HIV Treatment Bulletin (HTB) September/October 2009€¦ · HIV treatment bulletin C O N T E N T S...

November/December 2009

ISSN 1472-4863 h-tb

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Volume 10 Number 11/12

HIV treatment bulletin

C O N T E N T S

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EDITORIAL 2CORRECTION 2CONFERENCE REPORTS 212th European AIDS Society Conference (EACS), 11-14 November 2009, Cologne• Introduction• EACSreleasesthreeupdatedmanagementguidelinesCONFERENCE REPORTS 411thInternationalWorkshoponAdverseDrugReactionsandCo-morbiditiesinHIV(IWADRH),26-28October2009,Philadelphia• IntermusculartissueisdecreasedinHIVinfection• HighincidenceandriskfactorsfordiabetesinFrenchcohort• Genderandracedifferencesinlipodystrophysymptoms• LipodystrophyiscommoninchildrenfromthreeEuropean

cohorts• Visceral adipose tissue returns to baseline after stopping

therapeuticrHGH• ReducedlevelsofvitaminDinpatientstakingefavirenz• Association between inflammation and sleep apnea in the

MACS cohort• SportssupplementsimpactonserumcreatinineandeGFR

markersofrenalfunctionCONFERENCEREPORTS 89thAIDSVaccineConference,19-22October2009,Paris• Introduction• ThaiHIVVaccineTrialresultspresentedandpublishedCONFERENCE REPORTS 1049th International Conference on Antimicrobial Agents andChemotherapy(ICAAC),12-15September2009,SanFrancisco• Introduction• Smokingmasks the long-termbenefits ofHAARTon lung

function• Recent ARVs and the blood/brain barrier: CSF drug

concentrationsofdarunavir/randraltegravir

• Alcoholandmarijuanamayreducedruglevelsofatazanavirandefavirenz

• Raltegravirbodycompositionstudy:48-weekDEXAresultsCONFERENCEREPORTS 165thIASConferenceonHIVPathogenesis,TreatmentandPrevention,19-23July2009,CapeTown• Introduction• OverviewofpaediatricstudiesTREATMENT ACCESS 23• FDAapprovalofgenericARVs• AIDSandmortalityinSouthAfrica• PunishingsuccessintacklingAIDS:funders’retreatcouldwipe

outhealthgainsinHIVaffectedcountriesANTIRETROVIRALS 25• TibotecissuesDearDoctorletterinEuropeconcerningsevere

etravirinereactions:threecasereports• GSKandPfizerlaunchjointHIVcollaborationDRUGRESISTANCE 26• RateofaccumulationofTAMSslowinpatientscontinuingon

failingAZTord4TcontainingregimensDRUGINTERACTIONS 28• Reducedetravirinelevelsafterdirectswitchfromefavirenz• Gemfibrozilsignificantlyreducedbylopinavir/rBASIC SCIENCE 29• Aging,HIVinfectionandtheimmunesystem• Newneutralisingantibodiesdiscovered• TheendofthelineforIL-2PAEDIATRIC CARE 32• HIV,thebrainandchildrenOTHERNEWS 34• PresidentObamaannouncesendtoHIV-positiveimmigration

ban in the USONTHEWEB 34FUTUREMEETINGS 36PUBLICATIONSANDSERVICESFROMi-BASE 37DONATION FORM 42ORDER FORM 43

HIVi-Base publication

Vol10No11/12November/December 2009HIV Treatment Bulletin (e)

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EDITORIAL

WelcometotheNovember/DecemberissueofHTBthatincludesselectedreportsfromfiveconferences.

Ofinterest,threeoftheseconferencereportsincludestudieslookingatlipohypertrophy.

AlthoughthesideeffectprofileofARVshasdramaticallyimprovedsince1996,includingabetterunderstandingofhowtomanageandavoidmanyofthesymptomsoflipodystrophy,littleprogresshasbeenmadeonfataccumulation.

Noclassofdrugs,orindividualdrug,hasbeenclearedfromthisassociation,andrecentstudiesfailtoshowanycorrelationwithplasma lipids.Forexample,even drugswitha relativelybenign,oreven favourable, lipidprofile (nevirapine,atazanavirandraltegravir)havenotshowndifferencesinfataccumulationcomparedtostandardofcarecontrolgroups.

Geneticsarelikelytoexplainmanyinterpatientdifferencesbutthishasnotsofarresultedinsceeningtests.Wereportdifferencesby raceandgender fromaCanadianstudy thatwaspresentedat theLipodystrophyWorkshop,and thissupportspreviouslyannectodalexperiencethatlipohypertrophymayoccurmorefrequentlyinAfricanwomen.

Managementoptionsarealso limited.Reductions inVATfromtreatmentwitheither rHGHor tesamorlin (neitherofwhicharecurrentlylicensedinEuropeforthisindication)bothreturntobaselineifeitherinterventionisstopped.

Amultifocusapproachcanbecurrentlyrecommended:anddiet,exercise,treatmentswitchingandperhapsatherapeuticintervention,allbeingneededtoattempttoshifttheunderlyingmechanismresponsible-anditisdisappointingwhenresearchlooksatsingleinterventionsinisolation.

Also in this issue,RichardJeffreys fromTAGprovidesanexcellentanalysisof thecontroversial results fromtheRV144ThaiVaccineTrial-areportfromthe9thAIDSVaccineConference.Jeffreyshasprovidedaconsistentvoiceofreasonasthetrialdatawasreleasedamidamaelstromofconflictingpressandmediacoverage.

Otherarticlesinclude,druginteractionstudiespresentedatICAACfromtheHIVDrugInteractionsgroupinLiverpoolandanoverviewofpaediatricstudiesconductedintheSouthconcludesourreportsfromIAS2009.

AsthisisthelastHTBoftheyearwewouldalsoliketotaketheopportunitytothankourmedicalboardandotheradvisorsfortheirinvaluablecommentsandfeedback.

Andtoourreaders,wewouldliketowishyouallaHappyNewYear!

CORRECTION

HTBSep/Oct2009:LowviralloadsinelitecontrollersThearticlethatweincludedinthelastissueofHTBerroneouslystatedthatthecorrelationbetweenviralloadandneutralisingantibodyresponseswasinverse(thereisasectionheadinginthepaperthatmistakenlycitesthecorrelationasinverseinsteadofpositive).Thishassincebeencorrectedonboththeoriginalsourcewebsiteandthei-Basereprint.

CONFERENCE REPORTS

12th European AIDS Society Conference (EACS)

11-14 November 2009, Cologne

IntroductionThisissueofHTBwenttopressjustafterthe12thECASconferenceanddetailedreportsfromthismeetingwillbeincludedinournextissue.

Asastoppressweonlyincludeonearticle:

• EACSreleasesthreeupdatedmanagementguidelines

Although the abstracts from the meeting are not currently available online, this year a comprehensive programme of lectures and sessions are duetobecomeavailableaswebcasts:

http://www.multiwebcast.com/eacs/2009/12th



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EACSreleasesthreeupdatedmanagementguidelines

SimonCollins,HIVi-BaseTheEuropeanAIDSClinicalSocietypublishesthreemanagementguidelinesthatmakeextensiveuseofsummaries,bulletpointlistandsupportivetablestoproduceresourcesthatareeasytofollowresources.Thethreemainupdates(version5)werelaunchedatthisyear’sconference.

PDFversionsarenowavailabletodownloadfromthesocietieswebsite.AdditionaltablesnotincludedinthePDFandprintedbookletsarealsoavailableonline.

http://www.europeanaidsclinicalsociety.org/

Themainchangestoeachguidelineareoutlinedbelow.

ARVguidelines• Achecklistforinitialandroutineclinicmanagementandanewflowchartforassessingandsupportingapatientsreadinessto

startARVtreatment.Thisincludestheimportanceofaskingaboutdepressionandmentalhealth,andalcoholandrecreationaldruguse.

• Inprimaryinfection,althoughaCD4count<350threemonthsafterinfectionisincludedasacriteriatostarttreatment,theguidelinesrecognisethatmostpatientsarelikelytowaitatleastuntilsixmonths.

• TreatmentisrecommendedforanypatientwithaCD4count<350,andatbetween350-500inpatientsolderthan50years,coinfectionwithHCV,HBVorotherlistedhealthcomplications.

• AnewsectionfocusesonHIVandTBcoinfection.

• Switchingdrugsfortoxicityisoverlycautiousforanyoneotherthannaivepatients,perhapsunderestimatingtheimportanceoftolerabilitywhenmodifyingtreatmenthoweverpre-treatmentsomeonemaybe.

• PEPisrecommendedideallywithin4hoursofexposure,andnotlaterthan48hours.SurprisinglythereisnoreferencetoviralloadoftheHIV-positivepartnerasafactorinassessingrisk.

Preventionandmanagementofnon-infectiouscomorbiditiesThis management guideline has expanded considerably, now addressing many of the comorbidities associated with an older HIV cohort, especially cardiovascular, renal, hepatic, metabolic, neoplastic, done and mental health complications. Recommendations are not graded based on the quality of evidence.

• Screeningsectionshavebeenexpandedforrenal,bone,neurocognitivedisorders,depressionandcancer.

• Lipidmanagementiscoveredinaseparatetable,whichnotablydoesnotincludetriglyceridemanagementduetolessevidencesuggestingelevatedTGasanindependentriskfactorforclinicalcomplications.

• BonescreeningrefersdoctorstotheFRAXcalculator(www.shef.ac.uk).

• KidneyscreeningincludeseGFRatbaselineandanewrecommendationtoincludedipsticktesting.

• Manyadditionaltablesareavailableaswebresources(ieforneurocognitivescreening,lipoatrophytreatmentsetc).

HepatitiscoinfectionThe main changes in the hepatitis coinfection guidelines include:

• TostartappropriateARVswhenCD4countis<500c/mm3inpeoplewhoneedHBVtreatment.

• ThatthisislikelytobelifelongunlessthepatientisHBVeAg+whomayclearHBVandthattreatmentcouldbecautiouslystoppedsixmonthsafterconversiontoeAg–.

• NewinformationonhepatitisD(HDV)whichincreasetheriskoffibrosisprogressioninHBVinfection.

• ThatpeoplewithCD4count<350shouldprobablystartARVspriortoHCVtreatmenttoincreasethechanceofsuccess(SVR).

• EarlyHCVtreatmentisrecommendedforHIV-positivepeopleidentifiedinacuteHCVinfection.

• Nonresponders(<2logHCVRNAdropatweek12)shouldstoptreatmenttowaitfornewoptions.

• Peoplewhorelapsecanconsiderretreatingwithlongerduration.

• ThatHIVisnolongeracontraindictationforlivertransplantandthattimelyreferraltotransplantlistsisthereforeimportant.



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CONFERENCE REPORTS

11thInternationalWorkshoponAdverseDrugReactionsandCo-morbiditiesinHIV(IWADR)

26-28October2009,Philadelphia

IntroductionThenewlynamed11thInternationalWorkshoponAdverseDrugReactionsandCo-morbiditiesinHIVwasheldthisyearfrom26–28October2009inPhiladelphia.Theworkshophasexpandeditsearlierfocusonlipodystrophytoincludecoinfection,particularlyhepatitisandage-relatedmorbiditiesincludingbone,cardiovascular,oncologyandneurocognitivecomplications.

Theformatfortheworkshopcontinuestoprovideafocusedforumfortherangeofmetaboliccomplicationsbutalsorecognisesthatthesesymptomsarebecomingmoredifficulttoviewinisolation.

Reportsformthemeetingthisyearinclude:

• IntermusculartissueisdecreasedinHIVinfection

• HighincidenceandriskfactorsfordiabetesinFrenchcohort

• Genderandracedifferencesinlipodystrophysymptoms

• LipodystrophyiscommoninchildrenfromthreeEuropeancohorts

• VisceraladiposetissuereturnstobaselineafterstoppingtherapeuticrHGH

• ReducedlevelsofvitaminDinpatientstakingefavirenz

• AssociationbetweeninflammationandsleepapneaintheMACScohort

• SportssupplementsimpactonserumcreatinineandeGFRmarkersofrenalfunction

Webcastsfromthemeetingareduetobepostedtotheconferencewebsiteshortly.

https://lipo09.events-register.com/lipodystrophy/

IntermusculartissueisdecreasedinHIVinfection

SimonCollins,HIVi-BaseThefirststudyinthemainconferencelookedataintermuscularadiposetissue(IMAT)-thedistributionoffatthatisbeneaththemusclefaciaandmuscletissue–asanewparameterofmetabolicdisturbances.LedbyCarlGrunfeldwiththeFRAMstudy,thisgrouphasprovidedimportantinsightintotheassociationofHIVtometabolicchangesbyusingfullbodyMRItoidentifychangesandincludinganHIV-negativecontrolgroup.ResultsfromthestudyconcludedthatfatlossandfatgainareseparateunrelateddysfunctionsandthatfatlossratherthanfataccumulationisthedrivingmechanismbehindHIV-relatedchanges.

ThisyearthegrouphypothesisedthatIMAT,whichhasbeenreportedasincreasinginobeseHIV-negativewomenandhavingastrongrelationshiptoinsulinsensitivity,wouldbehavesimilarlytovisceraladiposetissue(VAT)andwouldbeincreasedinHIV-positivepatients.IMATispreservedinfamilialanddecreasedingeneralisedcongenitallipodystrophy.

Infact,theyreportedthatIMATwas51%lowerwhencomparing425HIV-positivepatientsto211HIV-negativecontrols,evenafteradjustingfordemographicsandlifestyle(adjustedto-48%),althoughsomewhatattenuatedaftercontrollingforVAT,SATandskeletalmusclevolume(adjustedto-21%).Allcomparisonsweresignificant(p<0.0001).

InHIV-positivepeoplebutlesssoincontrols,IMATwasassociatedwithhigherlevelsofVAT,trunkSATandlegSAT.

AsbothIMATandsubcutaneousadiposetissue(SAT)weredecreasedwithexposuretod4T,thestudyconcludedthatIMATsharedsimilarcellularoriginstoSAT.Althoughtheclinicalimplicationsarelesssignificantincountriesthathavemovedawayfromusingd4TandddI,thisfindingislikelytobemostrelevanttothosewhereitisstillwidelyused.

Ref:GrunfeldCetal.IntermusculartissueisdecreasedinHIVinfection.11thIntlWorkshoponAdverseDrugReactions.26-28October2009,Philadelphia.OralabstractO-01.Antiviraltherapy2009;14Suppl2:A3.



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HighincidenceandriskfactorsfordiabetesinFrenchcohort

SimonCollins,HIVi-BaseTheincidenceofdiabetesandrelatedriskfactorsfromtheANRSC08APROCO-COPILOTEcohortwaspresentedbyJacquelineCapeau.[1]

Thecohortincluded643patientsontheirfirstproteaseinhibitor-basedregimen,followedfrom1997-8fornineyears,40%ofwhowereARV-naivewhenthestudystarted.Approximately80%weremaleand4,500patientyearsoffollow-up(PYFU)contributedtotheanalysis.

Diabeteswasdiagnosedasfastingglycaemia>7.0mmol/Lor2-houroralglucosetolerancetest(OGTT)>11.1mmol/Land/ortreatmentfordiabetes.CardiovascularriskwascalculatedusingFramingham.

Thegroupreportedahighincidenceofdiabetesinbothmen(10.8per1000PYFU;95%CI:7.9-14.3)andwomen(11.4;9%CI:5.7-20.3).Afteradjustingforfamilyhistory,age,BMIandwaist:hipratio,thefollowingfactorswereassociatedwithnewonsetdiabetes:age>40years,BMI>25,WHR>0.97inmenand>0.92inwomenanduseofd4Torindinavir.HIV-relatedmarkersincludingCD4,CD4:CD8ratio,viralload,ethnicityandHCVstatuswerenotassociated.

Whencomparedtopatientswithnormalglycaemicfunction,peoplewithdiabeteswereolder(median43vs35years),hadhigherBMI(median24vs21),hadhigherratesofhypertension(50%vs18%)andfamilyhistoryofdiabetes(37%vs16%),allp<0.001.Diabeticpatientsalsohadasignificantlyhigher10-yearcardiovascularrisk(13%vs3%).

TheresearcherscommentedthattheserateswerefourtimeshigherthaninHIV-negativecontrolcohortwithsimilaradiposeprofile.[2]

c o m m e n t

Thestudyhasn’tsofarfoundthatimpairedglucosetolerancehaspredicteddevelopmentofdiabetes.Overtimetheincidenceofnewcasesappearstohavelevelledout,perhapsrelatingtoreduceduseofd4TandddI.NaivepatientsusingneitheroftheseRTIsseemtobeprotected,althoughfurtheranalysesareneededtoseewhetherlevelsremainhigherthaninthegeneralpopulation.

References1. CapeauJetal.Highincidenceandriskfactorsfordiabetesoverthe9-yearfollow-upafterfirstgenerationproteaseinhibitors’initiationinthe

ANRSC08APROCO-COPILOTEcohort.11thIntlWorkshoponAdverseDrugReactions.26-28October2009,Philadelphia.OralabstractO-05.Antiviraltherapy2009;14Suppl2:A5.

2. MeisingerCetal.SexdifferencesinriskfactorsforincidentType2DiabetesMellitus:theMONICAAugsburgCohortStudy.ArchInternMed2002;162:82-89.

http://archinte.ama-assn.org/cgi/content/abstract/162/1/82

Genderandracedifferencesinlipodystrophysymptoms

SimonCollins,HIVi-BaseThe prevalence, type and severity of lipodystrophy in theOntarioCohort Studywas assessed using theACTGbody imagequestionnaire.Resultsfromacohortstudyof746CanadianpatientsonstableHAARTconfirmedpreviouslyreportedsideeffectprofilesinrelationtogenderandrace.

Thiswasalargelymale(85%)andnon-Black(85%)study.Medianagewas48years(IGR42-55)andmediandurationofHIVinfectionwas13years(IQR7-18).

Theoverallprevalenceof58%lipodystrophywassimilarbygenderandrace.However,menreportedfatlossmorefrequentlythanwomen(31%vs11%,p<0.0001),especiallyintheface(45%vs30%,p=0.03)butsimilarlyinthelegsandbuttocks.Womenweremorelikelytoreportcentralfataccumulation(26%vs15%,p<0.0001)especiallyintheabdomen(5%vs46%,p<0.001)andbreasts(31%vs17%,P<0.0001).Womenwerealmosttwiceaslikelytoreportbothsymptoms(21%vs12%,p<0.0001).

Thestudyreportednodifferencesbyrace(Blackvsnon-Black)formen,butBlackwomenhadasignificantlyhigherrateoffataccumulationthannon-Blackwomen(57%vs38%,p=0.05).

c o m m e n t

Althoughtherearelimitationsinthisstudyintermsoflimitedracialandgenderbalance,andrelianceonpersonalperception,theoverallobservationsareimportantforsensitivityofindividualpatientmanagement.Thisisespeciallytrueasnocombinationhasbeenidentifiedthathasnotbeenassociatedwithfataccumulation,includingstudieswithrecentlyapproved‘lipid-friendly’proteaseinhibitorsorwithraltegravir.

Theassociatedbetweenlipohypertrophy,genderandracedeservesfurtherstudy.

Ref:LoutfyMetal.GenderandethnicitydifferencesinbodychangeanddistressofHIV-positiveindividualstakingantiretroviraltherapyinOntario.11thIntlWorkshoponAdverseDrugReactions.26-28October2009,Philadelphia.PosterabstractP-08.Antiviraltherapy2009;14Suppl2:A29.



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LipodystrophyiscommoninchildrenfromthreeEuropeancohorts

SimonCollins,HIVi-BaseResearchersfrom14sitesinBelgium,PolandandItalyreportedtheprevalenceoflipodystrophyinacohortof468childrenandadolescents(92%infectedatbirth).Datacollectedincludeddemographicandclinicalhistoryandusedstandardisedassessmenttodeterminefatlossoraccumulationintheface,limbs,buttocks,breasts,neckandtrunk.

Thecohortwasevenlysplitbygender,withmedianage13.5years(IQR9.9-17.0).Tannerpubertystageincluded28%stageIand34%stageV.Inthisgroup,73%werewhiteand22%BlackAfrican.HIVtreatmentwasusedby95%ofthecohortforamedian8.8years,with62%havingviralloadsuppressed<50copies/mL.ThemedianCD4%was31%(IQR24-38)andjustover300childrenwerecurrentlyasymptomatic.

Assessmentofsymptomswasbyclinician-completedquestionnaire.Over40%ofchildrenhadatleastonelipodystrophysymptom:15%hadjustfatloss,13%justfataccumulation(mostlytrunk)and13%hadbothsymptoms.Thisgroupincluded14casesofseverefataccumulationand11casesofbothseverefatlossandfataccumulation.

Inmultivariateanalysis,aftercontrollingfordurationoftreatment,maternallipodystrophy,maximalCDCstatus,andhavingeverusedd4T,indinavir,d-drugsandefavirenz,significantassociationswerefoundford4Tuse(AOR4.23;2.02,8.85),efavirenzuse(AOR=2.72;1.36,5.46),indinaviruse(AOR3.23)andclinicalstage(AOR3.30;1.28,8.02)andeitherfatlossorfataccumulation.Evenstrongerassociationswerefoundforchildrenwhohadbothsymptoms.

MaternallipodystrophywasalsoassociatedwithanadjustedORof3.01(1.78,5.57)foranysymptomand4.75(1.60,14.20)forbothsymptoms.

Ref:AlamNMetal.RiskfactorsforbodyfatredistributioninaEuropeancohortofHIV-infectedchildrenandadolescents.11thIntlWorkshoponAdverseDrugReactions.26-28October2009,Philadelphia.PosterabstractP-06.Antiviraltherapy2009;14Suppl2:A27.

VisceraladiposetissuereturnstobaselineafterstoppingtherapeuticinterventionwithrHGH

SimonCollins,HIVi-BaseCentral fataccumulation remainsoneof themostdistressingbut leastunderstoodmetaboliccomplications,withvery limitedmanagementoptions.SeveralstudieshavereportedthatrecombinantHumanGrowthHormone(rHGH)canreducecentralvisceraladiposetissue(VAT),althoughearlieststudiesathigherdoses(4-6mg/day)wereassociatedwithsignificanttoxicity.Additionally,anybenefitseemeddependentonmaintainingtreatment,andtheoptimaldoseremainedtobeestablished.

Itwasimportanttoseethe3-yearsresultsfromastudyfromtheMassachusettsGeneralHospital,presentedbyStevenGrinspoon,carriedoutinpeoplewithreducedgrowthhormone(GH)secretion(peakGH<7.5ng/mL).[1]Thiswasarandomiseddouble-blindstudyoflowdoserHGH(anaveragedoseof0.33mg/day:startingat2mcg/kg/daybutincreasingto6mcg/kg/day,titratingtotheupperquartileofnormalIGF-1range).After18monthspatientscrossedovertoeitheractivedrugorplacebo,dependingontheiroriginalrandomisation.The18monthinitialresultshavealreadybeenpublished.[2]

Pooledanalysisforbotharmsshowedthat18monthstreatmentsignificantlyreducedmean(+SD)VATcomparedtoplacebo(-7.3+21.3%vs+4.8+22.7%,p<0.0001)andtrunkfat(-3.2+15.3%vs+2.4+13.1%,p=0.003).rHGHalsohadastatisticallypositiveeffectonreducingsystolicanddiastolicbloodpressure,triglyceridesandLDL-cholesterolandincreasinglowerlimbfat,buthadanegativeglyceamicaffect:increasingfastingglucoseand2-hourglucoseonOGTT(seeTable1).Noimpactforseenforintimamediathickness,thoughthiswasnotelevatedatbaseline.

Duringthecrossoverperiod,thebenefitsofrHGHonVATreversedtobaselinewithin6months.TheincreaseinIFG-1seenduring18monthtreatment(approximately+100ng/mLincreasefrombaseline)alsodroppedwithin2-4weeksofdiscontinuation.

Table1:PooledeffectofrHGHvsplaceboat18months(mean%,+SD)

rHGH placebo p

VAT -7.3+21.3% +4.8=+22.7% <0.0001Trunk fat -3.2+15.3% +2.4+13.1% 0.003Lowerlimbfat +4.9+13.3% +1.1+11.8 0.03Systolic BP -2.0+13.9% +2.6+12.0% 0.007Diastolic BP -1.1+13.7% +5.8+17.1% 0.0009Triglycerides -0.9+43.4% +11.0+52.9% 0.05LDL-chol -2.7+23.7% +4.9+28.7% 0.03Fastingglucose 6.7+11.7% 2.5+11.4% 0.0072-hour glucose 16.5+48.6% 0.1+26.9% 0.002



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c o m m e n t

The importanceofcontinuingtreatment inorder tomaintainanyreduction inVAThasalsobeenreportedwith tesamorelin,whichalthoughhasreducedtoxicity,appearstoreversebenefitsbacktobaselineVATlevelsifdiscontinued.AnFDAdecisiononapprovaloftesamorelinisexpectedinthesecondquarterof2010.

References1. GrinspoonSetal.Effectsof treatmentanddiscontinuationof lowdosephysiologicgrowthhormone inHIVpatientswithabdominal fat

accumulation:arandomised,placebo-controlled36-monthcrossovertrial.11thIntlWorkshoponAdverseDrugReactions.26-28October2009,Philadelphia.OralabstractO-02.Antiviraltherapy2009;14Suppl2:A3.

2. Loetal.Low-dosephysiologicalgrowthhormoneinpatientswithHIVandabdominalfataccumulation.JAMA2008;300(5):509-519.(6August2008).

http://jama.ama-assn.org/cgi/content/full/300/5/509

ReducedlevelsofvitaminDinpatientstakingefavirenz

SimonCollins,HIVi-BaseToddBrownandcolleaguesfromJohnsHopkinsUniversitypresentedresultsfromaretrospectiveanalysisthatsupportsalinkbetweenefavirenzandreducedlevelsofvitaminD.[1]

Thestudycompared25-(OH)vitaminDlevelsfromstoredsamplesfrom87treatmentnaivepatientsandcomparedthistolevels6-12monthsafterstartingtreatmentcontainingefavirenz(n=51)ornon-efavarinz(n=36;89%PI-based).

SeveralstudieshavereportedanassociationbetweenNNRTIsandreducedlevelsofvitaminD,includingarecentUKstudylinkinglowlevelstotheuseofefavirenz.[2]

Thecurrentstudyreportedaprevalenceofmild,moderateandseverevitaminDdeficiencyatbaselinein84%(<32ng/mL/<80nmol/L),56%%(<20ng/mL/<50nmol/L)and33%(<15ng/mL/<37.5nmol/L)patientsrespectively.Medianlevelswerelowerinnon-whitecomparedtowhitepatients(16vs30ng/mL,p<0.0001)andinwintercomparedtosummer(15vs27ng/mL,p<0.001).Factorsassociatedwithlowlevelsatbaselineincludedrace(PrevalenceRatio6.795%CI:1,7,25.6;p=0.006),season(PR4.6;1.2,17.8;p=0.03)anddurationofHIVinfection(PR1.06;1.02,11.09;p=0.003).

Pre-andpost-HAARTlevelsintheefavirenzgroupdroppedfrom22.6to18.4andincreasedfrom21.2to22.9inthenon-efavirenzgroup(p=0.05betweengroupcomparisonpost-HAART).Afteradjustingforbaseline25(OH)D,raceandseason,theadjustedmeandifferencebetweengroupwas-5.1+1.5ng/mL,(p=0.001).Usingthe<15nmol/mLcut-offthepercentageofpatientswithseveredepletionincreasedform27%to48%intheefavirenzgroupandreducedfrom42%to31%inthenon-efavirenzgroup.Theadjustedprevalenceratioforefavirenzusewas1.8(95%CI1,2,2,8,p=0.007).

Noassociationwasfoundwithuseoftenofovir,abacavirofAZT.

References:1. BrownTTetal.Associationbetweeninitiationofantiretroviraltherapywithefavirenzanddecreasesin25-hydroxyvitaminD.11thIntlWorkshop

onAdverseDrugReactions.26-28October2009,Philadelphia.OralabstractO-20.Antiviraltherapy2009;14Suppl2:A15.2. Welzetal.EfavirenzuseisassociatedwithsevereVitaminDdeficiencyinalarge,ethnicallydiverseurbanUKHIVcohort.Posterabstract

TUPEB186.5thIASconference,19-22July2009,CapeTown. http://www.ias2009.org/pag/Abstracts.aspx?AID=3402

AssociationbetweeninflammationandsleepapneaintheMACScohort

SimonCollins,HIVi-BasePromptedbytheconcernthatsystemicinflammationmaycontributetosleepapnea,SusheelPatilandcolleaguesfromJohnsHopkinsUniversitypresentedaninterestinganalysisfromthegentlynamedSIESTAstudy(StudyofImmuneEffectsonSleep,(HIV)TreatmentandApnea).

Thestudylookedatobstructivesleepapnea(OSA)andtherelationshipwithinflammationmarkers(TNF-alphasolubleTNF-areceptorsIandIIandIL-6),inthreegroupsofmenfromtheMACScohort:HIV-positiveandnotonHAART(n=41),HIV-positiveandonHAART(n=58)andHIVnegative(n=60).SeverityofOSIwasdefinedbythenumberofeventsperhourdetectedduringanocturnalsleepstudy:5-15=mild,15-30=moderate,and>30=severe.ObesityisthestrongestpredictorofOSI,butOSIisalsoindependentlyassociatedwithhypertension,cardiovasculardisease,stroke,diabetesmellitusandreducedqualityoflife.

OSI>15washigherintheHIV-negativegroup(57%)comparedtotheHAART(41%)andno-HAART(44%)groups.However,theHIV-negativegrouphadasignificantlygreatermeanBMI(28.6+7.2kg/m2)andwaistcircumference(98.6+16.9cms)comparedtotheHAART(25.5+4.5kg/m2and93.8+11.5cm)andno-HAART(25.4+4.1kg/m2and91.8+12.8)HIV-positivegroupsandatrendtogreatertrunkweight.



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WhenlookingatparticipantswithnormalBMI(<25kg/m2)however,therelationshipindicatedatrendforhigherprevalenceintheno-HAARTgroup:25%HIV-negative(n=20),24%onHAART(n=29)and50%inthenoHAARTgroup(n=22);(p=0.1).

MedianlevelsofallfourinflammatorymarkerswerehigherintheHIV-positivemencomparedtotheHIV-negativemen,andwerehigherintheno-HAARTgroupcomparedtotheHAARTgroup.Withintheno-HAARTgroup,menwithmoderate–severeOSAhadhigherlevelsofTNF-aandIL-6comparedtomenwithnoorlesssevereOSI,althoughthisdifferencewasnotobservedbetweenmenintheothergroups.

ThestudyconcludedthatratesofOSIwerehighinHIV-positivemen,evenwhenBMIwasnormal,andthatmoreseveresymptomswasassociatedwithsystemicinflammationsuggestingadifferentaetiologycomparedtomenwhoareHIV-negative.

Ref:PatilSPetal.Associationbetweensystemic inflammationandobstructivesleepapnea inmenwithorat risk forHIV infection from theMulticenterAIDSCohortStudy(MACS).11thIntlWorkshoponAdverseDrugReactions.26-28October2009,Philadelphia.OralabstractO-25.Antiviraltherapy2009;14Suppl2:A19.

SportssupplementsimpactonserumcreatinineandeGFRmarkersofrenalfunction

SimonCollins,HIVi-BaseSeveralcasestudiesshowingtheimpactofcreatininesupplementationoneGFRresults,werepresentedinaposterbyGraemeMoyle,fromtheChelseaandWestminsterHospital,London.EstimatedGFRisnowroutinelyincludedinrenalmonitoringusingtheMDRDcalculation,whichincorporatesserumcreatinine,togetherwithage,sexandethnicity.

SixHIV-positivemalepatients(aged25-55)onstableHAARTwerereferredtoanHIV/renalclinicduetoelevatedserumcreatinine(range131-257umol/L)andloweGFR.Allwerenormalbloodpressureandnohistoryofdiabetes.Proteinurialevelswerenormalandconfirmedbyurinaryprotein:creatinineratio.Eachpatientroutinelyusedproteinandcreatinesupplementationaspartofamuscle-buildinggymroutine.

Threemonthsafter5/6patientsdiscontinuedthesupplements,serumcreatininelevelsconsistentlydroppedtobetween98and118umol/LandeGFRreportedtonormalise(eGFRdatawasnotshown).

Although dietary intake of creatine is 1g/day, supplementation can increase this 20-30 fold, and intramuscular concentrations canremainelevatedforseveralweeks.Creatineisconvertedtocreatininerelativetoitsconcentrationwhichcanincreaseserumcreatininedespitenormalrenalfunction.ThepostersuggestedthatARVexposuremayalsobeinvolvedbutalsothattheassociationofraisedserumcreatininewithcreatineingestionhasnotbeenpublishedoutsideoftheHIVcontext.

c o m m e n t

ThisstudyhighlightstheimportancetakingahistoryofsupplementusetoconsiderthisasacauseforelevatedcreatinineorloweGRF.

Ref:MoyleGetal.Thepitfallsoftheestimatedglomerularfiltrationrate–‘hittingthegymandcreatinesupplementation’.11thIntlWorkshoponAdverseDrugReactions.26-28October2009,Philadelphia.PosterabstractP27.Antiviraltherapy2009;14Suppl2:A49.

CONFERENCE REPORTS

9thAIDSVaccineConference

19-22October2009,Paris

IntroductionTheAIDSVaccineconferenceisoneofthemostimportantscientificmeetingsonAIDSvaccineresearchanddevelopment.Itwasattendedbymorethan1,000delegatesandincludedover400scientificpresentations.

Programmehighlightsthatincreasedtheprofileofthemeetingthisyear,includedafullpresentationfromtheThaiphaseIIItrialthatcontroversiallyreportedtoplevelresultsafewweeksearlierinapressrelease.

Wereportthisstudyhere,whichcoincidedwithpublicationintheNEJM.

• ThaiHIVVaccineTrialresultspresentedandpublished

Conference programme:

http://www.hivvaccineenterprise.org/conference/2009/scientific_program.aspx



9

Severalsessionsincludingthepressconferences,areavailableaswebcasts,togetherwithsearchableonlineabstractsandPDFfilesofmanyorthe posters or presentations:

http://www.hivvaccineenterprise.org/conference/2009/webcasting.html

AbstractsfromtheconferencearepublishedasanopenaccessonlinesupplementinRetrovirology:

http://www.retrovirology.com/supplements/6/S3

ThaiHIVVaccineTrialresultspresentedandpublished

RichardJeffreys,TAGIntandemwiththepresentationofthedatathattookplaceattheAIDSVaccine2009conferenceinParis,theresultsoftheRV144trialwerepublishedonlineintheNewEnglandJournalofMedicine.Accesstothepaperandtheaccompanyingeditorialisfreeofcharge.Threedifferentanalysesof theresultsarepresented insequence: the intent-to-treatanalysis(ITT),which includeseveryoneenrolledandrandomisedtoreceivevaccineorplacebo,aperprotocol(PP)analysislimitedtoeveryonewhoreceivedallimmunisationsonschedule,andfinallyamodifiedITT(mITT)analysisthatexcludessevenindividualswhoreportedlyturnedouttobeHIV-infectedatthetimeoftheirfirstimmunisation.

• ITT:Totaln=16,402.CasesofHIVinfection:76placebo,56vaccine.Efficacy:26.4%(95%confidenceinterval[CI],–4.0to47.9;p=0.08)

• PP:Totaln=12,452.CasesofHIVinfection:50placebo,36vaccine.Efficacy:26.2%(95%CI,–13.3to51.9;p=0.16)

• mITT:Totaln=16,395.CasesofHIVinfection:74placebo,51vaccine.Efficacy31.2%(95%CI,1.1to51.2;p=0.04)

Thedatasuggeststhepossibilityofamarginalprotectiveeffect,almostentirelyconcentratedduringthefirstyearofthestudy.Kaplan-Meierplotsoftheinfectionrateovertimeshowadivergenceinitially,buttheratesinthevaccineandplacebogroupsaresuperimposablefromweek52onwards.Subgroupdataarealsoreported,butthestatisticsareuncorrectedformultipleanalysesandshouldbeinterpretedwithgreatcaution.Withthiscaveat,thereisahintthatthedifferencebetweenthevaccineandplacebowasgreatestamongthoseatlowestriskofHIVexposure.Theagegroupbreakdownalsoindicatesthedifferencebetweenvaccineandplacebogroupswasconcentratedinthe20-25agegroup;thereisnodifferenceinthenumberofinfectionsbetweenthegroupsamongthoseunder20,andverylittledifferenceamongthoseover26.Amongparticipantsaged20-25,therewere20infectionsinthevaccinegroupand40inplacebo.

Intermsoftheviralloadoutcomesinpeoplewhoacquiredinfection,theITTanalysisshowsatrendinthewrongdirection;viralloadwashigheronaverageamongvaccinerecipients(4.36logvs.4.21log,p=0.09).HoweverthistrenddisappearsinboththePPandmITTanalyses.Therewerenodifferencesinpost-infectionCD4Tcellcountsinanyoftheanalyses.

Astowhytheonlystatisticallysignificantresult isreportedlast inthepublishedpaper(incontrasttotheSeptember24pressannouncement,inwhichthemITTwastheonlyresultgiven),itappearsthattheRV144protocolspecifiedthattheprimaryanalysiswouldbeITT.ThepaperstatesthatthemITTanalysiswasusedastheprimaryanalysisfortheinterimefficacyevaluation(whichwasconductedbytheDataSafetyMonitoringBoardinJulyof2007)andthen,fivemonthsbeforethestudywasunblinded,adecisionwasmadetomakethemITTtheprimaryanalysis.Readingbetweenthelines,perhapsthereviewersofthemanuscriptwerenotsatisfiedthatthislateadoptionofthemITTastheprimaryanalysisjustifiedlistingtheresultfirstinthepaper.ItiscurrentlyunclearwhytheRV144protocoldidnotspecifythemITTastheprimaryefficacyanalysisfromthestart.Astheimportofthetrialresultsaremulledbythelargercommunity,itwillbeimportanttogainsomeclarityastoexactlyhowtheseeventsplayedout.

So far, in the limited time observers have had to digest the data, the main issues that are being discussed are the suggestion of a transient,time-limitedeffectandwhatmightexplainit(vaccinesgenerallyworkbytheinductionofimmunologicalmemory,whichistypicallylong-lived)andthehintthatvaccine-mediatedprotectionmightbeeasiertoachieveinindividualswithlessfrequentHIVexposurecomparedtothoseathighrisk.

Regrettably,thereleaseofthedatatodaydoesnotchangethefactthatitwasanappallingandwoefullyshort-sighteddecisiontoonlyreleasethemITTanalysistothepressonSeptember24.OntheconferencecallhostedbyAVACthattookplacethatdaywithinvestigatorMerlinRobbandPeggyJohnstonfromNIAID,Robbexplicitlystatedthatonly16,395peoplehadbeenenrolledintothetrial.Notonlywasthisnottrue,butitturnsoutthatvaccine/placebodistributionofthe7peopleexcludedfromthemITTwascrucialtotheattainmentofstatisticalsignificance:fiveoftheseindividualswereinthevaccinegroupandtwoinplacebo.Bycherry-pickingthemITTtoannounce,theRV144investigatorshavecreatedsuspicionanduncertaintyinafieldthattheywellknowisalreadyplaguedbycontroversy.Theirdecisionwillonlyservetocomplicateeffortstogleanusefulinformationfromthetrialdata.

Source:www.tagbasicscienceproject.typepad.com(20Oct2009)

Thewebcastofthepressconferenceaboutthetrialresultsisnowavailableonline(scrolldowntothebottomofthepagetotheTuesday,20Octoberpressconferencelink).

http://www.hivvaccineenterprise.org/conference/2009/webcasting.html



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References1. SupachaiRerks-Ngarmetal.VaccinationwithALVACandAIDSVAX topreventHIV-1 infection inThailand.20October2009 (10.1056/

NEJMoa0908492).

http://content.nejm.org/cgi/content/full/NEJMoa09084922. DolinR.HIVvaccinetrialresults-anopeningforfurtherresearch.NEJMEditorial.20October2009(10.1056/NEJMe0909972).

http://content.nejm.org/cgi/content/full/NEJMe0909972

Additional reading:

Earlier articles detailing the unfolding controversies around this study and the early press release focusing on a positive trial result are covered in anumberofarticlesfromtheTAGbasicscienceweblog.

http://tagbasicscienceproject.typepad.com

MarginalHIVvaccinetrialresultraiseshopes,eyebrows.(25Sep2009).

ThaiHIVvaccinetrial:additionalhistory&links.(28Sep2009).

DeconstructingtheThaitrialvaccines.(29Sep2009).

Didtheworldgeta“fairglimpse”oftheThaivaccinetrialdata?(05Oct2009).

ThaiHIVvaccinetrialupdate:uncertaintyreigns.(15Oct2009).

CONFERENCE REPORTS

49thInternationalConferenceonAntimicrobialAgentsandChemotherapy(ICAAC)

12-15September2009,SanFrancisco

IntroductionThefollowingshortreportsaresummariesfromsomeoftheinterestingstudiespresentedatICAACthisyear.Aswerenotabletocoverthismeetinginperson,allinformationisdependentontheonlineposters.

ReportsinthisissueofHTBinclude:

• Smokingmasksthelong-termbenefitsofHAARTonlungfunction

• RecentARVsandtheblood/brainbarrier:CSFdrugconcentrationsofdarunavir/randraltegravir

• Alcoholandmarijuanamayreducedruglevelsofatazanavirandefavirenz

• Raltegravirbodycompositionstudy:48-weekDEXAresults

ICAACunfortunatelyroutinelyremovesonlineaccessshortlyafterthemeetingandisoneofthefewmedicalmeetingscoveringHIVcarethatdoesnotsupportcontinuedopenaccesstothisresource.

Aswewenttopressthesewerestillavailableonline:

http://www.posters2view.com/icaac

[Username:ICAAC;Password:SanFran]

Smokingmasksthelong-termbenefitsofHAARTonlungfunction

SimonCollins,HIVi-BaseAposterbyJanGerstoftandcolleaguesfromCopenhagenUniversityHospitallookedattheinteractionbetweenchangesinlungfunctioninrelationtosmokingandHIVtreatment.

BetweenOctober2000andNovember2001,63HIV-positivepatientshadinitiallungfunctionassessedbyapaneloftests(includingforcedexpiredvolume,functionalvitalcapacity,peakflow,residualvolume[RV%]andtotalcapacityanddiffusingcapacity/alveolarvolume[DLCO/VA%]),withfollow-upassessmentsamedianof4.5yearslater(range3.8-4.7years).

Mostparticipants(87%)werealreadyonHAARTatbaselineforamedianofaboutfiveyears(range16-79months)withallbuttwoonHAARTatthefollow-upvisit(with85%and89%ofthesepatientshavingviralload<100copies/mLateachtimepoint,respectively).

Someabnormallungfunctionparameterswerepresentatbaselineinbothsmoking(n=30)andnon-smoking(n=33)participants,andsomewerefurtherreducedinsmokers.Specifically,DLCO/VA%wasdecreasedinbothgroups,withlungfunctioncompatible



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withearlyobstructivelungdisease.Atfollow-uptheselevelsnormalisedinnon-smokersandimprovedinsmokerstothebaselinelevelsofthenon-smokinggroup.However,resultsforresidualvolume,whichreturnedtonormalfornon-smokers,increasedfurtherinthesmokinggroup.

TheresearchersconcludedthatthisstudyshowedthatHAARTwasbeneficialforlungstatusandthatHIV-relatedchangescanreverseovertimeinnon-smokers.However,smokingmasksmanyofthesepotentialbenefits.

c o m m e n t

AsmostparticipantshadalreadybeenonHAARTformanyseveralyearsatbaseline,andresultswerenotdividedbyHAARTuseandviralload,thestudydidnotquantifytheextentandtimelineofthebenefitsduetoantiretroviraltherapy.Nevertheless,thesuggestedpositiveimpactofHAARTonlungfunctionisimportantandtheresultsreinforcetheimportanceofsmokingcessation.

Ref:GerstoftJetal.ChangesoflungfunctioninanoptimallytreatedHIVpopulation:a4.5yearfollowupstudy.49thICAAC,12-15September2009,SanFrancisco.PosterabstractH-1561.http://www.posters2view.com/icaac/view.php?nu=H-1561

RecentARVsandtheblood/brainbarrier:CSFdrugconcentrationsofdarunavir/randraltegravir

SimonCollins,HIVi-BaseTheissueofdrugpenetrationintothecerebrospinalfluid(CSF)isanincreasingfocusforallantiretrovirals,buthasparticularimportancegiven the interest innucleoside-sparingregimens.These includestudies lookingatboosted-PImonotherapyasamaintenancestrategyafterinitialviralsuppressionwithtripledrugtherapyanddualNNRTI+PI/rorraltegravir+PI/rcombinations.

ScottLettendre’sgrouppresentedencouragingresultsfromtwostudiesatICAAC:ondarunavir/randonraltegravir,supportedbyTibotecandMerckrespectively.

Thedarunavirstudymeasured29CSFandplasmapairsfrom16HIV-positivepatientsbetweenAugust2006andAugust2008,andcomparedlevelstothemedianIC50forwild-typevirus(2.75ng/mL).[1]

Participantswereamedian48years,62%wereCaucasianand19%hadHCVco-infection.MedianCD4cellcountwas197cells/mm3.Viralloadwasdetectablein38%ofbloodand10%ofCSFsamples.Mediandurationofdarunavirwas7.5months(IQR3.6-14.6).

DarunavirwasdetectedinallCSFspecimenswithamedianconcentrationof56.9ng/mL(IQR39.6-81.4).Themediantotalplasmaconcentration(AUC)was4,094ng/mL(IQR2,993-6,410)withamedianCSF-to-plasmaratioof1.4%.Themedianunboundplasmaconcentrationwas542ng/mL(IQR376-971)withamedianCSF-to-plasmaunboundratioof9.4%(IQR6.8-14.2%).DRVconcentrationsinCSFexceededtheIC50ofwild-typeHIVinallspecimensbyamedianof20-fold.

Theraltegravirstudyhadasimilardesign,with22matchedplasma/CSFsamplesfrom18HIV-positivepatients.Demographicswerealsosimilar:medianage46years,89%Caucasian,12%HCVcoinfectionwithamedianCD4of276cells/mm3.[2]Themedianraltegravirinhibitoryconcentration(IC50)forwild-typeHIVis3.4ng/mL.

RaltegravirwaspresentinallCSFspecimenswithamedianconcentrationof14.5ng/mL.Themedianplasmaconcentrationwas260.9ng/mL(IQR2.0-640.4)withamedianCSF-to-plasmaratioof5.8%(IQR2.1%-17.8%).CSFconcentrationscorrelatedwithplasmaconcentrations(r=0.49,p=0.02)butnotwithpost-dosesamplingtime(p>0.50).RaltegravirconcentrationsinCSFexceededtheIC50ofwild-typeHIVinallspecimensbyamedianof4.3-fold(IQR2.7-7.7).HIVRNAlevelswereundetectablein20of21(95%)CSFspecimensandin13of21(62%)plasmaspecimens.

EachstudyconcludedthatthestudydrugpenetratedCSFinconcentrationsthatareinthetherapeuticrangetosuppresswild-typeHIVandwouldbeexpectedtocontributeantiviralactivityintheCSFaspartofcombinationtherapy.

DruglevelsofbothdrugsinCSFcorrelatedbetterwithtotallevelsinplasmasuggestingthattherapeuticdrugmonitoringcouldindicateeffectivenessinthenervoussystem.Unboundplasmaconcentrationsofdarunavirwerelesscloselycorrelated.

References1.BestBetal.DarunavirconcentrationsinCSFexceedthemedianinhibitoryconcentration.49thICAAC,12-15September2009,SanFrancisco.

PosterabstractA1-1312. http://www.posters2view.com/icaac/view.php?nu=A1-13122. BestBetal.RaltegravirconcentrationsinCSFexceedthemedianinhibitoryconcentration.49thICAAC,12-15September2009,SanFrancisco.

PosterabstractA1-1311. http://www.posters2view.com/icaac/view.php?nu=A1-1311



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Raltegravirbodycompositionstudy:48-weekDEXAresults

SimonCollins,HIVi-BaseWhile someaspects of the lipodystrophy syndromeare better understoodandmanaged, fat accumulation (lipohypertrophy),principallycentralvisceraladiposetissue(VAT),remainsunexplainedandisstillassociatedwithallfamiliesofantiretrovirals.Whilethismechanismisunknown,itappearstohavelittlerelationshiptotheatherogeniclipidandglucosechangesthatappeartobeaseparatesetoflipodystrophysymptoms.

TheDEXAresultsreportedherearefromasub-setof76/563naivepatientsfromthedouble-blindplacebo-controlledSTARTMRKtrial,randomisedtoeitherraltegravirorefavirenz,eachwithtenofovir/FTC.Thisanalysiscomparedbaselinetoweek48,withfollow-upplannedtoweek96.MetabolicparametersincludedfastinglipidandglucosechangesandrelationshiptoNCEPgoals.

BaselinecharacteristicsforpatientsinthesubstudyweresimilartothelargergroupandaresummarisedinTable1.MedianCD4countandviralload(inthesubstudy)wasapproximately200cells/mm3and5logcopies/mL.

At48weekstherewerefewoverallchangesandnosignificantdifferencesbetweenthetwoarms.Totalfatincreasedinbotharmsbyaround16-20%inbothlimbsandtrunk(seeTable2).Investigatorreportedobservationalchangesweretwocasesofmildfataccumulationintheblindedefavirenzarm.Nopatientsreportedlipodystrophysymptoms.

Lipidchangesweresignificantlygreatintheefavirenzgroup:TC+33vs+10;HDL+10vs+4;LDL+16vs+6;andTG+37vs-3mg/dL(allp<0.001).ThechangeintheTC:HDLratiowas-0.1vs-0.3intheefavirenzandraltegravirgroups(p=0.292).

Table1:BaselineCharacteristicsintheDEXASub-Study

raltegravir(n=54) efavirenz(n=57)

Male,n(%) 50(92.6) 48(84.2)Female,n(%) 4(7.4) 9(15.8)White 33(61.1) 33(57.9)Black 14(25.9) 9(15.8)MedianCD4(range) 230(1to573) 202(6to567)Medianviralload,log(range) 4.9(4to6) 5.0(4to6)B/lineCD4<50 8(14.8) 9(15.8)B/lineVL>100K 24(44.4) 30(52.6)

Table2:BodycompositionchangesinSTARTMRKat48weeks

raltegravir 400 mg bid efavirenz600mgqdRegion n Baselinemean(gm) Mean%change†(95%CI) n Baselinemean(gm) Mean%change†(95%CI)Arms 35 1873.08 23.33(5.95,40.72) 41 1724.23 18.94(11.80,26.07)Legs 35 7055.66 16.31(3.85,28.77) 41 6305.59 15.63(9.59,21.67)Appendicular 35 8928.73 17.38(4.34,30.42) 41 8029.83 16.09(10.15,22.03)Trunk 35 11683.73 17.01(2.87,31.15) 41 10142.54 20.46(11.72,29.19)Total 35 20612.46 16.92(3.52,30.32) 41 18172.37 17.98(10.89,25.07)

N = # of patients in the treatment group. † Mean % changes from baseline are based on the measurements of the pts who were measured at baseline and the time point assessed.

c o m m e n t

Thelipohypertrophyprofileofeachnewdrugshouldbeincludedroutinely inallPhaseIIIantiretroviraltrials.Whileraltegravirwasoriginallyapprovedovertwoyearsago(October2007intheUS),thefirstinformationonfataccumulationwasonlypresentedatICAACthisyear(September2009).ItisnowunfortunatethatthisisbasedonDEXAratherthanCTscans:whileDEXAcanprovideinformationaboutlimbfatloss,itisnotabletoseparatevisceralfatfromsubcutaneousfat.

Whilenosignalofearlyproblemsisreassuring,48-weeksisprobablytooearlytoseesignificantchanges.Asefavirenzhaspreviouslybeenlinkedtofataccumulation,similarresultsatthistimepointshouldbeinterpretedcautiously.

References1.BergerDetal.Metabolicprofilesandbodycompositionchangesintreatment-naïveHIV-infectedpatientstreatedwithraltegravir(RAL)-based

vs.efavirenz(EFV)-basedcombinationtherapy:48-weekdata.49thICAAC,12-15September2009,SanFrancisco.PosterabstractH-1571. http://www.posters2view.com/icaac/view.php?nu=H-1571



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Alcoholandmarijuanamayreducedruglevelsofatazanavirandefavirenz

SimonCollins,HIVi-BaseTwosmallstudiesfromthesameresearchgrouplookedattheassociationbetweensubstanceuse,includingalcoholandmarijuana,andlevelsofHIVdrugs.

Thefirststudyreportedthattroughconcentrationsofatazanavirwereinverselyrelatedtouseoftobaccoandmarijuanain32‘substanceusing’(SU)patientsfromfourUSsitescomparedto35non-using(non-SU)patients.[1]

Substanceuse(%ofSUpatients)followedNIDAcriteriaandincludedalcohol(41%),cocaine(19%),marijuana(38%),opioids(22%)andtobacco(91%).43%ofthesepatientsusedmultiplesubstances.

Duringthestudyperiod,patientshadtocompletethreeclinicvisits,forentry,troughanddirectlyobservedtherapy(DOT),andtakescheduleddosesofatazanaviratthesametimefor4daysbeforeeachvisit.

Adherenceassessmentandcounselingpriortoplasmasamplingandeachscheduledclinicvisitwereperformedandrecorded.

Multiplelinearregressionmodelswereusedtodeterminefactorsassociatedwithatazanavirconcentrations,immunologicalandvirologicresponseswhileadjustingforcovariates.Otherdemographicsincludingrace,gender,ethnicityandBMIwereincludedintheanalysis.

SignificantreductionsinATVtroughconcentrationswereassociatedwithtobaccoandmarijuanause(p<0.05)butnotwithothersubstances.36%and50%oftobaccoandmarijuanausers,respectivelyhadATVconcentrationsbelowthetherapeuticrange(p<0.05).However,nosignificantdirecteffectswerelinkedtoviralloadorCD4count.

Table1.Substanceuse(SU)andatazanavirtroughlevels*

SU Non-SU P

Tobacco 0.31(0.12-0.79) 0.96(0.32-1.20) 0.009Marijuana 0.24(0.05-0.80) 0.59(0.27-1.11) 0.03Alcohol 0.53(0.13-0.91) 0.56(0.22-1.08) 0.60Cocaine 0.77(0.05-1.39) 0.54(0.19-1.05) 0.92Opioids 0.32(0.15-0.77) 0.71(0.19-1.10) 0.22

*Median,ug/ml(IQR).ForHTB,roundedtotwodecimalpoints.

Theresearchersconcludedthattheunderlyingmechanismmayincludeenzymeinduction,butthatfurtherstudieswereneededforthistobedetermined.

ThesecondstudylookedatefavirenzmetabolisminrelationtotheG516Tsinglenucleosidepolymorphisms(SNPs)intheCYP2B6enzyme.PreviousstudieshavedemonstratedthatGG>GT>TTpolymorphismsinhibitefavirenzmetabolismresultinginhigherplasmaconcentrations,slowerdrugclearance,andsometimesincreasedtoxicity.

Basedon516genotypes,37patients(SUn=18;non-SUn=19)werecategorisedasextensive(GG,n=19), intermediate(GT,n=13),andslow(TT,n=5)metabolisers.Thesegenotypeswithweresignificantlyassociatedwithefavirenztroughconcentrations(p=0.04).Significantlylowermedian(IQR)efavirenzconcentrationswerelinkedtotobaccouse(1.76ug/mL;(1.31-2.13)vs2.29ug/mL(1.88-4.01),p=0.04)andalcoholuse(1.41ug/mL(0.66-1.88)vs2.25ug/mL(1.76-2.48),p=0.02)intheextensivemetabolisergroupwithlowerCD4countsandhigherviralloads.

Aswiththeatazanavirstudy,substanceusehadnosignificantrelationshiptoantiviralresponses.

References1. FehintolaFAetal.Tobaccoandmarijuanausessignificantlydecreaseatazanavir(ATV)troughconcentrationsinHIVinfectedindividuals.49th

ICAAC,12-15September2009,SanFrancisco.PosterabstractH-231. http://www.posters2view.com/icaac/view.php?nu=H-2312. BrazeauDetal.EffectsofCYP2B6singlenucleotidepolymorphisms(SNPs)andsubstanceabuseonefavirenz(EFV)pharmacokinetics.

49thICAAC,12-15September2009,SanFrancisco.PosterabstractH-228. http://www.posters2view.com/icaac/view.php?nu=H-228



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OtherdruginteractionstudiesatICAAC

HIV-druginteractions.orgThesesummariesareselectedfromalongerreportpublishedbythisgroupontheLiverpoolUniversitysite.AllreferencesaretotheProgrammeandabstractsforthe49thICAAC,12-15September2009,SanFrancisco.

InteractionswithvicrivirocDruginteractionswithvicriviroc(30mgaloneorwithRTV)werestudiedinHIV-negativevolunteers.

Therewasnoeffectonmidazolamwhenadministeredwithvicrivirocalone,buttherewasamarkedincreasewhenadministeredwithritonavir.KetoconazoleincreasedvicrivirocAUCby136%whenadministeredaloneandby503%whenadministeredwithritonavir.

Therewasnoeffectonvicrivirocexposurewithrifabutinwhenadministeredwithritonavir(200mgoncedaily).RifampicinmarkedlydecreasedvicrivirocexposurewhencoadministeredwithRTV(100mgtwicedaily)-therelativeoralbioavailabilitywas11.6%basedonAUC.Coadministrationofrifampicinwithvicrivirocisnotrecommended.

Carbamazepinehadnoeffectonvicrivirocwhenadministeredwithritonavir(100mgtwicedaily).Inthepresenceofritonavir,additionofanotherCYP3A4inhibitorormodestlypotentCYP3A4inducerwillnotrequiredoseadjustmentofvicriviroc.IfcarbamazepineorrifabutinarecoadministeredwithvicrivirocinaRTV-boostedPI-containingregimen,novicrivirocdoseadjustmentisrequired,butritonavirshouldbeincreasedto100mgtwicedailyor200mgoncedaily.

Ref:KasserraCetal.AssessmentofpharmacokineticandsafetyinteractionsbetweenvicrivirocandCYP3A4substrates,inhibitors,andinducers.AbstractH-230.

OpiatesubstitutiontherapyandantiretroviralsThreestudiesprovidedinformationontheinteractionsbetweenopiatesubstitutiontherapyandARVs.

Theeffectofdarunavir/r(600/100mgtwicedailyfor7days)onthepharmacokineticsofbuprenorphinewasassessedin17HIV-negativesubjectsstableonbuprenorphine/naloxonemaintenancetherapy(dailydosesupto24/6mg).TherewasnoeffectonbuprenorphineAUC,Cmaxortroughconcentrations;however,norbuprenorphineCmaxincreasedby36%andAUCincreasedby46%.Nosubjectrequireddoseadjustmentofbuprenorphine/naloxone.Giventheincreaseinnorbuprenorphineconcentrations,closeclinicalmonitoringofpatientsisrecommended.[1]

Theeffectofraltegravir(400mgtwicedaily)onthepharmacokineticsofmethadonewereinvestigatedin12HIV-negativesubjectsstableonmethadone.ThisstudyreportedthattherewasnochangeineithermethadoneAUCorCmaxinthepresenceofraltegravirandnodoseadjustmentisrequired.[2]

TheinteractionbetweenbuprenorphineandddI,3TCandtenofovirwasinvestigatedin27HIV-negative,buprenorphine/naloxonemaintained subjects. Data for ddI and tenofovir were compared to values obtained from 20 control subjects not receivingbuprenorphine;3TCwascomparedtocontroldata.NosignificantchangesinbuprenorphinepharmacokineticswereobservedwhencoadministeredwithddI,3TCandtenofovir.Whencomparedtocontrols,buprenorphinehadnostatisticallysignificanteffectonNRTIconcentrations.[3]

References1. SekarVJetal.Pharmacokinetic(PK)Interactionbetweendarunavirincombinationwithlow-doseritonavir(DRV/r)andbuprenorphine/naloxone

(bup/nlx).AbstractH-232.2. AndersonMSetal.Effectofraltegravir(RAL)onthepharmacokinetics(PK)ofmethadone.AbstractA1-1295.3. Baker K et al. Interactions between buprenorphine and antiretrovirals: nucleos(t)ide reverse transcriptase inhibitors (NRTI) didanosine,

lamivudineandtenofovir.AbstractA1-1306.

DarunavirandfoodTheoralbioavailabilityandsteadystatepharmacokineticsofapaediatricoralsuspensionofdarunavirwereassessed in twostudiesin23HIV-negativeadultsubjects.Firstly,ritonavir(100mgtwicedaily)wasadministeredondays1-5andasingle600mgdoseofdarunavironday3asa)tabletwithfood,b)suspensionfasted,andc)suspensionwithfood.Inthesecondpart,darunavirpharmacokineticswereassessedfollowingadministrationofthesuspension(600mgtwicedaily)withritonavir(100mgtwicedaily)for7days.Inthefirststudythecriteriaforbioequivalence(90%CIofLSMratioswithinlimitsof80-125%)weremetforCmaxandAUCwhencomparingtablet(withfood)andsuspension(withorwithoutfood).Pharmacokineticdataobtainedwiththesuspensioninthesecondstudywerecomparabletohistoricaldataobtainedwiththesamedoseinthetabletformulation.TheoralsuspensionwillbefurtherevaluatedinpaediatricHIV-positivesubjects.

Ref:SekarVJetal.Bioavailabilityandfoodeffectofdarunavir(DRV)followingadministrationofanoralsuspension.AbstractH-233.



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RaltegavirandrifabutinCoadministration of raltegravir (400mg twice daily) and rifabutin (300mg once daily) was investigated in 16 HIV-negativesubjects.RaltegravirAUCincreasedby19%,Cmaxincreasedby39%andCtroughdecreasedby20%.Thesechangeswerenotdeemedtobeclinicallysignificantandnodoseadjustmentisrequired.

Ref:BrainardDMetal.LackofaClinicallyimportanteffectofrifabutin(RFB)onraltegravir(RAL)pharmacokinetics.AbstractA1-1296.

Raltegavirandfosamprenavirorfosamprenavir/ritonavirThe interactionbetween raltegravirandatazanaviroratazanavir/ritonavirand theeffectof foodwasstudied inHIV-negativesubjects.Raltegravir(400mgtwicedaily)andfosamprenavir(1400mgtwicedaily)orfosamprenavir/ritonavir(700/100mgtwicedailyor1400/100mgoncedaily)wereadministeredaloneandincombinationwithandwithoutalightmeal. TheeffectsaresummarisedinTable1below.Table1.PKinteractionsoffosamprenavirdoseswithraltegravir

raltegravir amprenavir

AUC Cmax Cmin AUC Cmax Cmin

FPV 1400 mg twice daily + light meal:-29% -5% -68% -19% -17% -33%

FPV 1400 mg twice daily, fasted:-37% -28% -38% -36% -27% -43%.

FPV/r 700/100 mg twice daily + light meal:-30% -15% -41% +13% +27% -27%.

FPV /r 700/100 mg twice daily, fasted:-15% +6% -25% -24% -18% -50%.

FPV/r 1400/100 mg once daily + light meal:-254% -56% -54% -25% -25% -33%.

FPV /r 1400/100 mg once daily, fasted:-55% -51% -36% -16% -14% -19%.

Althoughraltegravirexposuredecreasedwithfosamprenavir,especiallyathigherdosesofritonavir,raltegravirCminwere3-to9.4-foldhigher than the IC95 forWTHIV (14.6ng/ml). Amprenavirconcentrationsweredecreased,however,Cmins for theboostedregimenswere2.1-to7.8-foldhigherthantheEC90forPI-naïveHIV+patients(228ng/ml).Theclinicalimplicationsoftheseresultshaveyettobedetermined.

Ref:LuberAetal.Steady-statepharmacokinetics(PK)offosamprenavir(FPV)andraltegravir(RAL)aloneandcombinedwithunboostedandritonavir-boostedFPVAbstractA1-1297.

Etravirineandlopinavir/rThis study looked at the interaction between etravirine (200mg twice daily) and the tablet formulation of lopinavir/ritonavir(400/100mgtwicedaily)in16HIV-negativesubjects.CoadministrationdecreasedetravirineAUC,CmaxandCminby35%,30%and45%,respectively;lopinavirAUC,CmaxandCmindecreasedby13%,11%and20%,respectively.Therewasnochangeinthepharmacokineticsofritonavir.Theseetravirineresultsareincontrasttopreviousdataobtainedwithcapsuleformulationoflopinavir/ritonavirwhichshowedincreasedetravirineexposure.Nodoseadjustmentofetravirineisrequiredastheeffectoflopinavir/ritonavirtabletsissimilartotheeffectofdarunavir/ritonavirseeninclinicaltrialswhichdemonstratedfavourableetravirineefficacyandsafety.Thedecreaseinlopinavirconcentrationswassimilartoearlierdataandisnotconsideredclinicallyrelevant.

Ref:Scholler-GyureMetal.Pharmacokinetic(PK)Interactionbetweenetravirine(ETR)andlopinavir/ritonavir(LPV/r).AbstractA1-1298.

EtravirineandfluconazoleorvoriconazoleThepharmacokineticinteractionbetweenetravirine(200mgtwicedaily)andfluconazole(200mgoncedaily)orvoriconazole(200mgtwicedaily)wasstudiedinHIV-negativesubjects.FluconazoleincreasedetravirineAUC,CmaxandCminby86%,75%and2.09-fold,respectively(n=16);fluconazoleAUC,CmaxandCmindecreasedby6%,8%and9%,respectively(n=15).VoriconazoleincreasedetravirineAUC,CmaxandCminby36%,26%and52%,respectively(n=16);voriconazoleAUCandCminincreasedby14%and23%,butCmaxdecreasedby5%(n=14).Combinationsweregenerallysafeandwelltolerated.

Ref:Scholler-GyureMetal.Pharmacokinetic(PK)interactionbetweenetravirine(ETR)andfluconazole(FLU)orvoriconazole(VOR)inHIV-negativevolunteers.AbstractA1-1299.



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LPV/randechinaceaTheeffectofechinacea(500mgthreetimesdailyfortwoweeks)onthepharmacokineticsoflopinavir/ritonavir(400/100mgtwicedaily)wasstudiedin16HIV-negativesubjects.Neitherlopinavirnorritonavirpharmacokineticswerealteredbycoadministrationofechinacea(lopinavirAUCdecreaseby4%andtherewasnochangeinCmax).AlthoughechinaceahasbeenshownmodulateP4503A4invitro,thesedatasuggestaclinicallysignificantinteractionisunlikely.

Ref:MalatiCYetal.Echinaceapurpureadoesnotalterthesteadystatepharmacokineticsoflopinavirorritonavirinhealthyhumanvolunteers.AbstractA1-1307.

“Quad”fixed-dosecombinationandfoodA“quad”fixeddosecombinationtabletcontainingemtricitabine(200mg),tenofovir(300mg),elvitegravir(150mg)andtheboostingagentGS-9350(150mg)iscurrentlyindevelopment.Thisevaluatedtheeffectsnofood,orlight(373kcal,20%fat)orhigh(800kcal,50%fat)mealsonsingledosesofthe“quad”tabletin24HIV?subjects.Thepharmacokineticsofemtricitabinewereequivalentwhengivenfastedorwitheithermeal.Comparedtothefastingstate,tenofovirAUCincreasedby24%withalightmealandby23%withahighfatmeal;Cmaxincreaseby20%withalightmeal,butwassimilartofastingwithahighfatmeal.ElvitegravirAUCandCmaxincreasedby34%and22%withalightmealandincreasedby87%and56%withahighfatmeal(allcomparedtofasting).TheAUCofGS-9350wassimilarwithalightmeal,butdecreasedby17%withahighfatmeal(allcomparedtofasting).

Ref:GermanPetal.Effectoffoodonpharmacokinetics(PK)ofelvitegravir(EVG),emtricitabine(FTC),tenofovirDF(TDF)andthepharmacoenhancerGS?9350asafixeddosecombinationtablet.AbstractA1-1300.

GS-9350orritonavirtoboostGS-9350GS-9350isCYP3A4inhibitorcurrentlyindevelopmentasanalternativeboostingagenttoritonavir.ThestudycomparedtheeffectsofGS=9350(100or150mgoncedaily)andritonavir(100mgoncedaily)onthepharmacokineticsofatazanavir(300mgoncedaily)in33HIV-negativesubjects.ThehigherdoseofGS-9350wasfoundtobebioequivalent(80-125%)to100mgritonavir(atazanavirGMRsof1.01forAUC,0.92forCmaxand0.98forCmin).AtazanavirexposurewaslowerwiththelowerdoseofGS-9350.

Ref:RamanathanSetal.PharmacokineticboostingofatazanavirwiththepharmacoenhancerGS-9350versusritonavir.AbstractA1-1301.

NVPextendedreleaseformulationNevirapine is licensed for twicedailyadministration,but is frequentlygivenoncedaily. Twoextended release formulationofnevirapinearecurrentlyindevelopment.Patientswhowerestableontwicedailynevirapinewereswitchtooneoftwoextendedreleaseformulations(XR25%andXR20%).Inthe92patientstreatedwithXR,absorptionwasdecreased-Tmaxincreasedfrom<2hwiththetwicedailydosingto6.7-8.6hwiththeXRformulations.CminofXRformulationswerecomparabletothetwicedailyformulation,whereasCmaxoftheXRformulationswerelower.Relativebioavailability(basedonAUC0-24)was80%fortheXR25%formulationand71%fortheXR20%formulation.Novirologicalfailureswereobserved.TheXR25%formulationhasbeenselectedforfurtherdevelopmentduetoitsincreasedbioavailabilityanddecreasedvariabilitycomparedtoXR20%.

Ref:QuinsonAetal.Steadystateevaluationoftwoextendedrelease(XR)nevirapine(NVP)tablets400mgQDcomparedwithimmediaterelease(IR)NVPtablets200mgBIDinHIV-1infectedpatients.AbstractA1-1310.

CONFERENCE REPORTS

5thIASConferenceonHIVPathogenesis,TreatmentandPrevention

19-23July2009,CapeTownIntroduction

Weconcludeourreportsfromthisimportantconferencewiththefollowingarticleonpaediatricstudies.

• Overviewofpaediatricstudies

Overviewofpaediatricstudies

PollyClayden,HIVi-BaseAwealthofpaediatricdatawaspresentedatIAS2009heldinCapeTowninJuly.Alsoprecedingtheconferencewasthe1stInternationalWorkshoponHIVPediatrics,whichlooksasifitwillbecomeanannualfixtureontheconferencecalendarandgaveanadditionalopportunitytopresentanddiscussthestateoftheartinthefield.



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Overall,fartoomuchwaspresentedtoreviewhere.Abstracts,someslidesand,forIAS2009,webcastscanbeviewedontherespectiveconferencewebsites.

Severalthemesoccurredoverandoveragainatbothmeetings.

Nationalcapacityforearlyinfantdiagnosis,whichnotonlyenablesearlyinitiationoftreatmentbutalsogivesaclearerpictureofhowwellpreventionofmother-to-childtransmission(PMTCT)programmesareperforming,withthegoalofvastlyreducingcasesofpaediatricHIV,isnotyetnearlysufficientinmostplaces.

Whereinfantsarediagnosedintime,earlyinitiationoftreatmentisnotwithoutitsdifficulties.Itcan,however,beextremelybeneficialinyoungchildren.

TreatmentofchildrenwhoareHIV-infecteddespiteexposuretosingle-dosenevirapinethroughPMTCTisanotherchallenge,asiswhattodointhelongertermwithexposedchildreninitiatedonaproteaseinhibitor-containingHAARTtoovercometherisksofNNRTIresistance.

Strategiestosimplifyregimens,includingpaediatricfixed-dosecombinationsandonce-a-daydosing,areessentialforsuccessfulmanagementofchildrenwithHIV,asarestrategiestoenableco-treatmentoftuberculosisinthispopulation.

Theresearchsummarisedbelowaddressestheseissues.

EarlyinfantdiagnosisSeveralguidelinesnowrecommenduniversaltreatmentforHIV-infectedinfants.However,inresource-limitedsettingsearlyinfantdiagnosis(EID)isfrequentlyanobstacletoearlyinitiationofantiretrovirals.

AsurveybyWorldHealthOrganization(WHO)asked,“Whatisavailableforearlyinfantdiagnosis?”andfoundthenumberoflaboratoriesinseveralcountriesmismatchedtotheestimatednumberofHIV-exposedinfantsandnecessarytests.Thisassessmentofnationalcapacitywasconductedtoinformrevisionstotheirguidelinesforinfantdiagnosisandtreatment.[1]

Forthissurvey,aquestionnaireonclinicalandlaboratorycapacitywassenttoHIVexpertsin34high-burdencountriesanddatawerecollectedbetweenFebruaryandApril2008.Replieswerereceivedfrom18ofthe34selectedcountries:12African,twoSouthAmerican,twoAsianandoneMiddleEastern.

Thisrevealedhugevariationinthenumberofchildrenassessedperlaboratory(range7-190000duringthestudyperiod).Whenvirologicaltestswereoffered,theentrypointswereusuallyinpatient/outpatientservices,preventionofmother-to-childtransmission(PMTCT)orantiretroviraltherapy(ART)sites,andlaboratorieswerecentralisedandusuallylocatedincapitalcities.SixcountriessurveyedimplementHIVDNApolymerasechainreaction(PCR),5RNAPCRand7both.Tencountriesusedfilterpaperwithdriedbloodspots(DBS)totransportsamples.AllthecountriesthatrespondedhadcapacitytomeasureCD4%andabsoluteCD4cellcounts.

Althoughthesurveyconfirmedthatseveralhigh-burdencountriesarebuildingcapacityforEID,itshowedthatatpresentinmanycountriescapacitydoesnotreflectestimatedneed.

Inmanyresource-limitedcountriesitisonlypossibletouseasinglediagnostictest.Theoptimaltimetoperformthisisunclear,however,particularlywhenchildrenarebreastfed.TheWHOresearchersusedamodeltocalculatethenumberofchildrenbecominginfectedandbeingdiagnosedatdifferenttimepointsfrombirthinordertoestimatetheoptimaltimetodiagnosethemaximumnumberofchildrenbutatthesametimeminimisemortality.[2]

Thismodellingshowedadecreasingtrendof infantsurvivalat6months,dependingonthetimethetestwasperformed.Theinvestigatorssuggestedthat4-6weeksofageistheoptimaltimeforinfanttestinginabreastfeedingpopulation.

Withgreaterlaboratorycapacityandnewertechnology,testingearlierthan6weekscouldmeanearlierinitiationoftreatment.Butthesensitivityofviraldetectiontestsbefore6weeksofageisunknown,particularlywhenperformedoninfantswithantiretroviralexposureforPMTCT.

ASouthAfricanstudylookedatthesensitivityofassaysatearliertimepointsininfantsborntoHIV-positivewomenatRahimaMoosaHospital,Johannesburg.3Bloodwassampledatbirthandat2,4,6and10weeks,andstored.HIV-exposedinfantswereroutinelytestedat6weekswithHIVDNAPCRusingaliquidbloodsample.

StoredDBSsamplesfromeachtimepointweretestedwithHIVDNAPCR(Amplicorv1.5),TaqManHIV-1(CAP/CTM)andAPTIMAHIV-1(GEN-PROBE)assays.Theinvestigatorsusedsamplesfromtwoage-matched,PCR-negativeinfantsascontrols.

MothersreceivedarangeofPMTCTinterventions:noantiretrovirals,single-dosenevirapine(NVP),single-doseNVPpluszidovudine(AZT)orHAART.

At9monthsof thestudy,253/373(68%) infantshad6-weekPCRresults; theremaining120(32%)didnotreturnfor testing.Eighteen(7.1%)wereHIVinfectedat6weeksdespitethemajorityreceivingformulamilkexclusivelyandallreceivingNVPandAZTPMTCTprophylaxis.

Ofthe17infectedinfantswithcompleteresults,bothCAP/CTMandAPTIMAassayswerepositivein11/17,13/13and14/14birth,4-and6-weeksamples,respectively.



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ThequantitativeCAP/CTMassayshowedlowerviralloadresultsat2weeksofage(theonlytimepointwhenfalsenegativesoccurred).TheinvestigatorsnotedthatthiswasprobablyduetoPMTCTprophylaxisincreasingtheproportionalnumberofinfantsinfectedinuterowhocanthereforebediagnosedatbirth.

BothassaysweremoresensitiveforearlierHIVdetectionthanHIVDNAPCR, whichdetected9/17birthsamples.CAP/CTMhadthehighestspecificity(100%)andHIVDNAPCRthelowest(95%).

Althoughthisisasmallsample,newertechnologiesappeartobemoresensitivethanstandardPCR.TheseinitialresultssuggestthatthemajorityofinuteroandperinatalinfectionscanbedetectedbyusingeitherCAP/CTMorAPTIMAassaysiftheyareavailable.

TherewerealsoreportsfromprogrammesusingDBS.

Asub-studyofthePMTCTKesoBoratrialconductedinBurkinaFasousedaquantitativeHIVRNAassay(Biocentric)andassessedDBSsamplescomparedwithpairedplasmasamplesobtainedfromHIV-exposedinfantsagedupto6weeks,3-6monthsand9-18months.[4]Allmeasurementswereperformedlocally.

Thestudyinvestigatorsreported100%sensitivity(102/102)andspecificity(105/105)(95%confidenceinterval(CI)97.2-100%,correlation0.906)usingDBS.Ofnote,BiocentricisthehomebrewANRSassay,sotheywouldhavetodeveloptheirownprobes,reagents,etc.

ACambodianstudyassessedthefeasibilityofveryearlydiagnosis(0-3daysofage)usingheel-pricksamplesonDBSandarealtimeDNAassay(Bicentric). [5]AsecondDBSwasperformedatweek6.Infantswithpositiveresultsat0-3daysor6weekswerefollowedupwithHIVRNAquantificationassoonaspossible.

At0-3days,3/370(0.8%)infantshadpositiveresults(1infantdiedbeforeweek6).327/333wereconfirmednegativeat6weeksand6wereDNApositive(1.8%)andsubsequentlyconfirmedRNApositive.

The investigators suggested that these preliminary results demonstrate the feasibility of a minimally invasive very early diagnosis usingDBS.

DifficultieswithimplementationAstudyfromSwaziland,conductedbythenationalARTprogrammeandtheClintonFoundation,highlightedthedifficultiesoftreatmentinitiationininfantsfollowingearlydiagnosis.[6]

SinceMarch2007theEIDprogrammeusingDNAPCRwasexpandedinresponsetohighinfantmortalityinHIV-infectedchildren.ByNovember2008,however,thishadledtoneitheranincreaseininfantsreceivingtreatmentnoradecreaseinmortality.

Thestudywasaretrospectiverecordreviewofallinfantstestingpositiveat15healthfacilitiesintheManziniRegionfromJanuarytoAugust2008.Theinvestigatorsreportedthat78%ofresultswereavailableatthefacility,and44%ofresultsweredocumentedashavingbeenreceivedbythecaregiver.Only58/176(33%)ofchildrenwereenrolledatanARTcentreand34initiatedontreatment.Ofthosewithdataavailable81%wereeligibleforART,andamongeligiblechildren,82%initiatedtreatment.Overall19%ofinfantstestingpositivewereinitiatedontreatmentatthetimeoftheevaluation.

ThisstudyfoundthatthegreatestpointsoflossarereturnoftheresulttocaregiversandinfantenrollmentattheARTcentrefortreatment.

InfantoutcomesTherearelimiteddatadescribingoutcomesforinfantsinitiatingtreatmentatlessthan1year.

TheMTCTPlusInitiativeshoweddatafromsitesineightAfricancountriesandThailandcomparinginfantswitholderchildreninitiatedbetweenFebruary2003andSeptember2008. [7]

TheinvestigatorslookedatchangeinCD4percentagefrombaselineusinglinearmodellingadjustedfordurationofhighlyactiveantiretroviraltherapy(HAART),country,baselineCD4percentage,NVPexposureforPMTCT,andageatinitiation.

Of542childreninitiatingtreatmentandfollowedupforamedianof30months(intraquartilerange(IQR)12-39),190(35%)wereaged<12monthsatinitiationandtheremainder>12months(median36months,IQR19.5-67),51%weremale,and18%hadCentersforDiseaseControl(CDC)stageCdisease.

Theinfantshadahighermortalityratethantheolderchildren,7.5v.3.2/100person-years.Of31(54%)infantdeaths,81%occurredwithin3monthsoftreatmentinitiation.

Amongthechildrenforwhomdatawere availabletherewasnodifferencebetweeninfantsandolderchildreninchangeofCD4percentagefrombaseline.BaselineCD4percentage(p<0.01)andtimeonHAART(p<0.001)weresignificantlyassociatedwithanincreaseinCD4percentageinmultivariateanalysis.

Inthisanalysis,althoughinfantsinitiatingHAARThadahighermortalityatthestartoftreatment,theinfantswhosurvivedhadgoodimmunologicalresponseover>3yearsoffollow-up,similartothatofolderchildren.

ASouthAfricanreviewofinfantsinitiatedonHAARTattheFamilyClinicforHIVatTygerbergHospitalandIkwezicommunityclinic



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fromJune2007toAugust2008showedhighlevelsofvirologicalsuppressionto24weeks.[8]

Infantsreceivedlopinavir/ritonavir(LPV/r)withstavudine(d4T)andlamivudine(3TC)inaccordancewithSouthAfricanguidelines.Of98initiated,47had24weeksoffollow-up.Oftheremainder,6(6%)werelosttofollow-up,6(6%)diedand33(33.7%)weretransferred.

Themedianageat initiationwas4.5monthsand33 (70%) infantswere≤6monthsold (medianage3.68months).All hadimmunologicalorclinicalcriteriafortreatment.Themajority,42/47(89.4%)ofallinfantsand30/33(91%)≤6monthsofage,hadWHOstage3or4disease.

Tuberculosis(TB)isacommonco-morbidityinthispopulation,and11/47infantsrequiredco-therapywithrifampicin(givenwithadditionalritonavir).

At24weeks37/47children(79%)inthe>6monthsagegroup and26/33(82%)aged<6monthshadviralloads<50copies/mL.

TheinvestigatorsnotedthatthelowageofinitiationoftreatmentinthiscohortreflectedyounginfantswithsevereHIVdiseaseratherthanearlyinitiationoftreatmenttopreventmortalityandmorbidity.

mprovedneurodevelopmentaloutcomesThedevelopingbrainisamajortargetforHIV.Itisnotyetknownwhethertimingofinitiationofantiretroviraltherapywillaffectneurodevelopmentaloutcomesininfants.

AsubstudyofCHERcomparedneurodevelopmentaloutcomesof115infantsinthisstudyfromTygerbergChildren’sHospitalwith84controlinfantsenrolledinalinkedvaccinestudy,CIPRA-SAProject4.[9]

Inthisprospectivestudy,theinvestigatorslookedattheneurodevelopmentalprofile,accordingtotheGriffithsMentalDevelopmentalScales(GMDS),at10-15monthsofageinfourgroupsofinfants:

-HIV-unexposed,uninfected

-HIV-exposed,uninfected

-HIV-infected,HAARTinitiatedbefore12weeksofage

-HIVinfected,HAARTdeferreduntileligibilitycriteriamet.

Theinvestigatorswereblindedtotheinfants’groupsandatranslatorwasusedforXhosa-speakingparticipants.

Of115infantsfromCHERenrolled,13withdrewfromthestudyand/orwerenotco-enrolled(10early,3deferred),8died(alldeferred)and4wereexcluded(3early,1deferred).

TheinvestigatorsfoundthatinfantsinitiatedonearlyARThavesignificantlybetterlocomotorandgeneralscoresontheGriffithsMentalDevelopmentScalesatamedianageof11monthscomparedwithinfantsondeferredHAART.Althoughmeanquotientswerelowerontheothersubscalesinthedeferredgroup,thedifferenceswerenotsignificant.Themeanscoresonallsubscalesintheunexposed,uninfectedgroupandtheearlyHAARTgroupweresimilar.Theynotedtheseresultswere“despitecarefulmonitoringandreadyaccesstoARTinthelatter”(TableI).

TableI.MeanquotientsofinfantsfordeferredvsearlyHAARTandHIV-exposeduninfectedandunexposedinfants

DeferredART Early ART HIV-exposeduninfected

HIV-unexposed p-value early vsdeferred

No.assessed 26 66 28 34 Medianageinmonths(range) 11.0(10.1-14.4) 11.0(10.0-15.5) 11.4(10.1-15.5) 11.5(9.9-13.6) Meanlocomotorquotient(±1SD) 88.9(±16.3) 97.6(±12.5) 105.3(±14.3) 101.6(±3.7) 0.01Meangeneralquotient±1SD 100.1(±13.8) 106.3(±10.6) 106.0(±10.1) 106.9(±11.7) 0.02

TreatingchildrenexposedtosingledosenevirapineforPMTCTTwostudieslookedattreatmentofHIV-infectedchildrenwithpriorexposuretoNVPtopreventMTCT.

Preliminary findings from IMPAACT 1060 confirmed concerns thatNVP-exposed children could do lesswell receivingNVPcontainingHAARTthanproteaseinhibitor(PI)-containingHAART.[10,11]

Thiswasarandomisedtrialoftreatment-eligiblechildrenaged6months-3yearsconductedinsevenAfricancountries.NVP-exposed(cohort1,n=288)andunexposed(cohort2,n=288)childrenreceivedeitherLPV/rorNVP,plus3TCandAZT.Childrenwerestratifiedbyage<12monthsv.≥12monthswithanequalnumbertobeenrolledineachagegroup.

Asimilarstudyofexposedandunexposedmothershadalsobeenconducted(A5208).Inthistrial,thearminwhichexposedmothersreceivedNVP-containingHAART,wasstoppedearlybytheDataSafetyMonitoringBoard(DSMB).ThiswasduetosuperiorperformanceoftheLPV/r-containingHAARTarm.[12,13]



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FollowingascheduledDSMBreviewofIMPAACT1060on20April2009,enrolmenttocohort1alsoclosedprematurelyowingtoatrendtowardsconsistencywiththeA5208results.At24weeks,virologicalfailure(<400copies/mL)wasobservedin40%ofthe60infants<12monthsv.23%≥12monthsreceivingNVPandLPV/r,respectively.Amongtheolderchildren,29%outof22and17%of19receivingNVPandLPV/rexperiencedfailure.

SeveralguidelinesalreadyrecommendusingLPV/r-basedtreatmentforsingle-doseNVP-exposedinfants.

TheNEVERESTstudyinvestigatedwhetherNVP-exposedchildren,initiallysuppressedonLPV/r-basedHAART,cansafelyswitchtoaNVP-basedregimen.[14,15]

Inthisstudychildrenaged6weeks-2yearsandeligiblefortreatment(n=323)wereinitiatedonLPV/rplus3TCandd4T.Childrenachievingaviralload<400copies/mLandstablefor≥3monthswererandomised(N=195)toeitherremainonLPV/r(control,n=99)orswitchtoNVP(switch,n=96),andthenfollowedupto52weeks.

Whentheinvestigatorslookedatviralload<50copies/mlto52weekstheyfoundthat42.4%ofchildreninthecontrolgroupand56.2%intheswitchgroupsustainedviralsuppression(p=0.01).However,allowingforoneelevatedresult(blip)thetwogroupsweresimilar,72.8%vs73.4%inthecontrolandswitchgroups,respectively.

Theysuggestedthatpooreradherenceinthecontrolgroup,duetotheunpleasantnessintasteofLPV/rsyrup,mayhaveledtomoreblippingand,inturn,unsustainedviralsuppressionto50copies/mLduringfollow-up.

Incontrast,whentheylookedatsustainedsuppressionto<1000copies/mL,98%v.80%ofchildreninthecontrolandswitchgroupsachievedthis(p=0.001).

The investigators suggest that this study provides proof of concept that re-use of NVP is possible under some circumstances for HIV-infectedchildrenexposedtoNVPprophylaxisandshouldbefurtherinvestigated.Theynotethattheclinicalsignificanceoflow-levelviraemiainthecontrolgroupneedsfurtherstudy.

Thisgroupalsoshoweddatafromanevaluationoflipidprofilesinchildreninthecontrolandswitchgroups.[16]

Theyfoundnodifferencebetweenthetwogroupsatrandomisation.Butat9monthsafterthechangeinregimennon-fastingtotalcholesterol(TC)andhigh-densitylipoprotein(HDL)weresignificantlyhigheramongtheswitchgroup(meanTC4.13,HDL1.36mmol/l)comparedwiththecontrolgroup(meanTC3.73,HDL1.07mmol/l).Significantlylowertriglyceride(TG)levelswerefoundintheswitchgroup(meanTG1.36mmol/l)comparedwiththecontrolgroup(meanTG1.53mmol/l).

Theynotedthattheclinicalsignificanceofthesenon-fastinglipidchangesrequiresfurtherinvestigation.

SwitchingmayprovideapromisingoptionforchildrenoriginallyinitiatedonPI-basedHAARTtopreservesecond-lineoptions.Atthisstage,switchingrequiresclosevirologicalmonitoringaftertheswitchinordertobedonesafely.

AnotherNEVERESTtrialofefavirenz(EFV)vsLPV/risplannedinnevirapine-exposedchildren>3yearsold.

Thesestudiesallunderscorethelimitedtreatmentoptionsavailableforchildren,particularlyinresource-limitedsettings.

Usinganevirapine-containingfixeddosecombinationintheCHAPAStrial

Paediatricfixeddosecombination(FDC)tabletsprovidesimpleralternativestoliquidsforchildren.

Ciplahaveproducedscored,dispersibletabletsofd4T/3TC/NVP(babyandjuniorTriomune)withthecorrectdoseratiosforchildren.

Asub-studyoftheCHAPAStrial(ChildrenwithHIVinAfricaPharmocokineticsandAdherenceofSimpleAntiretroviralRegimens),inZambia,evaluatedtheneedfordoseescalationofNVP.[17]Thisstrategyiscurrentlyrecommendedbutrequiresdosingwithseparatetablets,makinginitialtreatmentmorecomplex.

Childrenwererandomisedtostartantiretroviraltherapywithfull-doseNVP(Triomuneam/pm)vsdoseescalation,usinganinitial14daysofhalf-doseNVP(Triomuneam;Lamivir-S(combinedd4T/3TC)pm)followedbyfulldose.ChildrenweredosedinaccordancewithWHOweightbandtables.Theprimaryendpointwasclinical/laboratorygrade3/4adverseevents(AEs)relatedtoNVP.

Inthiscomparison,211childrenaged2-9yearswithamedianCD4percentageof13%werefollowedforamedianof92weeks.Severestunting,wastingandimmunosuppressionwerecommoninthechildren.Seventeenchildrenwerelosttofollow-up.

Theinvestigatorsreported31(18per100person-years)vs29(16.5per100person-years)grade3/4AEsdefinitely/probablyoruncertainlyNVP-relatedinchildrenreceivingfull-dosevsdose-escalation(incidencerateratio(IRR)1.09(95%CI0.63-1.87),p=0.74).

Twelve(11%)full-dosevs2(2%)doseescalationchildrenhadgrade2disseminatedskinrashand1receivingfulldosehadgrade1rash.Twochildren(onefromeacharm)substitutedwithEFV;3continuedfull-doseNVP;9(8fulldoseand1doseescalation)stoppedNVPandrestartedwithsuccessfuldoseescalation;and1fulldosestopped,startedalowerNVPdose,hadanotherrashandsubstitutedEFV.

Overall90%ofchildrenwhostartedwithfull-doseNVPcontinueduninterruptedinthisstudy.Asdoseescalationrequiresprovisionofseparatedrugformulations,theevaluationofpolicyimplicationsfordoseescalationofNVPinfixed-dosecombinationHAARTisongoing.



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TheCHAPAStrialalsoinvestigatedthepharmacokineticsofNVPinchildrentreatedwithTriomuneBaby/Juniorandrifampicin-basedtuberculosistreatment.[18]

EFV-basedregimensarecurrentlyrecommendedforconcomitantusewithrifampicin,butEFVisnotcurrentlyindicatedforchildrenbelow3yearsofage.EarlierCHAPASdatasuggest that thehigherdoseratioofNVPtoNRTI inTriomuneBaby/Juniormaycompensateforthedosereductioninducedbyrifampicin.

Pharmacokineticsamplingwasperformedin22childrenafter4weeksofconcurrentNVPandrifampicin-containingregimens.Rifampicinwasdosedat10-20mg/kgperday.Sampleswerepre-dose(C0) and 1, 2 and 6 hours post-dose, and nevirapine plasmaconcentrationsweredeterminedusingLC-MS/MS.NVPpharmacokineticsinchildrenwithoutTBtreatment(n=16)werecomparedinmultivariatelinearregressionanalysis.Themedianageofthe21childrenanalysedwas1.55(range0.66-3.18)years,and10weregirls.

Theinvestigatorsfoundthatonly11(52%)ofthechildrenreceivingTBtreatmentreachedsufficientNVPtroughlevels(C0 <3.0mg/L).Multvariateanalysisrevealeda41%(95%CI24-55%)reductioninnevirapineAUCwithconcomitantrifampicin.Theynoteda3.4%increaseinAUCforeach10mg/m2increaseinNVPdose/m2.

Theyrecommendcautionwiththisapproachinyoungchildrenuntilmoreefficacyandsafetydataareavailable.TheysuggestthatanincreasedNVPdoseislikelytobenecessaryandrequiresfurtherevaluation.

Onceadaylamivudineandabacavir,andabacavirhypersensitivityintheARROWtrial

SimplificationofHAARTregimensprovidesbenefitforchildren,caregiversandhealthworkers.Todatetherearenodataononce-dailyuseof3TCandabacavir(ABC)inresource-limitedsettings.

AsubstudyfromtheARROWtrial(arandomisedtrialofmonitoringandfirst-lineinduction-maintenancestrategies)comparedthePKofonce-v.twice-daily3TCandabacavir(ABC)(Kivexa).[19]Thiswasacross-overstudyperformedin41Ugandanchildrenaged3-12yearsreceivingHAART,dosedaccordingtoweightbands.TheARROWtrialusesscoredtabletsofABC/3TCtoensurebetteraccuracyofdivisionandmoreflexibledosing.Totaldailydoseswere150+300mg,225+450mgand300+600mgforchildrenweighing12-20kg,20-25kgand>25kg,respectively.

PKsamplingwasperformedfortwice-dailydosingatsteadystate(36weeks)pre-dose,and1,2,4,6,8and12hourspostdose.Childrenwerethenswitchedtotheonce-dailydoseandfurthersamplingwasperformedat4weekswithanadditionalsamplingat24hours.

Dailyareaunderthecurve(AUC0-24)andpeaklevel(Cmax)werecomparedbygeometricmeanratios(GMR).GMRwith90%CIwithin0.80-1.25wasconsideredtobebioequivalent.

PKparameterswereavailablefor35and36childrenfor3TCandABC,respectively.Approximatelyhalfwereintheyoungeragegroup.

Theinvestigatorsreportedthatinchildren3-12years,AUC0-24 ofboth3TCandABCwerebioequivalentwithonceandtwicedailyregimensbutCmaxwas76%and64%higherfor3TCandABCrespectively.Nograde3/4adverseeventswerereportedandnochilddiscontinuedaftertheswitchtoonce-dailydosing.

Inthisanalysis,incontrasttodatafromEuropeanchildreninPENTA13,3TCAUClevelsin3-6-and7-12-year-oldchildrenweresimilarforbothonce-andtwice-dailydosingandsimilartolevelsinolderchildren.TheinvestigatorsnotedthatmanyyoungerchildreninPENTA13,whose3TClevelswerelower,receivedsyrups,butARROWchildrenreceivedtablets.Theyconcludedthattheseresultssuggestthatonce-dailydosingof3TCandABCisfeasibleinresource-limitedsettings.

TheARROWinvestigatorsalsoshoweddatadescribingsuccessfulmanagementofhypersensitivityreactionsamongchildreninthistrialinUgandaandZimbabwe.[20]

TheWHOrecommendsABCforpaediatricfirst-linetreatment.Hypersensitivityreactions(HSR)occurin2-5%ofpeoplereceivingABC in clinical trails and are strongly associatedwiththepresenceoftheHLA-B*5701allele.ProspectivescreeningforHLA-B*5701issometimesrecommended,butthispharmacogenetictestisrarelyavailableinresource-limitedsettings.

ClinicaldiagnosisandmanagementmaybecomplicatedinthissettingduetowidespreaduseofNVPandcotrimoxazoleandfebrileinfections.

Healthworkersandcaregiverswere trained in recognitionandmanagementofABC-HSRandall suspectedHSRunderwentindependentclinicalreview.ABCwasonlydiscontinuedin7cases.

TheinvestigatorsreportedthatsuspectedABC-HSRwasrare(3/1207,0.2%(95%CI,0.05-0.7%))inthistrial,consistentwithreportsofalowerprevalenceofHLA-B*5701inblackpopulations.Clinicalsymptoms(fever,rash)occurred9-13daysafterinitiationofHAART;2/3caseshadadditionalgastro-intestinalandrespiratorysymptomsandrequiredhospitalisation.

ABC-HSRwassuccessfullymanageddespiteco-administrationofcotrimoxazoleandNVP,andtheinvestigatorsrecommendthatABCcanbeusedsafelyinresource-limitedsettings.

Thisarticlefirstappearedinissue36oftheJournalofHIVMedicine,thejournaloftheSouthernAfricanCliniciansSociety.

http://www.sahivsoc.org

References



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Unlessotherwisestated,all referencesare to theprogrammeandabstractsof the5th IASConferenceonHIVPathogenesis,TreatmentandPrevention,19-22July2009,CapeTown.1. PenazzatoM,CrowleyS.Whatisavailableforearlyinfantdiagnosis?:resultsfromWHOsurvey2008.AbstractWEPEB269. http://www.ias2009.org/pag/Abstracts.aspx?AID=26442. PenazzatoM,CrowleyS.Earlyinfantdiagnosisinresourcelimitedsettings:determiningtheoptimumtiminginabreastfeedingpopulation.

AbstractWEPEB270. http://www.ias2009.org/pag/Abstracts.aspx?AID=26563. ShermanGetal.EarlierdiagnosisofHIVinfectionininfantsinlowresourcesettings.AbstractWEPEB267. http://www.ias2009.org/pag/Abstracts.aspx?AID=20934. GampiniSEetal.EarlydiagnosisofpaediatricHIV-1infectionamongWest-Africanbreast-fedchildrenusingdriedbloodspotsandaquantitative

HIV-1RNAassay.AbstractWEPEB264. http://www.ias2009.org/pag/Abstracts.aspx?AID=9385. Ngin Setal.VeryearlydiagnosisofHIVinfectioninnewbornatday0-3onDBSinCambodia.AbstractMOPEB009. http://www.ias2009.org/pag/Abstracts.aspx?AID=22126. SundaramMetal.IdentificationpatientlosspointsfromtestingtotreatmentinitiationamonginfantstestedinSwaziland.AbstractMOPDD103. http://www.ias2009.org/pag/Abstracts.aspx?AID=19817. CarterRJetal.Immunologicresponseandsurvivalofinfantsinitiatingantiretroviraltreatment(ART)atlessthanoneyearofagecompared

toolderchildrenenrolledatMTCT-PlusInitiativesitesin8AfricancountriesandThailand.AbstractMOPEB048. http://www.ias2009.org/pag/Abstracts.aspx?AID=20218. RabieHetal.24weekoutcomeofinfantsstartedonlopinavir/ritonavirbasedHAARTinaresourcelimitedsetting.AbstractMOPEB076. http://www.ias2009.org/pag/Abstracts.aspx?AID=4929. LaughtonBetal.EarlyantiretroviraltherapyisassociatedwithimprovedneurodevelopmentaloutcomeinHIVinfectedinfants:evidencefrom

theCHER(ChildrenwithHIVEarlyAntiretroviralTherapy)trial.AbstractMOPEB080. http://www.ias2009.org/pag/Abstracts.aspx?AID=162910. ViolariAetal.Nevirapinevs.lopinavir-ritonavir-basedantiretroviraltherapy(ART)insingledosenevirapine(sdNVP)-exposedHIVinfected

infants:preliminaryresultsfromtheIMPAACTP1060trial.HIVPediatrics,17-18July2009,CapeTown.AbstractO_08. http://www.hivpresentation.com/index.cfm?vID=5B52BC82-423A-F6F7-C31E763DE1C6FAB711. PalumboPetal.Nevirapine(NVP)vs.lopinavir-ritonavir(LPV/r)-basedantiretroviraltherapy(ART)insingledosenevirapine(sdNVP)-exposed

HIV-infectedinfants:preliminaryresultsfromtheIMPAACTP1060trial.AbstractLBPEB12.12. http:/www.i-base.info/htb/v9/htb9-11-12/OCTANE.html13. http://www.i-base.info/htb/v10/htb10-3-4/lopinavir.html14. CoovadiaAetal.RandomizedclinicaltrialofswitchingtoNVP-basedtherapyforinfectedchildrenexposedtonevirapineprophylaxis.HIV

Pediatrics,17-18July2009,CapeTown.AbstractO_09. http://www.hivpresentation.com/index.cfm?vID=5B526AE8-423A-F6F7-C3840703869307AA15. CoovadiaAetal.Randomizedclinicaltrialofswitchingtonevirapine-basedtherapyforinfectedchildrenexposedtonevirapineprophylaxis.

AbstractMOAB103. http://www.ias2009.org/pag/Abstracts.aspx?AID=374616. StrehlauRetal.Changesinlipidprofilesafterswitchingyoungchildrenfromasuppressivelopinavir/ritonavir-basedregimentoanevirapine-

basedregimen.Abstract TUPEB166. http://www.ias2009.org/pag/Abstracts.aspx?AID=112517. KabambaDetal.StrategiesfornevirapineinitiationinHIV-infectedchildrentakingpaediatricfixed-dosecombination‘babypills’inZambia:

arandomisedcontrolledtrial. AbstractMOPEB090. http://www.ias2009.org/pag/Abstracts.aspx?AID=301118. OudijkJMetal.PharmacokineticsofnevirapineinyoungchildrenduringcombinedARTandrifampicin-containingantituberculosistreatment.

AbstractLBPEB10. http://www.ias2009.org/pag/Abstracts.aspx?AID=371519. MusiimeVetal.PharmacokineticsofonceversustwicedailylamivudineandabacavirinHIV-1infectedUgandanchildrenintheARROWtrial.

AbstractWEPEB271. http://www.ias2009.org/pag/Abstracts.aspx?AID=159420. Nahirya-Ntege Petal.Successfulmanagementof suspectedabacavir hypersensitivity reactionsamongAfricanchildren in theARROW

(AntiRetroviralResearchforWatoto)trial.Abstract TUPEB183. http://www.ias2009.org/pag/Abstracts.aspx?AID=1737



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TREATMENT ACCESS

FDAapprovalofgenericARVsSincethelastissueofHTB,theUSFoodandDrugAdministration(FDA)hasgrantedtentativeapprovalforthefollowingnewgenericARVproducts.

Drugandformulation Manufacturer, Country

Approvaldate

Efavirenztablets50,100and200mgtablets Matrix,India 24 November 2009Lopinavir/ritonavirtablets200/50mg Cipla, India 20 November 20093TC/tenofovirDF300/300mgFixedDoseCombination(FDC)

Hetero, India 05November2009

“TentativeApproval”meansthatFDAhasconcludedthatadrugproducthasmetallrequiredquality,safetyandefficacystandards,butbecauseofexistingpatentsand/orexclusivityrights,itcannotyetbemarketedintheUnitedStates.Tentativeapprovaldoes,howevermaketheproducteligibleforconsiderationforpurchaseunderthePEPFARprogramforuseoutsidetheUnitedStates.

Effectivepatentdatesarelistedintheagency’spublicationtitledApprovedDrugProductswithTherapeuticEquivalenceEvaluations,alsoknownas the Orange Book:http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm

c o m m e n t

ThisbringsthetotalofFDAapprovedgenericdrugsandformulationsto104sincetheprogrammestarted.AnupdatedlistofgenerictentativeapprovalsisavailableontheFDAwebsite:

http://www.fda.gov/oia/pepfar.htm

Source:FDAlistserve:

http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm122951.htm

AIDSandmortalityinSouthAfrica

NathanGeffen,aidstruth.orgOn2November2009,StatisticsSouthAfricareleasedthelatestmortalitydata,whichgoesupto2007(StatsSA,2009),detailedinTable1.[1]

Youdonotneedtobeastatisticiantobeastoundedbythis.Recordeddeathshaveincreasedover90%inadecade.Improveddeathregistrationandpopulationgrowthcanaccountforonlyasmallportionofthisincrease.ThevastmajorityofadditionaldeathsareduetotheHIVepidemic.Ahugebodyofevidenceshowsthis.Forexample,therehasbeenathree-foldincreaseinTBdeathsoverthesameperiodandTBistheleadingcauseofdeathinpeoplewithHIV.Alsotheagepatternofthedeaths-youngerinsteadofolderadultscomprisethebulkofthem-andthedropinthemedianageofdeathfrom51in1997to44in2007areconsistentwiththewayAIDSworks.[2,3,4]Table1:Numberofrecordedannualdeathsandpeopleontreatment

Year Number of recorded deathsbyStatsSA[1]

No people on treatment [5]

1997 317,131 `1998 365,852 `1999 381,820 `2000 415,983 `2001 454,847 6,0002002 502,031 15,0002003 556,769 26,0002004 576,700 47,0002005 598,054 1090002006 612,462 229,0002007 601,033 371,0002008 - 568,000



24

Alsonoticeableisthatthenumberofdeathsappearstohavestabilisedfrom2005to2007andperhapshasevenbeguntodecreaseslightly.Thisismostlikelyduetothestate’santiretroviral(ARV)treatmentprogramme.Unfortunatelybecausethepublicsectorprogrammehasnotbeenwellmonitoredandtherearenumeroustreatmentprovidersintheprivatesector,thereisnotaccuratedataonthenumberofpeopleontreatment.Butbyusingseveralsourcesofdata,includingfigurespublishedbytheDepartmentofHealth,medicalaiddataandpublicsectorARVprocurementdatait ispossibletomakereasonableestimates.MuhammadAarifAdamofSanlamandLeighJohnsonoftheCentreforActuarialResearchhavemadeplausiblecalculationsofthenumberofpeopleontreatmentinthemiddleofeachyearupuntilmid-2008,shownalsoinTable1.[5]

Theprogrammebeganinearnestin2004andthestabilisationofthedeathratehascoincidedwithit.Ifyouconsiderthatmany,perhapsmost,ofthepeopleontheprogrammewouldbedeadbynowthatwouldeasilyaccountforstemmingrisingdeaths.Makenomistake;therehasbeenamassivesurgeindeathsinSouthAfricaformorethanadecadeandAIDSdeathscontinuetobeveryhigh;deathsmighthavestabilisedbutataveryhighnumber.Lifeexpectancydeclinedtothelow-50s.Atleastthough,weareimplementingthemosteffectiveknownscientificmedicalinterventiontomitigatetheeffectsofthediseaseanditnowappearsthatlifeexpectancyisincreasingagain.

Butmanyunnecessarydeathsoccurredbecauseof thedelayedrolloutof theARVtreatmentprogramme.TwostudieshaveconservativelyestimatedthatformerPresidentThaboMbeki’sAIDSdenialistpoliciescostwellover300,000lives.[6,7]

Mbekididnotpursuethisdeadlypolicywithouthelpthough.Officials ingovernment,civilservantsandevensomejournalistssupportedhispolicy,triedtogiveitlegitimacyandforatimesucceededinquashingthedemandforatreatmentrolloutfromhealthworkersandAIDSactivistorganisations,liketheTreatmentActionCampaign(TAC).Thankfully,wehavemovedbeyondthisawfuleraofSouthAfricanhistory.

InthelasttwoweekshaveseenwhatIbelieveisthefinaldeath-knellofstate-supportedAIDSdenialism.BothPresidentZumaandMinisterofHealthMotsoaledihavedeliveredimportantspeechesshowingtheirintentiontofighttheepidemic.Onpage35ofhispresentationMotsoalediquotedmortalitydatafor2008fromHomeAffairswhichappearstobefartoolarge.Iamunawareofhowthisnumberwasderivedanditappearstobeanerror.InotherrespectsMotsoaledi’sspeechwasexcellentandhismistakeisofnogreatimportance.

References1. StatisticsSouthAfrica.2009.MortalityandcausesofdeathinSouthAfrica,2007:Findingsfromdeathnotification.2. DorringtonRetal.2006.TheDemographicImpactofHIV/AIDSinSouthAfrica.3. DorringtonRetal.2001.TheimpactofHIV/AIDSonadultmortalityinSouthAfrica.4. StatisticsSouthAfrica.2002.CausesofdeathinSouthAfrica1997-2001:Advancereleaseofrecordedcausesofdeath.5. AdamMandJohnsonL.2009.EstimationofadultantiretroviraltreatmentcoverageinSouthAfrica.September2009,Vol.99,No.9SAMJ6. NattrassN.2008.AIDSandtheScientificGovernanceofMedicineinPost-ApartheidSouthAfrica.AfricanAffairs2008107(427):157-176.7. ChigwedereP.2008.EstimatingtheLostBenefitsofAntiretroviralDrugUseinSouthAfrica.JAIDSJournalofAcquiredImmuneDeficiency

Syndromes.49(4):410-415,December1,2008.

Source:www.aidstruth.org(16November2009).http://www.aidstruth.org/features/2009/aids-and-mortality-south-africa

PunishingsuccessintacklingAIDS:funders’retreatcouldwipeouthealthgainsinHIVaffectedcountries

MSFpressreleaseA retreat from international funding commitments for AIDS threatens to undermine the dramatic gains made in reducing AIDS-related illnessanddeathinrecentyears,accordingtoanewreportbyMédecinsSansFrontières(MSF).[1]

Thereportexpressesconcernthattheinternationalcommunityisbackingoffofcommitmentstosupportuniversalaccesstargetsand point to a number of troubling signs including:

• ThefundingproblemsoftheGlobalFundtoFightAIDS,TB,andMalaria(GFATM).ThefundingshortfallsledtosubstantialcutsinRound8approvedproposals(10%inPhase1,and25%inPhase2)andmayleadtoadditionalcutsonRound9approvedproposals.Also,weareveryconcernedthattheBoardofDirectorsoftheGFATMmayapprovearesolutionbeingtabledtodelayRound10until2011,againbecauseoflackoffunds.

• TheflatliningoftheUSgovernment’sbudgetforPEPFARin2010and2011andcapsonnewpatientsonART,aswellasanxietyandmixedmessagesleadingtocappingenrollmentinUganda.

• ThechangesinthedonorlandscapeincludingNetherlands,thethirdlargestdonorthroughbilateralchannels,iscuttingitsaidby30%,andtheUKwhichhadledthecampaigntosupportuniversalaccesstotreatmentattheG8Summit2005providinglessmoneytosupportscale-up.

• ThedangeroustrendsintheglobalpolicyarenawheredetractorsofAIDSfundingarecallingforadiversionofHIV/AIDSfundsfor other health issues, rather than building upon the success of the mobilisation of resources for AIDS by insisting that global health,ofwhichHIVisapart,beadequatelysupported.



25

Italsopointstotheprogressofthelastyears,especiallyinSouthAfricaandMalawi,ofscaling-upARTandtheresultingimpactinreducingmortalityandmorbidityandwarnthatunlesssustainedandincreasedfundingforHIV/AIDSisprovided–bynationalgovernmentsaswellasdonors–weriskpunishingthesuccessofthelastyears.

TheMSFreporthighlightshowexpandingaccesstoHIVtreatmenthasnotonlysavedthelivesofpeoplewithAIDSbuthasbeencentraltoreducingoverallmortalityinanumberofhighHIVburdencountriesinsouthernAfricainrecentyears.InMalawiandSouthAfrica,MSFobservedverysignificantdecreasesinoverallmortalityinareaswhereantiretroviraltherapy(ART)coveragewashigh.Increasedtreatmentcoveragehasalsohadanimpactontheburdenofotherdiseases,forexampletuberculosiscaseshavebeensignificantlyreducedinThyolo,MalawiandWesternCapeprovince,SouthAfrica.

InternationalsupporttocombatHIV/AIDSisfalteringasreflectedinsignificantfundingshortfalls.TheboardofdirectorsoftheGlobalFund,akeyfinancerofAIDSprogrammesinpoorcountriesisunabletorespondtocountries’needsandwillnextweekinAddisAbabavotewhetherornottosuspendallnewfundingproposalsin2010;andPEPFAR,theUSAIDSprogrammeisflatliningfundingfortwomoreyears.

The report provides evidence that, particularly in high HIV-prevalence settings, treating AIDS has a positive impact on other important healthgoals,inparticularmaternalandchildhealth.

Atpresent,overfourmillionpeoplelivingwithHIV/AIDSinthedevelopingworldreceiveantiretroviraltherapy.Anestimatedsixmillionpeoplewhoareinneedoflife-savingtreatment,arestillwaitingforaccess.MSFoperatesHIV/AIDSprogrammesinaround30countriesandprovidesantiretroviraltreatmenttomorethan140,000HIV-positiveadultsandchildren.

Source:MSFPress release: “Punishingsuccess in tacklingAIDS:Funders’ retreatcouldwipeouthealthgains inHIVaffectedcountries”. (5November2009).

DownloadPDFreport:

http://www.msf.org.za/punishing_success.pdf

ANTIRETROVIRALS

TibotecissuesDearDoctorletterinEuropeconcerningsevereetravirinereactions:threecasereports

Followingtheapprovalofetravirine,threecasesofsevereskinrashorhypersensitivityinpatientsonetravirinecontainingregimensresulted,inAugust2009,intheissuingofaDearHealthcareProfessional(DHCP)letterintheUnitedStates,thatwepublishedinthelastissueofHTB.[1]

On19thOctober,TibotecissuedasimilarlettertohealthcareworkersintheUK.Asthisletterhasnotbeenpublishedonline,pleaseseetheSeptember/OctoberissueofHTBfortheUSletter.[2]

ThethreecasestudiesthatledtotheUSletteraresummarisedbelow.

Case1:A49yearoldHIVpositivefemaledevelopedTEN,resultinginherfatality.Firstsymptomsofrash(widespreadrashwithintenseitching)appeared10daysafterstartingetravirine/darunavir/raltegravir.Fourdayslater,therashwasdescribedaspapularandpruritic.Afurther4dayslater,prurituswasincreasinglywidespreadwithfinemacropapularerythemaonthepatient’sback.Darunavirwaswithdrawnafter19daysoftreatmentandlopinavir/rwasprescribed.Atthistime,theoralcavitywasclear.After3days,therashhadimprovedbutthepatientexperiencedongoingcutaneousirritation.Therashhadsettledsevendayslater;however,thepatientstillexperiencedcutaneousirritationanddevelopedheadacheandarthralgia.Allmedicationswerewithdrawn(etravirinewaswithdrawnafter29daysoftreatment).Thepatientwashospitalizedwitherythroderma,oralulceration,andafever(40.5°C).Thepatientexperiencedarashthatinvolvedmorethan30%ofherbodysurfacearea,mucosalulceration,likelyvaginalinvolvement,andhemorrhagicconjunctivitis.TENwasdiagnosed.Thepatientunderwentanemergencytracheotomyanddied.ThereportingphysicianfeltthatthecauseofTENwasanAdverseDrugReaction(ADR),astherewasnoobviousprecedinginfectionoralternativecause.

Case2:A49yearoldHIVpositivefemaleexperiencedseverehypersensitivityreactionwithhepaticfailure,fromwhichsherecovered.Thepatienthadahistoryofincreasedhepaticenzymeswhileonnelfinavirandnevirapinetherapy,andhypersensitivitytoefavirenz,indinavir,andsulfamethoxazole/trimethoprim.ARVtreatmentwithlopinavi/r,raltegravir,andetravirinewasstartedsimultaneously.SeventeendaysafterstartingART,shedevelopedarash(notfurtherspecifiedregardingseverityorclinicalaspect).AllARVswerestopped2dayslater.Sevendayslater,thepatientwashospitalisedforhepatitis.Thepatient’sliverfunctiontests(LFTs)peakedat3,000u/Landshesubsequentlydevelopedprogressivehepaticencephalopathy.Thepatientrespondedtohighdosesteroidsandrecoveredfromtheevents.Liverbiopsyresultsrevealedprogressivediffuseactivedestructivehepatitiswithgloballobulardisarray,infiltratingmononuclearcells,andextensivehepatocellularnecrosis.Thesefindingswerenotcompatiblewithaviralortoxic/metabolic/druginducedhepatitis.



26

Case3:A31yearoldHIVpositivemaleexperiencedTEN(reportedasLyell’ssyndrome)whileonetravirinetreatmentforHIVinfection.Thesubjectexperiencedagrade4rashwithmucosalinvolvement,22daysafterstartingtreatmentwithETR.Fullbloodcountandbiochemistrywerereportednormal.TreatmentwithETRwasstopped8dayslater.Thepatientwashospitalised2dayslaterwithgeneralizederythematousrash,itchy,withpinkandhydratedmucousmembraneswithdiffuseconfluenterythematousrashonthetrunkandlimbs.Therewerenolesionsintheoralmucosa,butthereweremucosallesionsinthegenitalandperianalregion.ThiswasdiagnosedasToxicodermatosis(subsumedunderLyell’ssyndrome).Approximatelytwoweeksafterstoppingtreatmentwithetravirine,thepatientdiedfrommyocardialinfarction.ThephysicianconsideredtherelationshipbetweenLyell’ssyndromeandetravirineaspossibleandthedeathfrommyocardial infarctionasnotrelatedtoetravirine.Inseptember2009,theinvestigatordowngradedthecasetoaStevensJohnsonSyndrome.Thesubject’smedicalhistoryandconcurrentconditionsincludedalcoholism,cardiacinsufficiency,coronaryangioplastyanddilatedmyocardiopathy.

ForfurtherinformationpleasecontacttheMedicalVirologydepartmentsatTibotecdirectlyon+44(0)1494568313.

References1. TibotecUSHealthProfessionalLetter,October2009. http://www.tibotectherapeutics.com/tibotectherapeutics/documents/INTELENCE_DHCP.pdf2. Etravirine(Intelence)labelchangeintheUSduetoseverehypersensitivityreactions.HTBSeptember/October2009. http://www.i-base.info/htb/v10/htb10-9-10/Intelence.html

GSKandPfizerlaunchjointHIVcollaborationFollowingtheinitialannouncementinApril2009ofacollaborationbetweenGlaxoSmithKlineandPfizer’stocreateanewspecialistcompanydedicatedtoHIV,calledViiVHealthcarewaslaunchedon3November2009.GSKholdsan85%interestinViiVHealthcareandPfizerholds15%.

ViiVHealthcarehas10licensedmedicineswhichgenerated£1.6billionin2008andapipelineofseveninvestigativecompounds,includingfiveinphaseIIdevelopmentand10otherpotentialmoleculestodevelopnewHIVtreatments.

GSK previous PositiveAction programmewill be at the core of ViiVHealthcare’s partnership programmes, supporting localcommunitiesimpactedbyHIV/AIDSglobally.

TheViiVwebsiteprovidesanoverviewofthenewcompanyanditscurrentactivities,includingPositiveActionandCommunityPartnerships,theR&Dpipeline,initiativestoimproveaccess,andcorporategovernance:

Source:CompanyPressRelease:“ViiVHealthcare-aglobalspecialistHIVcompanyestablishedbyGlaxoSmithKlineandPfizertodeliveradvancesintreatmentandcareforpeoplelivingwithHIV”.(3November2009).http://www.viivhealthcare.com

DRUGRESISTANCE

RateofaccumulationofTAMSslowinpatientscontinuingonfailingAZTord4Tcontainingregimens

PollyClayden,HIVi-BaseFirstlineregimensinresourcelimitedsettings(RLS)–ascurrentlyrecommendedbyWHO-areusuallytwonucleosides,3TCplusathymidineanalogue(TA)eitherd4TorAZT,andoneNNRTI.

Mostprogrammeshavelimitedaccesstovirologicalmonitoringandgenotyperesistancetesting.Becauseofthismosttreatmentswitchesarebasedonclinicalorimmunologicalfailure.

AconsiderablenumberofpatientsareexpectedtoreceivefailingTAcontainingregimensforextendedperiodsbeforeswitchingtosecondline.SincethenucleosidedrugsinsecondlineregimensmaybecompromisedbypresenceofTAMSthereisconcernovertheconsequencesofaccumulationofTAMSbeforeswitching.

AlessandroCozzi-Lepriand investigators for theEuroSIDAStudyGroupusedEuropeancohortdata toestimate therateandpredictorsofaccumulationofTAmutations(TAMS)inpatientswhocontinuetoreceivefailingregimens.Inanarticlepublishedinthe1September2009issueoftheJournalofInfectiousDiseasestheyreportlowerthananticipatedaccumulationofTAMsinpatientsexperiencingvirologicalfailure.

TheinvestigatorsanalyseddatafrompatientsintheEuroSIDAstudywhoexperiencedvirologicalfailure(definedasfirstviralload>=500copies/mLafter>=6months),with>=2genotyperesistancetests(GRTs)whilereceivingthesameTA-containingregimen,withaviralloadof>500copiesatboth.Thetimeofthefirstgenotypetestresultsinapairwasdefinedast0,thedateoftheveryfirstgenotypeusedintheanalysisasbaseline-t0.



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Inthisanalysis,themajority(87%)ofgenotyperesultswereobtainedretrospectivelyfromstoredsamples.

TherateofTAMaccumulationwascalculatedasthenumberofTAMsdetectedatt1thatwerenotpresentatt0dividedbytheintervalbetweent0andt1.TheinvestigatorsusedamultivariatePoissonregressionmodeltoidentifyindependentpredictorsofTAMaccumulation.

Theyalsosimulatedascenario inwhichallpatientsstudiedwereswitchedtoaWHOrecommendedsecondlinenucleosides(egAZT+ddIorABC+ddI)aftertheextendedperiodonfailingTA-containingHAART.ThiswasusedtoestimatethedecreaseinsusceptibilityofsubsequentregimensduetheaccumulationofTAMs.

Thestudypopulationof339patientsprovided603pairsofGRTs.Att0theirmedianagewas39yearsand14%werefemale.Ofthisgroup67%hadonepairofGRTs;18%hadtwo;6%had3and9%morethanthreepairsofGRTs.Theirmedianviralloadwas4.11logcopies/mLandCD4244cells/mm3.Theywereverytreatmentexperienced,53%hadfailed1-3drugsbeforebaselinet-0andtheremainder4ormoredrugs;35%hadfailedanNNRTIand72%aPI.

Duringtheintervalt0-t1(median6months,range1-89months)theinvestigatorsreportedthepatientshavingverystableviralloads(meanabsolutechange+0.03logcopies/mL,95%CI-0.3to+0.09,p=0.29)andCD4counts(meanabsolutechange-5.74cells/mm3,95%CI-2.52to+14,p=0.17).

Overt0-t1allpatientswerereceivingeitherAZTord4T,whichtheyreceivedforamedianof9and15monthsdurationrespectivelyfromvirologicalfailuretot1.Twenty-ninepercentreceivedanAZT-containingregimen(176pairs)and71%ad4T-containingregimen(427pairs).BesidestheTA,themajority(70%)ofpatientswerereceiving3TCatt0.OtherfrequentlyusednucleosideswereddI(25%)andabacavir(18%).ThemostcommonNNRTIswereNVP(34%),EFV(18%),butsomepatientswerealsoreceivingPIs,NFV(19%),IDV(26%)andLPV(9%).TheinvestigatorsnotedfrequentswitchinginthedrugsbesidestheTAbetweent0andt1.In478(79%)patients,morethan1drugusedatt0wasnolongerusedatt1.

Att0,90%ofthestudypopulationhadatleastoneTAMandamedianof3(range0-6).Ofthese81%hadTAMprofile1(TAM1)–41L,210Wand215Fmutations,and62%TAMprofile2(TAM2)–67N,70Rand219EQ;65%had41Land68%215YTAM1mutationsand52%67NTAM2mutations.

Att193%hadatleastonenewTAM.TheinvestigatorsnotedthatherateofaccumulationofTAM1mutationswastwiceasfastasthatofTAM2.

Betweent0andt1,126additionalTAMswereaccumulatedduring548patientyearsoffollowup(PYFU),whichtheinvestigatorsestimatedtogivearateof0.23peryear(95%CI0.20-0.27)or,inotherwords,1in4.3years(95%CI3.7-5.0).

Theratewasfaster(0.3peryear)inthesubset(330pairs)with0-3TAMsatt0andwasslower,witharateof0.11peryearinthepatientswhoalreadyhad4-5TAMsatbaseline(245pairs).

UsingtheRegaISandtheANRSsystemstheinvestigatorspredictedtheresponsetosubsequentWHOrecommendednucleosidepairs.Bothsystemsappearedtoshowthatregimenscontainingtenofovir(particularlywith3TC)werelikelytohavethegreatestactivityatt0andtheleastreductioninactivityt0-t1.Thesepredictionshoweverdependontheaccuracyofcurrentexpertknowledgeregardingwhichmutationsmayreducesusceptibilitytotenofovir.

When they looked at predictors of TAM accumulation, they found that also greater susceptibility to non thymidine analogues in thefailingregimenwasassociatedwithfasteraccumulationofTAMs(50%fasterperadditionalactivedrug,RR1.5[95%CI,1.05-2.14],p=0.02).

OtherpredictivefactorswereacquisitionofHIVthroughheterosexualcontact(vshomosexualalmost2-folddifferenceinrateRR1.89[95%CI1.01-3.57]p=0.05)andTAM2profilesatt0(vsTAM1,87%faster,RR1.87[95%CI1.06-3.27],p=0.03).NNRTI+PIorPIbasedregimensatt0wereassociatedwithsloweraccumulationofTAMs(RR0.32[95%CI,0.12-0.84],p=0.02).

Theinvestigatorsconcludedthattheirdatasuggest,“InpatientswhocontinuetoreceiveTA-based,virologicallyfailingregimens,therateofaccumulationofTAMSisrelativelyslow,onaverage,thoughthehighertheinitialpredictedactivityoftheregimen,thefastertherateatwhichTAMsaccumulate.Nucleosidepairsincludingtenofovir,althoughexpensive,seemmorelikelytobeactiveagainstvirusesharbouringTAMsandalsotoexperiencethehighestdropofactivityinthefaceofTAMaccumulation.AdditionalresearchinthisareaisneededtoinformprogrammeplanninginRLS.”

c o m m e n t

ThattwodistinctpathwaysofTAMscanemergeunderpressureofTA-containingHAARTthatisnotfullysuppressiveiswelldescribed.TAM1hasbeenassociatedwithhigh-levelresistancetoAZTandmostotherNRTIs,includingtenofovirandabacavirandTAM2withlowerlevelsofresistancetoTDFandotherNRTIs.

ThefindingthattherateofemergenceofTAMswasslowerthanexpectedinthisestimationbyCozzi-Lepriandcolleaguesisreassuringforprogrammeswithlimitedaccesstomonitoringand,alongsideDARTresults,willmakeabigcontributiontoongoingdiscussionsabout“Whattomeasure?”“Howoften?”and“Whataretheconsequences?”

Theauthorsnotethatonly9%oftheirpatientshadnon-Bsubtypesandthat24%werereceivingWHOrecommendedfirstlineregimens,whichcouldlimittheextenttowhichtheirresultsmightbegeneralisabletopatientsinRLS.However,theysuggestthatthesimilarities



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betweentheirestimationandthatobservedinRLSmaymakethisbiasnegligible.TheyalsowerenotabletoestablishanexplanationwhypatientsinEuroSIDAwereleftonfailingregimensfromthesedata,andsocouldnotruleoutselectionbias.

WhiletheaveragerateaccumulationofTAMsisrelativelyslowandsuggestsapublichealthapproachwouldbegood,therestillneedstobeworkonidentifyingwhysomepatientsdofailfast.Isitafunctionofthevirus?Thedrugselection?Genes?Whatmonitoringisneededtocatchthesmallpercentageofpatientsthatdon’trespond?

WhiletheaveragerateaccumulationofTAMsisrelativelyslowandsuggestsapublichealthapproachwouldbegood,therestillneedstobeworkonidentifyingwhysomepatientsfailmorerapidlyandwhatmonitoringisneededtocatchthesmallpercentageofpatientsthatdon’trespond?

Oneofthemainpredictorsoffasteraccumulationsuggestedbythisanalysis(andothers)wasafunctionofthevirusanddrugselection.Forexample,thegreatertheamountofresistancealreadyaccumulatedatthetimeoffailuretheslowertherateofaccumulationofadditionalmutations.

And,astheauthorsstress“allpossibleeffortsshouldbecontinuedtoincreasetheavailabilityofdrugoptionsinRLS.”

Ref:Cozzi-LepriAetal.Rateofaccumulationof thymidineanaloguemutations inpatientscontinuing toreceivevirologically failingregimenscontainingzidovudineorstavudine:implicationsforantiretroviraltherapyprogramsinresourcelimitedsettings.JInfectiousDis200:687-97,1September2009.

DRUGINTERACTIONS

EssentialnewsfromLiverpoolUniversitydruginteractionresource(HIV-druginteractions.org).Seealsothecomprehensivedruginteractionandpharmacologyreportsfromthe49thICAACearlierinthisissueofHTB.

ReducedetravirinelevelsafterdirectswitchfromefavirenzThisstudyin25healthyvolunteersassessedthepharmacokineticsofetravirine(400mgoncedailyand200mgtwicedaily)withoutandwithaprecedingefavirenzintakeperiod(600mgoncedailyfor14days).Etravirinepharmacokineticswereassessedbeforeandafterefavirenzintake.

Steadystateetravirinepharmacokineticparametersweresignificantly lowerafterefavirenz intake in theoncedailyand twicedailyarms.EtravirineAUC,CmaxandCtroughwhengivenoncedailydecreasedby29%,22%and33%,respectively.Whengiventwicedaily,etravirineAUC,CmaxandCtroughdecreasedby28%,21%and37%,respectively.Allsubjectshaddetectableefavirenzconcentrations7daysafterstoppingefavirenzintake;5/25hadconcentrationsabovethesuggestedminimumeffectiveconcentrationof1000ng/ml.

Theauthorsconcludethattheinductioneffectofefavirenzpersistsforatleast2weeksafterstoppingdrugintake,butthatthedecreaseinetravirineisnotlikelytobeclinicallysignificant.However,furtherclinicaldataarewarranted.

Ref:BoffitoM,JacksonA,LamordeM,etal.Pharmacokineticsandsafetyofetravirineadministeredonceortwicedailyafter2weekstreatmentwithefavirenzinhealthyvolunteers.JAcquirImmuneDeficSyndr,2009,52(2):222-227.

http://www.ncbi.nlm.nih.gov/pubmed/19620877

Gemfibrozilsignificantlyreducedbylopinavir/rThiswasanopenlabel,singlesequencestudyin15healthyvolunteerscomparinggemfibrozilpharmacokineticsparametersbeforeandaftertwoweeksoflopinavir/ritonavir(400/100mgtwicedaily).

TheGMR(90%CI)forgemfibrozilAUCafter14daysoflopinavir/ritonavircomparedwithbaselinewas0.59(0.52to0.67)(P<0.001).GMR(90%CI)forgemfibrozilapparentoralclearanceandCmaxwere1.69(1.41to1.97)and0.67(0.49to0.86),respectively(P<0.0001andP<0.01,respectively).Therewasnochangeingemfibrozilhalflife.

Itisnotclearwhatthemechanismisforthereductioninthesystemicexposureofgemfibrozil.However,clinicianstreatingHIV-infectedpatientsforhypertriglyceridemiashouldbeawareofthisinteraction.

Ref:BusseKH,HadiganC,ChairezC,etal.Gemfibrozilconcentrationsaresignificantlydecreasedinthepresenceoflopinavir-ritonavir.JAcquirImmuneDeficSyndr,2009,52(2):235-239.http://www.ncbi.nlm.nih.gov/pubmed/19648824



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BASIC SCIENCE

RecentbasicscienceupdatesfromRichardJefferysexcellentweblog.

Aging,HIVinfectionandtheimmunesystem

RichardJeffreys,TAGIntheNovember9thissueofNewYorkMagazine,DavidFrancereportsontheemergingissueofacceleratedaginginpeoplewithHIVinfection.Thearticleoffersaseriesofdisturbingvignettesaboutthecomplicationssomeindividualsarefacingastheyage,suchasboneproblemsandimpairedcognitivefunction,andraisesimportantquestionsabouthowmuchattentionisbeingpaidtotheissuebycurrentresearch,particularlyintermsofpursuingnewtherapeuticoptions.[1]

However,beyondmentioninginflammation,thepiecedoesnotreallydelveintotheunderlyingimmunologicalparallelsbetweenHIVinfectionandagingandconsiderhowtheymightfitintothepicture.Thisisapotentiallyimportantomission,asthereisaccumulatingevidencethattheacceleratedagingoftheimmunesystemthathasbeendocumentedinpeoplewithHIVislikelytoberelatedtomanyoftheclinicalphenomenadescribedinFrance’sarticle.

Although it’s not the sort of research that makes the front pages, the last decade or so has seen considerable progress in understanding therelationshipbetweenimmuneparametersandaging,andthesestudiesprovideavaluableframeofreference.Perhapsmostimportantly,an“immuneriskphenotype”associatedwithmortalityintheelderlyhasbeendescribedinconsiderabledetail.[2]

ThemajorfeaturesareaninvertedCD4/CD8Tcellratio,decreasedproliferativeresponsesandIL-2productionbyTcells,increasedlevelsofinflammatorycytokines(suchasIL-6)andincreasednumbersofCD8TcellslackingtheCD28co-stimulatoryreceptor(typicallydescribedassenescentcells).AlloftheseimmunologicalperturbationsarealsoseeninHIVinfection.

Studieshavealsofoundthatpeoplewiththechronicviralinfectionscytomegalovirus(CMV)andEpstein-Barrvirus(EBV)faceagreaterlikelihoodofacquiringtheimmuneriskphenotypeinoldage.Theclinicalmanifestationsassociatedwiththephenotypeinclude bone loss and increased fracture risk, cognitive impairment, increased susceptibility to infections and an increased incidence ofcancersandcardiovascular,kidneyandliverdisease.

Theoverarchingthemethatisemergingfromthisresearch–althoughitisstillinitsinfancy-isthatalifetimeofantigenicchallenges(intheformofallthepathogensanindividualisexposedto)graduallyerodesimmunesystemresources,andthisplaysamajorroleinaging.Thiserosionofimmunesystemresourceshasmultiplefacets:

• AsteadydeclineinnaiveTcellproductionbythethymusfromatorrentinchildhoodtoatrickleinoldage.

• Activationofantigen-specificnaiveTcellseverytimeanewpathogenisencountered,whichdepletesthenaiveTcellpoolandleadstoasubsetofthesepathogen-specificcellsmaturingintomemorycells(theimpactoftheseepisodesofnaiveTcellactivationisminorwhenthethymusisvigorouslyproducingnewcellstoreplacethoselost,butincreasesasthymicoutputdeclines).

• RepeatedstimulationofmemoryTcellsbypathogens,whichcaneventuallyleadtomemoryTcellsenescence.

Chronicpathogens(thatarecontrolledratherthancleared)playaparticularlyimportantrolebecausetheyplaceapersistentdrainonimmunesystemresources,asindicatedbythewaythatmemoryTcellresponsestoCMVaccumulateovertime,suchthat25-30%ofCD8TcellscanbeCMV-specificinaninfectedelderlyperson.UntreatedHIVinfectionhasanevengreatereffect;ayoungindividualwithAIDStypicallywillhavelostalmostalltheirnaiveTcellsand20-50%oftheirmemoryCD8TcellswillbeHIV-specific.AsshownrecentlyinastudyoftheMACScohort,afastaccumulationofsenescentCD8TcellslackingtheCD28moleculeisassociatedwithrapidprogressionfromHIVinfectiontoAIDS.[3]

Additional insightintohowimmunologicalagingrelatestohealthmaycomefrompeoplewhohavehadtheirthymusremoved(athymectomy)atbirth.Thisprocedureissometimesperformedtoenablebetteraccesstothehearttocorrectcongenitalheartdefects.ArecentstudypublishedintheJournalofClinicalInvestigationreportedthatthymectomisedindividualsshowevidenceofacceleratedagingoftheimmunesystemsimilartotheimmuneriskphenotype,butitisnotyetknownwhetherthiswillleadtothesameclinicalmanifestationsseenintheelderly.[4]Continuedfollow-upwillbecrucialtogainingabetterunderstandingoftherelationshipbetweentheimmunologicalandclinicalconsequencesofaging.

IntermsofHIVinfection,theissueofacceleratedagingraisesmanynewquestionsandconsiderationsforfutureresearch:

• IsimmunologyresearchinHIVadequatelyprioritised?ThemainclinicalresearchnetworkintheUS,theAIDSClinicalTrialsGroup(ACTG),oncehadaspecificimmunologyresearchcommitteebutitwasdissolvedafewyearsagoandsquishedintoabroadercommitteedesignated“TranslationalResearchandDrugDevelopment”(TRADD).Theremaybeacaseforre-establishingaspecificimmunologycommitteewithinthenetwork.

• Docurrentresearchfundingmechanismsofferadequatesupportformultidisciplinaryandtranslationalresearch?Thespectrumofclinicalmanifestationsassociatedwithacceleratedagingcalls forcollaborative researchbetweengroupsspecialising inmanydifferentdisciplines(e.g.immunology,virology,pharmacology,toxicology,musculoskeletalsystem,cardiovascular,renal,liver,etc.),andsupportforthistypeofcomplexcollaborationmaycallforthedesignofaspecificfundingmechanism(RFA).



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Explorationofnoveltherapiesalsorequiressupportforconductingtranslationalclinicalresearch,whichcanbedifficultandcomplicatedtoobtainundercurrentgrantprocedures.

• Willearlierinitiationofantiretroviraltherapypreventacceleratedaging?Longtermfollow-upfromstudiessuchasACTG384clearlyshowthatearliersuppressionofHIVisassociatedwithanalmostcompletenormalizationofmanypotentiallyimportantimmune parameters including the CD4/CD8 T cell ratio, the ratio of naive T cells to memory T cells and levels of immune activation.[4]Incontrast,amongindividualsinitiatingtherapyatlowerCD4Tcellcounts,theseparametersimprovebutdonotcomeclosetomirroringthoseofuninfectedindividualsevenaftersevenormoreofcontinuousHIVsuppression.Thismaysuggestthatpeoplewhostarttreatmentearlierwillbeatlessriskforacceleratedaging,butthishasnotyetbeenestablished.

• Towhatextentdodrugtoxicitiescontributetoacceleratedaging?ThefactthattherearemanycloseparallelsbetweentheimmunologyofHIV infectionandagingarguesstronglyagainstdrugtoxicitybeingtheprimarycause,but thereareclearlyspecifictoxicitiesthatcancontributetoproblemssuchasbonelossandcardiovasculardisease.Researchneedstoparseouttheroleofdrugtoxicitiessothatsafertreatmentscanbedeveloped.

• Cannoveltherapiesbedevelopedtodelayorreverseacceleratedaging?Thecurrentdatasuggestanumberofkeytargetsfor therapeutic research, including: enhancing thymic function to boost naive T cell production, reducing immune activation/inflammationandreducingnumbersofsenescent immunecells.Research isongoing in theseandotherareasbutgreaterresources,coordinationandprioritizationisneeded.

TAG’sHepatitisCoinfectionProjectandMichaelPalmProjectarecurrentlycollaboratingwithseveralothercommunityactivists,includingHIVi-Base,toproduceacomprehensivereportandadvocacyrecommendationsonHIVandaging.ThereportwillbereleasednextyearpriortotheInternationalAIDSConference.References1. FranceD.AnotherkindofAIDScrisis.NewYorkMagazine.(November2009). http://nymag.com/health/features/617402. WikbyAetal.Animmuneriskphenotype,cognitiveimpairment,andsurvivalinverylatelife:impactofallostaticloadinSwedish

octogenarianandnonagenarianhumans.TheJournalsofGerontologySeriesA:BiologicalSciencesandMedicalSciences60:556-565(2005).

http://biomed.gerontologyjournals.org/cgi/content/full/60/5/5563. CoaWetal.PrematureagingofTcellsisassociatedwithfasterHIV-1diseaseprogression.JAcquirImmuneDeficSyndr.2009Jan7.

[Epubaheadofprint] http://www.ncbi.nlm.nih.gov/pubmed/191318964. RobbinsGKetal.IncompletereconstitutionofTcellscubsetsoncombinationantiretroviraltherapyintheAIDSClinicalTrialsGroup

protocol384.ClinInfDis2009;48:350–361. http://www.journals.uchicago.edu/doi/full/10.1086/5958885. SauceDetal.EvidenceofprematureimmuneaginginpatientsthymectomisedduringearlychildhoodJ.Clin.Invest.doi:10.1172/

JCI39269.(Freeaccesstofulltext)http://www.jci.org/articles/view/39269

6. GressREandDeeksS.Reducedthymusactivityandinfectionprematurelyagetheimmunesystem.Editorialcommentary.J.Clin.Invest.doi:10.1172/JCI40855.

http://www.jci.org/articles/view/40855

Newneutralisingantibodiesdiscovered

RichardJefferys,TAGApaperjustpublishedonlinebyScienceExpressreportsthediscoveryoftwonewantibodiescapableofneutralisingabroadarrayofdiverseHIVstrains.Theantibodiesinteractwithanovelconservedregionofthevirusenvelopethatisdifferentfromthesitestargetedbypreviouslydescribedneutralisingantibodies.

TheresearchrepresentsthefirstfruitsofamajorundertakinginitiatedbytheInternationalAIDSVaccineInitiative(IAVI)incollaborationwiththeScrippsInstitute,theBill&MelindaGatesFoundation,MonogramBiosciences,TheracloneSciences,aslewofscientistsandover1,800HIV-positivevolunteerswhodonatedblood.Perhapsinkeepingwiththeviewofsomescepticsthatthedesignofanantibody-basedHIVvaccinemaybeamissionimpossible,theprojectgoesbytheespionage-invokingnameof“ProtocolG.”

ThefirstinklingofprogresscameinapaperpublishedacoupleofmonthsagointheJournalofVirology,whichappearedwithlittlefanfare(abstractlinkbelow).AgroupofscientistsledbyMelissaSimekatIAVIdescribedtheidentificationofseveralplasmasampleswithbroadneutralisingactivityusinganew“highthroughput”neutralisationassaydevelopedbyMonogramBiosciences.Theassaymeasurestheabilityofantibodiestoneutraliseapanelof“pseudoviruses”thatarecapableofjustasingleroundofinfection.ThepseudovirusesconsistofacloneoftheHIVgenomecontainingafireflyluciferasegenethatemitslight,intowhichdifferentenvelopegenesfromprimaryHIVisolatesareinserted.Theextenttowhichantibodies(orplasmasamplescontainingantibodies)preventthevariouspseudovirusesfrominfectingsusceptibletargetcellsismeasuredbyquantifyingtheamountoflightemittedbythecells.

Atotalof1,798samplesfromHIV-positiveindividualsinAustralia,UK,Rwanda,Kenya,Uganda,Zambia,IvoryCoast,Thailand,SouthAfricaandtheUSwereevaluatedintheinitialstudy.Around1%ofthesampleswerefoundtohavebroadneutralisingactivity



31

against a panel of pseudoviruses containing envelopes from multiple different HIV isolates from clades A, B, C, D and several circulatingrecombinantformsincludingCRF01-AE.

ThenewSciencepaperfocusesonjustoneAfricanindividualwhoseplasmasamplewasamongthosecapableofbroadneutralisation.Inordertofindtheantibodiesthatwereresponsiblefortheactivity,theresearchershadtogofishingfortheBcellsthatwereproducingthem.Thisdauntingtaskinvolvedthecarefulcharacterisationof30,300Bcells,whichwerespreadacross23,328tiny“wells”inlabdishessuchthateachwellhadjust1-2(average1.3)Bcellsinit.TheBcellsweregiveneightdaystopumptheirantibodiesintothewells,thentheantibodiesweretakenfromeachandtestedtoseewhethertheyboundtoimmobilisedHIVenvelopeproteins(gp120orgp41)orwereabletoneutralisepseudovirusesintheMonogramBiosciencesassaydescribedpreviously.

Whenthewellscontainingantibodiescapableof thebroadestandmostpotentneutralisationwere identified, theresearchersextractedtheantibody-encodingsectionsofDNAfromtheBcells.TheprocessrequiresextractionoftwosectionsofBcellDNA,one responsible for producing a part of the antibody called the light chain and the other for the part of the antibody called the heavy chain.TheisolatedDNAsectionswereinsertedintoalaboratorycellline(293cells)whichthenstartedchurningouttheantibodiesencodedbytheDNA,allowingresearcherstofigureoutwhichDNAcodewasmakingtheantibodiestheywerelookingforbytestingtheantibodiesforneutralisationintheMonogramassay.ForthewellsthatcontainedmorethanoneBcell,multiplelightandheavychainDNAsectionswereextractedandinsertedinto293cellsinallpossiblecombinations,facilitatingtheidentificationofthelight/heavychainDNAcombinationresponsibleformakingtheantibodyofinterest.

Theultimateresultofthisstaggeringamountofworkwastheidentificationoftwoantibodies,namedPG9andPG16,withbroadandpotentneutralisingactivity.PG9neutralised127outofapanelof162pseudovirusescontainingadiverserangeofHIVenvelopesandPG16neutralised119pseudovirusesoutofthesamepanel.Thepotencyofneutralisationoftenexceededthatofthefourknownbroadlyneutralisingantibodiesthatwereusedascontrols(b12,2G12,2F5,and4E10),meaningthatlowerconcentrationsofPG9andPG16couldmediateequallystrongneutralisation.

WhilePG9andPG16wereveryeffectiveintheneutralisationassay,theydidnotefficientlybindtotheimmobilisedHIVenvelopeproteinsthatwereusedaspartofthescreeningprocess.Theresearchersconcludethatthisisbecausetheindividualproteinsdonotmaintainthesameshapeorconformationthattheyhavewhenpresentonanintactvirus,wheretheycombineintriplicatetoformwhatiscalledanenvelopetrimer.

ThediscoveryofPG9andPG16maybeimportantforseveralreasons.

ItofferscompellingvalidationoftheProtocolGapproachtoseekingeffectivenewantibodies,andsuggeststhatmanymorearelikelytobediscovered.Theworkhasbeendescribedasa“tourdeforce,”andthatalmostseemslikeanunderstatement.

The results indicate that although HIV’s envelope is notoriously mutable, there are conserved regions of the trimer that are susceptibletoantibodyattack.

The potency of neutralisation suggests that if a vaccine could induce similar antibodies, they could be protective against HIV infectionatconcentrationsknowntobeachievablewithvaccination.

Therearepotentialcaveatshowever.Itisunclearwhethertherelativelyraredetectionofbroadlyneutralisingantibodiesisrelatedtospecificgenetictraitsoftheindividualstheyhavebeenisolatedfrom.IfBcellsfrommostpeoplearenotcapableofmakingsimilarantibodies,thentheapplicabilitytovaccinationwillbelimited.ResearchershavealsolongbeenattemptingtobuildmimicsofHIV’snativeenvelopetrimer,andithasproventobeaconsiderablechallenge;resultstodatearereminiscentoftryingtobakeasoufflé,onlytohaveitcollapsewithinmomentsofremovingitfromtheoven.Nevertheless,thediscoveryofPG9andPG16islikelytosendscientistsworkingontheproblemscurryingbackintothekitchen.

Source:TAGBasicScienceweblog(04September09)


Ref:WalkerLMetal.BroadandpotentneutralisingantibodiesfromanAfricandonorrevealanewHIV-1vaccinetarget.Science,doi:10.1126/science.1178746.Publishedonline3September2009.

http://www.sciencemag.org/cgi/content/abstract/1178746

TheendofthelineforIL-2

RichardJeffreys,TAGResultsfromtwolargerandomisedstudiesofinterleukin-2(IL-2)havebeenpublishedintheNewEnglandJournalofMedicine.ThedatawerefirstpresentedearlierthisyearatCROIinMontreal.ThetrialswereSILCAAT,whichenrolled1,695peoplewithCD4countsbetween50and299,andESPRIT,whichenrolled4,111peoplewithCD4countsover300.InneithercasedidtheadditionofIL-2offeranyclinicalbenefitscomparedtoantiretroviraltherapyalone,despiteincreasingCD4Tcellcounts.TheresultsindicatethatexpandingCD4TcellnumberswithIL-2doesnotconferaddedbenefitbeyondtheincreaseinCD4TcellscausedbysuppressionofHIVreplication.TheresearchersnotethatCD4TcellsinducedbysignalingthroughtheIL-2pathwaymaybefunctionallycompromisedand/orhaveaphenotype(e.g.suppressive)orspecificitythatisnotclinicallybeneficial.AnalternativeoroverlappingexplanationisthattheincreasedrateofadverseeventsassociatedwithreceiptofIL-2counterbalancedanybenefitfromCD4increases.



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Althoughtheresultshavebeenseenasablowtoimmune-basedtherapy(IBT)developmentinHIV,theydonotnecessarilymeanthatotherapproachestoincreasingCD4Tcellnumbers(suchasIL-7orgrowthhormones)willsufferthesamefate.TheoutcomesofSILCAATandESPRITdohoweverstresstheneedtoevaluateIBTsforclinicalbenefit.AsthereareindividualswhoexperiencepoorCD4TcellreconstitutiondespiteHIVsuppression(sometimescalleddiscordantresponders)whoremainatincreasedriskforillness,thereisstillapotentialneedforIBTs.TrialsevaluatingtheclinicalbenefitofnewerIBTsinthispopulationshouldbefeasibleandwouldnotnecessarilyrequirethelargenumbersinvolvedinSILCAATandESPRIT.

Source:TAGBasicScienceBlog(21Oct2009)


Reference

INSIGHT–ESPRITStudyGroupandSILCAATScientificCommittee.Interleukin-2therapyinpatientswithHIVinfection.NewEnglandJournalofMedicine,Volume361:1548-1559,October15,2009,Number16.

http://content.nejm.org/cgi/content/full/361/16/1548

PAEDIATRIC CARE

HIV,thebrainandchildren

PollyClayden,HIVi-BaseThedevelopingbrainisknowntobeatargetforHIV,andthereisconcernaboutthelong-termeffectonthecognitiveandbehaviouraldevelopmentofHIV-positivechildren.Additionallybeforethe introductionofHAART,theprevalenceofHIVencephalopathy inHIV-positivechildrenwasupto50%.

Twostudiespublishedinthe10September2009editionofAIDS,examinelong-termneurocognitiveandpsychiatricoutcomesofvertically infectedadolescentsand the impactofHAARTonHHIVencephalopathyamongchildrenandadolescents in twoAmericancohorts.

ImpactofAIDSdiagnosesonneurocognitiveandpsychiatricoutcomesofverticallyinfectedadolescentsSarahWoodsandcolleaguesconductedaretrospectivecohortstudyattheChildren’sHospitalofPhiladelphia,USA,toexaminetheassociationbetweenpreviousAIDSandneurocognitiveandpsychiatricoutcomesinverticallyinfectedadolescentlong-termsurvivors.[1]

AdolescentsattendingtheHIVclinic,bornbefore1September1995andabove11yearsofagewereenrolledthisstudyinwhichthosewithpreviousCDCClassCdiagnosis(AIDSdefining)werecomparedtothosewithnon-ClassCdiagnosis.

Ofthe172meetingthesecriteria39(23%)patientshaddied,45(26%)transferredand7(4%)werelosttofollowup.Theremaining81adolescentswereeligibleforevaluationofwhom38(46.9%)weregirlsand58(71.6%)wereAfrican-American.Theirmedianagewas15.2years(range11.1-23.8,IQR13.2-17.2years).Almosthalf(47%)theparticipantswereClassCandtherewerenosignificantdifferencesinsex,raceorcurrentagebetweentheclassCandnon-ClassCgroups.

HIVdiagnosiswasatamedianof9monthsandClassCdiagnosiswasatamedianof3.1yearsofage.OftheClassCgroup,51%hadatleastoneadditionalClassCdiagnosis.

Mostrecentviralload,CD4percentageandCDCimmunologicalcategoryweresimilarinbothgroups.Bytheendofthestudyperiod93%ofthecohortwerereceivingHAART.TherewasnodifferencebetweenthegroupsinthoseachievingandnotachievinganundetectableviralloadwhenonHAART.ThecohortwasheavilytreatmentexperiencedandpatientswithClassCdiagnosishadreceivedagreaternumberofregimensp=0.002.Ofthisgroup68.4%hadinitiatedHAARTbeforetheirAIDSdiagnosis.

Themedianfullscale intelligencequotient (FSIQ)of thecohort,measuredontheWeschler IntelligenceScale forChildren-IV(WISC-IV)or theWeschlerAbbreviatedScaleof Intelligence,was87 (IQR78-99),which fallswithin the “average” category.However,ClassCpatientshadsignificantlylowermedianFSIQthannon-classC,82(IQR73-90)vs93.5(IQR84-100)respectively,p=0.0003.Learningdisabilitieshadbeendiagnosedin42%ofthecohortand17%hadalifetimehistoryofHIV-relatedprogressiveencephalopathy(HPE).

Almosthalf thecohort (47%)hadadiagnosedpsychiatric illnessand18.5%hadmultiplepsychiatric illnesses.Treatmentwithpsychotropicmedicationshadbeenprescribedto32%ofthecohort,and16%hadahistoryofmentalhealthhospitalisation.

Theinvestigatorsperformedamultivariatelogisticregressionanalysis,adjustedforageatARTinitiation,tolookattheassociationbetweenClassCdiagnosisandneurocognitiveandpsychiatricstatus.

TheyfoundasignificantassociationbetweenpreviousClassCdiagnosisandneurocognitiveimpairment: learningdisabilities,adjustedOR4.1(95%CI1.5-11.1),p=0.014andlowerFSIQ(median),-12.1(-18.7to5.5),p=0.002.TherewasalsosignificantassociationwithpsychiatricdiagnosisAOR3(95%CI,1.1-8.1),p=0.027,inparticularmultiplepsychiatricdiagnosisAOR19.3



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(95%CI,2.3-162.6),p=0.001;mooddisorderAOR3.3(95%CI,1.1-10),p=0.023andreceivingmentalhealthtreatmentAOR4(95%CI,1.3-13),p=0.042.

TheinvestigatorsfoundnodifferenceinFSIQorratesoflearningorpsychiatricdisordersbetweenClassCpatientsstartingHAARTbeforeandaftertheirAIDSdiagnosis.ButtheynotedthatthenumberofpatientswithClassCdiseasewassmallandtheywereunderpoweredtodetectevenmodestassociationsinthissub-analysis.

ImpactofHAARTonencephalopathyKunjalPatelandcolleaguesfromThePACTG219studyteamlookedattheeffectsofHAARTandCNSpenetratingregimensontheincidenceofHIVencephalopathyinperinatallyinfectedchildrenandadolescents.[2]Thisstudywasconductedbetween1994and2006inalargeAmericanmulticentrepaediatriccohort.

Thestudyfollowed2398perinatallyinfectedchildrenwithatleastoneneurologicalexamination.

TheinvestigatorsusedCoxregressionmodelstoestimatetheeffectsoftimevaryingHAARTvsnonHAARTandtimevaryingmediumandhighCNSpenetratingregimensvslowCNSpenetratingregimensontheincidenceofHIVencephalopathy.Theyalsolookedatoverallsurvivalandsurvivalfollowingencephalopathydiagnosis.CovariatesincludedbaselineageandCD4percentage,sex,ethnicityandbirthweight.SecondaryanalysesusedCoxmodelstoestimatetheeffectsofHAARTandCNSpenetratingregimensonHIVencephalopathyalsoadjustedforviralloadandtoevaluatetheeffectofHIVencephalopathyonmortality.

Therewere2398children,withamedianof6.4yearsoffollowup,includedinthisanalysis.Atbaselinethe2272childrenfollowedforincidentHIVencephalopathyandsurvivalanalyseswereequallydividedbetweenthesexes,themajority(85%)werelessthanorequalto10yearsofage,24%hadlowbirthweight,56%hadaCD4percentageabove25%andtherewerenoviralloaddatafor54%.

At the timeof theirfirstneurologicalexamination35%ofchildrenwereonaHAARTregimenand27%wereonahighCNSpenetratingregimen.Duringthestudyperiodtherewere77incidentcasesofHIVencephalopathy,givinganincidentrateof5.1per1000personyears(95%CI4-6.3).

Theinvestigatorsreporteda10-folddeclineinincidenceofHIVencephalopathy.Thisbeganin1996andstablisedafter2002.ThisdecreaseparalleledasignificantincreaseintheuseofHAARTinthecohort.

TheyfoundtheriskofdevelopingHIVencephalopathyinchildreninitiatedonHAARTwashalvedcomparedtothosewhowerenotonHAART(hazardratio0.5,95%CI0.29-0.86),p=0.01.BaselineCD4lessthan15%wasassociatedwithover8-foldincreaseinriskofdevelopingHIVencephalopathy(hazardratio8.41,95%CI4.79-14.76).Infantswerealsoatgreaterrisk,agelessthanorequalto1yearatfirstneurologicalexaminationwasassociatedwithaover3-foldincreaseinHIVencephalopathy(hazardratio3.38,95%CI1.36-8.44).

In thesubanalysis lookingat rankedCNSpenetrating regimens, the investigators founda41%reduction in incidenceofHIVencephalopathyinhighCNSpenetratingregimenscomparedtolow(hazardratio0.59,95%CI0.31-1.10).Duetothesmallsamplesizeinthisanalysis,thisassociationwasnotsignificant,p=0.64.

Acrossthecohort(n=2272)bothHAARTandhighCNSpenetratingregimenswereassociatedwithincreasedsurvival,hazardratio0.41(95%CI0.29-0.58),andhazardratio0.31(0.22-0.45),bothp<0.0001,comparedtonoHAARTandlowCNSpenetratingregimensrespectively.

ChildrenwithanHIVencephalopathydiagnosishada12-foldincreaseinriskofdeathcomparedtothosewithout(hazardratio12.42,95%CI8.46-18.24).

Therewasa50%increasedsurvivalbenefitassociatedwithHAARTuseamongthe77childrenwithanincidentdiagnosisofHIVencephalopathy(hazardratio,0.51,95%CI0.25-1.05)but thiswasnotstatisticallysignificant,p=0.07.HighCNSpenetratingregimenswereassociatedwithgreatersurvivalbenefit,givinga74%reductioninriskofdeath(hazardratio0.26,95%CI0.11-0.61,p=0.002)comparedtolowpenetratingregimens.

c o m m e n t

WoodandcolleagueswritethattheirfindingssuggestthatearlyHAART,initiatedbeforetheonsetofsymptomaticHIV,maybewarrantedtoprotectthedevelopingCNSinchildrenwithHIV.Forinfants,theysuggestthatalongsideCHERfindings,andinkeepingwithsomerecentguidelinechanges,thatHAARTshouldbegiventoallinfantsimmediatelyafterbirth.However,inanaccompanyingcommentary,MarcTadieusuggeststhatitisnotpossibletoconcludedirectlyfromthisstudythatveryearlytreatmentwouldhavepreventedclassCeventsandpossiblyensurenormalcognitiveandbehaviouraldevelopment,“although,itistemptingtodoso.”

PatelandcolleaguesfoundHAARTusetobehighlyeffectiveinreducingtheriskofHIVencephalopathy.TheysuggestthatamongchildrenwithHIVencephalopathydiagnosis,treatmentdecisionsshouldtakeintoaccounttheeffectivenessofARVsinpenetratingtheCNS,ashighCNSpenetratingregimensofferedincreasedsurvivalbenefit(74%reductioninriskofdeathcomparedtolowpenetrating).EditorialcommentaryfromBruceBrewdescribesHIV,thebrain,childrenand“neuro-HAART”as“acomplexmix”andsuggestsitistimeforrandomisedclinicaltrialstoestablishwhether“neuro-HAART”treatsbraindiseasebetterthanstandardHAART.



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References1. WoodSMetal.TheimpactofAIDSdiagnosesonlong-termneurocognitiveandpsychiatricoutcomesofsurvivingadolescentswithperinatally

acquiredHIV.AIDS2009,23:1859-1865.2. PatelKetal.ImpactofHAARTandCNS-penetratingantiretroviralregimensonHIVencephalopathyamongperinatallyinfectedchildrenand

adolescents.AIDS2009,23:1893-1901.

OTHERNEWS

PresidentObamaannouncesendtoHIV-positiveimmigrationbanintheUSOn2November2009,theUSDepartmentofHealthandHumanServicespublishedfinalregulationsthatwillremoveHIVfromitslistofcommunicablediseasesofpublichealthsignificanceandwillremovetheHIVtestfromtheroutinemedicalexamforlawfulpermanentresidentapplicants.Theregulationswillgointoeffecton4January2010,followingaroutineimplementationperiod.

ThiswasannouncedduringthepresidentialpressbriefingforthefourthreauthorisationoftheRyanWhiteCAREAct,andincludedthefollowingstatement:

“Twenty-twoyearsago,inadecisionrootedinfearratherthanfact,theUnitedStatesinstitutedatravelbanonentryintothecountryforpeoplelivingwithHIV/AIDS.Now,wetalkaboutreducingthestigmaofthisdisease-yetwe’vetreatedavisitorlivingwithitasathreat.WeleadtheworldwhenitcomestohelpingstemtheAIDSpandemic-yetweareoneofonlyadozencountriesthatstillbarpeoplefromHIVfromenteringourowncountry.IfwewanttobethegloballeaderincombatingHIV/AIDS,weneedtoactlikeit.Andthat’swhyonMonday,myadministrationwillpublishafinalrulethateliminatesthetravelbaneffectivejustaftertheNewYear.CongressandPresidentBushbeganthisprocesslastyear,andtheyoughttobecommendedforit.Wearefinishingthejob.It’sastepthatwillencouragepeopletogettestedandgettreatment,it’sastepthatwillkeepfamiliestogether,andit’sastepthatwillsavelives.”(Applause)

Source:ObamaB.PressStatement“RemarksbythePresidentatsigningoftheRyanWhiteHIV/AIDSTreatmentExtensionActof2009.(30October2009).

http://www.whitehouse.gov/the-press-office/remarks-president-signing-ryan-white-hivaids-treatment-extension-act-2009

Relatedlinks:

ImmigrationresourcewithfocusonHIV

http://immigrationequality.org/template.php?pageid=177

ReportonKaiserNetwork

http://globalhealth.kff.org/Daily-Reports/2009/November/02/GH-110209-HIV-Travel.aspx

IASpressrelease“IASapplaudsWhiteHouseannouncementofrepealoftheUnitedStates’discriminatoryandineffectiveHIVentryandimmigrationban”.(30October2009).

http://www.iasociety.org/Default.aspx?pageId=379

Global database on HIV travel restrictions

http://www.hivrestrictions.org

ONTHEWEB

Conference reports and online abstracts:

BHIVAAutumnConferenceandCHIVAParallelSessions

8-9October2009,LondonSomeofpresentationsfromtheBHIVAAutumnConferencearenowpostedontheBHIVAwebsite:

http://www.bhiva.org/cms1224475.asp

5thIASConferenceonHIVPathogenesis,TreatmentandPrevention

19-23July2009,CapeTownTheconferencewebsiteincludesallabstractsandmanyPDForpowerpointslidesofpostersandoralpresentations,togetherwithalimitedamountofwebcasts.

http://www.ias2009.org



35

WHOmeeting:theimpactofARVtreatmentonpreventionA WHO consultation meeting held from 2-4 November 2009 focused on the increasingly important impact that HIV treatment has onreducingtransmission.Areportfromthemeetingwillbeproduced,buttherelatedpapersandpresentationsfromthismeetinghavealsobeenpostedonline.

http://www.who.int/hiv/events/artprevention/day1/en/index.html

Reports and journals:

JAIDSSupplement:HIVscale-upandglobalhealthsystemsFreeonlineaccesstothissupplementtoJAIDS,guest-editedbyWafaaEl-SadrandKevinDeCock.

November2009-Volume52-Supplementpp:S1-S68

http://journals.lww.com/jaids/toc/2009/11011

Returnedtorisk:deportationofHIV-positivemigrantsThe27-pagereportwaspreparedbyHumanRightsWatch,DeutscheAIDS-Hilfe,theEuropeanAIDSTreatmentGroup,andtheAfricanHIVPolicyNetwork.ItdescribescasesinSouthKorea,SaudiArabia,theUnitedArabEmirates,SouthAfrica,andtheUnitedStatesinwhichHIV-positivemigrantsweredeported,anddescribestheneedtodeveloppoliciesguaranteeinguninterruptedtreatmentforthispopulation.

The report documents:

• InSaudiArabia:mandatoryHIVtesting;detentionforuptoayearwithoutaccesstomedication;anddeportationofHIV-positivemigrants.

• IntheUnitedArabEmirates:deportationof1,518non-citizenresidentsinfectedwithHIV;hepatitistypesBandC;ortuberculosisin2008.

• InSouthAfrica:theinabilitytocontinuetreatment–amountingtoadeathsentence–forpeoplelivingwithHIVwhoaresentbacktoZimbabwe.

• IntheUnitedStates:pooraccesstotreatmentindetentionandharshconditionsorlackofaccesstomedicaltreatmentforsomeHIV-positiveindividualswhoaredeported.

• InSouthKorea:mandatoryHIVtestingofmigrantsandthedeportationofthosefoundtobeHIVpositive,despiteSouthKorea’sinternational legal obligations and a recent Seoul High Court ruling that such deportation is not the most effective means of protectingpublichealth.

ToreadtheHumanRightsWatchreportvisit:

http://www.hrw.org/en/node/85610

Community resources and publications:

UKpatientsurvey:you,yourGPandHIVThissurveyhasbeencompiledbytheForumLinkProject–anetworkthatcurrentlylinkspatientsupportgroupsfrom15HIVclinics.ThesurveyhasbeendesignedbyHIV-positivepeopletohelpunderstandtherelationshipwithGPsandhowtodevelopPrimaryCareservicesinthefuture.

ThegroupbelievethatthisisthefirstonlinesurveyintheUKofGPservicesinrelationtoHIVcarethathasbeenorganised,compiledandrunbyHIV-positivepeople.ThedatacollectedwillbeusedbyForumLinkmembersduringconsultationscurrentlybeingundertakenbyPatientGroupsandPCTs.

The survey is anonymous and is online here:

http://www.forum-link.org/research/gp/survey



36

PLoSMedicine–November2009http://www.plosmedicine.org

Effectsofgenitalulcerdiseaseandherpessimplexvirus type2on theefficacyofmalecircumcision forHIVprevention:analysesfromtheRakaitrialsGrayRHetal.

TheunintendedconsequencesofclinicaltrialsregulationsMcMahonADetal.

ThisarticlearguesthatrecentEUtrialregulationshavedramaticallyreducedlevelsofnoncommercialresearchintheUK,andthatpatientshavesufferedasaresult.

FUTUREMEETINGS

2010conferencelistingThefollowinglistingcoverssomeofthemostimportantupcomingHIV-relatedmeetingsandworkshops.

Registrationdetails,includingforcommunityandcommunitypressareincludedontherelevantwebsites.

16-19February:17thCROI

http://www.retroconference.org/2010

8thEuropeanDrugResistanceWorkshop

17-19 March 2010, Sorrento, Italy

http://virology-education.com

11th International Workshop on Clinical Pharmacology of HIV Therapy

7-9 April 2010, Sorrento, Italy


6th International Workshop on HIV and Hepatitis Co-Infection

June2010,Israel.Thedateandvenuetbc.


5thInternationalWorkshoponHepatitisC-ResistanceandNewCompounds

and5thInternationalWorkshoponClinicalPharmacologyofHepatitisTherapy

June2010,Boston,USA.Thedatesandvenuetbc.


5thInternationalWorkshoponHIVTransmission-PrinciplesofIntervention

15-16July2010,Vienna


2nd International Workshop on HIV Pediatrics




XVIIIInternationalAIDSConference(AIDS2010)

http://www.aids2010.org

3rd International Workshop on Clinical Pharmacology of Tuberculosis Drugs

September2010,USA.Dateandvenuetbc.




37

PUBLICATIONS&SERVICESFROMi-BASE

i-BasewebsiteThefullysearchablewebsiteisdesignedtobefasttoaccess,easytouse,andsimpletonavigate.http://www.i-Base.infoAlli-Basepublicationsareavailableonline,includingeditionsofthetreatmentguides.Thesitegivesdetailsabouti-Base,theUKCommunityAdvisoryBoard(UK-CAB),ourphoneserviceandmeetings,aswellasaccesstoourarchivesandanextensiverangeoflinks.Itcanbeusedtoorderpublicationsandregularsubscriptionstobedeliveredbypostoremail(asPDFfiles).

Thesitealsoincludesaweb-basedQ&Asectionforpeopletoaskquestionsabouttheirowntreatment:http://www.i-base.info/questionsRSSnewsfeedhasbeenintroducedforHIVTreatmentBulletinforwebandPDAaccess-wewelcomeyourfeedbackonthisnewwaytoprovidetreatmentupdates.

AsectiononEducation,AdvocacyandTrainingincludesourtrainingmanualforadvocateswitheight2-hourmodulesthatincludequestionsandevaluation.Trainingmodulesstartwithbasics,includingCD4,viralloadandothermonitoringtests,combinationtherapyandsideeffects,andincludeoverviewsofthemainopportunisticinfections.ThereisamoduleonpregnancyandanothermoduleonIVdrugusersandtreatment.

Anaverageof6000pagesareservedfromthesiteeachday.

i-BaseannouncementslistAfreeemailNewsandAnnouncementslist.Bysubscribingyoucanbekeptup-to-dateonnewandrevisedpublicationsfromi-Base.Thisisanannouncementonlylistwithlowtraffic,mainlytoannouncenewandupdatedpublicationsandservices.MessageswillcontainalinktoaPDFfileofthepublicationand/oralinktothewebversion.

Tosubscribepleasefillouttheformatthislink:http://www.i-base.info/forms/newssub.html

Trainingmanual–revised,updatedandnowfullyonlineThisestablishedtrainingresourcehasbeenrevisedandupdatedandisnowonlineinnewformat.http://www.i-base.info/educationTheTrainingManualforAdvocatesprovidesentry-levelcurriculumrelatingtoHIVandtreatment.

Itismadeupof8modulesforlearningaboutaspectsofHIVcarehasbeenupdatedandpublishedonlineasaninteractiveresource.Itprovidesentry-levelcurriculumrelatingtoHIVandtreatment.

Additionalsupportmaterialisincludedonhowtounderstandaspectsofsciencethatmightbenewtoalayreader.

http://www.i-base.info/manual/en/index.html

Sections include:

1.ImmunesystemandCD4count

2.Virology,HIVandviralload

3.Introductiontoantiretrovirals(ARVs)

4.SideeffectsofARVs

5.Opportunisticinfectionsandcoinfections

6.HIVandpregnancy

7.DrugusersandHIV

8.Clinicaltrialdesignandtheroleofadvocates

Eachmoduleincludeslearningobjectives,non-technicalreviewmaterial,testquestions,anevaluationandaglossary.

WehopethiswillbeusefulfortrainingadvocatesandotherrelatedhealthcareworkersaswellasforHIV-positivepeoplewhowanttoknowmoreaboutaspectsoftheirhealthcare.

ThetrainingmanualwaspreviouslyonlyavailableonlineasaPDFdocumentandhasbeenwidelytranslated.EarliereditionsareavailableinRussian,Portuguese,HindiandNepaleseasareavailableasPDFfiles.



38

GenericclinicformsWehavealsopostedonlineasetofgenericclinicforms,developedwiththeRoyalFreeCentreforHIVMedicine,whichmaybeausefulresourceforotherhospitals.

ThesePDFfilesincluderecordsheetstotrackCD4andviralloadresults,cardiovascularrisk,hepatitis,firstpatientvisit,patientupdate,daycaseandsummarynotes.http://www.i-base.info/clinicformsPleasecontactthei-BaseofficeifyouwouldlikehelpaddingyourownhospitalorTrustlogototheseforms.

ReportassessingthetreatmentinformationneedsAfricanpeopleintheUKlivingwithHIV

ThisreportbyWinnieSserumaandi-BaseincludesananalysisfromworkshopsheldlastyearanddetailsAfricanuseandexperienceofcurrenttreatmentinformationresources.http://www.i-Base.info/pdf/africantreatmentneeds.pdf

i-BaseBook:“WhywemustprovideHIVtreatmentinformation”

PhotographybyWolfgangTillmansi-Basehasworkedasatreatmentliteracyprojectforoversixyears.Overthistimewehavealwaysproducedcopyright-freematerialandencouragedotherorganisationstouse,translateandadaptourmaterial.Throughthiswork,wehavebeenveryluckytodeveloplinkstomanyotheradvocacyprojectsoutsidetheUK.

Arecentmeeting,heldinCapeTownearlierthisyear,focusedonhowtoraisetheprofileoftreatmentliteracy.Oneresultfromthemeetingisapublication“WhywemustprovideHIVtreatmentinformation”.

Withtextprovidedbyactivistsfrom25countriesand50fullcolourphotographsbyWolfgangTillmans,thislimitededition100-pagepublicationisbeingsoldbyi-Basetoraisefundstohelpsupportourinternationaltreatmentliteracyprojects.

UKCAB:reportsandpresentationsTheUKCommunityAdvisoryBoard(UKCAB)isanetworkforcommunitytreatmentworkersacrosstheUKthathasbeenmeetingsince2002.Itnowincludesover300membersformover100organisations.Eachmeetingincludestwotraininglecturesandameetingwithapharmaceuticalcompanyorspecialistresearcher.

TheCABhasaseparatewebsite,wherereadingmaterial,reportsandpresentationsfromthesemeetingsareposted.Membershipis free,

http://www.ukcab.net

WorldCAB-reportsoninternationaldrugpricingTworeportsfrommeetingsbetweencommunityadvocatesandpharmaceuticalcompanies,thatfocusedonpricingissuesandglobalaccesstotreatment,andthatarenowavailableonline.

BothareavailabletodownloadasaPDFfilefromthei-Basewebsite.

http://www.i-base.info/wcab/index.html

IntroductiontocombinationtherapyJune2009edition

Thisnon-technicalpatientguidetotreatmentexplainscombinationtherapy,howwellitworks,whocanbenefitfromit,whentostarttakingit,somedifferencesbetweentreatingmenandwomen,sideeffects,thebestcombinations,changingtreatment,takingpartindrugtrials,yourrelationshipwithyourdoctor,theimportanceofadherence,andhowtoavoiddrugresistance.

Printedand/orPDFversionsofearlierversionsofthisbookletareavailableinotherlanguages.



39

GuidetohepatitisCforpeoplelivingwithHIV:testing,coinfection,treatmentandsupport

March2009editionThisisanewi-Baseguide.Itisanon-technicalpatientguidetoHepatitisCandcoinfectionwithHIV.

This booklet mainly covers treatment related aspects of coinfection including transmission, natural history, tests and monitoring, HCVtreatmentandsideeffects,researchintonewdrugsandlivingwithcoinfection.Italsoincludescontributionsfromawiderangeofpeoplewithdirectexperienceofcoinfection.Theonlineversionofthisguideincludesadditionaltext.

Guidetochangingtreatment:whattodowhenyourtreatmentfailsSeptember2008edition

Thisisanon-technicalpatientguidetochangingtreatment,drugresistanceandwhattodoiftreatmentfails.Itisupdatedtoincluderecentadvancesinnewtreatmentsandstrategies,especiallyinrelationtouseofnewandexpandedaccesstreatments.

Thisbooklethelpspatientsindiscussionswithdoctors,andcoverswhatcanbedoneifviralloadstartstorise,andtheimportanceofconsideringorfindingoutwhythecurrentcombinationfailed,treatmentstrategiesandnewpipelinetreatments.

GuidetoHIV,pregnancy&women’shealthJanuary2009edition

Updatedandrevised,thispatientguidehelpswomengetthemostoutofHIVtreatmentandcarebefore,duringandafterpregnancy.Itshouldhelpwhetherontherapyornotandincludesinformationforthemothershealthandforthehealthofthebaby.

Theguidegivesinformationonmedication,Caesareansectionandbreastfeeding,aswellasdetailsofothersourcesofhelp.ItisaimedatpeopleinawiderangeofcircumstancesincludingpositivewomenthinkingabouthavingchildrenandpregnantwomenwhohaverecentlybeendiagnosedHIV-positive.

Guidetoavoiding&managingsideeffectsMay2008edition

Thisisacomprehensive72-pageA5guidethatisaimedathelpinganyoneusingHIVdrugstogetthemostoutoftheirtreatment,themostoutoftheirrelationshipswiththeirdoctorandotherhealthprofessionals,togetbettermedicalcaretoimprovetheirhealthand,mostimportantly,toenjoyabetterqualityoflife.

Translationsofi-BaseguidesOriginalmaterialpublishedbyi-Basecanbetranslatedandreprinted,andhassofarbeenproducedinover35languages.

Moreinformationaboutthisprocessisavailableonthei-Basewebsite.

Inaddition,PDFfilesofsomeofthetranslatedpublicationsareavailableonthei-Basesite.

Pleasebeawarethatsomeofthesetranslationsarefromearliereditionsofthetreatmentguides,andcheckthepublicationdatebeforerelyingonallinformation.

http://www.i-base.info/about/downloads.htmlLanguages currently include:Bosnian,Bulgarian,Chinese,Czech/Slovak,Croatian,French,Greek,Hindi,Indonesian,Italian,Kosovo,Macedonian,Nepali,Polish,Portuguese,Romanian,Russian,SerbianandSpanish.

Treatment‘Passports’ThesepopularbookletsareforHIV-positivepeople-whethernewlydiagnosedorpositiveforalongtime-tokeeparecordofhealthandtreatmenthistory.Likealli-Basepublications,theyareavailablefreeassinglecopies,orinbulk.

HIVTreatmentBulletin(HTB)Thisisthejournalyouarereadingnow:areviewofthelatestresearchandothernewsinthefield.HTBispublished10timesayearinaprintedversion,inapdffilethatwecanemailtoyou,andonourwebsite.

TheprintedversionisavailableatmostHIVclinicsintheUKandisavailablefreebypost.



40

HTBSouth

AquarterlybulletinbasedonHTBbutwithadditionalarticlesrelevanttoSouthernAfrica.HTBSouthisdistributedinprintformatbytheSouthernAfricanHIVCliniciansSociety(www.sahivsoc.org)toover20,000doctorsandhealthcareworkers.ItisalsoavailableasaPDFfileandispostedonlinetothei-Basewebsite.

ARV4IDUs

Anelectronivpublication,producedinEnglishandRussianlanguageeditions,toprovideanoverviewofresearchrelatedtoIV-druguseandantiretroviraltreatment.

Treatmentinformationrequestservice-08088006013i-Baseoffersspecialisedtreatmentinformationforindividuals,basedonthelatestresearch.

Wecanprovideinformationandadviceoverthephone,andwecanmailoremailcopiesofthelatestresearchstudiesrelevanttothecaller.

Forfurtherdetails,callthei-Basetreatmentinformationfreephonelineon08088006013.ThelineisusuallystaffedbypositivepeopleandisopenMondays,TuesdaysandWednesdaysfrom12noonto4pm.AllcallsareinconfidenceandarefreewithintheUK.

OnlineQ&AserviceAnonline‘questionandanswer’servicethatnowhasover900questionsonline.Questionscaneitherbeansweredprivately,orifyougivepermission,wewillposttheanswersonline(omittinganypersonallyidentifyinginformation).

http://www.i-base.info/questions

Recentquestionsinclude:

• Cand4TbereplacedbyAZT?

• HowcanIdealwithmyGP?

• WhatfoodshallIeatwithmycombination?

• DoHIV-positivepregnantwomenhavetohaveanabortion?

• Willstoppingmedsreducefatigue?

• WhyarescientistsnotabletofindacureforHIV?

• Shalltheyuseacondomagain?

• IhaveoftenoralthrushregardlessthatIamonARVs;whatshallIdo?

• MyCD4is350;whatcanmyviralloadbe?

• CanIhaveaglassofwinewithmymeds?

• HowcanIdecreaseviralload?

• IfwearebothHIV-positive,howcanwehaveababythatisnotinfected?

• WhatshallIswitchto?

• Issperm-washingneededifbothpartnersareHIV-positive?

• Howoftenshouldmyviralloadbetested?

• WhatcanIdoaboutmyhighcholesterollevels?

• CanIworkasamassagetherapist?

• IsthereaproblemworkingasawaiterandbeingHIV-positive?

• Worryingaboutlifeexpectancy…

• DoeshavingpsoriasismeanthatyourCD4countisverylow?

• Ihaveitchinginmygroinarea,whatshallIdo?

• DoesthismeanthatIamprogressingtoAIDS?

• MyfriendhasneurologicalproblemsonAtripla…



41

h-tbHIV Treatment Bulletin HTBisamonthlyjournalpublishedinprintandelectronicformatbyHIVi-Base.Aswithalli-Basepublications,subscriptionsarefreeandcanbeordereddirectlyfromthei-Basewebsite:http://www.i-Base.info;byfaxorpostusingtheformonthebackpagebysendinganemailto:[email protected]

Editor: Simon CollinsContributing Editor: Polly Clayden

Medical Consultants: DrKarenBeckerman,AlbertEinsteinCollegeofMedicine,NYC.DrSanjayBhagani,RoyalFreeHospital,London.PaulBlanchard,BritishSchoolofOsteopathy,London.DrMartinFisher,Brighton&SussexUniversityHospitals.Prof.DianaGibb,MedicalResearchCouncil,London.GreggGonsalves,AIntlTreatmentPreparedessCoalition(ITPC).DrGarethHardy,CaseWesternReserveUniv.Cleveland.DrSayeKhoo,UniversityofLiverpoolHospital.Prof.CliveLoveday,InternationalLaboratoryVirologyCentre.Prof.JamesMcIntyre,ChrisHaniBaragwanathHosp.SouthAfricaDrGraemeMoyle,Chelsea&WestminsterHosp,London.DrStefanMauss,Düsseldorf.ProfCarolineSabin,UCLMedicalSchool,London.DrGrahamPTaylor,ImperialCollege,London.DrStephenTaylor,BirminghamHeartlandsHospital.DrGarethTudor-Williams,ImperialCollege,London.

HTBisanot-for-profitcommunitypublicationthataimstoprovideareviewofthemostimportant medical advances related to clinical management of HIV and its related conditions aswellasaccesstotreatments.Commentstoarticlesarecompiledfromconsultant,authorandeditorialresponses.Some articles are reproduced from other respected sources and copyright for these articles remainswiththeoriginalauthorsandsources,asindicatedattheendofeacharticle.WethankthoseorganisationsforrecognisingtheimportanceofprovidingwidelydistributedfreeaccesstoinformationbothtopeoplelivingwithHIVandtothehealthcareprofessionalsinvolvedintheircare.WealsothankthemforpermissiontodistributetheirexcellentworkandweencourageHTBreaderstovisitthesourcewebsitesforfurtheraccesstotheircoverageofHIVtreatment.Articleswrittenandcreditedtoi-Basewriters,aswithalli-Baseoriginatedmaterial,remainsthe copyright of HIV i-Base, but these articles may be reproduced by community and not-for-profitorganisationswithoutindividualwrittenpermissionandreproductionisencouraged.Acreditandlinktotheoriginalauthor,theHTBissueandthei-Basewebsiteisalwaysappreciated.HIV i-Base receives unconditional educational grants from Charitable Trusts, individual donorsandpharmaceuticalcompanies.Alleditorialpoliciesarestrictlyindependentoffundingsources.

HIV i-BaseThirdFloorEastThrale House44-46SouthwarkStreetLondonSE11UNT:+44(0)2074078488F:+44(0)2074078489

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FindHTBonAEGiSAEGiS.org-thelongestestablishedandlargestglobalresourceofonlineHIVinformation-includesHTBintheregularjournalsthatitputsonline.Youcanfindusat:

http://www.aegis.org/pubs/i-base/2009The AEGiS daily email news service also carries i-Baseconferencereports.

Orderi-Basepublicationsviatheinternet,postorfax

Peoplewithinternetaccesscanuseourwebsitetoorderandreceivepublications.Youcanaccessourpublicationsonlineorsubscribetoreceivethembyemailorbypost;andyoucanordersingle copies or bulk deliveries by using the forms at:

http//www.i-base.info/formsCopiesofpublicationscanalsobeorderedbypostorfaxusingtheformonthebackpageofHTB.Thesemethodsoforderingare suitable for all our publications: HIV Treatment Bulletin (HTB),HTBSouth,Treatment‘Passports’andallourguidestomanagingHIVandadditionalreports.



42

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Whicheveroftheaboveschemesyoumightchosetodonatetoi-Basewewouldliketothankyouverymuchforyoursupport.

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