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Transcript of Anti Retro Viral Therapy
AntiretrovirAl therApy for hiv infection in Adults
And Adolescents
Recommendations for a public health approach
2010 revision
Antir
etro
vira
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rapy
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HIV
infe
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n in
adu
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and
adol
esce
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Rec
omm
enda
tions
for
a pu
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lth
appr
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201
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visi
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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
All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]).
The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.
Printed in Austria
AntiretrovirAl therApy for hiv infection in Adults
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
recommendAtions for A public heAlth ApproAch
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
6AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
8AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
10AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
12AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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.
14AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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.
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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
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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
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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
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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.
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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.
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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).
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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)
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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-
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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)
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14.1. Recommendations
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
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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.
14.4. Benefits and risks
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.
14.5. Acceptability and feasibility
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;
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• 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.
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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.
Risk, benefits and acceptability
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
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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)
Risk, benefits and acceptability
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
Risk, benefits and acceptability
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)
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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.
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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.
(Strong recommendation, moderate quality of evidence)
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
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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
InitiateanNNRTIregimen
Ifpossible,checkviralload3at6monthsandif>5000copies/ml,switchtosecond-lineARTwithPI
Option A4
AntepartumAZT(fromasearlyas14weeksofgestation)
sdNVPatonsetoflabour*
AZT+3TCduringlabouranddelivery*
AZT+3TCtailfor7dayspostpartum*
*sd-NVPandAZT+3TCcanbeomittedifmotherreceives>4weeksofAZTantepartum
InitiateanNNRTIregimen
Ifpossible,checkviralload3at6monthsandif>5000copies/ml,switchtosecond-lineARTwithPI
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.
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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.
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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.
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16.1. Recommendations
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.
16.3. Summary of findings
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.
16.4. Benefits and risks
Benefits
Moreaccurateassessmentoftreatmentfailurewillreducethedelayinswitchingtosecond-linedrugs.TargeteduseofVLcanlimitunnecessaryswitchingandroutineuseofVLcanreducetheriskofresistance.Whileexpensive,VLhasthepotentialtosavethecostofexpensivesecond-linedrugsbyconfirmingthattheyareneeded.
Risks
TheoptimumthresholdfordefiningVLfailureinapublichealthapproachisstillunknown,andtherearelimiteddataonthediagnosticaccuracyofVLinresource-limitedsettings.ThereisariskthatresourcesusedtoexpandlaboratorycapacityorconductVLtestingwoulddivertfundsawayfromexpandingaccesstotreatment.
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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.
16.5. Clinical considerations
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
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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
17.1. Recommendations
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.
(Strong recommendation, moderate quality of evidence)
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.
17.3. Summary of findings
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
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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.
17.4. Benefits and risks
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).
17.5. Acceptability and feasibility
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.
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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
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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)
57
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)
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18.1. Recommendations
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.
18.3. Summary of findings
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)
18.4. Benefits and risks
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.
18.5. Acceptability and feasibility
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.
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18.6. Clinical considerations
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
Possibleincreasedbleedingepisodesinpatientswithhaemophilia
Raltegravir (RAL)
Nausea
Headache
Diarrhoea
Pyrexia
CPKelevation
Etravirine (ETV)
Rash(2%discontinuationbecauseofrashduringclinicaltrials)
Hypersensitivityreactionshavebeenreported,characterizedbyrash,constitutionalfindings,andsometimesorgandysfunction,includinghepaticfailure
Nausea
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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
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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.
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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
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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.
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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
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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
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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
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ARV drug Common associated toxicity Suggested substitute
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
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ARV drug Common associated toxicity Suggested substitute
LPV/r
GIintolerance,nausea,vomiting,diarrhoea
Asthenia
Hyperlipidaemia(especiallyhypertriglyceridaemia)
Elevatedserumtransaminases
Hyperglycaemia
Fatmaldistribution
Possibleincreasedbleedingepisodesinpatientswithhaemophilia
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.
72AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
74AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Clinical event Clinical diagnosis Definitive diagnosis
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
Clinical event Clinical diagnosis Definitive diagnosis
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
76AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Clinical event Clinical diagnosis Definitive diagnosis
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
Clinical event Clinical diagnosis Definitive diagnosis
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)
78AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Clinical event Clinical diagnosis Definitive diagnosis
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
Clinical event Clinical diagnosis Definitive diagnosis
Disseminatednon-tuberculousmycobacteriainfection
Nopresumptiveclinicaldiagnosis
Diagnosedbyfindingatypicalmycobacterialspeciesfromstool,blood,bodyfluidorotherbodytissue,excludinglung
Progressivemultifocalleukoencephalopathy(PML)
Nopresumptiveclinicaldiagnosis
Progressiveneurologicaldisorder(cognitivedysfunction,gait/speechdisorder,visualloss,limbweaknessandcranialnervepalsies)togetherwithhypodensewhitematterlesionsonneuroimagingorpositivepolyomavirusJC(JCV)PCRonCSF
Cryptosporidiosis(withdiarrhoealastingmorethan1month)
Nopresumptiveclinicaldiagnosis
CystsidentifiedonmodifiedZNmicroscopicexaminationofunformedstool
Chronicisosporiasis Nopresumptiveclinicaldiagnosis IdentificationofIsospora
Disseminatedmycosis(coccidiomycosis,histoplasmosis)
Nopresumptiveclinicaldiagnosis
Histology,antigendetectionorculturefromclinicalspecimenorbloodculture
Recurrentsepticemia(includingnon-typhoidsalmonella)
Nopresumptiveclinicaldiagnosis Bloodculture
Lymphoma(cerebralorBcellnon-Hodgkin)orothersolidHIV-associatedtumours
Nopresumptiveclinicaldiagnosis
Histologyofrelevantspecimenor,forCNStumours,neuroimagingtechniques
Invasivecervicalcarcinoma
Nopresumptiveclinicaldiagnosis Histologyorcytology
80AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Clinical event Clinical diagnosis Definitive diagnosis
Atypicaldisseminatedleishmaniasis
Nopresumptiveclinicaldiagnosis
Histology(amastigotesvisualized)orculturefromanyappropriateclinicalspecimen
HIV-associatednephropathy
Nopresumptiveclinicaldiagnosis Renalbiopsy
HIV-associatedcardiomyopathy
Nopresumptiveclinicaldiagnosis
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*
82AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
84AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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.
86AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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).
88AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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.
90AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
imprecisionReporting
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
imprecisionReporting
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.
92AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
limitations1Noserious
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
limitations1Noserious
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
limitations1Noserious
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
limitations1Noserious
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
94AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
limitations1Noserious
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
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combinationantiretroviraltherapies.A
IDS2007;21:1579-89.9.deBeaudrapP,EtardJF,GuèyeFN,GuèyeM,LandmanR,GirardPM,
SowPS,NdoyeI,DelaporteE;ANRS1215/1290StudyGroup.Long-termefficacyandtoleranceofefavirenz-andnevirapine-containing
regimensinadultHIVtype1Senegalesepatients.A
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rm T
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inCambodia.A
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IV M
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M
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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.
98AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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.
2 Numberofevents<300and/orconfidenceintervalsincludepotentialharmandbenefit.
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.
100AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Au
tho
rs:
GeorgeRutherford,AlicenSpaulding
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
limitations5Noserious
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
limitations2Noserious
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
limitations2Noserious
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.
102AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Au
tho
rs:
GeorgeRutherford,AlicenSpaulding
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
limitations1Noserious
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:
GeorgeRutherford,AlicenSpaulding
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.
104AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
l imitations2Noserious
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
limitations2Noserious
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
l imitations2Noserious
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
limitations2Noserious
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
limitations2Noserious
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
l imitations2Noserious
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.
4 Numberofevents<300and/orconfidenceintervalsincludepotentialharmandbenefit.
5 7of9studieswereindustry-funded,althoughsomewerefundedsimultaneouslybycompetitors.
6 Only1study(Kumaretal)reportedondrugresistance,suggestingselectivereporting.
106AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Au
tho
rs:
GeorgeRutherford,AlicenSpaulding
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
1 Numberofevents<300and/orconfidenceintervalsincludepotentialharmandbenefit.
2 1of5observationalstudieswereindustry-funded,althoughsomewerefundedsimultaneouslybycompetitors.
3 And1observationalstudy(Laurentetal)reportedondrugresistance,suggestingselectivereporting.
108AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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.
110AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Au
tho
rs:
LarryWilliamChang,JamalHarris
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.
4 Abstractsonly,nopeer-reviewedprintpublicationsofthesedataareavailable;however,asasignificantamountofdatawasavailablefromabstracts/
conferencepresentationsnodowngradingoccurred.
5 Numberwitheventnotreported.
6 Inclinicalarm7.57events/100patients-year,invirological+immunological+clinicalarm4.80events/100patients-year.
112AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Au
tho
rs:
LarryWilliamChang,JamalHarris
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.
4 Abstractsonly,nopeer-reviewedprintpublicationsofthesedataareavailable;however,asasignificantamountofdatawasavailablefromabstracts/
conferencepresentationsnodowngradingoccurred.
5 Numberwitheventnotreported.
6 Inclinical+immunologicalarm5.97events/100patients-year,invirological+immunological+clinicalarm4.80events/100patients-year.
7Totalnumberofeventsisverysmall.
114AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
Au
tho
rs:
LarryWilliamChang,JamalHarris
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.
5 Numberwitheventnotreported.
6 ProgrammeswithvirologicalmonitoringCD4cellcountattimeofswitchingwas161cells/µlcomparedto102cells/µlinthosewithout(p=0.001).
116AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
limitations3Noserious
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
l imitations2Noserious
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).
118AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
limitations1Noserious
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
limitations1Noserious
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
limitations1Noserious
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
limitations1Noserious
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
l imitations1Noserious
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.
120AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
limitations1Noserious
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
l imitations1Noserious
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
limitations1Noserious
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
limitations1Noserious
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.
122AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
limitations1Noserious
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
limitations1Noserious
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
l imitations1Noserious
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
limitations1Noserious
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
limitations1Noserious
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.
124AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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
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
Fo
sam
pre
-n
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
med
ian
48
wee
ks)
1Random-
izedtrials
Noserious
limitations1Noserious
inconsis-
tency
Serious2
Serious3
None
4/443
(0.9%)
1/444
(0.2%)
RR4.01
(0.45 to
35.73)
7more per
1000(from
1fewerto
78more)
⊕⊕
OO
LOW
CRITICAL
Sev
ere
adve
rse
even
ts (
follo
w-u
p m
edia
n 4
8 w
eeks
; ad
vers
e ev
ents
lead
ing
to
dis
con
tin
uat
ion)
1Random-
izedtrials
Serious1
Noserious
inconsis-
tency
Serious2
Serious3
None
53/436
(12.2%)
43/443
(9.7%)
RR1.25
(0.86to
1.83)
24more
per1000
(from14
fewerto81
more)
⊕O
OO
VERYLOW
CRITICAL
Clin
ical
dis
ease
pro
gre
ssio
n o
r d
eath
(fo
llow
-up
med
ian
48
wee
ks)
1Random-
izedtrials
No serious
limitations1Noserious
inconsis-
tency
Serious2
Serious3
None
11/443
(2.5%)
11/444
(2.5%)
RR1(0.44
to2.29)
0fewerper
1000(from
14fewerto
32more)
⊕⊕
OO
LOW
CRITICAL
Ad
her
ence
/to
lera
bili
ty/r
eten
tio
n (
follo
w-u
p m
edia
n 4
8 w
eeks
; ad
her
ence
by
pill
co
un
ts r
epo
rted
as
med
ian
per
cen
tag
e)
1Random-
izedtrials
Serious1
Noserious
inconsis-
tency
Serious2
Noserious
imprecision
None
427/443
(96.4%)
435/444
(98%)
RR0.98
(0.96to
1.01)
20fewer
per1000
(from39
fewerto10
more)
⊕⊕
OO
LOW
CRITICAL
125
Imm
un
olo
gic
al r
esp
on
se (
follo
w-u
p m
edia
n 4
8 w
eeks
; m
easu
red
wit
h:
med
ian
incr
ease
in C
D4
cou
nt
fro
m b
asel
ine;
bet
ter
ind
icat
ed b
y h
igh
er v
alu
es)
1Random-
izedt rials
Noserious
l imitations1Noserious
inconsis-
tency
Serious2
Noserious
imprecision
None
443
444
-Not
estimable4
⊕⊕
⊕O
MODER-
ATE
IMPORTANT
Vir
olo
gic
al r
esp
on
se, p
rop
ort
ion
<5
0 co
pie
s/m
l (fo
llow
-up
med
ian
48
wee
ks)
1Random-
izedt rials
Noserious
l imitations1Noserious
inconsis-
tency
Serious2
Noserious
imprecision
None
285/443
(64.3%)
288/444
(64.9%)
RR0.99
(0.9to1.09)
6 fewerper
1000(from
6 5f ewert o
58more)
⊕⊕
⊕O
MODER-
ATE
IMPORTANT
Dru
g r
esis
tan
ce (
follo
w-u
p m
edia
n 4
8 w
eeks
), r
epo
rted
as
acq
uir
ed m
ajo
r P
I mu
tati
on
s
1Random-
izedt rials
Noserious
l imitations1Noserious
inconsis-
tency
Serious2
Serious3
None
0/443 (0%)0/444 (0%)-
Not
estimable5
⊕⊕
OO
LOW
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.
126AntiretrovirAl therApy for hiv infection in Adults And Adolescents
recommendAtions for A public heAlth ApproAch
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4. EmeryS,NeuhausJA,PhillipsAN,BabikerA,CohenCJ,GatellJM,etal.Majorclinicaloutcomesinantiretroviraltherapy(ART)-naiveparticipantsandinthosenotreceivingARTatbaselineintheSMARTstudy.J Infect Dis2008;197(8):1133-44.
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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)
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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