisionReporting

bias2

6/539(1.1%)24/526

(4.6%)

RR0.26

(0.11to

0.62)

34fewerper

1000(from

17fewerto

4 1fewer)

⊕⊕

⊕O

MODERATECRITICAL

Tub

ercu

losi

s2

Random-

izedtrials

Noserious

limitations1

Noserious

inconsis-

tency

Noserious

indirectness

Noserious


bias2

19/539

(3.5%)

36/526

(6.8%)

RR0.54

(0.26to

1.12)

31fewerper

1000(from

51fewerto

8more)

⊕⊕

⊕O

MODERATECRITICAL

91

Dis

ease

pro

gre

ssio

n m

easu

red

by

op

po

rtu

nis

tic

dis

ease

(fo

llow

-up

mea

n 1

8 m

on

ths;

op

po

rtu

nis

tic

dis

ease

eve

nts

)1

Random-

izedtrials

Noserious

limitations1

Noserious

inconsis-

tency

Serious3

Noserious


bias2

1/131(0.8%)3/118(2.5%)RR0.30

(0.03to

2.85)

18fewerper

1000(from

2 5fewerto

44more)

⊕⊕

OO

LOW

CRITICAL

An

y G

rad

e 3

or

4 ad

vers

e ev

ent

– aw

aiti

ng

co

nfi

rmat

ion

of

gra

din

g a

nd

fre

qu

ency

of

SA

E

CRITICAL

Sex

ual

tra

nsm

issi

on

– n

ot

mea

sure

d0

--

--

--

--

IMPORTANT

Imm

un

olo

gic

al r

esp

on

se –

no

t m

easu

red

0-

--

--

-

--

IMPORTANT

Ad

her

ence

/to

lera

nce

/ret

enti

on

– n

ot

mea

sure

d0

--

--

--

--

IMPORTANT

HIV

dru

g r

esis

tan

ce –

no

t m

easu

red

0-

--

--

--

-IMPORTANT

Vir

olo

gic

al r

esp

on

se –

no

t m

easu

red

0-

--

--

--

-IMPORTANT

1 TheSMARTstudyisaposthocanalysisofasubsetofalargertrial.

2 AstheSMARTsubsetisaposthocanalysistheremaybeothertrialswhichdidnotconductorpublishsimilaranalysesofpotentialsubsetswithinthe

o riginalt rials.Thisi saf ormofpublicationbiasa ndweh avedowngradedt her esultsaccordingly.

3 Thisresultisaposthocsubsetanalysisfromonlyonetrialandtheevidenceisthereforenotdirectlyabletoanswertheoutcomeofdiseaseprogression.



Wh

at A

RT

to

sta

rt

Au

tho

rs:

GeorgeRutherford,AlicenSpauldin

Dat

e:

8Oct2009

Qu

esti

on:

ShouldEFVvsNVPbeusedforinitialART?(Randomizedclinicaltrials)

Set

tin

gs:

Multiplelocations

Bib

liog

rap

hy:1.AyalaGaytanJJ,delaGarzaERZ,GarciaMC,ChavezSBV.Nevirapineorefavirenzincombinationwithtwo

nucleosideanaloguesinHIVinfectedantiretroviralnaivepatients.M

ed I

nter

n M

ex2004;20:24.2.ManosuthiW,

SungkanuparphS,TantanathipP,LueangniyomkulA,MankatithamW,PrasithsirskulW,BuraptarawongS,Thongyen

S,LikanonsakulS,ThawornwaU,PrommoolV,KuxrungthamK,2NRStudyTeam.Arandomizedtrialcomparing

plasmadrugconcentrationsandefficaciesbetween2nonnucleosidereverse-transcriptaseinhibitor-basedregimens

i nHIV-infectedpatientsr eceivingrifampicin:t heN2RStudy.C

lin I

nfec

t D

is2009;48:1752-9.3.NúñezM,SorianoV,

Martín-CarboneroL,BarriosA,BarreiroP,BlancoF,García-BenayasT,González-LahozJ.SENC(SpanishEfavirenz

v s.NevirapineComparison)t rial:ar andomized,o pen-labelstudyi nHIV-infectednaiveindividuals.

HIV

Clin

Tria

ls

2002;3:186-94.4.SowPG,BadianeM,DialloPD,LoI,NdiayeB,GayeAM.

Effic

acy

and

safe

ty

of

lam

ivud

ine+

zid

ovud

ine+

efav

irenz

an

d la

miv

udin

e+zi

dov

udin

e+né

vira

pin

e in

tr

eatm

ent

HIV

1 in

fect

ed

pat

ient

s.

A ré

tros

pec

tive

cros

s st

udy

anal

ysis[AbstractCDB0584].XVI International AIDSConference,Toronto, Canada,13−18

August2006.5.vandenBerg-WolfM,HullsiekKH,PengG,KozalMJ,NovakRM,ChenL,CraneLR,MacarthurRD;

CPCRA058StudyTeam,theTerryBeirnCommunityProgramsforClinicalResearchonAIDS(CPCRA),andThe

InternationalNetworkforStrategicInitiativeinGlobalHIVTrials(INSIGHT).Virologic,immunologic,clinical,safety,

a ndresistanceo utcomesfromalong-termcomparisonofe favirenz-basedversusn evirapine-basedantiretroviral

regimensasinitialtherapyinHIV-1-infectedpersons.

HIV

Clin

Tria

ls2008;9:324-36.6.vanLethF,KappelhoffBS,

Johnson D, LossoMH, Boron-Kaczmarska A, Saag MS, Hall DB, LeithJ, Huitema AD, Wit FW, BeljnenJH, Lange JM;

2NNStudyGroup.Pharmacokineticparametersofnevirapineandefavirenzinrelationtoantiretroviralefficacy.A

IDS

Res

Hum

Ret

rovi

ruse

s2006;22:232-39.

93

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

EF

VN

VP

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(fo

llow

-up

2 s

tud

ies

at 4

8 w

eeks

, 1 s

tud

y at

65

mo

nth

s)

3Random-

izedtrials

Nos erious

limitations1Noserious

inconsis-

tency

Noserious

indirect-

ness2

Serious3

None4

29/582(5%)33/575

(5.7%)

RR0.89

(0.5to1.57)

6f ewerper

1 000(from

2 9f ewert o

33more)

⊕⊕

⊕O

MODER-

ATE

CRITICAL

Clin

ical

res

po

nse

(fo

llow

-up

2 s

tud

ies

at 4

8 w

eeks

, 1 s

tud

y at

65

mo

nth

s)

3Random-

izedtrials

Noserious


inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

44/541

(8.1%)

34/532

(6.4%)

RR1.31

(0.78to2.2)

20more

per1000

(from14

fewerto77

more)

⊕⊕

⊕O

MODER-

ATE

CRITICAL

Ser

iou

s ad

vers

e ev

ents

(fo

llow

-up

2 s

tud

ies

at 4

8 w

eeks

, 1 s

tud

y at

65

mo

nth

s)

4Random-

izedtrials

Noserious


inconsis-

tency

No serious

indirect-

ness2

Noserious

imprecision

None4

96/612

(15.7%)

140/603

(23.2%)

RR0.68

(0.54to

0.86)

74fewer

per1000

(from33

fewerto

107fewer)

⊕⊕

⊕⊕

HIGH

CRITICAL

Vir

olo

gic

al r

esp

on

se (

follo

w-u

p 2

stu

die

s at

48

wee

ks, 1

stu

dy

at 6

5 m

on

ths)

5Random-

izedtrials

Noserious


inconsis-

tency

Noserious

indirect-

ness2

Noserious

imprecision

None4

508/643

(79%)

500/639

(78.2%)

RR0.99

(0.91to

1.09)

8fewerper

1000(from

70fewerto

70more)

⊕⊕

⊕⊕

HIGH

CRITICAL

Ad

her

ezce

/to

lera

bili

ty/r

eten

tio

n (

follo

w-u

p 4

stu

die

s at

48

wee

ks, 1

stu

dy

at 6

5 m

on

ths,

1 s

tud

y d

id n

ot

rep

ort

fo

llow

-up

per

iod

)

6Random-

izedtrials

Noserious


inconsis-

tency

Noserious

indirect-

ness2

Noserious

imprecision

None4

335/678

(49.4%)

304/674

(45.1%)

RR1.11

(0.95to

1.28)

50more

per1000

(from23

fewerto

1 26more)

⊕⊕

⊕⊕

HIGH

CRITICAL



Imm

un

olo

gic

al r

esp

on

se (

follo

w-u

p 4

stu

die

s at

48

wee

ks, 1

stu

dy

at 6

5 m

on

ths,

1 s

tud

y at

6 m

on

ths;

bet

ter

ind

icat

ed b

y h

igh

er v

alu

es)

5Random-

izedtrials

Noserious


inconsis-

tency

No serious

indirect-

ness2

Serious5

None4

643

639

-

MD3.95

higher

(11.58lower

to19.48

higher)

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

Dru

g r

esis

tan

ce (

follo

w-u

p m

edia

n 6

5 m

on

ths)

1Random-

izedtrials

Serious1,6

Noserious

inconsis-

tency

Nos erious

i ndirect-

ness2

Serious3

None4

32/111

(28.8%)

49/117

(41.9%)

RR0.69

(0.48to

0.99)

130f ewer

per1000

(from4

fewerto

218fewer)

⊕⊕

OO

LOW

IMPORTANT

Sex

ual

tra

nsm

issi

on

of

HIV

no

t re

po

rted

0-

--

--

None

0/0(0%)

0/0(0%)

--

1 4of6studieswereopen-label;1oftheremainingstudiesdidnotprovidesufficientinformationonblinding(Sow)andtheotherwasblinded(vanden

Berg-Wolf)butstudieswerenotdowngradedbasedonthesefacts.

2 1study(vandenBergetal.)lookedatmultipleindirectcomparisons.Also,only1of6studieswasonlyconductedinadevelopedcountrysetting

(Manosuthi).

3 Numberofevents<300and/orconfidenceintervalsincludepotentialharmandbenefit.

4 1of6studieswereindustry-funded(vanLethetal.),while1of6studieshadafundingsourcethatwasunclear.

5 NoneoftheincludedstudiesprovidedstandarddeviationsforthemeanoutcomesothesameestimatedSDvaluewasusedforallstudies.

6 Only1studyreportedondrugresistance(vandenBerg-Wolfetal.),suggestingselectivereporting.

95

Au

tho

rs:GeorgeRutherford,AlicenSpaulding

Dat

e:8Oct2009

Qu

esti

on:ShouldEFVvsNVPbeusedforinitialART?(observationalstudies)

Set

tin

gs:Multiplelocations

Bib

liog

rap

hy:1.AnnanT,MandaliaS,BowerM,GazzardB,NelsonM.

The

effe

ct o

f ye

ar o

f tr

eatm

ent

and

nucl

eosi

de

anal

ogue

b

ackb

one

on d

urab

ility

of N

NR

TI b

ased

reg

imen

s[AbstractWePe12.2C03].3rdConferenceonHIVPathogenesisandTreatment,Rio

deJaneiro,Brazil,24-27July2005.2.AranzabalL,CasadoJL,MoyaJ,QueredaC,DizS,MorenoA,MorenoL,AntelaA,Perez-Elias

MJ,DrondaF,MarínA,Hernandez-RanzF,MorenoA,MorenoS.Influenceofliverfibrosisonhighlyactiveantiretroviraltherapy-

associatedhepatotoxicityinpatientswithHIVandhepatitisCviruscoinfection.C

lin In

fect

Dis2005;40:588-93.3.AurpibulL,Puthanakit

T,LeeB,MangklabruksA,SirisanthanaT,SirisanthanaV.LipodystrophyandmetabolicchangesinHIV-infectedchildrenonnon-

nucleosidereversetranscriptaseinhibitor-basedantiretroviraltherapy.A

ntiv

ir Th

er2007;12:1247-54.4.BannisterWP,RuizL,Cozzi-

LepriA,MocroftA,KirkO,StaszewskiS,LovedayC,KarlssonA,MonforteA,ClotetB,LundgrenJD.Comparisonofgenotypic

r esistanceprofilesandvirologicalresponsebetweenpatientss tartingn evirapinea ndefavirenzi nEuroSIDA.A

IDS2008;22:367-76.5.

BerenguerJ,BellonJM,MirallesP,AlvarezE,CastilloI,CosinJ,LopezJC,SanchezCondeM,PadillaB,ResinoS.Association

betweenexposuretonevirapineandreducedliverfibrosisprogressioninpatientswithHIVandhepatitisCviruscoinfection.C

lin In

fect

D

is2008;46:137-43.6. BoulleA, OrrelC, Kaplan,VanCutsemG, McNallyM, HilderbrandK, Myer L, EggerM, CoetzeeD, Maartens G,

WoodR.Substitutionsduetoantiretroviraltoxicityorcontraindicationinthefirst3yearsofantiretroviraltherapyinalargeSouth

Africancohort.

Ant

ivir

Ther2007;12:753-60.7. BoulleA, VanCutsemG, CohenK, HilderbrandK, Mathee S, Abrahams M, Goemaere

E,CoetzeeD,MaartensGT.Outcomesofnevirapine-andefavirenz-basedantiretroviraltherapywhencoadministeredwithrifampicin-

basedantituberculartherapy.J

AM

A2008;300:530-9.8.BraithwaiteRS,KozalMJ,ChangCC,RobertsMS,FultzSL,GoetzMB,Gibert

C,Rodriguez-BarradasM,MoleL,JusticeAC.Adherence,virologicalandimmunologicaloutcomesforHIV-infectedveteransstarting

combinationantiretroviraltherapies.A

IDS2007;21:1579-89.9.deBeaudrapP,EtardJF,GuèyeFN,GuèyeM,LandmanR,GirardPM,

SowPS,NdoyeI,DelaporteE;ANRS1215/1290StudyGroup.Long-termefficacyandtoleranceofefavirenz-andnevirapine-containing

regimensinadultHIVtype1Senegalesepatients.A

IDS

Res

Hum

Ret

rovi

ruse

s2008;24:753-60.10.EnaJ,AmadorC,BenitoC,Fenoll

V,PasquauF.Riskanddeterminantsofdevelopingseverelivertoxicityduringtherapywithnevirapine-andefavirenz-containing

regimens inHIV-infectedpatients.In

t J S

TD A

IDS2003;14:776-81.11.George C, Yesoda A, JayakumarB, LalL. Aprospective study

evaluatingclinicaloutcomesandcostsofthreeNNRTI-basedHAARTregimensinKerala,India.J

Clin

Pha

rm T

her2009;34:33-40.12.

HartmannM,WitteS,BrustJ,SchusterD,MosthafF,ProcacciantiM,RumpJA,KlinkerH,PetzoldtD.Comparisonofefavirenzand

nevirapineinHIV-infectedpatients(NEEFCohort).In

t J S

TD A

IDS2005;16:404-9.13.KeiserP,NassarN,WhiteC,KoenG,MorenoS.

Comparisonofnevirapine-andefavirenz-containingantiretroviralregimensinantiretroviral-naïvepatients:acohortstudy.H

IV C

lin

Tria

ls2002;3:296-303.14.MadecY,LaureillardD,PinogesL,FernandezM,PrakN,NgethC,MoeungS,SongS,BalkanS,Ferradini



L,QuilletC,FontanetA.Responsetohighlyactiveantiretroviraltherapyamongseverelyimmuno-compromisedHIV-infectedpatients

inCambodia.A

IDS2007;21:351-9.15.ManosuthiW,SungkanuparphS,VibhagoolA,RattanasiriS,ThakkinstianA.Nevirapine-versus

efavirenz-basedhighlyactiveantiretroviraltherapyregimensinantiretroviral-naivepatientswithadvancedHIVinfection.H

IV M

ed

2004;5:105-9.16.ManosuthiW,MankatithamW,LueangniyomkulA,ChimsuntornS,SungkanuparphS.Standard-doseefavirenzvs.

standard-dosenevirapineinantiretroviralregimensamongHIV-1andtuberculosisco-infectedpatientswhoreceivedrifampicin.

HIV

M

ed2008;9:294-99.17.Martín-CarboneroL,NúñezM,González-LahozJ,SorianoV.Incidenceofliverinjuryafterbeginning

antiretroviraltherapywithefavirenzornevirapine.H

IV C

lin T

rials2003;4:115-20.18.MatthewsGV,SabinCA,MandaliaS,LampeF,

PhillipsAN,NelsonMR,BowerM,JohnsonMA,GazzardBG.Virologicalsuppressionat6monthsisrelatedtochoiceofinitialregimen

inantiretroviral-naivepatients:acohortstudy.A

IDS

2002;16:53–61.19.NachegaJB,HislopM,DowdyDW,GallantJE,ChaissonRE,

RegensbergL,MaartensG.Efavirenzversusnevirapine-basedinitialtreatmentofHIVinfection:clinicalandvirologicaloutcomesin

SouthernAfricanadults.

AID

S2008;22:2117-25.20.PalmonR,KooBC,ShoultzDA,DieterichDT.Lackofhepatotoxicityassociated

withnonnucleosidereversetranscriptaseinhibitors.J

Acq

uir I

mm

une

Def

ic S

ynd

r2002;29:340-5.21.PatelAK,PujariS,PatelK,Patel

J ,ShahN,PatelB,GupteN.Nevirapinev ersusefavirenzbasedantiretroviralt reatmenti nnaiveIndianpatients:comparisonof

effectivenessinclinicalcohort.

J A

ssoc

Phy

sici

ans

Ind

ia 2006;54:915-18.22.SanneI,Mommeja-MarinH,HinkleJ,BartlettJA,

LedermanMM,MaartensG,WakefordC,ShawA,QuinnJ,GishRG,RousseauF.Severehepatotoxicityassociatedwithnevirapine

use inHIV-infectedsubjects.J

Infe

ct D

is2005;191:825-9. 23.Shipton LK, Wester CW, StockS, Ndwapi N, Gaolathe T,ThiorI,Avalos

A,MoffatHJ,MboyaJJ,WidenfeltE,EssexM,HughesMD,ShapiroRL.Safetyandefficacyofnevirapine-andefavirenz-based

antiretroviral treatment inadultstreatedforTB-HIVco-infection inBotswana.I

nt J

Tub

erc

Lung

Dis

2009;13:360-6. 24. Varma J,

NateniyomS,AkksilpS,MankatitthamW,SirinakC,SattayawuthipongW,BurapatC,KittikraisakW,MonkongdeeP,CainKP,WellsCD,

TapperoJW.HIVcareandtreatmentfactorsassociatedwithsurvivalduringTBtreatmentinThailand:anobservationalstudy.B

MC

In

fect

Dis2009;9:42.

97

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o. o

f st

ud

ies

Des

ign

Lim

ita-

tio

ns

Inco

nsi

s-te

ncy

Ind

irec

t-n

ess

Imp

reci

-si

on

Oth

er

con

sid

er-

atio

ns

EF

VN

VP

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(ob

serv

atio

nal

)

5Observa-

tional

s tudies

Noserious

l imitations

Noserious

i nconsis-

tency

Noserious

indirect-

ness

No serious

i mpreci-

sion

None

270/2899

(9.3%)

108/2542

(4.2%)

RR1.47

(0.67to

3.22)

20more

per1000

(from14

fewerto94

more)

⊕⊕

OO

LOW

CRITICAL

Ser

iou

s ad

vers

e ev

ents

(o

bse

rvat

ion

al)

14Observa-

tional

s tudies

Nos erious

l imitations

Nos erious

i nconsis-

tency

Noserious

indirect-

ness

Noserious

impreci-

sion

None

256/3066

(8.3%)

373/3281

(11.4%)

RR0.7

(0.49to

1 .01)

34fewer

per1000

( from58

fewerto1

more)

⊕⊕

OO

LOW

CRITICAL

Vir

olo

gic

al r

esp

on

se (

ob

serv

atio

nal

)

11Observa-

tional

studies

Nos erious

l imitations

Nos erious

i nconsis-

tency

Noserious

indirect-

ness

Nos erious

impreci-

sion

None

4023/6661

( 60.4%)

3263/4731

( 69%)

RR1.03

(0.92to

1.15)

21more

per1000

(from55

fewerto

103more)

⊕⊕

OO

LOW

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n (

ob

serv

atio

nal

)

5Observa-

tional

studies

Noserious

limitations

Noserious

inconsis-

tency

Nos erious

i ndirect-

ness

Noserious

i mpreci-

sion

None

3791/4784

(79.2%)

1894/2635

(71.9%)

RR1.11

(0.94to

1.32)

79more

per1000

(from43

fewerto

230more)

⊕⊕

OO

LOW

CRITICAL

Imm

un

olo

gic

al r

esp

on

se (

ob

serv

atio

nal

) (B

ette

r in

dic

ated

by

low

er v

alu

es)

4Observa-

tional

studies

Noserious

limitations

Noserious

inconsis-

tency

Nos erious

i ndirect-

ness

Noserious

i mpreci-

sion1

None

1523

1566

-

MD7.51

higher(0.7

lowerto

15.73

higher)

⊕⊕

OO

LOW

IMPORTANT

1 NoneoftheincludedstudiesprovidedstandarddeviationsforthemeanoutcomesothesameestimatedSDvaluewasusedforallstudies.



Au

tho

rs:

GeorgeRutherford,AlicenSpaulding

Dat

e:

8 Oct2009

Qu

esti

on:

ShouldTDF vsABCbe usedfor initialART?(randomizedclinicaltrials)

Set

tin

gs:

Multiplelocations

Bib

liog

rap

hy:1.Sax P,TierneyC, Collier A, FischlM, GodfreyC, JahedN, Droll K, Peeples L,MyersL, ThalG, Rooney J,Ha B,

WoodwardW, Daar E.

AC

TG 5

202:

sho

rter

tim

e to

viro

log

ic f

ailu

re (

VF)

with

ab

acav

ir/la

miv

udin

e (A

BC

/3TC

) th

an

teno

fovi

r/em

tric

itab

ine

(TD

F/FT

C)

as p

art

of c

omb

inat

ion

ther

apy

in t

reat

men

t-na

ïve

sub

ject

s w

ith s

cree

ning

HIV

RN

A ≥

100,

000

c/m

L [AbstractTHAB0303].XVIIInternationalConferenceonAIDS,MexicoCity,August3-8,2008.2.Smith

KY,PatelP, Fine D, Bellos N, SloanL, Lackey P,KumarPN, Sutherland-Phillips DH, Vavro, C, YauL, WannamakerP,

ShaeferMS,HEATStudyTeam.Randomized,double-blind,placebo-matched,multicentertrialofabacivr/lamivudine

ortenofovir/emtricitabine withlopinavir/ritonavir for initialHIVtreatment.

AID

S2009;Jul31;23(12):1547-56.

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o. o

f st

ud

-ie

sD

esig

nL

imit

atio

ns

Inco

nsi

s-te

ncy

Ind

irec

t-n

ess

Imp

reci

-si

on

Oth

er

con

sid

er-

atio

ns

TD

FA

BC

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

– n

ot

rep

ort

ed

0-

--

--

None

0/0 (0%)

0/0(0%)

--

Clin

ical

res

po

nse

(fo

llow

-up

mea

n 9

6 w

eeks

)

1Random-

izedtrials

Noserious

limitations

Noserious

inconsis-

tency

Serious1

Serious2

None3

1/345

(0.3%)

0/343(0%)RR2.98

(0.12to

72.96)

0moreper

1000(from

0fewerto0

more)

⊕⊕

OO

LOW

CRITICAL

Sev

ere

adve

rse

even

ts (

follo

w-u

p m

ean

96

wee

ks)

1Random-

izedtrials

Nos erious

limitations

Nos erious

inconsis-

tency

Serious1

Noserious

imprecision

None3

97/345

(28.1%)

103/343

(30%)

RR0.94

(0.74 to

1.18)

18fewer

per1000

(from78

fewerto54

more)

⊕⊕

⊕O

MODER-

ATE

CRITICAL

99

Vir

olo

gic

al r

esp

on

se (

follo

w-u

p 1

stu

dy

at 4

8, 1

stu

dy

at 9

6 w

eeks

)

2Random-

izedt rials

Noserious

l imitations

Noserious

i nconsis-

tency4

Serious1

Noserious

imprecision

None3

550/744

(73.9%)

533/741

(71.9%)

RR1.03

(0.95to

1.11)

22more

per1000

(from36

fewerto79

more)

⊕⊕

⊕O

MODER-

ATE

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n (

follo

w-u

p m

ean

96

wee

ks)

1Random-

izedtrials

Noserious

limitations

Noserious

inconsis-

tency

Serious1

Noserious

imprecision

None3

221/345

(64.1%)

234/343

(68.2%)

RR0.94

(0.84 to

1.05)

41fewer

per1000

(from109

fewerto34

more)

⊕⊕

⊕O

MODER-

ATE

CRITICAL

Imm

un

olo

gic

al r

esp

on

se (

follo

w-u

p m

ean

96

wee

ks;

Bet

ter

ind

icat

ed b

y h

igh

er v

alu

es)

1Random-

izedtrials

Noserious

limitations

Noserious

inconsis-

tency

Serious1

Serious2

None3

345

343

-

MD3

higher

(12.69

lowerto

18.69

higher)

⊕⊕

OO

LOW

IMPORTANT

Dru

g r

esis

tan

ce –

no

t re

po

rted

0-

--

--

None

0/0 (0%)

0/0(0%)

--

Sex

ual

tra

nsm

issi

on

of

HIV

– n

ot

rep

ort

ed

0-

--

--

None

0/0(0%)

0/0(0%)

--

1 BothstudieslookedattheindirectbasiccomparisonofTDF+FTCvs.ABC+3TC-containingregimens.Onestudywasconductedonlyindeveloped

countrysettings(Smith);thefinalstudydidnotreportalocationforthestudy.


3Onestudywasindustry-funded(Smithetal.)whilethesourceoffundingfortheother(Saxetal)wasunclear;studieswerenotdowngradedbasedonthese

f acts.

4 Treatmentfailureinhigh-PVLgroup(viralload≥100000copies/ml)inconsistentwithfindingsfromameta-analysis(Pappaetal2008)ofpatientsstarting

ABC+3TC-containingregimensinwhichpatientswithHIV-1RNAlevelsof<100000copies/mland≥100000copies/mlhadsimilarexperiencesandthat

between87%and95%didnotexperiencevirologicalfailure.



Au

tho

rs:


Dat

e:

8 Oct2009

Qu

esti

on:

ShouldTDF vs(d4Tor AZT) be usedfor initialART?(randomizedclinicaltrials)

Set

tin

gs:

Multiplelocations

Bib

liog

rap

hy:1.GallantJE, Staszewski S, PozniakAL,DeJesusE, SuleimanJM, MillerMD, CoakleyDF,Lu B, TooleJJ,ChengAK;

903 Study Group. Efficacy andsafety oftenofovir DF vsstavudine incombination therapy inantiretroviral-naive

patients:a3-yearrandomizedtrial.

JAM

A2004;292:191-201.2.GallantJE,DeJesusE,ArribasJR,PozniakAL,

GazzardB,CampoRE,LuB,McCollD,ChuckS,EnejosaJ,TooleJJ,ChengAK;Study934Group.TenofovirDF,

emtricitabine,andefavirenzvs.zidovudine,lamivudine,andefavirenzforHIV.

N E

ngl J

Med

2006;354(3):251-60.3.

ReyD,HoenB,ChavanetP,SchmittMP,HoizeyG,MeyerP,PeytavinG,SpireB,AllavenaC,DiemerM,MayT,Schmit

JL, DuongM, Calvez V,Lang JM. High rateof earlyvirologicalfailurewiththeonce-dailytenofovir/lamivudine/

nevirapine combinationinnaiveHIV-1-infectedpatients.J

Ant

imic

rob

Che

mot

her2009;63:380-8

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

TD

F(d

4T o

r Z

DV

)R

elat

ive

(95%

CI)

Ab

solu

te

Mo

rtal

ity

(fo

llow

-up

mea

n 1

44

wee

ks)

1Random-

izedtrials

Serious1,2

Noserious

inconsis-

tency

No serious

indirect-

ness3

Serious4

None

6/303(2%)5/299

(1.7%)

RR1.18

(0.37 to

3.84)

3moreper

1000(from

11fewerto

47more)

⊕⊕

OO

LOW

CRITICAL

Clin

ical

res

po

nse

– n

ot

rep

ort

ed

0-

--

--

none

0/0(0%)

0/0(0%)

--

Sev

ere

adve

rse

even

ts (

follo

w-u

p 1

stu

dy

at 3

6 w

eeks

, 1 s

tud

y at

48

wee

ks, 1

stu

dy

at 1

44

wee

ks)

3Random-

izedtrials

Noserious


inconsis-

tency

No serious

indirect-

ness3

Noserious

imprecision

None6

250/591

(42.3%)

247/595

(41.5%)

OR1.04

(0.81 to

1.34)

10more

per1000

(from50

fewerto72

more)

⊕⊕

⊕⊕

HIGH

CRITICAL

101

Vir

olo

gic

al r

esp

on

se (

follo

w-u

p 1

stu

dy

at 3

6 w

eeks

, 1 s

tud

y at

48

wee

ks, 1

stu

dy

at 1

44

wee

ks)

3Random-

izedtrials

No serious


inconsis-

tency

Noserious

indirect-

ness3

Noserious

imprecision

None6

384/595

(64.5%)

384/593

(64.8%)

RR1(0.76

to1.3)

0 fewerper

1000(from

155fewer

to194

more)

⊕⊕

⊕⊕

HIGH

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n (

follo

w-u

p 1

stu

dy

at 3

6 w

eeks

, 1 s

tud

y at

48

wee

ks, 1

stu

dy

at 1

44

wee

ks)

3Random-

izedtrials

Serious5

Noserious

inconsis-

tency

Noserious

indirect-

ness3

Noserious

imprecision

None6

445/591

( 75.3%)

400/597

( 67%)

RR1.13

(1.05to

1 .21)

87more

per1000

( from34

moreto141

more)

⊕⊕

⊕O

MODER-

ATE

CRITICAL

Imm

un

olo

gic

al r

esp

on

se (

follo

w-u

p 1

stu

dy

at 4

8 w

eeks

, 1 s

tud

y at

14

4 w

eeks

)

2Random-

izedt rials

Noserious

l imitations2Noserious

inconsis-

tency

Noserious

indirect-

ness3

Serious4,7

None6

559

558

-

MD5.88

higher

(45.08

lowerto

56.84

higher)

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

Dru

g r

esis

tan

ce (

follo

w-u

p 1

stu

dy

at 3

6 w

eeks

, 1 s

tud

y at

14

4 w

eeks

)

2Random-

izedtrials

Noserious


inconsis-

tency

No serious

indirect-

ness3

Serious4

None6

18/335

(5.4%)

2/338

(0.6%)

RR6.12

(1.43to

26.15)

30more

per1000

( from3

moreto149

more)

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

Sex

ual

tra

nsm

issi

on

of

HIV

– n

ot

rep

ort

ed

0-

--

--

None

0/0 (0%)

0/0(0%)

--

1 Only1of3studiesreportedonmortality(Gallantetal),suggestingselectivereporting.

2 2studiesof3wereopen-label(GallantetalandReyetal)butstudieswerenotdowngradedonthisbasis.

3 1studyof3wasanindirectcomparisonofTDF/FTC/EFVvs.ZDV/3TC/EFV(Gallantetal)and2studiesof3(Gallantetal,Reyetal)wereconductedonlyin

developedcountrysettings,butstudiesweren otdowngradedbasedont hesef acts.

4Numberofevents<300and/orconfidenceintervalsincludepotentialharmandbenefit.

5Assessmentofadherence/retention/tolerabilityorassessmentofadverseeventsmaybesubjecttobiasinanopen-labelstudy,sodowngradedforthisoutcome.

6 All3studieswereindustry-funded;theywerenotdowngradedforthis,however,asstudydrugdidnotshowbenefitsolessconcernforreportingbias.

7NoneoftheincludedstudiesprovidedstandarddeviationsforthemeanoutcomesothesameestimatedSDvaluewasusedforallstudies.



Au

tho

rs:


Dat

e:

8Oct2009

Qu

esti

on:

ShouldTDFvs(d4TorAZT)beusedforinitialART?(observationalstudies)

Set

tin

gs:

Multiplelocations

Bib

liog

rap

hy:1.MocroftA,PhillipsAN,LedergerberB,KatlamaC,ChiesiA,GoebelFD,Knysz

B,AntunesF,ReissP,LundgrenJD.Relationshipbetweenantiretroviralsused

aspartofacARTregimenandCD4cellcountincreasesinpatientswith

suppressedviremia.A

IDS

2006;20:1141-50.

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o. o

f st

ud

-ie

sD

esig

nL

imit

atio

ns

Inco

nsi

s-te

ncy

Ind

irec

t-n

ess

Imp

reci

-si

on

Oth

er

con

sid

er-

atio

ns

TD

F(d

4T o

r A

ZT

)R

elat

ive

(95%

CI)

Ab

solu

te

Imm

un

olo

gic

al r

esp

on

se (

ob

serv

atio

nal

) (B

ette

r in

dic

ated

by

hig

her

val

ues

)

2Observa-

tional

studies

Noserious


inconsis-

tency

No serious

indirect-

ness

Noserious

impreci-

sion2

None

3618

20377

-

MD6.33

lower(22.5

lowerto

9.84higher)

⊕⊕

OO

LOW

IMPORTANT

1 Thisisfrom1studybutwith2comparisons.

2 NoneoftheincludedstudiesprovidedstandarddeviationsforthemeanoutcomesothesameestimatedSD

valuewasusedforallstudies.

103

Au

tho

rs:


Dat

e:

8Oct2009

Qu

esti

on:

ShouldAZTvsd4TbeusedforinitialART?(randomizedclinicaltrials)

Set

tin

gs:

Multiplelocations

Bib

liog

rap

hy:1.CarrA,ChuahJ,HudsonJ,etal.Arandomised,open-labelcomparisonofthreehighlyactiveantiretroviraltherapy

regimensincludingtwonucleosideanaloguesandindinavirforpreviouslyuntreatedHIV-1infection:theOzComboI

study.A

IDS2000;14:1171-80.2.EronJJJr,MurphyRL,PetersonD,PottageJ,ParentiDM,JemsekJ,SwindellsS,

SepulvedaG,BellosN,RashbaumBC,EsinhartJ,SchoellkopfN,GrossoR,StevensM.Acomparisonofstavudine,

didanosineandindinavirwithzidovudine,lamivudineandindinavirfortheinitialtreatmentofHIV-1infectedindividuals:

selectionofthymidineanalogregimentherapy(STARTII).A

IDS2000;14:1601-10.3.FrenchM,AminJ,RothN,CarrA,

LawM,EmeryS,DrummondF,CooperD;OzCombo2investigators.Randomized,open-label,comparativetrialto

evaluatetheefficacyandsafetyofthreeantiretroviraldrugcombinationsincludingtwonucleosideanaloguesand

n evirapinef orpreviouslyu ntreatedHIV-1I nfection:theOzCombo2s tudy.H

IV C

lin T

rials2002;3:177-85.4 .GatheJJr,

BadaroR,GrimwoodA,AbramsL,KlesczewskiK,CrossA,McLarenC.Antiviralactivityofenteric-coateddidanosine,

stavudine,andnelfinavirversuszidovudinepluslamivudineandnelfinavir.

J A

cqui

r Im

mun

e D

efic

Syn

dr2002;31:399-

403.5. GeijoMartínezMP,MaciáMartínezMA, Solera Santos J,Barberá Farré JR, Rodríguez Zapata M, Marcos Sánchez

F,MartínezAlfaroE,CuadraGarcía-TenorioF,SanzMorenoJ,MorenoMendañaJM,BeatoPérezJL,SanzSanzJ;

GECMEI. Ensayo clínico comparativo de eficaciayseguridadde cuatropautas de tratamiento antirretroviral de alta

eficacia(TARGA)enpacientesconinfecciónporVIHavanzada.R

ev C

lin E

sp2006;206:67-76.6.KumarPN,Rodriguez-

FrenchA,ThompsonMA,TashimaKT,AverittD,WannamakerPG,WilliamsVC,ShaeferMS,PakesGE,PappaKA,

ESS40002StudyTeam.Aprospective,96-weekstudyoftheimpactofTrizivir,Combivir/nelfinavirandlamivudine/

stavudine/nelfinavironlipids,metabolicparamertersandefficacyinantiretorviral-naïvepatients:effectofsexand

ethnicity.H

IV M

ed2006;7:85-98.7.RobbinsGK,DeGruttolaV,ShaferRW,SmeatonLM,SnyderSW,PettinelliC,Dubé

MP,FischlMA,PollardRB,DelapenhaR,GedeonL,vanderHorstC,MurphyRL,BeckerMI,D’AquilaRT,VellaS,

MeriganTC,HirschMS;AIDSClinicalTrialsGroup384Team.Comparisonofsequentialthree-drugregimensasinitial

therapy for HIV-1infection.N

Eng

l J M

ed. 2003;349:2293-303. 8. Squires KE, Gulick R, TebasP, SantanaJ, Mulanovich

V,ClarkR,YangcoB,MarloweSI,WrightD,CohenC,CooleyT,MauneyJ,UffelmanK,SchoellkopfN,GrossoR,Stevens

M.Acomparisonofstavudinepluslamivudineversuszidovudinepluslamivudineincombinationwithindinavirin

antiretroviralnaiveindividualswithHIVinfection:selectionofthymidineanalogregimentherapy(STARTI).A

IDS

2000;14:1591-600.9.LiT,DaiY,KuangJ,JiangJ,HanY,QiuZ,XieJ,ZuoL,LiY.Threegenericnevirapine-based

antiretroviraltreatmentsinChineseHIV/AIDSpatients:multicentricobservationcohort.P

LoS

One2008;3:e3918.



Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o. o

f st

ud

-ie

sD

esig

nL

imit

atio

ns

Inco

nsi

s-te

ncy

Ind

irec

t-n

ess

Imp

reci

-si

on

Oth

er

con

sid

er-

atio

ns

ZD

Vd

4TR

elat

ive

(95%

CI)

Ab

solu

te

Mo

rtal

ity

(fo

llow

-up

3 s

tud

ies

at 4

8 w

eeks

, 1 s

tud

y at

52

wee

ks, 1

stu

dy

at 9

6 w

eeks

1)

6Random-

izedt rials

Noserious


inconsis-

tency

Serious3

Serious4

Reporting

bias5

3/593

(0.5%)

5/586

(0.9%)

RR0.74

(0.18 to

2.93)

2 fewerper

1000(from

7fewerto

16more)

⊕O

OO

VERYLOW

CRITICAL

Clin

ical

res

po

nse

(fo

llow

-up

3 s

tud

ies

at 4

8 w

eeks

, 2 s

tud

ies

at 5

2 w

eeks

)

7Random-

izedtrials

Noserious


inconsis-

tency

Serious3

Noserious

imprecision

Reporting

bias5

8/360

(2.2%)

6/361

(1.7%)

RR1.26

(0.46to

3.45)

4moreper

1000(from

9f ewert o

41more)

⊕⊕

OO

LOW

CRITICAL

Sev

ere

adve

rse

even

ts (

follo

w-u

p 4

stu

die

s at

48

wee

ks, 3

stu

die

s at

52

wee

ks)

9Random-

izedt rials

Noserious


inconsis-

tency

Serious3

Noserious

imprecision

Reporting

bias5

137/680

(20.1%)

169/685

(24.7%)

RR0.85

(0.71 to

1.02)

37fewer

per1000

(from72

fewerto5

more)

⊕⊕

OO

LOW

CRITICAL

Vir

olo

gic

al r

esp

on

se (

follo

w-u

p 4

stu

die

s at

48

wee

ks, 3

stu

die

s at

52

wee

ks, 1

stu

dy

at 9

6 w

eeks

)

10Random-

izedtrials

Noserious


inconsis-

tency

Serious3

Noserious

imprecision

Reporting

bias5

396/771

(51.4%)

409/768

(53.3%)

RR0.97

(0.89to

1.07)

16fewer

per1000

(from59

fewerto37

more)

⊕⊕

OO

LOW

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n (

follo

w-u

p 4

stu

die

s at

48

wee

ks, 3

stu

die

s at

52

wee

ks, 1

stu

dy

at 9

6 w

eeks

, 1 s

tud

y at

14

4 w

eeks

)

12Random-

izedtrials

Noserious


inconsis-

tency

Serious3

Noserious

imprecision

Reporting

bias5

632/1081

(58.5%)

585/1078

(54.3%)

RR1.08

(0.97to1.2)

43more

per1000

(from16

fewerto

109 more)

⊕⊕

OO

LOW

CRITICAL

105

Imm

un

olo

gic

al r

esp

on

se (

follo

w-u

p 4

stu

die

s at

48

wee

ks, 3

stu

die

s at

52

wee

ks, 1

stu

dy

at 9

6 w

eeks

; B

ette

r in

dic

ated

by

hig

her

val

ues

)

10Random-

izedt rials

Noserious


inconsis-

tency

Serious3

Noserious

imprecision

Reporting

bias5

771

768

-

MD9.61

lower

(36.82

lowerto

17.6higher)

⊕⊕

OO

LOW

IMPORTANT

Dru

g r

esis

tan

ce (

follo

w-u

p a

t 9

6 w

eeks

)

1Random-

izedtrials

Serious2,6

Noserious

inconsis-

tency

Serious3

Serious4

None

10/91(11%)6/83(7.2%)RR1.52

(0.58to4)

38more

per1000

(from30

fewerto217

more)

⊕O

OO

VERYLOW

IMPORTANT

Sex

ual

tra

nsm

issi

on

of

HIV

– n

ot

rep

ort

ed

0-

--

--

None

0/0(0%)

0/0(0%)

--

1 Separatecomparisonarmsfrom3studies(Carretal,Frenchetal,Robbinsetal)contributedmorethanonceforanumberofoutcomes.Therewere9

studiesintotal.

26of9studieswereopen-labelstudiesandsomestudieshadlargeratesoflosstofollow-up,butstudieswerenotdowngradedbasedonthesefacts.

3 5of9studieslookedatindirectcomparisonsofdrugregimens.


5 7of9studieswereindustry-funded,althoughsomewerefundedsimultaneouslybycompetitors.

6 Only1study(Kumaretal)reportedondrugresistance,suggestingselectivereporting.



Au

tho

rs:


Dat

e:

8Oct2009

Qu

esti

on:

ShouldAZTvsd4TbeusedforinitialART?(observationalstudies)

Set

tin

gs:

Multiplesettings

Bib

liog

rap

hy:1.GeorgeC,YesodaA,JayakumarB,LalL.Aprospectivestudyevaluatingclinicaloutcomesandcostsofthree

NNRTI-basedHAARTregimensinKerala,India.J

Clin

Pha

rm T

her2009;34:33-40.2.LaurentC,BourgeoisA,Mpoudi-

NgoléE,CiaffiL,KouanfackC,MougnutouR,NkouéN,CalmyA,Koulla-ShiroS,DelaporteE.Tolerabilityand

effectivenessoffirst-lineregimenscombiningnevirapineandlamivudinepluszidovudineorstavudineinCameroon.

AID

S R

es H

um R

etro

viru

ses2008;24:393-9.3.MocroftA,PhillipsAN,LedergerberB,KatlamaC,ChiesiA,GoebelFD,

KnyszB,AntunesF,ReissP,LundgrenJD.RelationshipbetweenantiretroviralsusedaspartofacARTregimenand

CD4cellcountincreasesinpatientswithsuppressedviremia.

AID

S 2006;20:1141-50.4.NjorogeJ,ReidyW,John-

StewartG,AttwaM,KiguruJ,NgumoR,WambuaN,ChungMH.I

ncid

ence

of p

erip

hera

l neu

rop

athy

am

ong

pat

ient

s re

ceiv

ing

HA

AR

T re

gim

ens

cont

aini

ng s

tavu

din

e vs

. zid

ovud

ine

in K

enya[AbstractTUPEB179].5thConferenceo nHIV

PathogenesisandTreatmentandPrevention,CapeTown,SouthAfrica,19−22July2009.5.PazareAR,KhirsagarN,

GogatayN,BajpaiS.

Com

par

ativ

e st

udy

of in

cid

ence

of h

yper

lact

etem

ia/

lact

ic a

cid

osis

in s

tavu

din

e vs

. A

ZT

bas

ed

reg

ime[AbstractTHPE0159].XVII International AIDSConference,Mexico City, Mexico,3−8 August 2008.

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o. o

f st

ud

-ie

sD

esig

nL

imit

atio

ns

Inco

nsi

s-te

ncy

Ind

irec

t-n

ess

Imp

reci

-si

on

Oth

er

con

sid

er-

atio

ns

AZ

Td

4TR

elat

ive

(95%

CI)

Ab

solu

te

Mo

rtal

ity

(ob

serv

atio

nal

)

1Observa-

tional

studies

Noserious

limitations

Noserious

inconsis-

tency

Noserious

indirect-

ness

Noserious

imprecision

None

8/85(9.4%)11/84

(13.1%)

RR0.72

(0.3to1.7)

37fewer

per1000

(from92

fewerto92

more)

⊕⊕

OO

LOW

CRITICAL

107

Sev

ere

adve

rse

even

ts (

ob

serv

atio

nal

)

3Observa-

tional

studies

Noserious

limitations

Noserious

inconsis-

tency

No serious

indirect-

ness

No serious

imprecision

None

14/415

(3.4%)

383/1941

(19.7%)

RR0.42

(0.07 to

2.62)

114fewer

per1000

(from184

fewerto

320more)

⊕⊕

OO

LOW

CRITICAL

Vir

olo

gic

al r

esp

on

se (

ob

serv

atio

nal

)

1Observa-

tional

studies

Nos erious

limitations

Nos erious

inconsis-

tency

Noserious

i ndirect-

ness

Serious1

None

33/85

(38.8%)

49/84

(58.3%)

RR0.67

(0.48 to

0.92)

192fewer

per1000

(from47

fewerto

303fewer)

⊕O

OO

VERY LOW

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n (

ob

serv

atio

nal

)

2Observa-

tional

studies

Noserious

limitations

Noserious

inconsis-

tency

Noserious

indirect-

ness

No serious

imprecision

None

112/137

(81.8%)

108/135

(80%)

RR1.02

(0.91to

1.14)

16moreper

1000(from

72fewerto

112more)

⊕⊕

OO

LOW

CRITICAL

Imm

un

olo

gic

al r

esp

on

se (

ob

serv

atio

nal

) (B

ette

r in

dic

ated

by

hig

her

val

ues

)

2Observa-

tional

studies

No serious

limitations

Noserious

inconsis-

tency

Nos erious

indirect-

ness

Noserious

imprecision

Reporting

bias2

13123

7423

-

MD16.4

lower

(19.39to

13.41lower)

⊕O

OO

VERYLOW

IMPORTANT

Dru

g r

esis

tan

ce (

ob

serv

atio

nal

)

1Observa-

tional

studies

Serious3

Noserious

inconsis-

tency

Noserious

indirect-

ness

Serious1

None

4/85(4.7%)7/84(8.3%)RR0.56

(0.17to

1.86)

37fewer

per1000

(from69

fewerto72

more)

⊕O

OO

VERYL OW

IMPORTANT


2 1of5observationalstudieswereindustry-funded,althoughsomewerefundedsimultaneouslybycompetitors.

3 And1observationalstudy(Laurentetal)reportedondrugresistance,suggestingselectivereporting.



Mo

nit

ori

ng

str

ateg

ies

for

gu

idin

g w

hen

to

sw

itch

Au

tho

rs:

LarryWilliamChang,JamalHarris

Dat

e:

12Aug2009

Qu

esti

on:

Shouldclinicalmonitoringvsimmunologicalandclinicalmonitoringbeusedinguidingwhentoswitchfirst-line

antiretroviraltherapyinadultsinlow-resourcesettings?

Set

tin

gs:

Low-resource settings

Bib

liog

rap

hy:HBAC2008,DART 2009

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

or-

tan

ce

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

n

Clin

ical

m

on

ito

rin

g

Imm

un

o-

log

ical

an

d

Clin

ical

M

on

ito

rin

g

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(fo

llow

-up

med

ian

3-5

yea

rs)

2Random-

ized

izedtrials

Serious1

Noserious

inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

?/20375

?/20275

HR1.35

(1.12 to

1.63)

-⊕

⊕O

OLOW

CRITICAL

AID

S-d

efin

ing

illn

ess

– n

ot

rep

ort

ed

0-

--

--

--

--

-CRITICAL

AID

S-d

efin

ing

illn

ess

or

mo

rtal

ity

(fo

llow

-up

med

ian

3-5

yea

rs)

2Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Noserious

indirect-

ness2

Noserious

imprecision

None4

547/2037

(26.9%)6

414/2027

(20.4%)6

HR1.33

(1.16to

1.51)

58more

per1000

(from29

moreto88

more)

⊕⊕

⊕O

MODER-

ATE

CRITIC-AL

Ser

iou

s ad

vers

e ev

ent

(fo

llow

-up

med

ian

5 y

ears

)

17Random-

izedtrials

Serious1

Noserious

inconsist-

ency

Noserious

indirect-

ness2

Serious3

None4

?/16608

?/16568

HR1.12

(0.94to

1.31)

-⊕

⊕O

OLOW

CRITICAL

109

Un

nec

essa

ry s

wit

ch (

swit

ch t

o s

eco

nd

-lin

e th

erap

y w

ith

un

det

ecta

ble

vir

al lo

ad)

(fo

llow

-up

med

ian

3 y

ears

)

17Random-

izedtrials

Serious1

Noserious

inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

15/377(4%)0/371(0%)

RR30.5

(1.83to

508)

-⊕

⊕O

OLOW

CRITICAL

Sw

itch

to

sec

on

d-l

ine

ther

apy

(fo

llow

-up

med

ian

3−

5 ye

ars)

2Random-

izedtrials

Serious1

Serious9

Noserious

indirect-

ness2

Noserious

imprecision

None4

331/2037

(16.2%)

365/2027

(18%)

RR1.73

(0.37to

8.06)

13moreper

100(from

11fewerto

127more)

⊕⊕

OO

LOW

1Unclearsequencegenerationandallocationconcealmentandblindingwasnotpossibleforbothstudies;losttofollow-upanalysesnotextensivelypresented

foreithertrialbutabsolutenumberswererelativelysmall.

2 Patientpopulationspreselectedandwithinrelativelywell-resourcedARTdeliveryprogrammes;however,assettingwaslow-resource,nodowngrading

occurred.

3 Totalnumberofeventsissmall.

4 Abstractsonly,nopeer-reviewedprintpublicationsofthesedataareavailable;however,asasignificantamountofdatawasavailablefromabstracts/

conferencepresentationsnodowngradingoccurred.

5Numberwitheventnotreportedineitherstudy.DARTmortalityinclinicalarm2.94/100P-Y,inimmunological+clinicalarm2.18/100patients-year.

6 InDARTinclinicalarm6.94events/100patients-year,inimmunological+clinicalarm,5.24events/100patients-year.InHBACinclinicalarm7.57events/100

patients-yearinimmunological+clinicalarm5.97events/100patients-year.

7 DARTstudyonly.

8 Numberwitheventnotreported.

9 Numberofeventsandpointestimatevariedwidelybetweenthetwostudies.



Au

tho

rs:


Dat

e:

12Aug2009

Qu

esti

on:

Shouldclinicalmonitoringvsvirological,immunological,andclinicalmonitoringbeusedforguidingwhentoswitch

first-lineantiretroviraltherapyinadultsinlow-resourcesettings?

Set

tin

gs:

Low-resourcesettings

Bib

liog

rap

hy:HBAC2008

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

cis-

ion

Oth

er

con

sid

er-

atio

ns

Clin

ical

m

on

ito

rin

g

Vir

olo

gi-

cal,

imm

un

o-

log

ical

, an

d

clin

ical

m

on

ito

rin

g

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Noserious

i ndirect-

ness2

Serious3

None4

?/3775

?/3685

HR1.58

(0.97to2.6)-

⊕⊕

OO

LOW

CRITICAL

AID

S-d

efin

ing

illn

ess

– n

ot

rep

ort

ed

0-

--

--

--

--

-CRITICAL

AID

S-d

efin

ing

illn

ess

or

mo

rtal

ity

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Noserious

indirect-

ness2

Serious3

None4

72/377

(19.1%)6

47/368

(12.8%)6

HR1.88

(1.25to

2.84)

99more

per1000

(from29

moreto194

more)

⊕⊕

OO

LOW

CRITICAL

Un

nec

essa

ry s

wit

ch (

swit

ch t

o s

eco

nd

-lin

e th

erap

y w

ith

un

det

ecta

ble

vir

al lo

ad)

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Noserious

indirect-

ness2

Serious3

None4

15/377(4%)0/368(0%)RR30.3

(1.82to

504)

-⊕

⊕O

OLOW

CRITICAL

111

Vir

olo

gic

al t

reat

men

t fa

ilure

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedt rials

Serious1

Noserious

inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

19/377(5%)16/368

(4.3%)

RR1.16 (0.6

to2.19)

7 more per

1000(from

17fewerto

52more)

⊕⊕

OO

LOW

IMPORTANT

Sw

itch

to

sec

on

d-l

ine

ther

apy

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

17/377

(4.5%)

7/368

(1.9%)

RR2.37

(0.99 to

5.65)

26more

per1000

(from0

fewerto88

more)

⊕⊕

OO

LOW

1 Unclearsequencegenerationandallocationconcealment,losttofollow-upanalysesnotextensivelypresentedbutabsolutenumberswererelativelysmall,

andblindingwasnotpossible.

2 Patientpopulationspreselectedandwithinrelativelywell-resourcedARTdeliveryprogrammes;however,asthisstudywasinalow-resourcesettingitwas

notdowngraded.

3Totalnumberofeventswassmall.




6 Inclinicalarm7.57events/100patients-year,invirological+immunological+clinicalarm4.80events/100patients-year.



Au

tho

rs:


Dat

e:

12Aug2009

Qu

esti

on:

Shouldclinicalandimmunologicalmonitoringvsvirological,immunologicalandclinicalmonitoringbeusedinguiding

whentoswitchfirst-lineantiretroviraltherapyinadultsinlow-resourcesettings?

Set

tin

gs:

Low-resourcesettings.

Bib

liog

rap

hy:H.B.A.C.2008

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

Clin

ical

an

d

imm

un

o-

log

ical

m

on

ito

rin

g

Vir

olo

gi-

cal,

imm

un

o-

log

ical

an

d

clin

ical

m

on

ito

rin

g

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

?/3715

?/3685

HR1.14(0.7

to1.9)

-⊕

⊕O

OLOW

CRITICAL

AID

S-d

efin

ing

illn

ess

– n

ot

rep

ort

ed

0-

--

--

--

--

-CRITICAL

AID

S-d

efin

ing

illn

ess

or

mo

rtal

ity

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

58/371

(15.6%)6

47/368

(12.8%)

HR1.28

(0.84 to

1.97)

33more

per1000

(from19

fewerto

108more)

⊕⊕

OO

LOW

CRITICAL

Un

nce

ssar

y sw

itch

(sw

itch

to

sec

on

d-l

ine

ther

apy

wit

h u

nd

etec

tab

le v

iral

load

) (f

ollo

w-u

p m

edia

n 3

yea

rs)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Noserious

indirect-

ness2

Very

serious7

None4

0/371(0%)

0/368(0%)Not

estim-able

-⊕

OO

OVERYLOW

CRITICAL

113

Vir

olo

gic

al t

reat

men

t fa

ilure

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedt rials

Serious1

Noserious

inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

26/371(7%)16/368

(4.3%)

RR1.61

(0.88to

2.95)

27more

per1000

(from5

fewerto85

more)

⊕⊕

OO

LOW

IMPORTANT

Sw

itch

to

sec

on

d-l

ine

ther

apy

(fo

llow

-up

med

ian

3 y

ears

)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

No serious

indirect-

ness2

Serious3

None4

4/371(1.1%)7/368

(1.9%)

RR0.57

(0.17 to

1.92)

8fewerper

1000(from

16fewerto

18more)

⊕⊕

OO

LOW

1 Unclearsequencegenerationandallocationconcealment,losttofollow-upanalysesnotextensivelypresentedbutabsolutenumberswererelativelysmall,

andblindingwasnotpossible.

2 Patientpopulationspreselectedandwithinrelativelywell-resourcedARTdeliveryprogrammes;however,asthisstudywasinalow-resourcesettingitwasnot

downgraded.

3 Totalnumberofeventsissmall.




6 Inclinical+immunologicalarm5.97events/100patients-year,invirological+immunological+clinicalarm4.80events/100patients-year.

7Totalnumberofeventsisverysmall.



Au

tho

rs:


Dat

e:

14Sep2009

Qu

esti

on:

Shouldvirological, immunological, andclinicalmonitoringvs immunologicalandclinicalmonitoringbe usedin

guidingwhen toswitch first-lineantiretroviral therapy inadultsinlow-resource settings?

Set

tin

gs:

Low-resource settings.

Bib

liog

rap

hy:ARTLINC2006,2008

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

or-

tan

ce

No

of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

Vir

olo

gi-

cal,

imm

un

o-

log

ical

an

d

clin

ical

m

on

ito

rin

g

Imm

un

o-

log

ical

an

d

clin

ical

m

on

ito

rin

g

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(fo

llow

-up

12

mo

nth

s)

1Observ-

ational

studies

Serious1

Noserious

inconsis-

tency

Noserious

i ndirect-

ness

Nos erious

imprecision

None

See

comment2

See

comment2

HR2.28

(0.76to

6.79)

-⊕

OO

OVERY LOW

CRITICAL

Rat

e o

f sw

itch

ing

1Observ-

ational

studies

Serious3

Noserious

inconsis-

tency

Noserious

indirect-

ness

Noserious

i mprecision

None

236/6369

(3.7%)

340/13744

(2.5%)

RR1.60

(1.35to

1 .89)4

15moreper

1000(from

9moreto

22more)

⊕O

OO

VERYLOW

Tim

e to

sw

itch

(7-

18 m

on

ths)

1Observ-

ational

s tudies

Serious3

Noserious

inconsis-

tency

Noserious

indirect-

ness

Noserious

i mprecision

None

?/63695

?/137445

HR1.38

(0.97to

1.98)

-⊕

OO

OVERYLOW

Tim

e to

sw

itch

(19

-30

mo

nth

s)

1Observ-

ational

studies

Serious3

Noserious

inconsis-

tency

Noserious

indirect-

ness

No serious

imprecision

None

?/27015

?/64885

HR0.97

(0.58to1.6)-

⊕O

OO

VERY LOW

115

Tim

e to

sw

itch

(31

-42

mo

nth

s)

1Observ-

ational

studies

Serious3

Noserious

inconsis-

tency

No serious

indirect-

ness

No serious

imprecision

None

?/9235

?/28025

HR0.29

(0.11to

0.79)

-⊕

OO

OVERYLOW

CD

4 ce

ll co

un

t at

tim

e o

f sw

itch

1Observ-

ational

studies

Serious3

Noserious

inconsis-

tency

No serious

indirect-

ness

No serious

imprecision

None

141patients261

patients

See

com-ment.6-

⊕O

OO

VERYLOW

1 Thisoutcomewasasubgroupanalysis,selectionofnon-exposedcohortswerenotdrawnfromsamecommunitiesastheexposedcohorts.

2 Numberwitheventandatrisknotreported.

3 Selectionofnon-exposedcohortswasnotdrawnfromthesamecommunitiesastheexposedcohorts;incompletefollow-updataonmanyparticipants.

4 Programmeswithvirologicalmonitoringrateofswitchingwas3.2/100patients-year(95%CI2.2−2.6)versus2.0/100patients-year(95%CI1.9−2.3)inthose

without(p<0.0001);RRhereisarateratio.


6 ProgrammeswithvirologicalmonitoringCD4cellcountattimeofswitchingwas161cells/µlcomparedto102cells/µlinthosewithout(p=0.001).



Wh

at t

o u

se in

sec

on

d-l

ine

Au

tho

rs:

HumphreysEandHarrisJ

Dat

e:

21Aug2009

Qu

esti

on:

Shouldlamivudine(3TC)bemaintainedinsecond-lineantiretroviralregimensforpatientsfailingfirst-linetherapy?

Bib

liog

rap

hy:Fox Z,DragstedU,GerstoftJ,etal.Arandomizedtrialtoevaluatecontinuationversusdiscontinuationoflamivudine

inindividualsfailingalamivudine-containingregimen:theCOLATEtrial.

Ant

ivira

l the

rapy2006;11(6):761-770.

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

Mai

nta

in-

ing

3T

C in

2n

d li

ne

No

3T

C in

2n

d li

ne

(co

ntr

ol)

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

– n

ot

mea

sure

d1

0-

--

--

--

CRITICAL

Pro

gre

ssio

n o

f d

isea

se –

no

t m

easu

red

0-

--

--

--

CRITICAL

Sev

ere

adve

rse

even

ts (

follo

w-u

p 4

8 w

eeks

)

1Random-

izedtrials

No serious


inconsis-

tency

Serious4

Serious5

None

--

Not

estimable2

⊕⊕

OO

LOW

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n –

no

t re

po

rted

0-

--

--

--

CRITICAL

Vir

olo

gic

al r

esp

on

se (

follo

w-u

p 4

8 w

eeks

; m

easu

red

as:

mea

n r

edu

ctio

n f

rom

bas

elin

e lo

g10

co

pie

s/m

l of

HIV

RN

A;

bet

ter

ind

icat

ed b

y h

igh

er v

alu

es)

1Random-

izedtrials

Noserious

limitations

Noserious

inconsis-

tency

Serious4

Serious5

None

286

27-

MD0.4

lower(0.87

lowerto

0.07higher)

⊕⊕

OO

LOW

IMPORTANT

117

Pro

po

rtio

n a

chie

vin

g V

L <

50

cop

ies/

ml (

follo

w-u

p 4

8 w

eeks

)

1Random-

izedt rials

Noserious


inconsis-

tency

Serious4

Serious5

None

38/65

(58.5%)

30/66

(45.5%)

RR1.29

(0.92to

1.80)

132 more

per1000

(from36

fewerto

364more)

⊕⊕

OO

LOW

IMPORTANT

Imm

un

olo

gic

al r

esp

on

se (

follo

w-u

p 4

8 w

eeks

; m

easu

red

as:

med

ian

incr

ease

in C

D4

fro

m b

asel

ine7

; B

ette

r in

dic

ated

by

hig

her

val

ues

)

1Random-

izedtrials

Noserious

limitations

Noserious

inconsis-

tency

Serious4

Serious5

None

6566

-Median

increase11

⊕⊕

OO

LOW

IMPORTANT

1 Table1reports1deathinOff3TCarmamongpatientswhoinitiatedtreatmentbutdiscontinued.

2 Numbersprovidedarenon-fatalclinicaladverseeventsperarm/totaladverseevents(among49participants).Furtherinformationnotprovided.Nodifference

inadverseeventsbetweenarms;43/94(45.7%)eventsinOn3TCarmand51/94(54.3%)eventsinOff3TCarm(p=0.25).

3Open-labelstudy;notdowngradedforthis.PartialfundingfromIndustryinearlyphasesoftrial,alsonotdowngradedforthis(lowriskofbiassincestudydrug

notfavouredsignificantlybyresults).

4 Clinician-optimizedregimen;patientsnotfromresource-limitedsetting(studypopulationfrom12Europeancountries).

5Feweventsorlownumberofpatients.

6NumbersrepresentstratumA,anapriorisubgroupofpatientswithonly1prior3TC-containingregimen(n=55).SimilarresultsforstratumB,thosewithmore

than1priorregimen(n=76).ThemeanreductionsfrombaselineinHIVRNAinoverallgroupswere1.4log10copies/ml(95%CI1.1−1.6)inOn3TCgroupand

1.5(95%CI1.2−1.7)inOff3TCgroup.

7 NoSDor95%CIavailablefromstudy(IQRprovided);unabletoreportmeandifferencebetweengroupsalthoughmediandifferencereportedasnotsignificant

(+87inOn3TCcomparedto76inOff3TCgroup,p=0.41).



Qu

esti

on:

ShouldPImonotherapybeusedforpatientsfailingfirst-linetherapy?

Bib

liog

rap

hy:Arribas2005;Arribas2009a;Arribas2009b;Cameron2008;Delfraissy2008;Guttmann2008;Katlama2009;Nunes

2007;Singh2007;Waters2008.

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

PI

mo

no

ther

-ap

y cA

RT

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(fo

llow

-up

96

wee

ks)

2Random-

izedtrials

Noserious


inconsis-

tency

Serious2

Serious3

None4

3/207

(1.4%)

1/153

(0.7%)

RR1.46

(0.22 to

9.8)

3 more per

1000(from

5fewerto

58more)

⊕⊕

OO

LOW

CRITICAL

Clin

ical

dis

ease

pro

gre

ssio

n –

no

t re

po

rted

0-

--

--

none

--

--

CRITICAL

Ser

iou

s ad

vers

e ev

ents

(g

rad

e 3

or

4 ad

vers

e ev

ent;

fo

llow

-up

1 s

tud

y 24

wee

ks, 4

stu

die

s 4

8 w

eeks

, 2 s

tud

ies

96

wee

ks)5

7Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Serious2

Serious3

None

25/499(5%)26/472

(5.5%)

RR1.02

(0.5to2.07)

1moreper

1000(from

28fewerto

59more)

⊕O

OO

VERYLOW

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n (

pro

po

rtio

n o

n r

and

om

ized

tre

atm

ent

at s

tud

y en

d;

follo

w-u

p 1

stu

dy

24 w

eeks

, 4 s

tud

ies

at 4

8 w

eeks

, 3 s

tud

ies

at 9

6 w

eeks

)

8Random-

izedtrials

Noserious


inconsis-

tency

Serious2

Noserious

imprecision

None

506/607

(83.4%)

448/529

(84.7%)

RR0.99

(0.95to

1.04)

8fewerper

1000(from

42fewerto

34more)

⊕⊕

⊕O

MODER-

ATE

CRITICAL

Vir

olo

gic

al r

esp

on

se (

pro

po

rtio

n w

ith

HIV

RN

A <

50

cop

ies/

ml o

r lo

wes

t re

po

rted

val

ue;

fo

llow

-up

6 s

tud

ies

48

wee

ks, 3

stu

die

s 9

6 w

eeks

)

9Random-

izedtrials

Noserious


inconsis-

tency

Serious2

Noserious

imprecision

None

470/636

(73.9%)

460/560

(82.1%)

RR0.94

(0.89to

0.99)

49fewer

per1000

(from8

fewerto90

fewer)

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

119

Imm

un

olo

gic

al r

esp

on

se (

mea

sure

d w

ith

: m

ean

incr

ease

fro

m b

asel

ine

CD

4; b

ette

r in

dic

ated

by

hig

her

val

ues

; fo

llow

-up

1 s

tud

y 24

wee

ks, 2

stu

die

s 4

8 w

eeks

, 2 s

tud

ies

96

wee

ks)

5Random-

izedtrials

Nos erious


inconsis-

tency

Serious2

Noserious

imprecision

None

338

256

-Not

pooled6

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

Dru

g r

esis

tan

ce (

acq

uis

itio

n o

f m

ajo

r p

rote

ase

mu

tati

on

s; f

ollo

w-u

p 4

stu

die

s 9

6 w

eeks

, 2 s

tud

ies

96

wee

ks)

6Random-

izedt rials

Noserious


inconsis-

tency

Serious2

Serious3

None

10/551

(1.8%)

4/470

(0.9%)

RR1.55

(0.48to

5.01)

5moreper

1000(from

4fewerto

34more)

⊕⊕

OO

LOW

IMPORTANT

1 Open-labelstudies,notdowngradedforthisexceptforsevereadverseevents,whichmaybemorepronetobiasinopen-labeltrials.Sixof9studiesindustry-

sponsoredand3withunclearreportingofsponsorship.

2 Allbut2studies(Cameron2008andDelfraissy2008)weremonotherapystudiesthatenrolledpatientswithviralsuppressionand/orwhowereART-naive;

indirectcomparisontopopulationwhowoulduseactivePIinsecond-lineafterfailureonfirst-lineregimen.

3 Lownumberofevents(<300)andCIindicatespotentialforappreciablebenefitandharm.

4 Someconcernforlackofclearmortalityoutcomereportingintherestofthebodyofevidencesinceonly2studiesreportdeaths.DeathsreportedinCameron

2008andArribas2009awereunrelatedtostudydrugs;otherstudiespresumednottohaveanydeaths(andmortalitynotprimaryend-pointinanyofthe

studies).

5 ITT-Epopulationused(randomizedanddosed).Somevariabilityinreporting;“seriousadverseevents”or“adverseeventsleadingtodiscontinuation”used.

Cameron2008notincludedasreportstates“3patientsdiscontinuedduetoadverseevents”butdoesnotspecifywhicharm.

6 Estimatenotpooledbecauseofvariability(medianvs.mean)inreporting,orlackofrawnumbers.Allstudiesreportnonsignificantdifferencesbetweenarms

i ni mmunologicalchanges.



Qu

esti

on:

Shouldatazanavir/ritonavirvs.lopinavir/ritonavirbeusedforpatientsfailingfirst-linetherapy?

Bib

liog

rap

hy:Molina JM, Andrade-VillanuevaJ, EchevarriaJ, etal. Once-dailyatazanavir/ritonavir versustwice-dailylopinavir/

ritonavir,each incombination withtenofovir andemtricitabine,formanagement ofantiretroviral-naive HIV-1-infected

patients:48 week efficacy andsafety resultsof the CASTLEstudy.L

ancet 2008;372:646-55.Molina JM, Andrade-

VillanuevaJ, EchevarriaJ, et al.

Ata

zana

vir/r

itona

vir

vs. l

opin

avir/

riton

avir

in a

ntire

trov

iral n

aive

HIV

-1-i

nfec

ted

pat

ient

s:

CA

STLE

96-

wee

k ef

ficac

y an

d sa

fety

. 48tth AnnualICAAC/IDSAMeeting,October25−28,2008,WashingtonDC.

AbstractH-1250d.

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

Ata

zan

avir

/ ri

ton

avir

Lo

pin

avir

/ri

ton

avir

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(fo

llow

-up

48

wee

ks)

1Random-

izedtrials

Noserious


inconsis-

tency

Serious

indirect-

ness2

Serious3

None

6/440

(1.4%)

6/443

(1.4%)

RR1.01

(0.33to3.1)

0moreper

1000(from

9fewerto

28more)

⊕⊕

OO

LOW

CRITICAL

Sev

ere

adve

rse

even

ts (

follo

w-u

p 9

6 w

eeks

)4

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Serious

indirect-

ness2

Serious3

None

63/441

(14.3%)

50/437

(11.4%)

RR1.25

(0.88to

1.77)

29more

per1000

(from14

fewerto88

more)

⊕O

OO

VERYLOW

CRITICAL

Clin

ical

dis

ease

pro

gre

ssio

n –

no

t re

po

rted

0-

--

--

--

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n (

follo

w-u

p 4

8 w

eeks

; ad

her

ence

qu

esti

on

nai

re)

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Serious

indirect-

ness2

Noserious

imprecision

None

330/440

(75%)

316/443

(71.3%)

RR1.05

(0.97to

1.14)

36more

per1000

(from21

fewerto

100more)

⊕⊕

OO

LOW

CRITICAL

121

Vir

olo

gic

al r

esp

on

se, p

rop

ort

ion

<5

0 co

pie

s (f

ollo

w-u

p 9

6 w

eeks

)

1Random-

izedt rials

Noserious


inconsis-

tency

Serious

indirect-

ness2

Noserious

imprecision

None

308/440

(70%)

279/443

(63%)

RR1.08

(0.99to

1.18)5

54more

per1000

(from7

fewerto

121 more)

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

Imm

un

olo

gic

al r

esp

on

se (

follo

w-u

p m

ean

96

wee

ks;

bet

ter

ind

icat

ed b

y h

igh

er v

alu

es)

1Random-

izedtrials

Noserious


inconsis-

tency

Serious

indirect-

ness2

Noserious

imprecision

None

440

443

-

MD21.2

lower(43.3

lowerto0.9

higher)6

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

Dru

g r

esis

tan

ce (

follo

w-u

p 9

6 w

eeks

) re

po

rted

as

maj

or

PI m

uta

tio

n

1Random-

izedtrials

Noserious


inconsis-

tency

Serious

indirect-

ness2

Serious3

None

1/440

(2.3%)

0/443

(1.8%)

RR1.26

(0.5to3.16)

5 more per

1000(from

9fewerto

39more)

⊕⊕

OO

LOW

IMPORTANT

1 Open-labelstudy,sponsoredbyindustry.Notdowngradedforbeingopen-labelunlessoutcomeis“severeadverseevents”or“adherence”wherenon-blinded

treatmentcouldbiasoutcome.

2 StudyevaluatesART-naivepopulation,whichisindirectpopulationfromPI-naivepatientswhowouldusePIinsecond-linetherapyafterfailureonNNRTI-

basedregimen.

3Lownumberofevents,<300andCIindicatespotentialforappreciablebenefitandharm.

4 Reportedas,“seriousadverseevents”.Ofnote,evensubjectsdiscontinuedbecauseofdiarrhoeainLPV/rarmand3subjectsdiscontinuedbecauseof

j aundice/hyperbilirubinaemiai nATV/ra rm.

5 ITTanalysiswherenon-completerorrebound=failure(TLOVR).At48weekoutcomes,numbersforTLOVRandconfirmedvirologicalresponse(CVR)were

similar:forATV/r343/440andLPV/r338/443(CVR)comparedtoATV/r343/440andLPV/r337/443(TOLVR).CVRclassifiesrebounderswhoareresuppressed

asresponders.TLOVRclassifiesresponseas2measurements:<50copies/mlandmaintained(withoutdiscontinuationorrebound).

6 MeanincreasefrombaselineofCD4cellcountsimilarbetweengroups:268cells/µlinATV/rversus290cells/µlinLPV/rgroupat96weeks.



Qu

esti

on:

Shoulddarunavir/ritonavirvs.lopinavir/ritonavirbeusedforpatientsfailingfirst-linetherapy?

Set

tin

gs:

Bib

liog

rap

hy:MillsAM,NelsonM,JayaweeraD,etal.Once-dailydarunavir/ritonavirvs.lopinavir/ritonavirintreatment-naive,HIV-1-

infectedpatients:96weekanalysis.A

IDS2009;23:1679-88.

Qu

alit

y as

sess

men

tS

um

mar

y o

f fi

nd

ing

s

Imp

ort

ance

No

. of

pat

ien

tsE

ffec

t

Qu

alit

yN

o.

of

stu

d-

ies

Des

ign

Lim

itat

ion

sIn

con

sis-

ten

cyIn

dir

ect-

nes

sIm

pre

ci-

sio

n

Oth

er

con

sid

er-

atio

ns

Dar

un

avir

/ri

ton

avir

Lo

pin

avir

/ri

ton

avir

Rel

ativ

e (9

5% C

I)A

bso

lute

Mo

rtal

ity

(fo

llow

-up

96

wee

ks)

1Random-

izedtrials

Nos erious


inconsis-

tency

Serious

i ndirect-

ness3

Serious2

None

1/343

(0.3%)

5/346

(1.4%)

RR0.2

(0.02to

1.72)

12fewer

per1000

(from14

fewerto10

more)

⊕⊕

OO

LOW

CRITICAL

Sev

ere

adve

rse

even

ts (

follo

w-u

p 9

6 w

eeks

)4

1Random-

izedtrials

Serious1

Noserious

inconsis-

tency

Serious

indirect-

ness3

Noserious

imprecision

None

34/343

(9.9%)

55/346

(15.9%)

RR0.62

(0.42to

0.93)

60fewer

per1000

(from11

fewerto92

fewer)

⊕⊕

OO

LOW

CRITICAL

Clin

ical

dis

ease

pro

gre

ssio

n –

no

t re

po

rted

0-

--

--

--

CRITICAL

Ad

her

ence

/to

lera

bili

ty/r

eten

tio

n (

follo

w-u

p 9

6 w

eeks

; re

po

rted

as

rete

nti

on

, nu

mb

er s

till

on

ran

do

miz

ed s

tud

y d

rug

5 )

1Random-

izedtrials

Noserious


inconsis-

tency

Serious

indirect-

ness3

Noserious

imprecision

None

284/343

(82.8%)

265/346

(76.6%)

RR1.08(1

to1.17)

61more

per1000

(from0

moreto130

more)

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

123

Vir

olo

gic

al r

esp

on

se, p

rop

ort

ion

HIV

-1 R

NA

<5

0 co

pie

s/m

l (fo

llow

-up

96

wee

ks)

1Random-

izedt rials

Noserious


inconsis-

tency

Serious

indirect-

ness3

Noserious

imprecision

None

271/343

(79%)

246/346

(71.1%)

RR1.11

(1.02to

1.21)

78more

per1000

(from14

moreto149

more)

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

Imm

un

olo

gic

al r

esp

on

se (

follo

w-u

p 9

6 w

eeks

; b

ette

r in

dic

ated

by

hig

her

val

ues

)

1Random-

izedtrials

Noserious


inconsis-

tency

Serious

indirect-

ness3

Noserious

imprecision

None

343

346

-Not

estimable6

⊕⊕

⊕O

MODER-

ATE

IMPORTANT

Dru

g r

esis

tan

ce (

follo

w-u

p 9

6 w

eeks

), r

epo

rted

as

acq

uir

ed m

ajo

r P

I mu

tati

on

1Random-

izedtrials

Noserious


inconsis-

tency

Serious

indirect-

ness3

Serious2

None

0/343 (0%)0/346 (0%)-

Not

estimable7

⊕⊕

OO

LOW

IMPORTANT

1 Open-label,industry-sponsoredstudy.Downgradedforbeingopen-labelstudyforoutcomeofsevereadverseeventsbutnotothers.

2 Lownumberofevents<300andCIindicatespotentialforbenefitandharm.

3 Evaluationintreatment-naivepatientsisanindirectmeasureofPI-naivepatientswhowoulduseboostedPIinsecond-linetherapyafterfailureofNNRTI-based

regimen.

4 Reportedas“AnyseriousAE”.For“AnyAEleadingtowithdrawal,”therewere19/343inDRV/rarmand35/346inLPV/rarm.

5 Inposthocanalysisbyself-reportedadherence,thoseadherent(>95%adherence)hadsimilarVLresponse(<50copies/ml)ratesinbotharms(82and78%

inDRV/randLPV/r,respectively).Forthosesuboptimallyadherent(<95%),VLresponse76%inDRV/rarmcomparedto53%inLPV/rarm(p<0.0001).

6 MedianchangefrombaselineinCD4cellcountwas188cells/µlinLPV/rgroupand171cells/µlinDRV/rgroup.

7NomajorPImutationswerefoundamongthosewithVL>50copies/mlwhohadbaselineandend-pointgenotypes.



Qu

esti

on:

Shouldfos-amprenavir/ritonavirvs.lopinavir/ritonavirbeusedforpatientsfailingfirst-linetherapy?

Set

tin

gs:

Bib

liog

rap

hy:Eron J,Yeni P, GatheJet al. The KLEANstudy offosamprenavir-ritonavir versuslopinavir-ritonavir,each incombination

withabacavir-lamivudine,for initial treatment of HIVinfection over48 weeks: arandomisednon-inferiority trial.

Lanc

et

2006;368:476-82.

Qu

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um

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Imp

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Fo

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1Random-

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4/443

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1/444

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RR4.01

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Sev

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53/436

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43/443

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Serious2

Serious3

None

11/443

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11/444

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Serious2

Noserious

imprecision

None

427/443

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435/444

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RR0.98

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125

Imm

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⊕⊕

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285/443

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IMPORTANT

1 Open-labelstudy;sponsoredbyindustry.Notdowngradedforthisotherthanforsevereadverseeventsandadherence,whichmaybesubjecttobiasinopen-

labelstudy.

2 EvaluatescomparisoninART-naivepopulation,whichisindirecttoPI-naivepopulationsstartingPI-basedsecond-linetherapyafterNNRTIfirst-line.

3 Lownumberofevents<300andCIindicatespotentialforappreciablebenefitandharm.

4 MedianincreaseinCD4frombaseline176cells/µl(IQR106-281)inFPV/rgroupand191cells/µl(IQR124-287)inLPV/rgroup

5 NomajorPIassociatedmutationsineitherarmamongthe35patientswhohadprotocol-definedfailureandbaselineandend-pointgenotypesavailable.



1. WHO.Antiretroviraltreatmentworkinggrouptreatmentwhitepaper.2010.

2. Siegfried NL, Uthman OA, Rutherford GW. Optimal time for initiation of antiretroviraltherapy for asymptomatic, HIV-infected, treatment-naive adults.Cochrane Database of Systematic Reviews 2010.2010(Issue2(Inpress)).

3. SevereP,PapeJ,FitzgeraldD,etal.A randomized clinical trial of early versus standard antiretroviral therapy for HIV-infected patients with a CD4 cell count of 200-350 cells/mm3

(CIPRATH-001). 49thInterscienceConferenceonAntimicrobialAgentsandChemotherpy,SanFransisco,2009.

4. EmeryS,NeuhausJA,PhillipsAN,BabikerA,CohenCJ,GatellJM,etal.Majorclinicaloutcomesinantiretroviraltherapy(ART)-naiveparticipantsandinthosenotreceivingARTatbaselineintheSMARTstudy.J Infect Dis2008;197(8):1133-44.

5. SterneJA,MayM,CostagliolaD,deWolfF,PhillipsAN,HarrisR,etal.TimingofinitiationofantiretroviraltherapyinAIDS-freeHIV-1-infectedpatients:acollaborativeanalysisof18HIVcohortstudies.Lancet2009;373(9672):1352-63.

6. Moh R, Danel C, Messou E, Ouassa T, Gabillard D, Anzian A, et al. Incidence anddeterminantsofmortalityandmorbidity followingearlyantiretroviral therapy initiation inHIV-infectedadultsinWestAfrica.AIDS2007;21(18):2483-91.

7. BadriM,BekkerLG,OrrellC,PittJ,CilliersF,WoodR.Initiatinghighlyactiveantiretroviraltherapy insub-SaharanAfrica:anassessmentof therevisedWorldHealthOrganizationscaling-upguidelines.AIDS 2004;18(8):1159-68.

8. WongKH,ChanKC,ChengKL,ChanWK,KamKM,LeeSS.EstablishingCD4thresholdsforhighlyactiveantiretroviraltherapyinitiationinacohortofHIV-infectedadultChineseinHongKong.AIDS Patient Care STDS2007;21(2):106-15.

9. UNAIDS.Cost estimates: AIDS financing and economics.2009.

10. GranichRM,GilksCF,DyeC,DeCockKM,WilliamsBG.UniversalvoluntaryHIVtestingwith immediateantiretroviral therapyasastrategy foreliminationofHIV transmission:amathematicalmodel.Lancet2009Jan3;373(9657):48-57.

11. DanelC,MohR,MingaA,AnzianA,Ba-GomisO,KangaC,etal.CD4-guidedstructuredantiretroviraltreatmentinterruptionstrategyinHIV-infectedadultsinwestAfrica(TrivacanANRS1269trial):arandomisedtrial.Lancet2006;367(9527):1981-9.

12. Havlir DV, Getahun H, Sanne I, Nunn P. Opportunities and challenges for HIV care inoverlappingHIVandTBepidemics.JAMA2008;300(4):423-30.

13. Lawn SD, Churchyard G. Epidemiology of HIV-associated tuberculosis.Curr Opin HIV AIDS2009;4(4):325-33.

14. Hammer SM, Eron JJ, Jr., Reiss P, Schooley RT, Thompson MA, Walmsley S, et al.AntiretroviraltreatmentofadultHIVinfection:2008recommendationsoftheInternationalAIDSSociety-USApanel.JAMA 2008;300(5):555-70.

22. references

127

15. GangeSJ,KitahataMM,SaagMS,BangsbergDR,BoschRJ,Brooks JT, et al.Cohortprofile: the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).Int J Epidemiol2007;36(2):294-301.

16. NgomaD,MakombeSD,KamotoK,HarriesAD.WorldHealthOrganizationClinicalStage3 disease conditions inHIV-infected patientswho start antiretroviral therapy inMalawi.Trop Doct2008;38(3):159-60.

17. TeckR,AscurraO,GomaniP,ManziM,PasulaniO,KusamaleJ,etal.WHOclinicalstagingof HIV infection and disease, tuberculosis and eligibility for antiretroviral treatment:relationshiptoCD4lymphocytecounts.Int J Tuberc Lung Dis2005;9(3):258-62.

18. EdathoduJ,AliB,AlrajhiAA.CD4validationfortheWorldHealthOrganizationclassificationandclinicalstagingofHIV/AIDSinadevelopingcountry.Int J Infect Dis2009;13(2):243-6.

19. KassaE,RinkedeWitTF,HailuE,GirmaM,MesseleT,MariamHG,etal.EvaluationoftheWorld Health Organization staging system for HIV infection and disease in Ethiopia:associationbetweenclinicalstagesandlaboratorymarkers.AIDS1999;13(3):381-9.

20. Annam V, Yelikar BR, Inamadar AC, Palit A. Histopathological study of pruritic papulareruptions inHIV-infectedpatients in relationshipwithCD4,CD8counts. Indian J Pathol Microbiol2009;52(3):321-4.

21. LakshmiSJ,RaoGR,RaoKA,PrasadPG,KumarYH.PruriticpapulareruptionsofHIV:aclinicopathologicandtherapeuticstudy.Indian J Dermatol Venereol Leprol2008;74(5):501-3.

22. WHO.Guidance on provider-initiated HIV testing and counselling in health facilities.2007.

23. HoffmannCJ,CharalambousS, Sim J, Ledwaba J, SchwikkardG,ChaissonRE, et al.Viremia, resuppression, and time to resistance in human immunodeficiency virus (HIV)subtype C during first-line antiretroviral therapy in South Africa. Clin Infect Dis 2009;49(12):1928-35.

24. AminJ,MooreA,CarrA,FrenchMA,LawM,EmeryS,etal.Combinedanalysisoftwo-year follow-up from two open-label randomized trials comparing efficacy of threenucleoside reverse transcriptase inhibitor backbones for previously untreated HIV-1infection:OzCombo1and2. HIV clinical trials2003;4(4):252-61.

25. French M, Amin J, Roth N, Carr A, Law M, Emery S, et al. Randomized, open-label,comparativetrialtoevaluatetheefficacyandsafetyofthreeantiretroviraldrugcombinationsincluding two nucleoside analogues and nevirapine for previously untreated HIV-1Infection:theOzCombo2study. HIV clinical trials2002;3(3):177-85.

26. EronJJ,Jr.,MurphyRL,PetersonD,PottageJ,ParentiDM,JemsekJ,etal.Acomparisonof stavudine,didanosineand indinavirwith zidovudine, lamivudineand indinavir for theinitial treatment of HIV-1 infected individuals: selection of thymidine analog regimentherapy(STARTII).AIDS2000;14(11):1601-10.



27. GatheJ,Jr.,BadaroR,GrimwoodA,AbramsL,KlesczewskiK,CrossA,etal.Antiviralactivity of enteric-coated didanosine, stavudine, and nelfinavir versus zidovudine pluslamivudineandnelfinavir.J Acquir Immune Defic Syndr2002;31(4):399-403.

28. Carr A,Chuah J,Hudson J, FrenchM,Hoy J, LawM, et al. A randomised, open-labelcomparisonofthreehighlyactiveantiretroviraltherapyregimensincludingtwonucleosideanalogues and indinavir for previously untreatedHIV-1 infection: theOzCombo1 study.AIDS2000;14(9):1171-80.

29. GeijoMartínezMPMMM,SoleraSantosJ,BarberáFarréJR,RodríguezZapataM,MarcosSánchezF,MartínezAlfaroE,CuadraGarcía-TenorioF,SanzMorenoJ,MorenoMendañaJM, Beato Pérez JL, Sanz Sanz J; GECMEI. Ensayo clínico comparativo de eficacia yseguridad de cuatro pautas de tratamiento antirretroviral de alta eficacia (TARGA) enpacientesconinfecciónporVIHavanzada[Testcomparativeclinicalefficacyandsafetyoffour treatment guidelines highly active antiretroviral (TARGA) in patientswith advancedHIVinfection]. Rev Clin Esp 2006;206:67-76.

30. KumarPN,Rodriguez-FrenchA,ThompsonMA,TashimaKT,AverittD,WannamakerPG,et al. A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir, andlamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy inantiretroviral-naivepatients:effectofsexandethnicity.HIV Med 2006;7(2):85-98.

31. LiT,DaiY,KuangJ,JiangJ,HanY,QiuZ,etal.Threegenericnevirapine-basedantiretroviraltreatments in Chinese HIV/AIDS patients: multicentric observation cohort. PLoS ONE 2008;3(12):e3918.

32. Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, et al.Comparisonofsequentialthree-drugregimensasinitialtherapyforHIV-1infection.N Engl J Med2003;349(24):2293-303.

33. SquiresKE,GulickR,TebasP,SantanaJ,MulanovichV,ClarkR,etal.AcomparisonofstavudinepluslamivudineversuszidovudinepluslamivudineincombinationwithindinavirinantiretroviralnaiveindividualswithHIVinfection:selectionofthymidineanalogregimentherapy(STARTI).AIDS2000;14(11):1591-600.

34. TheAdultAntiretroviralTreatmentandResistanceStudyTshepo[databaseontheInternet]2009 [cited November 11, 2009]. Available from: http://clinicaltrials.gov/ct2/show/NCT00197613?term=Tshepo&rank=1.

35. GallantJE,StaszewskiS,PozniakAL,DeJesusE,SuleimanJM,MillerMD,etal.Efficacyand safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naivepatients:a3-yearrandomizedtrial.JAMA2004;292(2):191-201.

36. Rey D, Hoen B, Chavanet P, Schmitt MP, Hoizey G, Meyer P, et al. High rate of earlyvirologicalfailurewiththeonce-dailytenofovir/lamivudine/nevirapinecombinationinnaiveHIV-1-infectedpatients.J Antimicrob Chemother2009;63(2):380-8.

129

37. Arribas JR, PozniakAL,Gallant JE,DejesusE,GazzardB,CampoRE, et al. Tenofovirdisoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudineandefavirenzintreatment-naivepatients:144-weekanalysis.J Acquir Immune Defic Syndr 2008;47(1):74-8.

38. LapadulaG,CostarelliS,Quiros-RoldanE,CalabresiA,IzzoI,CarosiG,etal.Riskofearlyvirological failure of once-daily tenofovir-emtricitabine plus twice-daily nevirapine inantiretroviraltherapy-naiveHIV-infectedpatients.Clin Infect Dis2008;46(7):1127-9.

39. Towner W, Kerrigan HL, LaRivière M, et al. eds. Efficacy of a once-daily regimen of nevirapine(NVP), lamivudine (3TC) and tenofovir (TDF) in treatment-naive HIV-infected patients: a pilot study. SeventhInternationalCongressonDrugTherapyinHIVInfection;2004.

40. VicenteSorianoSK,HoracioMigroneetal,editors.Prospective randomised comparison of nevirapine and atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment-naive HIV-1 infected patients: ARTEN Study, week 48 results.5thIASConferenceon HIV Pathogenesis, Treatment and Prevention; 19-22 July 2009; Cape Town, SouthAfrica.

41. AlexandraCalmyAN,JLange,MBattegay,FdeWolf,PReiss,BHirschel,FWit,andforthe Swiss HIV Cohort Study and the Netherlands ATHENAObservational Cohort, eds.Nevirapine administered once daily is as efficient as a twice-daily dosing. A collaborative cohort study. 15thConferenceonRetrovirusesandOpportunisticInfecions;2009;Boston.

42. HavlirDV,KoelschKK,StrainMC,MargotN,LuB,IgnacioCC,etal.Predictorsofresidualviremia inHIV-infectedpatients successfully treatedwith efavirenz and lamivudinepluseithertenofovirorstavudine.J Infect Dis2005;191(7):1164-8.

43. Lodwick RK, Smith CJ, Youle M, Lampe FC, Tyrer M, Bhagani S, et al. Stability ofantiretroviralregimensinpatientswithviralsuppression.AIDS2008;22(9):1039-46.

44. WilligJH,AbromsS,WestfallAO,RoutmanJ,AdusumilliS,VarshneyM,etal.Increasedregimendurability in theeraofonce-daily fixed-dosecombinationantiretroviral therapy.AIDS2008;22(15):1951-60.

45. MocroftA,PhillipsAN,LedergerberB,KatlamaC,ChiesiA,GoebelFD,etal.RelationshipbetweenantiretroviralsusedaspartofacARTregimenandCD4cellcountincreasesinpatientswithsuppressedviremia.AIDS2006;20(8):1141-50.

46. WolbersM,BattegayM,HirschelB,FurrerH,CavassiniM,HasseB,etal.CD4+T-cellcountincreaseinHIV-1-infectedpatientswithsuppressedviralloadwithin1yearafterstartofantiretroviraltherapy.Antivir Ther2007;12(6):889-97.

47. Sanchez-delaRosaR,HerreraL,MorenoS.Cost-effectivenessanalysisofemtricitabine/tenofovir versus lamivudine/zidovudine, in combination with efavirenz, in antiretroviral-naive,HIV-1-infectedpatients.Clin Ther2008;30(2):372-81.



48. FernandezLisonLC.PDLLE,HeviaAlonsoA,GarridoMartinezMT,BocanegraMartinC.Cost-effectiveness analysis of tenofovir versus zidovudine in combination therapy withefavirenzandlamivudineforthetreatmentofHIVinnaivepatients.Farmacia Hospitalaria 2005(29):11-7.

49. AyalaGaytanJJdlGE,GarciaMC,ChavezSBV.Nevirapineorefavirenz incombinationwithtwonucleosideanaloguesinHIVinfectedantiretroviralnaïvepatients. Med Intern Mex 2004;20:24.

50. Manosuthi W, Sungkanuparph S, Tantanathip P, Lueangniyomkul A, Mankatitham W,Prasithsirskul W, et al. A randomized trial comparing plasma drug concentrations andefficacies between 2 nonnucleoside reverse-transcriptase inhibitor-based regimens inHIV-infectedpatientsreceivingrifampicin:theN2RStudy. Clin Infect Dis2009;48(12):1752-9.

51. NuñezM, Soriano V,Martin-Carbonero L, Barrios A, Barreiro P, Blanco F, et al. SENC(Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study inHIV-infectednaiveindividuals.HIV clinical trials2002;3(3):186-94.

52. Sow PG BM, Diallo PD, Lo I, Ndiaye B, Gaye AM, editor. Efficacy and safety of lamivudine+zidovudine+efavirenz and lamivudine+zidovudine+névirapine in treatment HIV1 infected patients. A retrospective cross study analysis. XVI International AIDSConference;13-18August2006:Toronto,Canada.

53. vandenBerg-WolfM,HullsiekKH,PengG,KozalMJ,NovakRM,ChenL,etal.Virologic,immunologic,clinical,safety,and resistanceoutcomes froma long-termcomparisonofefavirenz-basedversusnevirapine-basedantiretroviralregimensasinitialtherapyinHIV-1-infectedpersons.HIV clinical trials2008;9(5):324-36.

54. vanLethF,PhanuphakP,RuxrungthamK,BaraldiE,MillerS,GazzardB,etal.Comparisonof first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or bothdrugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study.Lancet 2004;363(9417):1253-63.

55. Clinicaltrials.gov. Comparison of nevirapine and efavirenz for the treatment of HIV-TBcoInfectedpatients (ANRS12146CARINEMO). 2009;Available from:http://clinicaltrials.gov/ct2/show/NCT00495326?term=ANRS+12146&rank=1.

56. Evaluationof4newsimplifiedantiretroviraltreatmentsinnaiveHIV-1infectedpatientsinAfrica (ANRS 12115 DAYANA) [database on the Internet] 2009. Available from: http://clinicaltrials.gov/ct2/show/NCT00573001?term=DAYANA&rank=1.

57. RajeshL,KarunaiananthamR,NarayananPR,SwaminathanS.Antiretroviraldrug-resistantmutationsatbaselineandattimeoffailureofantiretroviraltherapyinHIVtype1-coinfectedTBpatients.AIDS Res Hum Retroviruses2009;25(11):1179-85.

58. GileadSciences.Viread prescribing information.2010(Revised03/2010).

131

59. AnanworanichJ,MoorZ,SiangphoeU,ChanJ,CardielloP,DuncombeC,etal.IncidenceandriskfactorsforrashinThaipatientsrandomizedtoregimenswithnevirapine,efavirenzorbothdrugs.AIDS 2005;19(2):185-92.

60. WinstonA,PozniakA,SmithN,FletcherC,MandaliaS,ParmarD,etal.Doseescalationorimmediate full dose when switching from efavirenz to nevirapine-based highly activeantiretroviraltherapyinHIV-1-infectedindividuals?AIDS 2004;18(3):572-4.

61. LaureillardD,PrakN,FernandezM,NgethC,MoeungS,RielV,etal.Efavirenzreplacementbyimmediatefull-dosenevirapineissafeinHIV-1-infectedpatientsinCambodia.HIV Med 2008;9(7):514-8.

62. Isaakidis P, RaguenaudME, Phe T, Khim SA, Kuoch S, KhemS, et al. Evaluation of asystematicsubstitutionofzidovudineforstavudine-basedHAARTinaprogramsettinginruralCambodia.J Acquir Immune Defic Syndr2008;49(1):48-54.

63. SsaliF,StohrW,MunderiP,ReidA,WalkerAS,GibbDM,etal.Prevalence,incidenceandpredictorsofsevereanaemiawithzidovudine-containingregimensinAfricanadultswithHIVinfectionwithintheDARTtrial.Antivir Ther2006;11(6):741-9.

64. Amoroso A. Antiretroviral-associated drug toxicities leading to a switch in medication: Experience in Uganda, Kenya, and Zambia. 14th Conference on Retroviruses andOpportunisticInfections(CROI);25-28February2007;LosAngeles,USA.

65. FatuF,editor.Hematologic changes associated with zidovudine after single-drug substitution from stavudine in a home-based AIDS care program in rural Uganda.15th15thConferenceonRetrovirusesandOpportunisticInfections;3-6February2008;Boston,USA.

66. BannisterWP,RuizL,Cozzi-LepriA,MocroftA,KirkO,StaszewskiS,etal.ComparisonofgenotypicresistanceprofilesandvirologicalresponsebetweenpatientsstartingnevirapineandefavirenzinEuroSIDA.AIDS2008;22(3):367-76.

67. HittiJ,FrenkelLM,StekAM,NachmanSA,BakerD,Gonzalez-GarciaA,etal.Maternaltoxicity with continuous nevirapine in pregnancy: results from PACTG 1022. J Acquir Immune Defic Syndr2004;36(3):772-6.

68. JamisseL,BalkusJ,HittiJ,GloydS,ManuelR,OsmanN,etal.Antiretroviral-associatedtoxicityamongHIV-1-seropositivepregnantwomeninMozambiquereceivingnevirapine-basedregimens.J Acquir Immune Defic Syndr 2007;44(4):371-6.

69. Mocroft A, Staszewski S,Weber R,Gatell J, Rockstroh J, Gasiorowski J, et al. Risk ofdiscontinuationofnevirapineduetotoxicitiesinantiretroviral-naiveand-experiencedHIV-infectedpatientswithhighandlowCD4+T-cellcounts. Antivir Ther2007;12(3):325-33.

70. LyonsF,HopkinsS,KelleherB,McGearyA,SheehanG,GeogheganJ, et al.Maternalhepatotoxicitywithnevirapineaspartofcombinationantiretroviraltherapyinpregnancy.HIV Med 2006;7(4):255-60.



71. KiertiburanakulS,SungkanuparphS,CharoenyingwattanaA,MahasirimongkolS,SuraT,ChantratitaW. Risk factors for nevirapine-associated rash amongHIV-infected patientswithlowCD4cellcountsinresource-limitedsettings. Curr HIV Res 2008;6(1):65-9.

72. TaiwoBO.Nevirapinetoxicity.Int J STD AIDS2006;17(6):364-9.

73. KnobelH,GuelarA,MonteroM,CarmonaA,LuqueS,BerenguerN,etal.Riskofsideeffectsassociatedwiththeuseofnevirapineintreatment-naivepatients,withrespecttogenderandCD4cellcount.HIV Med2008;9(1):14-8.

74. KondoW,CarraroEA,PrandelE,DiasJM,PeriniJ,MacedoRL,etal.Nevirapine-inducedsideeffectsinpregnantwomen:experienceofaBrazilianuniversityhospital.Braz J Infect Dis2007;11(6):544-8.

75. Bonjoch A, Paredes R, Domingo P, CervantesM, Pedrol E, Ribera E, et al. Long-termsafetyandefficacyofnevirapine-basedapproachesinHIVtype1-infectedpatients. AIDS Res Hum Retroviruses2006;22(4):321-9.

76. DeLazzariE,LeonA,ArnaizJA,MartinezE,KnobelH,NegredoE,etal.HepatotoxicityofnevirapineinvirologicallysuppressedpatientsaccordingtogenderandCD4cellcounts.HIV Med 2008;9(4):221-6.

77. TortiC,CostarelliS,DeSilvestriA,Quiros-RoldanE,LapadulaG,CologniG,etal.Analysisof severe hepatic events associated with nevirapine-containing regimens: CD4+ T-cellcount and gender in hepatitis C seropositive and seronegative patients. Drug Saf 2007;30(12):1161-9.

78. ManfrediR,CalzaL.Nevirapineversusefavirenzin742patients:nolinkoflivertoxicitywithfemale sex, and a baseline CD4 cell count greater than 250 cells/microl. AIDS 2006;20(17):2233-6.

79. ManfrediR,CalzaL.SafetyissuesaboutnevirapineadministrationinHIV-infectedpregnantwomen.J Acquir Immune Defic Syndr2007;45(3):365-8.

80. Phanuphak N, Apornpong T, Teeratakulpisarn S, Chaithongwongwatthana S,TaweepolcharoenC,MangclavirajS,etal.Nevirapine-associatedtoxicity inHIV-infectedThaimenandwomen,includingpregnantwomen.HIV Med2007;8(6):357-66.

81. Kumarasamy N, Venkatesh KK, Devaleenal B, Palanivel V, Cecelia AJ, Muthu S, et al.Safetyofswitchingtonevirapine-basedhighlyactiveantiretroviraltherapyatelevatedCD4cellcountsinaresource-constrainedsetting.J Acquir Immune Defic Syndr 2007;45(5):598-600.

82. Wit FW, Kesselring AM, Gras L, Richter C, van der Ende ME, Brinkman K, et al.Discontinuationofnevirapinebecauseofhypersensitivityreactions inpatientswithpriortreatmentexperience,comparedwithtreatment-naivepatients:theATHENAcohortstudy.Clin Infect Dis2008;46(6):933-40.

133

83. Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr2004;35(5):538-9.

84. FeinbergJ.Reportfromthe16thConferenceonRetrovirusesandOpportunisticInfections.Lopinavir/r is superior to nevirapine in women who previously received single-dosenevirapine.AIDS Clin Care2009;21(4):33.

85. SaxPE,GallantJE,KlotmanPE.Renalsafetyoftenofovirdisoproxilfumarate.AIDS Read 2007;17(2):90-2,9-104,C3.

86. RolingJ,SchmidH,FischerederM,DraenertR,GoebelFD.HIV-associatedrenaldiseasesand highly active antiretroviral therapy-induced nephropathy. Clin Infect Dis 2006;42(10):1488-95.

87. CassettiI,MadrugaJV,SuleimanJM,EtzelA,ZhongL,ChengAK,etal.Thesafetyandefficacyof tenofovirDFincombinationwith lamivudineandefavirenzthrough6years inantiretroviral-naiveHIV-1-infectedpatients.HIV clinical trials2007;8(3):164-72.

88. NurutdinovaD,OnenNF,HayesE,MondyK,OvertonET.AdverseeffectsoftenofoviruseinHIV-infectedpregnantwomenandtheirinfants.Ann Pharmacother2008;42(11):1581-5.

89. WHO,UNAIDSandUNICEF. Towardsuniversal access:Scalingupof priorityHIV/AIDSinterventions in the health sector: Progress report 2009 [cited 2009 Nov 11, 2009]:Availablefrom:http://www.who.int/hiv/pub/2009progressreport/en/.

90. GallantJE,DeJesusE,ArribasJR,PozniakAL,GazzardB,CampoRE,etal.TenofovirDF,emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz forHIV.N Engl J Med2006;354(3):251-60.

91. SubbaramanR,ChaguturuSK,MayerKH,FlaniganTP,KumarasamyN.Adverseeffectsofhighlyactiveantiretroviraltherapyindevelopingcountries.Clin Infect Dis2007;45(8):1093-101.

92. McComsey G, Lonergan JT. Mitochondrial dysfunction: patient monitoring and toxicitymanagement.J Acquir Immune Defic Syndr2004;37Suppl1:S30-5.

93. Hawkins C, Achenbach C, Fryda W, Ngare D, Murphy R. Antiretroviral durability andtolerability in HIV-infected adults living in urban Kenya. J Acquir Immune Defic Syndr 2007;45(3):304-10.

94. vanGriensvenJ,ZachariahR,RasschaertF,MugaboJ,AtteEF,ReidT.Stavudine-andnevirapine-related drug toxicity while on generic fixed-dose antiretroviral treatment:incidence, timingand risk factors ina three-yearcohort inKigali,Rwanda.Trans R Soc Trop Med Hyg2010;104(2):148-53.

95. KallianpurAR,HulganT.Pharmacogeneticsofnucleosidereverse-transcriptaseinhibitor-associatedperipheralneuropathy.Pharmacogenomics2009;10(4):623-37.



96. vanGriensvenJ,DeNaeyerL,MushiT,UbarijoroS,GashumbaD,GazilleC,etal.Highprevalenceof lipoatrophyamongpatientsonstavudine-containingfirst-lineantiretroviraltherapyregimensinRwanda.Trans R Soc Trop Med Hyg2007;101(8):793-8.

97. MutimuraE,StewartA,RheederP,CrowtherNJ.Metabolicfunctionandtheprevalenceoflipodystrophy in a population of HIV-infected African subjects receiving highly activeantiretroviraltherapy.J Acquir Immune Defic Syndr2007;46(4):451-5.

98. Geddes R, Knight S, Moosa MY, Reddi A, Uebel K, Sunpath H. A high incidence ofnucleoside reverse transcriptase inhibitor (NRTI)-induced lacticacidosis inHIV-infectedpatientsinaSouthAfricancontext.S Afr Med J2006;96(8):722-4.

99. WHO.AntiretroviraltherapyforHIVinfectioninadultsandadolescents:Recommendationsforapublichealthapproach.2006.Availablefrom:http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf.

100. TaiJH,UdojiMA,BarkanicG,ByrneDW,RebeiroPF,ByramBR,etal.PregnancyandHIVdisease progression during the era of highly active antiretroviral therapy. J Infect Dis 2007;196(7):1044-52.

101. Theantiretroviralpregnancyregistry [databaseon the Internet].AntiretroviralPregnancyRegistry Steering Committee. 2009. Available from: http://www.apregistry.com/forms/interim_report.pdf.

102. Peltier CA, Ndayisaba GF, Lepage P, van Griensven J, Leroy V, Pharm CO, et al.Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIVpostnatalmother-to-childtransmissioninRwanda. AIDS2009;23(18):2415-23.

103. OuyangDW,ShapiroDE,LuM,BroglySB,FrenchAL,LeightyRM,etal.IncreasedriskofhepatotoxicityinHIV-infectedpregnantwomenreceivingantiretroviraltherapyindependentofnevirapineexposure.AIDS 2009;23(18):2425-30.

104. MusokeP,GuayLA,BagendaD,MirochnickM,NakabiitoC,FlemingT,etal.AphaseI/IIstudy of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnantUgandanwomenandtheirneonates(HIVNET006).AIDS 1999;13(4):479-86.

105. Kunz A, Frank M, Mugenyi K, Kabasinguzi R, Weidenhammer A, Kurowski M, et al.Persistenceof nevirapine inbreastmilk andplasmaofmothersand their childrenaftersingle-doseadministration.J Antimicrob Chemother 2009;63(1):170-7.

106. MuroE,DrosteJA,HofstedeHT,BoschM,DolmansW,BurgerDM.Nevirapineplasmaconcentrations are still detectable after more than 2 weeks in the majority of womenreceivingsingle-dosenevirapine: implications for interventionstudies.J Acquir Immune Defic Syndr2005;39(4):419-21.

107. RibaudoHJ,HaasDW,TierneyC,KimRB,WilkinsonGR,GulickRM,etal.Pharmacogeneticsofplasmaefavirenzexposureaftertreatmentdiscontinuation:anAdultAIDSClinicalTrialsGroupStudy.Clin Infect Dis2006;42(3):401-7.

135

108. ArriveE,KyabayinzeDJ,MarquisB,TumwesigyeN,KiefferMP,AzondekonA,etal.Cohortprofile: the paediatric antiretroviral treatment programmes in lower-income countries(KIDS-ART-LINC)collaboration.Int J Epidemiol2008;37(3):474-80.

109. FlysTS,MwathaA,GuayLA,NakabiitoC,DonnellD,MusokeP,etal.DetectionofK103Nin Ugandan women after repeated exposure to single dose nevirapine. AIDS 2007;21(15):2077-82.

110. FlysTS,DonnellD,MwathaA,NakabiitoC,MusokeP,MmiroF,etal.PersistenceofK103N-containingHIV-1variantsaftersingle-dosenevirapine forpreventionofHIV-1mother-to-childtransmission.J Infect Dis2007;195(5):711-5.

111. Wind-RotoloM,DurandC,CranmerL,ReidA,MartinsonN,DohertyM,etal.Identificationofnevirapine-resistantHIV-1inthelatentreservoiraftersingle-dosenevirapinetopreventmother-to-childtransmissionofHIV-1.J Infect Dis2009;199(9):1301-9.

112. CoovadiaH.Current issues inpreventionofmother-to-child transmissionofHIV-1.Curr Opin HIV AIDS2009;4(4):319-24.

113. CoovadiaA,HuntG,AbramsEJ,ShermanG,MeyersT,BarryG,etal.PersistentminorityK103N mutations among women exposed to single-dose nevirapine and virologicresponse tononnucleosidereverse-transcriptase inhibitor-basedtherapy.Clin Infect Dis 2009;48(4):462-72.

114. LockmanS,ShapiroRL,SmeatonLM,WesterC, Thior I, StevensL, et al.Response toantiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 2007;356(2):135-47.

115. LockmanS,McIntyreJA.ReductionofHIV-1drugresistanceafterintrapartumsingle-dosenevirapine.Lancet2007;370(9600):1668-70.

116. ChiBH,SinkalaM,StringerEM,CantrellRA,MtongaV,BulterysM,etal.EarlyclinicalandimmuneresponsetoNNRTI-basedantiretroviraltherapyamongwomenwithpriorexposuretosingle-dosenevirapine.AIDS 2007;21(8):957-64.

117. LockmanS,editor. Lopinavir/ritonavir + tenofovir/emtricitabine is superior to nevirapine + tenofovir/emtricitabine for women with prior exposure to single-dose nevirapine: A5208 (“Octane”).16thConferenceonRetrovirusesandOpportunisticInfections;8-11February2009;Montreal,Canada.

118. CoffiePA,EkoueviDK,ChaixML,Tonwe-GoldB,ClarisseAB,BecquetR,etal.Maternal12-month response to antiretroviral therapy following prevention of mother-to-childtransmissionofHIVtype1,IvoryCoast,2003-2006.Clin Infect Dis2008;46(4):611-21.

119. KuhnL,SemrauK,RamachandranS,SinkalaM,ScottN,KasondeP,etal.Mortalityandvirologicoutcomesafteraccesstoantiretroviral therapyamongacohortofHIV-infectedwomenwhoreceivedsingle-dosenevirapine inLusaka,Zambia.J Acquir Immune Defic Syndr2009;52(1):132-6.



120. McIntyreJAMN,GrayGE,etal.Addition of short course combivir to single-dose viramune for the prevention of mother to child transmission of HIV-1 can significantly decrease the subsequent development of maternal and paediatric NNRTI-resistant virus.3rdInternationalAIDSSocietyConferenceonHIVPathogenesisandTreatment;24-27July2005;RiodeJaneiro,Brazil.

121. ChiBH,SinkalaM,MbeweF,CantrellRA,KruseG,ChintuN,etal.Single-dosetenofovirandemtricitabineforreductionofviralresistancetonon-nucleosidereversetranscriptaseinhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: anopen-labelrandomisedtrial.Lancet2007;370(9600):1698-705.

122. VanDykeRJG,ShapiroD,etal.A phase II study of the incidence of nevirapine resistance mutations in HIV-infected Thai women receiving a single intrapartum dose of NVP followed by a postpartum tail of ZDV/ddI or ZDV/ddI/LPV/r: IMPAACT P1032. 16thConference onRetrovirusesandOpportunisticInfections;February8-112009;Montreal,Canada.2009.

123. FarrSNJ,Ng’ombeT,etal.Addition of 7 days of zidovudine + lamivudine to peripartum single-dose nevirapine effectively reduces nevirapine resistance at 2 and 6 weeks postpartum in HIV-infected mothers. 16thConferenceonRetrovirusesandOpportunisticInfections;8-11February2009;Montreal,Canada.

124. LallemantMJG,Ngo-Giang-HuongN,etal.Efficacy and safety of 1-month post-partum zidovudine and didanosine to prevent HIV-1 nevirapine resistance mutations following Intrapartum single-dose nevirapine. 16thConferenceonRetrovirusesandOpportunisticInfections;8-11February2009;Montreal,Canada.

125. ArriveE,ChaixML,NerrienetE,BlancheS,RouziouxC,CoffiePA,etal.Toleranceandviralresistanceaftersingle-dosenevirapinewithtenofovirandemtricitabinetopreventverticaltransmissionofHIV-1.AIDS 2009;23(7):825-33.

126. MarraFBrunoR,GalastriSeds.GP120inducesdirectionalmigrationofhumanhepaticstellatecells:alinkbetweenHIVinfectionandliverfibrogenesis.Hepatology 2007.

127. ThioCL,SeabergEC,SkolaskyR(Jr),PhairJ,VisscherB,MunozA,etal.HIV-1,hepatitisBvirus,andriskofliver-relatedmortalityintheMulticenterCohortStudy(MACS).Lancet 2002;360(9349):1921-6.

128. HoffmannCJ,SeabergEC,YoungS,WittMD,D’AcuntoK,PhairJ,etal.HepatitisBandlong-termHIVoutcomesincoinfectedHAARTrecipients.AIDS2009;23(14):1881-9.

129. MatthewsGV,AvihingsanonA,LewinSR,AminJ,RerknimitrR,PetcharapiratP,etal.Arandomized trial of combinationhepatitisB therapy inHIV/HBVcoinfectedantiretroviralnaiveindividualsinThailand. Hepatology2008;48(4):1062-9.

130. MatthewsGV,SeabergE,DoreGJ,BowdenS,LewinSR,SasadeuszJ,etal.CombinationHBV therapy is linked to greater HBV DNA suppression in a cohort of lamivudine-experiencedHIV/HBVcoinfectedindividuals.AIDS2009;23(13):1707-15.

137

131. BaletaA.TrialfindssimultaneousHIV/tuberculosistreatmentbeneficial. Lancet infectious diseases2008;8(11):669.

132. Middelkoop,ed.Can antiretoviral therapy contain a previously escalating TB epidemic in a high HIV prevalemce community.5thIASConferenceonHIVPathogenesis,TreatmentandPrevention;19-22July2009;CapeTown,SouthAfrica.

133. Golub JE, Astemborski J, Ahmed M, Cronin W, Mehta SH, Kirk GD, et al. Long-termeffectivenessofdiagnosingand treating latent tuberculosis infection inacohortofHIV-infectedandat-riskinjectiondrugusers.J Acquir Immune Defic Syndr2008;49(5):532-7.

134. AtunRA,LebcirRM,DrobniewskiF,McKeeM,CokerRJ.HighcoveragewithHAART isrequiredtosubstantiallyreducethenumberofdeathsfromtuberculosis:systemdynamicssimulation.Int J STD AIDS2007;18(4):267-73.

135. AvihingsanonA,ManosuthiW,KantipongP,ChuchotawornC,MoolphateS,SakornjunW,etal.Pharmacokineticsand48-weekefficacyofnevirapine:400mgversus600mgperdayinHIV-tuberculosiscoinfectionreceivingrifampicin.Antivir Ther 2008;13(4):529-36.

136. ChangSY,LinSW,HungCC.Dowestillneedlead-indosingofnevirapineinHIV-infectedpatientswhoarereceivingrifampicin-containingantituberculoustherapy?Clin Infect Dis 2009;49(9):1452-3;authorreply1453-4.

137. CohenK,MeintjesG.Managementof individuals requiringantiretroviral therapyandTBtreatment.Curr Opin HIV AIDS2010;5(1):61-9.

138. BhattEB,JaniIV,CiaffiL,LuggliM,BastosR,SamoGudoP,D.Arakaki,MichonC,CalmyA,BonnetM,and theANRS12146StudyGroup,editor.Preliminary safety results of co-administration of nevirapine (NVP) or efavirenz (EFV), and rifampicin (RMP) in HIV-tuberculosis (TB) co-infected patients in Maputo (Mozambique): CARINEMO-ANRS 12146 Trial.5thIASConferenceonHIVPathogenesisandTreatment;2009.

139. la Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, et al.Pharmacokineticsofadjusted-dose lopinavir-ritonavircombinedwith rifampin inhealthyvolunteers.Antimicrob Agents Chemother2004;48(5):1553-60.

140. NijlandHM,L’HommeRF,RongenGA,vanUdenP,vanCrevelR,BoereeMJ,etal.Highincidenceofadverseeventsinhealthyvolunteersreceivingrifampicinandadjusteddosesoflopinavir/ritonavirtablets.AIDS2008;22(8):931-5.

141. RollaVC,daSilvaVieiraMA,PereiraPintoD,LourencoMC,deJesusCdaS,GoncalvesMorgadoM, et al. Safety, efficacy and pharmacokinetics of ritonavir 400mg/saquinavir400mgtwicedailyplusrifampicincombinedtherapyinHIVpatientswithtuberculosis.Clin Drug Investig2006;26(8):469-79.

142. L’HommeRF,NijlandHM,GrasL,AarnoutseRE,vanCrevelR,BoereeM,etal.Clinicalexperiencewiththecombineduseof lopinavir/ritonavirandrifampicin.AIDS 2009;23(7):863-5.



143. WHO. Prioritizing second-line antiretroviral drugs for adults and adolescents: a public health approach – Report of a WHO working group meeting.Geneva:WHO;2007.

144. DHHSPoAGfAaADoHaHS.GuidelinesfortheuseofantiretroviralagentsinHIV-1-infectedadults and adolescents. 2009: Available from: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

145. Jenny-AvitalER,JosephK.Rifamycin-resistantMycobacteriumtuberculosisinthehighlyactiveantiretroviral therapyera:areportof3relapseswithacquiredrifampinresistancefollowing alternate-day rifabutin and boosted protease inhibitor therapy.Clin Infect Dis 2009;48(10):1471-4.

146. EbraertH,SaluP.ToxicuveitiscausedbypharmacodynamicinteractionsofRifabutinandproteaseinhibitors:acasereport.Bull Soc Belge Ophtalmol 2007;(303):57-60.

147. WHO.Operationalguidefornationaltuberculosiscontrolprogrammesontheintroductionanduseoffixed-dosecombinationdrugs.2002:Availablefrom:http://whqlibdoc.who.int/hq/2002/WHO_CDS_TB_2002.308.pdf.

148. CoutinhoAMJ,EkwaruJ,WereW,RBunnell,KaharuzaFetal.,editor.Utility of routine viral load, CD4 cell count, and clinical monitoring among HIV-infected adults in Uganda: A randomized trial. 15th Conference on Retroviruses and Opportunistic Infections;3-6February2008;Boston,USA.

149. Mugyenyi P WSHJ, Munderi P, Gibb D, Kityo C, et al., eds. Impact of routine laboratory monitoring over 5 years after antiretroviral therapy (ART) initiation on clinical disease progression of HIV-infected African adults: the DART trial final results 2009.5th IASConferenceonHIVPathogenesis,TreatmentandPrevention;19-22July2009;CapeTown,SouthAfrica.

150. Wilson D, Keiluhu AK, Kogrum S, Reid T, Seriratana N, Ford N, et al. HIV-1 viral loadmonitoring:anopportunitytoreinforcetreatmentadherenceinaresource-limitedsettinginThailand.Trans R Soc Trop Med Hyg2009;103(6):601-6.

151. KeiserO,TweyaH,BraitsteinP,DabisF,MacphailP,BoulleA,etal.Mortalityafterfailureofantiretroviraltherapyinsub-SaharanAfrica.Trop Med Int Health2009;15:2,251-258

152. KeiserO,MacPhailP,BoulleA,WoodR,SchechterM,DabisF,etal.AccuracyofWHOCD4cellcountcriteriaforvirological failureofantiretroviral therapy.Trop Med Int Health 2009;14(10):1220-5.

153. Phillips AN, Pillay D, Miners AH, Bennett DE, Gilks CF, Lundgren JD. Outcomes frommonitoringofpatientsonantiretroviraltherapyinresource-limitedsettingswithviralload,CD4 cell count, or clinical observation alone: a computer simulation model. Lancet 2008;371(9622):1443-51.

154. MurriR,LepriAC,CicconiP,PoggioA,ArlottiM,TosittiG,etal.IsmoderateHIVviremiaassociatedwithahigher riskof clinicalprogression inHIV-infectedpeople treatedwithhighlyactiveantiretroviraltherapy:evidencefromtheItaliancohortofantiretroviral-naivepatientsstudy.J Acquir Immune Defic Syndr 2006;41(1):23-30.

139

155. CozziLepriA,PhillipsAN,d’ArminioMonforteA,CastelliF,AntinoriA,deLucaA,etal.When to start highly active antiretroviral therapy in chronically HIV-infected patients:evidencefromtheICONAstudy.AIDS 2001;15(8):983-90.

156. HosseinipourM,vanOosterhoutJ,WeigelR,MzigangiraD,SaukilaN,MhangoB,PhiriR,PhiriS,KumwendaJandtheSAFEST2studyTeam. Validating clinical and immunological definitions of antiretroviral treatment failure in Malawi. 4th IAS Conference on HIVPathogenesis,TreatmentandPrevention;22-25July2009;Sydney,Australia.

157. FoxZ,DragstedUB,GerstoftJ,PhillipsAN,KjaerJ,MathiesenL,etal.Arandomizedtrialto evaluate continuation versus discontinuation of lamivudine in individuals failing alamivudine-containingregimen:theCOLATEtrial.Antivir Ther2006;11(6):761-70.

158. Sproat M, Pozniak AL, Peeters M, Winters B, Hoetelmans R, Graham NM, et al. TheinfluenceoftheM184VmutationinHIV-1reversetranscriptaseonthevirologicaloutcomeof highly active antiretroviral therapy regimens with or without didanosine. Antivir Ther2005;10(2):357-61.

159. MolinaJM,Andrade-VillanuevaJ,EchevarriaJ,ChetchotisakdP,CorralJ,DavidN,etal.Once-dailyatazanavir/ritonavirversustwice-dailylopinavir/ritonavir,eachincombinationwith tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infectedpatients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008;372(9639):646-55.

160. Ortiz R, Dejesus E, Khanlou H, Voronin E, van Lunzen J, Andrade-Villanueva J, et al.Efficacyandsafetyofonce-dailydarunavir/ritonavirversuslopinavir/ritonavirintreatment-naiveHIV-1-infectedpatientsatweek48.AIDS2008;22(12):1389-97.

161. MillsAM,NelsonM,JayaweeraD,RuxrungthamK,CassettiI,GirardPM,etal.Once-dailydarunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-weekanalysis.AIDS2009;23(13):1679-88.

162. PulidoF,EstradaV,BarilJG,LogueK,ScheweK,PlettenbergA,etal.Long-termefficacyand safety of fosamprenavir plus ritonavir versus lopinavir/ritonavir in combinationwithabacavir/lamivudineover144weeks.HIV clinical trials2009;10(2):76-87.

163. SmithKY,WeinbergWG,DejesusE,FischlMA,LiaoQ,RossLL,etal.Fosamprenaviroratazanavironcedailyboostedwithritonavir100mg,plus tenofovir/emtricitabine, for theinitialtreatmentofHIVinfection:48-weekresultsofALERT.AIDS Res Ther2008;5:5.

164. JohnsonM,GrinsztejnB,RodriguezC,Coco J,DeJesusE, LazzarinA, et al. 96-weekcomparisonofonce-dailyatazanavir/ritonavirandtwice-dailylopinavir/ritonavirinpatientswithmultiplevirologicfailures.AIDS2006;20(5):711-8.

165. JLundgrenRP,WormS,etal.Risk of myocardial infarction with exposure to specific ARV from the PI, NNRTI, and NRTI drug classes: The D:A:D Study. 16th Conference onRetrovirusesandOpportunisticInfections;8-11February2009:Montreal,Canada.



166. SLangM-KM,CotteL.Impact of specific NRTI and PI exposure on the risk of myocardial infarction: A case-control study nested within FHDH ANRSC04. 16th Conference onRetrovirusesandOpportunisticInfections;Montreal,Canada.2009.

167. ArribasJR,PulidoF,DelgadoR,LorenzoA,MirallesP,ArranzA,etal.Lopinavir/ritonavirassingle-drug therapy formaintenanceofHIV-1viralsuppression:48-week resultsofarandomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 2005;40(3):280-7.

168. Escobar I, PulidoF,PerezE,Arribas JR,GarciaMP,HernandoA. [Pharmacoeconomicanalysis of amaintenance strategy with lopinavir/ritonavir monotherapy in HIV-infectedpatients].Enferm Infecc Microbiol Clin2006;24(8):490-4.

169. CameronDW,daSilvaBarbaraA,ArribasJoseR,MyersRobertA,BellosNicholaosC,Gilmore N, et al. A 96/Week Comparison of Lopinavir/Ritonavir Combination TherapyFollowed by Lopinavir/Ritonavir Monotherapy versus Efavirenz Combination Therapy. J Infect Dis2008;198(2):234-40.

170. ArribasJ.JG,G.Fatkenheuer,M.Nelson,N.Clumeck,F.Pulidoetal.The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA < 50 copies/mL at baseline. 5th IAS Conference on HIV Pathogenesis,TreatmentandPrevention;CapeTown.2009.

171. CKatlamaVM,Algarte-GeninM,DuvivierC,Lambert-NiclotS,GirardPMetal.Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label non-inferiority trial, MONOI-ANRS 136. 5th IASConferenceonHIVPathogenesis,TreatmentandPrevention;CapeTown.

172. DelfraissyJF,FlandreP,DelaugerreC,GhosnJ,HorbanA,GirardPM,etal. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infectedpatients.AIDS 2008;22(3):385-93.

173. BiermanWF,vanAgtmaelMA,NijhuisM,DannerSA,BoucherCA.HIVmonotherapywithritonavir-boostedproteaseinhibitors:asystematicreview.AIDS2009;23(3):279-91.

174. Elliott JH, Lynen L, Calmy A, De Luca A, Shafer RW, Zolfo M, et al. Rational use ofantiretroviral therapy in low-income and middle-income countries: optimizing regimensequencingandswitching.AIDS2008;22(16):2053-67.

175. Evaluation of three strategies of second-line antiretroviral treatment in Africa (Dakar –Bobo-Dioulasso – Yaoundé) (2LADY) [database on the Internet] 2009. Available from:http://clinicaltrials.gov/ct2/show/NCT00928187?term=2LADY&rank=1.

176. MurphyRSunpathH,NijhawanA,McLellanM,KuritzkesD.Lopinavir/ritonavir (LPV/r) + 2 nucleoside analogues as second-line ART in Protease-inhibitor naïve adults in South Africa: Outcomes and adverse effects. 15th Conference on Retroviruses and OpportunisticInfections;3-6February2008;Boston,USA..

141

177. MHullMooreD,HarrisM,etal.A lamivudine (3TC)-based backbone in conjunction with a boosted protease inhibitor (PI) is sufficient to achieve virologic suppression in the presence of M184V mutations. 49th Interscience Conference on Antimicrobial Agents andChemotherapy;12-15September2009;SanFrancisco,USA.

178. ImazA,delSazSV,RibasMA,CurranA,CaballeroE,FalcoV,etal.Raltegravir,etravirine,and ritonavir-boosted darunavir: a safe and successful rescue regimen for multidrug-resistantHIV-1infection.J Acquir Immune Defic Syndr2009;52(3):382-6.

179. HicksCB,DeJesusE,SloanLM,SensionMG,WohlDA,LiaoQ,etal.Comparisonofonce-daily fos-amprenavirboostedwitheither100or200mgof ritonavir, incombinationwithabacavir/lamivudine: 96-week results from COL100758. AIDS Res Hum Retroviruses 2009;25(4):395-403.

180. ClotetB,BellosN,MolinaJM,CooperD,GoffardJC,LazzarinA,etal.Efficacyandsafetyofdarunavir-ritonaviratweek48intreatment-experiencedpatientswithHIV-1infectioninPOWER1and2:apooledsubgroupanalysisofdatafromtworandomisedtrials.Lancet 2007;369(9568):1169-78.

181. PozniakA,OpravilM,BeattyG,HillA,deBethuneMP,LefebvreE.Effectofbaselineviralsusceptibility on response to darunavir/ritonavir versus control protease inhibitors intreatment-experienced HIV type 1-infected patients: POWER 1 and 2. AIDS Res Hum Retroviruses 2008;24(10):1275-80.

182. RachlisA,ClotetB,Baxter J,MurphyR, LefebvreE.Safety, tolerability, andefficacyofdarunavir(TMC114)withlow-doseritonavirintreatment-experienced,hepatitisBorCco-infectedpatientsinPOWER1and3.HIV clinical trials 2007;8(4):213-20.

183. McKeageK,PerryCM,KeamSJ.Darunavir:areviewofitsuseinthemanagementofHIVinfectioninadults.Drugs2009;69(4):477-503.

184. SteigbigelRT,CooperDA,KumarPN,EronJE,SchechterM,MarkowitzM,etal.Raltegravirwith optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008;359(4):339-54.

185. CooperDA,SteigbigelRT,GatellJM,RockstrohJK,KatlamaC,YeniP,etal.SubgroupandresistanceanalysesofraltegravirforresistantHIV-1infection. N Engl J Med 2008;359(4):355-65.

186. Schiller DS, Youssef-BesslerM. Etravirine: a second-generation nonnucleoside reversetranscriptase inhibitor (NNRTI) active against NNRTI-resistant strains of HIV.Clin Ther 2009;31(4):692-704.

187. YazdanpanahY,FagardC,DescampsD,TaburetAM,ColinC,RoquebertB,etal.Highrateofvirologicsuppressionwithraltegravirplusetravirineanddarunavir/ritonaviramongtreatment-experiencedpatientsinfectedwithmultidrug-resistantHIV:resultsoftheANRS139TRIOtrial.Clin Infect Dis2009;49(9):1441-9.



188. LlibreJM,SantosJR,PuigT,MoltoJ,RuizL,ParedesR,etal.Prevalenceofetravirine-associatedmutations in clinical sampleswith resistance to nevirapine and efavirenz. J Antimicrob Chemother2008;62(5):909-13.

189. PovedaE,AntaL,BlancoJL,Perez-EliasMJ,GarciaF,LealM,etal.EtravirineresistanceassociatedmutationsinHIV-infectedpatientsfailingefavirenzornevirapineintheSpanishantiretroviralresistancedatabase.AIDS2010;;24(3):469–71..

190. GerettiAM.Shiftingparadigms:theresistanceprofileofetravirine.J Antimicrob Chemother 2008;62(4):643-7.

191. SungkanuparphS,ManosuthiW,KiertiburanakulS,PiyavongB,ChantratitaW.Evaluatinghe role of etravirine in the second-line antiretroviral therapy after failing an initial non-nucleoside reverse transcriptase inhibitor-based regimen in a resource-limited setting.Curr HIV Res 2008;6(5):474-6.

192. TibotecTheraputics.DearHealthcareProfessionalletter.August2009;Availablefromhttp://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm180480.htm

193. WHO.Essentialpreventionandcare interventions foradultsandadolescents livingwithHIV in resource-limitedsettings.2008.Available from:http://www.who.int/entity/hiv/pub/prev_care/OMS_EPP_AFF_en.pdf.

194. DiClemente RJ, Wingood GM, Del Rio C, Crosby RA. Prevention interventions for HIVpositiveindividuals.Sex Transm Infect 2002;78(6):393-5.

195. King-SpoonerS.HIVpreventionandthepositivepopulation. Int J STD AIDS1999;10(3):141-50.

196. WHO.PriorityInterventionsHIV/AIDSprevention,treatmentandcareinthehealthsector.2009.

197. KalichmanSC,CainD,KnetchJ,HillJ.Patternsofsexual riskbehaviorchangeamongsexuallytransmittedinfectionclinicpatients. Arch Sex Behav2005;34(3):307-19.

198. MargolinA,AvantsSK,WarburtonLA,HawkinsKA,ShiJ.Arandomizedclinicaltrialofamanual-guided risk reduction intervention for HIV-positive injection drug users. Health Psychol2003;22(2):223-8.

199. SterkCE, Theall KP, ElifsonKW,KidderD.HIV risk reduction amongAfrican-Americanwomenwhoinjectdrugs:arandomizedcontrolledtrial.AIDS Behav2003;7(1):73-86.

200. WHO. Intensified case finding (ICF), isoniazid preventive therapy (IPT) and TB infection control (IC) for people living with HIV.ReportofaJointWorldHealthOrganization,HIV/AIDSandTBDepartmentmeeting.Geneva:2008.

143

201. Walker AS, Ford D, Gilks CF, Munderi P, Ssali F, Reid A, et al. Daily co-trimoxazoleprophylaxis in severely immunosuppressed HIV-infected adults in Africa started oncombinationantiretroviraltherapy:anobservationalanalysisoftheDARTcohort.Lancet 2010;375(9722):1278-86.

202. Mitchell SK, Kelly KJ, Potgieter FE, Moon MW. Assessing social preparedness forantiretroviraltherapyinageneralizedAIDSepidemic:adiffusionofinnovationsapproach.AIDS Behav 2009;13(1):76-84.

203. Orrell C. Antiretroviral adherence in a resource-poor setting. Curr HIV/AIDS Rep 2005;2(4):171-6.

204. SodergardB,HoferS,HalvarssonM,SonnerborgA,TullyMP,LindbladAK.Astructuralequationmodelingapproachtotheconceptsofadherenceandreadinessinantiretroviraltreatment. Patient Educ Couns2007;67(1-2):108-16.

205. Tabarsi P, Saber-Tehrani AS, Baghaei P, Padyab M, Mansouri D, Amiri M, et al. Earlyinitiation of antiretroviral therapy results in decreased morbidity and mortality amongpatientswithTBandHIV.J Int AIDS Soc2009;12(1):14.

206. ZolopaA,AndersenJ,PowderlyW,SanchezA,SanneI,SuckowC,etal.EarlyantiretroviraltherapyreducesAIDSprogression/deathinindividualswithacuteopportunisticinfections:amulticenterrandomizedstrategytrial. PLoS ONE2009;4(5):e5575.

207. LawnSD,HarriesAD,WoodR.Strategiestoreduceearlymorbidityandmortalityinadultsreceiving antiretroviral therapy in resource-limited settings. Curr Opin HIV AIDS 2010;5(1):18-26.

208. WHO. Towards universal access. Scaling up priority HIV/AIDS interventions in the health sector.2009ProgressReport.2009.

209. GrayRH,WawerMJ,BrookmeyerR,SewankamboNK,SerwaddaD,Wabwire-MangenF,etal.ProbabilityofHIV-1transmissionpercoitalactinmonogamous,heterosexual,HIV-1-discordantcouplesinRakai,Uganda. Lancet2001;357(9263):1149-53.

210. PaoD,PillayD,FisherM.Potentialimpactofearlyantiretroviraltherapyontransmission.Curr Opin HIV AIDS 2009;4(3):215-21.

211. DARTTrialTeam.RoutineversusclinicallydrivenlaboratorymonitoringofHIVantiretroviraltherapyinAfrica(DART):arandomisednon-inferioritytrial. Lancet 2010;375(9709):123-31.

212. BraitsteinP,BrinkhofMW,DabisF,SchechterM,BoulleA,MiottiP,etal.MortalityofHIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-incomeandhigh-incomecountries.Lancet 2006;367(9513):817-24.

213. Effectiveness ofHIV viral loadmonitoring of patient outcome in resource-poor settings[database on the Internet]2009 [cited Februrary 28, 2010]. Available from: http://clinicaltrials.gov/ct2/show/NCT00929604?term=Saag&cntry1=AF:ZM&rank=1.



214. MonitoringhighlyactiveantiretroviraltherapyinHIV-infectedparentsinThailand[databaseon the Internet]2009LastUpdated:September14 [citedFrebbrury18,2010].Availablefrom: http://clinicaltrials.gov/ct2/show/NCT00162682?term=Lallemant&cntry1=SE:TH&rank=4.

215. Antiretroviral treatment simplified follow-up management assessment (ANRS 12110STRATALL)[databaseontheInternet]2008Lastupdated:April16,2008.Availablefrom:http://clinicaltrials.gov/ct2/show/NCT00301561?term=Laurent&cntry1=AF:CM&rank=1.

216. GoicoecheaM,LiuS,BestB,SunS,JainS,KemperC,etal.Greatertenofovir-associatedrenal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptaseinhibitor-basedtherapy. J Infect Dis 2008;197(1):102-8.

217. MohsenAH,EasterbrookPJ,TaylorC,PortmannB,KulasegaramR,MuradS,etal.Impactof human immunodeficiency virus (HIV) infection on the progression of liver fibrosis inhepatitisCvirusinfectedpatients.Gut2003;52(7):1035-40.

218. SmitC,vandenBergC,GeskusR,BerkhoutB,CoutinhoR,PrinsM.Riskofhepatitis-relatedmortalityincreasedamonghepatitisCvirus/HIV-coinfecteddruguserscomparedwithdrugusersinfectedonlywithhepatitisCvirus:a20-yearprospectivestudy.J Acquir Immune Defic Syndr2008;47(2):221-5.

219. BenhamouY,BochetM,DiMartinoV,CharlotteF,AzriaF,CoutellierA,etal.Liverfibrosisprogression inhuman immunodeficiencyvirusandhepatitisCviruscoinfectedpatients.TheMultivircGroup.Hepatology1999;30(4):1054-8.

220. ChenTY,DingEL,Seage IiiGR,KimAY.Meta-analysis: increasedmortalityassociatedwithhepatitisCinHIV-infectedpersonsisunrelatedtoHIVdiseaseprogression.Clin Infect Dis2009;49(10):1605-15.

221. MocroftA,RockstrohJ,SorianoV,LedergerberB,KirkO,VinogradovaE,etal.Arespecificantiretrovirals associated with an increased risk of discontinuation due to toxicities orpatient/physician choice in patients with hepatitis C virus coinfection? Antivir Ther 2005;10(7):779-90.

222. Roche.Copegus (ribavirin, USP) prescibing information.2010.

223. Bani-SadrF,DenoeudL,MorandP,Lunel-FabianiF,PolS,CacoubP,etal.Earlyvirologicfailure in HIV-coinfected hepatitis C patients treated with the peginterferon-ribavirincombination:doesabacavirplayarole?J Acquir Immune Defic Syndr2007;45(1):123-5.

224. Rodriguez-TorresM,TorrianiFJ,SorianoV,BoruckiMJ,LissenE,SulkowskiM,etal.Effectof ribavirin on intracellular and plasma pharmacokinetics of nucleoside reversetranscriptase inhibitors inpatientswithhuman immunodeficiency virus-hepatitisCviruscoinfection: results of a randomized clinical study. Antimicrob Agents Chemother 2005;49(10):3997-4008.

145

225. MiraJA,Lopez-CortesLF,BarreiroP,TuralC,Torres-TortosaM,deLosSantosGil I,etal.EfficacyofpegylatedinterferonplusribavirintreatmentinHIV/hepatitisCvirusco-infectedpatientsreceivingabacavirpluslamivudineortenofovirpluseitherlamivudineoremtricitabineasnucleosideanaloguebackbone.J Antimicrob Chemother2008;62(6):1365-73.

226. MontesRamírez MLRodríguezZapataM.Reportof threecasesofhyperlactacidemiae/lacticacidosisaftertreatmentofhepatitisCwithpegylatedinterferonandribavirininHIVcoinfectedpatientsRev Clin Esp2002;202:543-5.

227. CarratF,Bani-SadrF,PolS,RosenthalE, Lunel-FabianiF,BenzekriA, et al.Pegylatedinterferonalfa-2bvsstandard interferonalfa-2b,plus ribavirin, forchronichepatitisC inHIV-infectedpatients:arandomizedcontrolledtrial.JAMA 2004;292(23):2839-48.

228. Laguno M, Murillas J, Blanco JL, Martinez E, Miquel R, Sanchez-Tapias JM, et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin fortreatmentofHIV/HCVco-infectedpatients.AIDS2004;18(13):F27-36.

229. TorrianiFJ,Rodriguez-TorresM,RockstrohJK,LissenE,Gonzalez-GarciaJ,LazzarinA,etal.PeginterferonAlfa-2aplusribavirinforchronichepatitisCvirusinfectioninHIV-infectedpatients.N Engl J Med2004;351(5):438-50.

230. ChungRT,AndersenJ,VolberdingP,RobbinsGK,LiuT,ShermanKE,etal.PeginterferonAlfa-2aplusribavirinversusinterferonalfa-2aplusribavirinforchronichepatitisCinHIV-coinfectedpersons.N Engl J Med2004;351(5):451-9.

231. LagunoM,CifuentesC,MurillasJ,VelosoS,LarrousseM,PayerasA,etal.Randomizedtrialcomparingpegylatedinterferonalpha-2bversuspegylatedinterferonalpha-2a,bothplus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients.Hepatology 2009;49(1):22-31.

WHO Library Cataloguing-in-Publication Data

A guide for adaptation and implementation: revised principles and recommendations: ART for HIV infection in adults and adolescents: recommendations for a public health approach.

1.Anti-retroviral agents - therapeutic use. 2.Anti-retroviral agents - pharmacology. 3.HIV infections - drug therapy. 4.Adult 5.Adolescent. 6.Guidelines. 7.Developing countries. I.World Health Organization.

ISBN 978 92 4 159976 4 (NLM classification: WC 503.2)

© World Health Organization 2010

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Strengthening health services to fight HIV/AIDS

HIV/AIDS ProgrammeFor more information, contact:

World Health Organization Department of HIV/AIDS

20, avenue Appia 1211 Geneva 27 Switzerland

E-mail: [email protected]

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ISBN 978 92 4 159976 4

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