1 patient evaluation and antiretroviral treatment for adults and

ContentsI. Introduction ............................................................................................................................... 5

II. Management of patients with HIV ........................................................................................... 6 1. Initialpatientevaluation......................................................................................................... 6 1.1.Personal,familyandmedicalhistory.............................................................................. 6 1.2.Physicalexamination...................................................................................................... 8 1.3.Laboratoryandotherexaminations................................................................................ 9 2. CounsellingonissuesrelatedtolivingwithHIV................................................................ 10 3. Preventionofopportunisticandotherinfections................................................................. 11 4. Antiretroviraltreatment........................................................................................................ 11 4.1.InitiationofART........................................................................................................... 11 4.1.1.Clinicalandimmunologicalconsiderations........................................................ 12 4.1.2.Considerationsforviralload............................................................................... 12 4.1.3.Considerationsfordrugresistancetest............................................................... 12 4.2.First-lineHAARTregimen............................................................................................ 13 4.2.1.ConsiderationsforNRTIcomponent.................................................................. 13 4.2.2.ConsiderationsforNNRTIcomponent............................................................... 14 4.2.3.Alternative1stlineHAARTregimens................................................................ 14 4.3.AdherencetoART......................................................................................................... 15 4.3.1.Barrierstohighadherenceandcounteractingstrategies..................................... 16 4.4.ARTsuccessandfailure................................................................................................ 17 4.4.1.Virologicalresponse............................................................................................ 18 4.4.2.Immunologicalresponse..................................................................................... 18 4.4.3.Clinicalresponse................................................................................................. 18 4.4.4.Dissociatedvirologicalandimmunologicalresponses....................................... 18 4.5.Second-lineHAARTregimen....................................................................................... 19 4.5.1.ConsiderationsforNRTIcomponent.................................................................. 19 4.5.2.ConsiderationsforPIcomponent........................................................................ 19 4.6.Salvageregimens.......................................................................................................... 20 4.7.Structuredtreatmentinterruption.................................................................................. 20 5. ClinicalmonitoringofpatientswithHIV............................................................................ 21 5.1.MonitoringoflaboratoryindicatorsbeforeART.......................................................... 21 5.2.MonitoringoflaboratoryindicatorsinARTpatients.................................................... 21 5.3.Immunereconstitutioninflammatorysyndrome........................................................... 23 5.4.Monitoringadherence................................................................................................... 23 5.5.ManagementofARVtoxicityandside-effects............................................................. 24 5.6.Druginteractions........................................................................................................... 26

III. Suggested minimum data to be collected at the clinical level ............................................. 28

Annex 1. Essential information on personal history of HIV/AIDS treatment and care ......... 29

Annex 2. Revised WHO clinical staging of HIV/AIDS for adults and adolescents ................. 30

Annex 3. Resistance tests .............................................................................................................. 31

Annex 4. Essential information about ARVs .............................................................................. 32

Annex 5. Tools for adherence monitoring ................................................................................... 35

Annex 6. List of antiretroviral drugs .......................................................................................... 36

Annex 7. Glossary ......................................................................................................................... 39

Annex 8. Beyond the horizon ....................................................................................................... 40

References ...................................................................................................................................... 41

PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS

I. Introduction

HIV/AIDSischroniclifelongdiseasewithnoknowncure,andtherefore,peoplelivingwithHIV(PLHIV)havetobefollowedmedicallyfortherestoftheirlives(1–3).ThecorecomponentoftreatmentandcareofPLHIVisprovisionofantiretroviraltreatment(ART).OptimalARTincreasesthelengthandqualityoflifeofHIV-infectedpatients,andreducestheonwardtransmissionofthevirus.WHOpromotesapublichealthapproachtoART(4),whichpromotestherationalselectionandsequencingofdifferentdrugclassesintofirstandsecond-lineregimenswithsalvageoptions;simplifiedandstandardisedclinicalmanagement;andstandardisedrecordkeepinginordertopre-servetherapeuticoptions,minimizedrugtoxicityandside-effects,maximizeadherenceandtosup-portthegoalsofART.

ThegoalsofARTare:• clinical:prolongationoflifeandimprovementofitsquality;• immunological:quantitativeandqualitativeimmunologicalreconstitution,inordertoprevent

theonsetofopportunisticinfections;• virological:maximumpossiblereductionoftheviralloadforthelongestpossibletime,inorder

tohalttheprogressionofdiseaseandpreventanddelaythedevelopmentofdrugresistance;• epidemiological:reduction,ideallythepreventionofonwardHIVtransmission(5).

WHOhasproducedaseriesofguidelinestosupportARTdeliveryinnationalprogrammesandbytreatmentimplementers,whichareavailableontheWHOwebsitehttp://www.who.int/hiv/univer-salaccess2010/en/index.html. Particular reference ismade in this protocol to the guidelines andrecommendationsforclinicalandimmunologicalstagingandtoARTguidelinesforARTinadoles-centsandadults.

Medical history, examination findings, exact historyofART, laboratory results, results of othermedicalproceduresandsocialcircumstancesneedtobedocumentedfortheentiretreatmentperiod,whichmaybeyearsorevendecadeslong.Suchrecordsarecrucialfor theindividualpatientaswellasforretrospectiveanalysis(forexample,inendoscopicprocedures,CTscanning,advancedmicrobiologictestingorviralload(VL)testing).Forsuchpurposes,anelectronicrecord-keepingsystemisadvisable,especiallyattheclinicallevel.Confidentialityofmedicalinformationshouldbeensured.

OptimalHIV-related treatmentandcareshouldbedeliveredbyclinical teams.Thecoreclinicalteamprovidingbasicmedicalcase-managementofapatientshouldideallyconsistofaphysician(oftenaninfectiousdiseasespecialist),anurseandasocialworkeroranon-medicalservicepro-vider.Eachoftheteammembershasdistinctiverolesinprovidingtreatmentandcare,andtheirservicesshouldbecomplementary.Anetworkofotherspecialistsandself-helpgroupsshouldbeavailableinsupportingPLHIV(6).

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HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION

II. Management of patients with HIV

PropermanagementofpatientslivingwithHIVisacomprehensivelifelongprocessfocusedonthepatient’sneeds.Itshouldinclude:• initialHIVtestingandconfirmationoftheresult;• appropriatecounsellingduringtheprocessofidentifyingHIVinfection;• clinicalevaluation;• patientcounselling;• monitoringpatienthealth;• initiatingARTanditsmaintenance;• preventionandtreatmentofopportunisticinfections(OIs),othercoinfectionsandcomorbidi-

ties;• psychologicalsupport;• adherencesupport;and• referralstoprovidecontinuityofcare.

ClinicalevaluationofpatientsshouldincludetestingandcounsellingforhealthmaintenanceissuesrelatedtoHIVaswellastootherconditionsthatmayinteractwiththemanagementofHIVinfec-tion,especiallypotentialinteractionswithART.

1. Initial patient evaluationTheinitialevaluationofapatientaimsatdeterminingthefullstatusofhis/herHIVinfection,todevelopabasisforfurtherclinicalmanagementandforreferraltonon-medicalservicesasappropriate.

Initialpatientevaluationshouldinclude:• confirmationofHIVinfectionstatuswithpotentialtimeofinfectionestablished,ifpossible;• adetailedpersonal,familyandmedicalhistory;• physicalexamination;• laboratoryandotherexaminations;• specialistexaminations,asappropriate;and• clinicalandimmunologicalstaging.

1.1. Personal, family and medical historyPatientsnewlydiagnosedwithHIVinfectionorpatientswhoaretransferredin,havinghadtheirlong-termcareandARTbeinginitiatedelsewhere,shouldprovideacompletehistorybeforephysi-calexamination(7).SeeTable1.

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Table 1. Medical history information required at initial patient evaluation

General information:• patient’sname• dateofbirth• sex• dateofassessmentTesting information:• dateoffirstpositiveHIVtest• reasonforbeingtested• lastHIV-negativetest,ifknownHIV exposure risk and transmission category (if known):• injectingdruguse• sexual(heterosexual,homosexual,typesofsexualcontact:oral,vaginal,anal)• bloodorbloodproducttransfusion,organandtissuetransplantation• mother-to-childtransmission• occupationalexposure(describe)• unknown• HIVstatusofsexualpartner(s),ifknown• riskfactorofsexualpartner(s),ifknownTime and place (country) of infection most probable or knowna

History of HIV treatment and care: (seeAnnex1)• timeandplaceofprevioustreatmentorHIV-relatedservices,includingtreatmentinterruptions• drugregimens• side-effects• adherence• laboratorydata(CD4count,VL,electrolytes,liverfunction,renalfunction,fullbloodcount,inchronological

orderforpatientswithlongerinfections(severalyears’duration)(8))• documentedresultsofpreviousresistancetests(ifperformed)HIV-related illnesses and conditions and HIV clinical staging:• tuberculosis• respiratoryinfections• viral,otherbacterialandfungalinfections• hepatitisCandB• neoplasms• otherOther illnesses and conditions:• hospitalizations• surgery• mentalhealthconditions(e.g.depression)• kidneyorliverdiseases• endocrinologicaldisorders• sexuallytransmittedinfections(STIs)• vaccinations• allergies• bodychanges• currentmedicationsFamily medical history(diabetes,hypertension,skindisorders,malignancies,etc.)Cardiovascular disease and disease risks(obesity,smoking,hypertension,etc.)Exposure to tuberculosis (TB)(personalandhouseholdTBcontacts)b

Current medications(includingopioidsubstitutiontherapy(OST))

Substance use:• illicitdruguse(pastandpresent)• alcoholconsumptionReproductive and sexual health:• contraceptivemethodsinfemalepatients• pregnancies(past,current,planned)• sexualpractices(oral,anal,vaginal)

Social history• livingsituation(partners/spouses/familymembers,children,etc.)• employmentandoccupation• supportnetworks(socialandmedicalinsurance,communitygroups,whoknowsofpatient’sHIVstatus,etc.)

aUsefulforepidemiology,subtypeofvirusandpossiblyadrugresistanceprofile.bForfurtherevaluationonTBpleaserefertoProtocol4,Management of tuberculosis and HIV coinfection.

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1.2. Physical examinationThephysicalexaminationshoulddocumentpresentingsymptomsandsignsandreproduciblere-sultssothatotherphysicianscandeterminechangesinstatus.Astandardizedhistoryandexamina-tionquestionnaireispreferable;seeTable2.

Table 2. Initial physical examination

General appearance:• heightandweight• bodymorphology(lipodystrophy)• KarnowskyindexorotherstandardizedscaleforgeneralfitnessVital signs:• bloodpressure• temperature• pulse• respiratoryrateLymph nodesSkin (entire body):• inparticular,assessfor ° activeorformerherpeszoster ° liverdisease ° Kaposisarcoma ° seborrhoeicdermatitis ° injectionsitesininjectingdrugusers(IDUs)Thedocumentationofskindisorderssuchasdiscolouredbrownordarkpatchesisbestmadewithphotos;otherpos-sibilitiesincludedrawingtheareaofapatchontransparentfoil,tobeabletocompareinfutureinexaminations.Oro-pharynx:• oralhealthanddentalstatus• signsfor: ° oralcandidiasis ° oralhairyleukoplakia ° primarysyphilis

Thorax and lungs:• signs(breathing,cough,dyspnoea)• formofthorax• controlforriskofemphysemaMamma examination(infemaleandmalepatients)tocontrolforriskofcarcinomaCardiac examinationforbaselineinformationwhentheremaybehigherriskforcardiovascularcomplicationswithART(9, 10) orriskforendocarditisinIDUs

Abdominal examination(forbaselineinformationforARTside-effects,especiallyincasesofchronichepatitis,alcoholtoxicityandcirrhosis):• consistency,sizeandshapeofliverandspleen• bowelmovement• tenderness• rigidity• nausea,vomiting,disphagia

Genital and anal region examination:• signsfor: ° herpessimplex ° cytomegalovirus(CMV) ° syphilis ° Humanpapillomavirus(HPV),(condylomataacuminatae,analcarcinoma)(11),otherSTIs ° erectiledysfunction

Legs(movement,mobility,lipodystrophy)toprovidebaselineinformationforARTside-effectsNeurological status(alsosignsofneuropathy)Mental statusEye and ear functions

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1.3. Laboratory and other examinations

Table 3. Laboratory testing

HIV-related testing:• HIVserologicaltesting(typicallyanenzyme-linkedimmunosorbentassay(ELISA)orrapidbloodtest),fol-

lowedbyconfirmatorytest(typicallywesternblot)(12)• CD4cellcounttodeterminetheseverityofimmunodeficiency;inpregnantwomenCD4%(13, 14)• viralloadtestingbypolymerasechainreaction(PCR),todeterminelevelofviralreplicationa

Other infectious diseasetesting:Routine testing:• venerealdiseaseresearchlaboratory(VDRL)testforsyphilis• serologicaltestsforhepatitisCandBviruses(HCVandHBV)–i.e.HCVantibodiesandhepatitisBsurface

antigen(HBsAg)b

• toxoplasmaimmunoglobulinG(IgG)serologicaltestandinformationaboutriskofinfectionifnegativeIf indicated:• vaginal,penileoranal(asappropriate)swabforgonorrhoeaandChlamydia trachomatis• CryptococcusantigentitrewhenCD4cellcountis<200/mm3withclinicalsignsofcryptococcosis• CMVantigenaemia(pp65earlyantigen),whenCD4cellcountis<100/mm3.c

General laboratory testing:• electrolytes(sodium,potassium)• liverfunction(alanineaminotransferase(ALT),aspartateaminotransferase(AST),alkalinephosphatase)• bilirubin• renalfunction(bloodureanitrogen(BUN),creatinine)• lactatedehydrogenase(LDH)(generalturnoverofcellsinlymphomas,signsofpulmonaryinfections,myocar-

dialinfarction,muscledamage,etc.)• quick(internationalnormalizedratio(INR)testorprothrombinetime)• fullbloodcountwithdifferentialandplatelets• pregnancytestbeforeinitiatingART

If available:• fastingglucose• cholesterol(high-densitylipoprotein(HDL),very-low-densitylipoprotein(VLDL))• triglycerides• lipase• C-reactiveprotein(CRP)• thyroid-stimulatinghormone(TSH)

Table 4. Other examinations

• tuberculinskintestforthosewithnoTBsymptomsornoknownTBexposurea

• sputum-smearmicroscopyandchestX-rayifsignsandsymptomsofactiveTBarepresenta

• ECG–optional(mightbeusefulasabaselineforcomparisonduetogreaterriskforcardiovasculardiseasewithART)(15)

Other examinations may be necessary, depending on individual comorbidities, for example, inHCV/HIVorHBV/HIVcoinfection,abdominalultrasoundtoassesslymphnodes,sizeandshapeofliverandspleen;orinpresenceofclinicalsignsofgastrointestinal(GI)tractdisease,endoscopyoftheupperandlowerGItract.Endoscopicfindingsshouldbedocumentedwithphotos.

aPerformanceoftestsbythesamelaboratoryispreferabletoruleouttechnicaldiscrepancies.bForfurtherinformationontestingofhepatitis,pleaserefertoProtocols6and7,Management of hepatitis C and HIV coinfec-tion and Management of hepatitis B and HIV coinfection.cVeryearlydetectionofCMVinfectionispossible,andisagoodmarkerfortreatmentresponseinCMVinfection.

aForfurtherinformationpleaserefertoProtocol4,Management of tuberculosis and HIV coinfection.

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Table �. Specialist consultations if required

• neurologicalexamination(forperipheralpolyneuropathy)• ophthalmologicalexamination(usefultorepeateverythreemonthsforCMVretinitiswhenCD4countis

<100/mm3)• gynaecologicalexaminationincludingaPapsmeareverysixmonths(forhumanpapillomavirus-mediated(HPV-

mediated)carcinoma)a

• otherspecialistconsultationsasneeded

2. Counselling on issues related to living with HIVPatientcounsellingisanessentialcomponentofpatientmanagementstrategyandpatient-healthcareproviderrelationships.Itshouldstartwiththeassessmentanddiscussionofthepatient’ssocialconditions,whichmaybepredictorsofcooperationduringtreatment.Theseinclude:• partnershipstatusandquality• employmentstatus,typeofworkandconditions• peoplewhoareinformedandshouldbeinformedoftheHIVstatus• peoplewithwhomhealthcareworkerscandiscussthepatient’shealth-relatedmatters• familialrelationships• availabilityofsaferefrigeratedstorageformedications• lifestylefactorsthatmightinterferewithtreatment(16–18).

HealthcareproviderswhocounselPLHIVshouldensurethatcertaininformationisdiscussedandunderstoodbythepatient.• Riskreduction(safesex,injectingpractices,etc.)mustbeexplained,includingthedangerthat

unprotectedsexwithHIV-positivepartnerscouldleadtosuper-infectionwithanotherHIVstrainandpossibleresistancetoantiretrovirals(ARVs)(19).

• Importanceofdisclosuretosexualpartner(s),friendsandfamilymembersforafewreasons: ° obtainingpsychologicalandtreatmentsupport ° preventionofHIVtransmission ° testingofsexualpartner(s).• Availabilityoftreatment,itsbenefits,preparednesstoit, long-termconsequencesandimpor-

tanceofadherenceshouldbediscussedwitheverypatient.• PatientsneedtobeinformedaboutsignsofpossibleOIs,andencouragedtohavefurtherevalu-

ation.Forfurtherinformation,seeProtocol2,Management of opportunistic infections and gen-eral symptoms of HIV/AIDS.

• Theimportanceofstoppingillicitdruguseneedstobediscussedwithusers.Ifapatientisun-ableorunwillingtostop,themeritsofharm-reductionmeasuresshouldbediscussed,includingthemeritsofreducingdruguse;notinjecting;notsharingneedles,syringesorotherinjectingparaphernalia;anddrugdependencetherapy(suchasOST).Formoreinformation,pleaserefertoProtocol5,HIV/AIDS treatment and care for injecting drug users.

• Preventionofotherinfectionsshouldbediscussed.Pleaserefertosection3below.• Basedontheassessmentofsocialconditions,healthydailyhabits–sleep,nutrition,exercise

–shouldbeencouraged.• PatientsabouttoinitiateARTshouldbecounselledon: ° adherence(seesectionII.4.3below) ° possibleantiretroviral(ARV)toxicity(seesectionII.5.5below)

aThereisnohardevidencetorecommendroutinerectalPAPsmearsatthetimeofwritingthisprotocol.FormoreinformationpleaserefertoProtocol9,Support for sexual and reproductive health of people living with HIV.

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° druginteractions(seesectionII.5.6below) ° reliablecontraceptionwhentheARVregimenwillcontainefavirenz(EFV)(forfurtherin-

formationrefertoProtocol9,Support for sexual and reproductive health in people living with HIV)

° patientunderstandingoftreatmentprocessandrelatedtoitissuesshouldbeensuredbythehealthcareprovider.

• Patientsshouldalsobeinformedaboutlegalresponsibilities(ifapplicable)andtheirrightsandbereferredtootherappropriateservices.

• Patientsshouldbeinformedofissuesrelatedtoimmunization(includingtravel)andoccupa-tionalrisks.

3. Prevention of opportunistic and other infections• Preventionofactivetuberculosisisamongthefirstpriorities.Formoreinformationonmanage-

mentofTB/HIVcoinfectedpatientsandpreventionofactiveTBpleaseseeProtocol4,Manage-ment of tuberculosis and HIV coinfection.

• AsHBV/HIVandHCV/HIVcoinfectionsarecommonandpresentfurthermedicaldifficulties,theirpreventionmustbeemphasized.Itisequallyimportanttoadviseonreducingtheriskofliver-relatedharmandpreventingmother-to-childtransmission(MTCT).2

• PLHIVshouldbeimmunizedagainsthepatitisBandAandinfluenza.Forfurtherinformation,pleaserefertoProtocol12,Immunization of people living with HIV and people at risk for HIV.

• EverypatientwithaCD4cellcountlessthan200cells/mm3shouldbegivenprophylaxisagainstcertainopportunisticinfections,inparticularPneumocystis jiroveciipneumonia(PCP)andotherinfections.Co-trimoxazoleshouldbegivenuntiltheCD4cellcountis>200/mm3formorethanthreemonthsafterinitiatingART.FormoreinformationpleaserefertoProtocol2,Management of opportunistic infections and general symptoms of HIV/AIDS.

• Incaseofnegativetoxoplasmaserology,thetransmissionrouteandwaystopreventinfectionshouldbeexplained(includingrisksassociatedwithpets).ForfutherinformationseeProtocol2,Management of opportunistic infections and general symptoms of HIV/AIDS.

4. Antiretroviral treatment

4.1. Initiation of ARTThebestpointatwhichtostartARTisunderdiscussion(20).Areviewofseveralcohortstudiesandguidelinesshowsawidespreadviewthatclinicalstaging(stage3or4)andCD4countsarethebestprimarymarkersandviralloadthesecondarymarkerforthisdecision(21–31).PriortostartingART,supporttoensureadherenceshouldbeinitiated;seesectionII.4.3below.

2ForfurtherinformationseeProtocol6,Management of hepatitis C and HIV coinfection,Protocol7,Management of hepatitis B and HIV coinfection,Protocol8,Prevention of hepatitis A, B, C and other hepatotoxic factors in people living with HIV,andProtocol10,Prevention of HIV transmission from HIV-infected mothers to their infants.

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4.1.1. Clinical and immunological considerations

WHOrecommendsinitiationofARTusingclinicalandimmunologicalcriteriaasperTable6.

Table �. Recommendations for initiating ART in PLHIV

WHO clinical stagea CD4 cell count Recommendation

1<200/mm3 Treat

200–350/mm3 Considertreatmentb

2<200/mm3 Treat

200–350/mm3 Considertreatmentb

3 200–350/mm3 Treat

4 RegardlessofCD4count Treat

ThedecisiontoinitiateARTshouldbebasedontwodifferentCD4counts,ideallyatleast7daysapartbecauseofvariabilityintheCD4countitselfandtoruleoutlaboratorymistakesandothervariances(forexample,concurrentillnesses).Incaseofaconcurrentacuteillness,CD4cellcountshouldberepeatedonlyaftertheillnessiscured.Therapyshouldnothoweverbedelayedifapa-tientisunwellorifthesecondcountcannotreadilybeperformed.IftheCD4countisnotavailable,thedecisiontoinitiateARTcanstillbemadeonclinicalgroundsalone–withclinicalstage3or4illness.

BaselineCD4countattheonsetofART(ideallydeterminedwhenthepatientisfreefromanyactivemajoropportunisticinfection)isacriticalvalueindeterminingprognosis,responsetoARTandformonitoringthesubsequentimmunologicalresponsetoART.

4.1.2. Considerations for viral load

ViralloadisassociatedwithlossofCD4cells.ThoughonitsownitisnotamarkerforinitiatingART,incaseofviralload>100000copies/ml(thiscangoashighas1millioncopies),theprobabil-ityofrapidCD4cellcountdeclineisveryhigh.Therefore,itisrecommendedtoconsiderinitiationofARTatCD4cellcountof350/mm3iftheviralloadishigherthan100000copies/ml.

Whileviral load testing ismoreexpensiveandmaybe lessaccessible, it is important tohaveabaselineviralloadifatallpossible,asthisvalueisrelevantformonitoringART.Theabsenceofviralloaddatashouldnotbeacriterionfordelayingthestartoftreatment,orusedasareasonfortreatmentexclusion.

4.1.3. Considerations for drug resistance test

PrevalenceofHIVdrug resistancevaries in different countries and is linked to several factors,includingthedurationofARTavailability,historyoftreatment(mono-anddualtherapy)andad-herence.InwesternEurope,multicentricstudiesshoweda10%overallprevalenceofresistanceinnewlydiagnosedHIV-infectedindividualsbetween1996and2002(32).Astudyof40citiesintheUnitedStatesrevealedaresistancerateof14% (33).Thehighestresultsfromthesestudieswere26%inSpain(34)and19%inSanFrancisco(35).IncountrieswithashortornohistoryofART,riskofHIVdrug resistantvirus transmission is significantly lower, and the first-linehighlyac-tiveantiretroviraltreatment(HAART)regimenrecommendedbelow(sectionII.4.2)iseffectivefortreatmentofnaïvepatients.Itisimportanttohavepopulation-basedHIVdrugresistancestrategiesinplacetomonitorfortheappearanceandspreadofHIVdrugresistance;andtoactontheearlywarningindicatorsfordrugresistanceemergenceinordertominimizeitsappearanceandonwardspread.

aSeeAnnex2foradescriptionoftheclinicalstages.bWhentheCD4countisaround350cells/mm3,begindiscussionswiththepatientontheadvancingneedforinitiatingARTandonpreparationsforstarting.

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WHOdoesnotrecommendindividualdrugresistancetestingpriortoinitiationofARTinsettingswhereonlyonefirst-lineregimenisprovidedinthepublicsectorbecauseanyresultswillnotin-fluenceART. Instead, sentinel surveys thatdemonstrate resistanceatpopulation levelabove thethresholdof5%(36, 37)shouldbetakenintoconsiderationinadaptingnationalrecommendationsfor first-lineART.Refer toAnnex3 for additional informationon resistance testing.Where re-sourcespermit,andthepublicsectorprovidesmorethanonefirst-lineregimen,thendrugresistancetestingatbaselinemayhelpdeterminethechoiceofoptimalART;costandavailabilitywilllikelylimitthewidespreaduseofthisinmanysettings(38–40).

4.2. First-line HAART regimenItisrecommendedthattwonucleoside/nucleotidereversetranscriptaseinhibitors(NRTIs)andonenon-nucleosidereversetranscriptaseinhibitor(NNRTI)becombinedinthefirst-lineHAARTregi-men.

Table �. Recommended first-line HAART

ARV drug classes HAART regimens

2NRTIs+1NNRTI

ZDV+3TC+(EFVaorNVP)or

TDF+FTC+(EFVaorNVP)or

ABC+3TC+(EFVaorNVP)

(Forrecommendeddosages,pleaserefertoAnnex4.)

4.2.1. Considerations for NRTI component

• The“backbone”offirst-lineARTisacombinationoftwoNRTIs.Oneshouldbelamivudine(3TC)oremtricitabine(FTC);FTCisconsideredanequivalentdrugto3TCinbothefficacyandtoxicity(41).Thesecondismostoftenthethymidineanaloguezidovudine(ZDValsoknownasAZT).AlargebodyofdataandproviderexperienceisavailableforZDV,asitwasthefirstknownARVdrug.

• Stavudine(d4T)isanotherthymidineanalogue.Itisavailableinseveralfixed-dosecombina-tions(FDCs),ischeaperthanZDVandconsequentlywidelyusedinmanycountries.However,ithasapoortoxicityprofileandrecentstudieshaveshownahigherrateoflongtermside-ef-fectswithd4T(42–49).Manynationalandinternationalrecommendationsaremovingawayfromrecommendingitforinitialtherapy.ItisincreasinglybeingreservedasanalternativeforZDV(awithinclasssubstitution)whenZDVhastobesubstitutedorchangedforsideeffectsortoxicity.Thelowerdose30mgisnowrecommendedforallweightstoreducelong-termtoxic-ity.

• Otherpossiblenon-thymidineanaloguesforfirst-linearetenofovir(TDF)orabacavir(ABC)incombinationwith3TCorFTC.Recently,onestudyhasshownaslightsuperiorityofTDF/FTCoverZDV/3TCwhenusedincombinationwithEFV(42),probablyduetoalowerrateofside-effectsintheTDFarm.Furtherstudiesareneeded.ItshouldbenotedthatABChasariskofdangeroushypersensitivitysyndrome;and,TDFcancauserenaldamage,sopre-screeningforrenalfunctionisusuallyrecommended.

• TheadvantageofTDFandABCistheirresistanceprofile,whichpotentiallyallowsmoreNRTIcombinationstosupportsecond-lineproteaseinhibitors(PIs).Thedisadvantagesarecost,avail-

aEFVishighlightedasthepreferredNNRTI.

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abilityandlicensing,andtherelativelackofprogrammaticexperienceandeffectivenessdata,whichislesscomprehensivethanthedataforthethymidineanalogues(43).

• NRTIsareavailable(orarelikelysoontobeprequalifiedandavailable)inthefollowingFDCs,orone-pillformulationsfromoriginatorandgenericmanufacturers:

° ZDV+3TC ° TDF+FTC,TDF+3TC ° ABC+3TC ° d4T+3TC• AnadditionaladvantageofTDF/FTCandABC/3TCis theavailabilityofaonce-daily regi-

men.

OtherNRTIsandcombinationsarenotrecommendedforfirst-lineART(44).CertainrulespertaintotheuseofNRTIs.• Donotcombine“d-drugs”(ddI(didanosine),d4T).• Donotgivesingled-drugswithpre-existingpolyneuropathy.• DonotcombineZDVandd4T.• Donotcombine3TCandFTC.

4.2.2. Considerations for NNRTI component• TherearetwoNNRTIs,EFVandnevirapine(NVP),whichareavailableandrecommendedfor

first-lineART.TheeffectivenessofNVPiscomparabletothatofEFV(50).Bothhaveimpor-tanttoxicitiesandside-effectswhichlimithowtheycanwidelybeused.

• ThebestavailabledataarefortheregimenofZDV+3TC+EFV(51–53).Thisthree-pillcom-binationisgivenintwodosesperday.Itisfastacting,theviralloadfallsrapidlyinthefirsttwoweekswithEFV,theincreaseofCD4countiscomparabletootherregimensandproblemsarelimited.

• EFVshouldbeavoided inpatientswithahistoryofseverepsychiatric illness, inwomenofchildbearingagewhodonotuseeffectivecontraceptives,andduringthefirsttrimesterofpreg-nancy.NVPisanalternativeoptionforthesecases.

• NVPcancauseseverehepatictoxicitywhichseemstoberelatedtothelevelofimmunosup-pression(54)soitsuseislimitedtofemalepatientswithCD4count<250cells/mm3andmaleswithCD4count<400cells/mm3.CD4countshigherthantheseareassociatedwithmoreriskofhepatictoxicity.

• NVPneedstobedose-escalated.Thereisarecommended14-daylead-inperiodwith200mgNVPoncedaily(OD)whenstartingthisregimen,forbettertolerance.After14days,thedosageshouldbeincreasedtothestandardregular200mgtwicedaily(BID).

• EFVisusuallypreferredwhenthepatientisbeingco-treatedforTBwithrifampicin(seeProto-col4,Management of tuberculosis and HIV coinfectionforfurtherinformation).

• ThecombinationoftwoNNRTIswithoneNRTIisnotrecommended(55).

4.2.3. Alternative first line HAART regimens

• TripleNRTI-basedfirst-lineregimenssuchasZDV+3TC+ABCandZDV+3TC+TDFcanberecommended in specific circumstanceswhereNNRTI is contraindicatedor too complex tomanageandhavetheadvantagethattheystillpreservethePIclassforsecond-lineART.Theseregimenscanbeusedinthefollowingcircumstances:

° intoleranceorresistancetoNNRTIs; ° psychiatricdisorders; ° pre-existingliverdisease–anincreaseoftheALTlevelbymorethan3–5fold–andestab-

lishedcirrhosis; ° coinfectionwithHBVorHCV; ° HIV-2infectionduetointrinsicresistancetoNNRTIclass;and ° cotreatmentofTBinwomenofchild-bearingageandwhereadequatecontraceptioncannot

beguaranteed,andwhenNVPandboostedPIscannotbeused.

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• ZDV+3TC+ABChasshort-terminferiorvirologicalefficacyatleastinpatientswithhighini-tialviralloadsbutcomparativeimmunologicalefficacytoZDV+3TC+EFVregimen(51, 56).ZDV+3TC+TDFisapromisingregimenbuttherearelimiteddatatodate(seethefollowingProtocols:4,Management of tuberculosis and HIV coinfection; 6, Management of hepatitis C and HIV coinfection; and7, Management of hepatitis B and HIV coinfection).

• OthertripleNRTI-basedregimens,suchasZDV+TDF+ABCorTDF+3TC+ddIhaveunaccept-ablyhighvirologicalfailureratesandhighincidenceoftheK65Rmutation(57, 58)andshouldnotbeused.

• BoostedPIsareusuallyreservedforsecond-lineART.Theycanexceptionallybeusedaspartoffirst-lineARTincombinationwithtwoNRTIswhentripleNRTIregimenisnotavailableordeemedinappropriateorwhentherearecontraindicationsforNNRTIs(i.e.neitherEFVnorNVPcanbeprescribed)including:

° psychiatricdisorders; ° anincreaseoftheALTlevelbymorethan3–5fold; ° cirrhosis; ° pregnancywithCD4countof250–350cells/mm3,particularlyinthe1sttrimesterofpreg-

nancy(asEFViscontraindicated); ° HIV-2infectionduetointrinsicresistancetoNNRTIclass;and• Ifafirst-lineARTregimencontainingaPIfails,thereareverylimitedoptionsforsubsequent

regimensatleastwithinapublichealthapproachandwithinthepublicsectorinmanycountries.AfailingPIregimenhas,inconsequence,moreresistancepatternsthanafailingNNRTIregi-men(pointmutationinNNRTIclass).Ingeneraltherefore,itisrecommendedthatPIsbelefttosecond-lineART.

4.3. Adherence to ARTOptimaltreatmentbenefitsrequirestrictadherencetoART.Itiswellrecognizedthatwhenadher-enceishigh,thereisadramaticreductioninHIV-associatedmorbidityandmortality(59),whereaslowadherenceleadstorapiddevelopmentofdrugresistance(60).EffectiveadherencelevelshavenotbeenfullydefinedforART(therebeingdifferencesbetweenanumberofregimens),butlevelslower than95%havebeenassociatedwithpoorvirologicaland immunological response,whilelevelsof100%seemtoachieveevengreaterbenefitthan95%(61, 62).ThemostrecentdatashowacorrelationbetweendrugresistanceinvariousclassesofARVsandadherence(63).

Lowor insufficient adherencehas consequences for patients, public health andnational econo-mies.• Patientsareindangerofdevelopingsignificantviralresistance,treatmentfailureanddisease

progression(64, 65).Changingtoanewregimenaftertreatmentfailureresults,inmostcases,inmoredifficult adherence (morepills, side-effects, dietary restrictions, toxicity anddosingcomplexity).

• Theincreaseinresistantvirusesislikelytoresultintheirtransmissiontonewlyinfectedindi-viduals.DatafromtheUnitedStates(66)andEurope(67)suggestthatsuchprimaryresistanceisincreasing,andthatacquiredresistancehasanegativeeffectonARTresponse.

• Economically,thepresenceofresistantstrainswillresultinincreaseduseofsecond-lineandsalvageregimens,whichareingeneralmoreexpensivethanfirst-lineregimens.

• Lowadherencealsomeansahigherriskofdiseaseprogression,resultinginhighercostsfortreatingopportunisticinfections(68).

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4.3.1. Barriers to high adherence and counteracting strategies

Healthcareworkersshouldidentifypossiblefactorswhichmightleadtopooradherencetotreat-mentandaddressitaccordingly.

4.3.1.1. Patient factors and supportive methods

Theroleofpatientsthemselvesisfundamental.Onecannotpredictpatients’adherencepotential.Studiesinvestigatingtheroleofgender,race,age,modeoftransmissionandeducationallevelasin-dicatorsofadherencehaveproducedinconsistentresults(69).Individualadherenceratesalsovaryovertime(70).MostPLHIVundertreatmentwillexhibitlowadherenceatsometime.

Barriers to adherence include:• drugandalcoholuse(mayimpairroutineuseofmedication)• poordietduetopovertyorduetootherreasons• religiousbeliefs(71)• fearofdisclosingHIVstatusthroughroutinemedications• psychiatricconditions(72)• fearofside-effectsanddoubtsaboutthenecessityofmedication(73).

Methods to support adherence include:• educationontheneedforART• addressingpatientmisconceptionspromptly• regularevaluationofpatientcommitmenttoART• peerintervention(groups,friends,patientsupporters)• regularassessmentofmentalhealthproblems• assessingbehavioralskillsneededforadherence3

• contactingspecializedsocialcareservicesandotherinstitutions.

4.3.1.2. Provider factors

Healthcareprovidersshouldclearlyunderstandadherenceanditsroleinresistancedevelopmentwhenprovidingadherencesupport.ProfessionalsworkingintheareaofHIV/AIDSrequirecon-tinuouseducationinadherenceissues.Thereareseveralstrategiesthathealthcareworkersshouldemploytoincreaseadherence:• EveryHIVtreatmentcentreshouldhaveawrittenandregularlyreviewedadherencestrategy.• Healthprofessionalsneedtobeengagedinadherencesupportprogrammes(74).• Exploringpatientpreferencesforinvolvementmayactasacatalysttoadherence.• Adherenceservicesshouldbeofferedtoallpatients,takingintoaccountthevaryingdegreesof

adherencethatallpatientsshowoverthecourseoftreatment.• Adherencesupportshouldbecontinuedforsecond-lineandsalvageregimens.Treatmentfailure

isakeypointforreinforcingadherenceandsupportinterventions(75).• Ashighadherenceisaprocessandnotasingleevent(76),supportmustbeofferedwhenstart-

ingART,changingARTandasaroutinefollow-up.• ProvidersmustensurethatpatientshavesufficientunderstandingofHIV,therelationshipbe-

tweenadherenceandresistance, therequirementsoftheirregimenandpotentialside-effects.Verbalinformationshouldbesupportedbywritteninformation.

• Pilldiaries,pillcharts,medicationcontainers,electronicreminders,andenlistmentoffamilyandfriendsasreminderscanallberecommendedbyhealthcareproviders(77).

• Adherence toART is improvedwherepatientsview their relationshipwith their doctor andotherhealthcareproviderspositively(78).

3Thesecanbeaugmentedbycontactingpeoplewhocanhelp(nurses,pharmacy,family),andbyusingtimetables,pillboxeswithclocks,pill-takingroutines,strategiesfortravelandmanagingdisclosureordiscoverybyothers.

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• Earlyfollow-upshouldoccurtwodaysafterinitiatingorchangingaregimen,toevaluatewheth-erthepatientneedsmoreinformationorhasunregisteredproblems.

• Thepartnershipbetweenclinicsandcommunity-basedorganizationscanimprovetheuptakeofinformation,especiallyamonghard-to-reachpopulationsandsomeethnicgroups.

4.3.1.3. Regimen factors and strategies

• Dosingmorethantwotimesadayisassociatedwithloweradherencelevels(79),whilethereisprobablynoadherencedifferencebetweenoneor twodailydoses (80). In regimenswithsingleordoubledailydosing,moreofthedosesaretakenatatime.Takingthedoselaterthanprescribedhasbeenassociatedwithtreatmentfailureinmultivariateanalysis(81).

• Alowpillburdenisassociatedwiththelikelihoodofhavingaviralloadbelow50copies/mlafter48weeks(80).

• AdherencelevelsarenotcorrelatedwithanyARVclass.However,conflictingdietaryrulesfordifferentdrugscanbeaproblem(82).

• Harmfuldruginteractionsandside-effectscaninfluenceadherence.Dosescanbemissedduetovomitingordiarrhoea,andfatiguecancausepatientstosleeppastdoses(83).

Methods to support adherence include:• evaluatinglifestylefactorslikeeating,sleepingandworkingpatternsandadjustingtheregimen

accordingly;• assessingindividualpreferencesforregimencharacteristicssuchaspillsize,formulation,bur-

den,dietaryrestrictions,etc.;• showingpatientsthepillspriortoregimenselection;• educationaboutside-effects,promptpalliationofthemandinformationaboutsupport;• dispensingmedicationinsmallamountsatfrequentintervals,whichcanfacilitate: ° opportunitiestoaddressadherenceproblemsbeforetheyleadtoresistance; ° limitingtreatmentdisruptionsandmisuse;• utilizationofonce-dailyoptionsandFDCs,whichcanlowerthepillburdenandbebeneficial

earlyintreatment;and• directlyobservedtreatment(DOT),particularlyinhospitals.

4.4. ART success and failureAllpatientsshouldberegularlymonitoredbyskilledclinicians.Ideallyallshouldhaveaccesstobothimmunologicalandvirologicaltests.SuccessfulARTcanbedefinedbyclinical,immunologi-calorvirologicalcriteria(seeTable8).

Table �. Criteria for treatment success

Virological Immunological ClinicalMarker ViralLoad CD4cellcount Clinicalstage

Timea 24weeks 48weeks 24–48weeks By12weeksoftreatmentinitiationshouldbeasymptomaticorhavefewsymptoms

Suggested rangesa

<400copies/ml <50copies/ml Increasefrombaselinebyatleast50-100cells/mm3

Stage1or2b

Failureoffirst-lineARTcanbedefinedandidentifiedinthreedifferentways:clinically,immuno-logicallyandvirologically.Thethreemayreflectdifferentaspectsoffailure.Further,itisprovingdifficultintheabsenceofgoodclinicalend-pointdataonthesubsequentdurabilityofsecond-lineresponses,toknowwhichisthebestindicatorofwhentoswitchandwhatvalueorlevelshouldbeused.Therearedifferingviewsaboutwhetherapatientwitha“failing”regimen,regardlessof

aTimeandsuggestedrangesshouldnotbeseenasabsoluteandstrictnumbers.bPleaseseesectionII.5.3belowformoreinformationonimmunereconstitutioninflammatorysyndrome(IRIS).

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criterionused,shouldswitchtosecond-lineART,andwhentodoso.Thereisnoclearconsensusgloballyonthedefinitionoftreatmentfailure.Currently,differentbiologicalend-pointsareusedtorepresentvirological,immunologicalandclinicalfailureindifferentsettings.

4.4.1. Virological response

• VListheearliestindicatoroftreatmentsuccessorfailure,followedbyCD4cellcountapproxi-matelyamonthlater.Inrarecases,aparadoxicalreactionofvirologicalresponseandimmuno-logicalfailureoccurs;consequently,VLshouldbeseenincombinationwithCD4cellcount.

• Failuretodecreaseviralloadto<400copies/mlbyweek24oftreatmentor<50copies/mlbyweek48meansincompletevirologicalresponse.

• Whentheviralloadhasalreadydecreasedtoanundetectablelevel,buttwomeasurementsare>400–1000copies/mlin4to8weeks,itmeansthereisariskofvirologicalfailure(84).3

• “Blips”areslightelevationsofviralload,fromunderthetestingthresholdtoaround50–200copies/ml.Theymayhappenwithoutthedevelopmentofresistantvirusstrains(laboratoryer-rors),butshouldbeanindicatorforadiscussionofadherence(86).Inthissituation,therapeuticdrugmonitoring(TDM)mayalsobehelpful,ifavailable.Anyblipshouldbecontrolledwithinfourweeks.

• Ifnoreasonisfoundforvirologicalfailure(pooradherence,suboptimaldruglevels,drug–druginteractions,etc.),asecond-lineregimenshouldbediscussed.

4.4.2. Immunological response

• CD4cellcountresponseonitsowncanbeusedasanindicatoroftreatmentfailureorsuccess.• Onaverage,aCD4cellincreaseofabout150cells/mm³occursinthefirstyearintreatment-na-

ivepatients(87, 88).FailuretoincreaseCD4cellcountmorethan50cells/mm³duringthefirstyearofARTisconsideredimmunologicalfailure.

• IftheCD4cellcountdoesnotincreaseforsixmonths,adherencetotreatmentshouldbereas-sessedandensured.

4.4.3. Clinical response

• Patientswillusuallyreverse theirclinicalstageandbecomeasymptomatic(stage1)orhaveminimalorminorHIV-relatedsignsandsymptoms(stage2).

• Somestage3or4OIscanrecurandtheprognosticsignificanceoforalandoesophagealcandidainparticularisnotalwaysclear-cut.

• Usuallyhowever,presentationofaneworrecurrentstage3or4event(OIorotherHIV-relatedillness)afterinitiationofARTisanindicatorofclinicalfailure.

4.4.4. Dissociated virological and immunological responses

Despitethepersistenceoflowbutdetectableviremia(VLsuppressedtolessthanthenaturalsetpoint),CD4cellcountmayremainstableorevenincreaseinsomepatientstakingHAART(89–91).Inalargeintercohortanalysiseveninthosepeoplewhohadexperienced3-classvirologicalfailureandcontinuetotakeHAART,viremialessthan10000copies/mlorsuppressionofatleast1.5logcopies/mllessthanthepretherapyvalue,wasnotassociatedwithadeclineinCD4cellcount(92, 93).

4WHOheadquartersnotesthattheoptimalviralloadvalueatwhichARTshouldbeswitchedhasnotbeendefined.However,valuesofmorethan10000copies/mlhavebeenassociatedwithsubsequentclinicalprogressionandappreciableCD4cellcountdecline.Inresource-limitedsettings,WHO,atthegloballevel,hasprovisionallyoptedfor10000copies/ml,asanin-terimrecommendationforswitchingtosecond-lineHAART,iftheVLindicatorisusedasacriterion(85).

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4.�. Second-line HAART regimen• Whenfailureofthefirst-lineregimenhasbeenidentified,itisrecommendedthatalldrugsare

changedandthenthepatientswitchestosecond-linetreatment.• Second-lineART is thenext regimenused in sequence immediatelyafter first-lineARThas

failed.ThePIclass is reservedforsecond-lineuse. Ideally, ritonavir-boostedPIsarerecom-mended,supportedbytwoagentsfromtheNRTIclass.SeeTable9forsecond-lineARVregi-mens.

Table �. Recommended second-line HAART for adults and adolescents

First-line HAART regimens Second-line HAART regimens after treatment failure

ZDV+3TC+(EFVorNVP)

LPV/ra(orATV/r,SQV/r,FPV/r,IDV/r)+ddI+ABCor

LPV/ra(orATV/r,SQV/r,FPV/r,IDV/r)+TDF+ABCor

LPV/ra(orATV/r,SQV/r,FPV/r,IDV/r)+TDF+(ZDV+3TC)b

TDF+FTC+(EFVorNVP)LPV/ra(orATV/r,SQV/r,FPV/r,IDV/r)+ddI+ABC

orLPV/ra(orATV/r,SQV/r,FPV/r,IDV/r)+ddI+ZDV

ABC+3TC+(EFVorNVP)LPV/ra(orATV/r,SQV/r,FPV/r,IDV/r)+ddI+ZDV

orLPV/ra(orATV/r,SQV/r,FPV/r,IDV/r)+ZDV+TDF(+3TC)b

(ForrecommendeddosagesofARVs,pleaserefertoAnnex4.)

4.�.1. Considerations for NRTI component

• Minimumchangesforasecond-lineregimenaretwonewNRTIdrugs.Neverchangeonlyonedrugincasesofsuspectedresistance.

• Ifthefirst-lineARTincludedZDV+3TC,thenABCincombinationwithddI(orTDFwithdose-adjustedddIandclosemonitoring)maybeanoption(94).

• PatientswhobeganwithTDForABCmaynowbenefitfromZDV(95),duetothehigherlike-lihoodofresistance.For instance, theK65RmutationpromotedbyTDFandABCincreasessusceptibilitytoZDV(96, 97).

• 3TCisalsousefulincasesof3TCresistance,astheregularlyacquired184VmutationreducesviralfitnessandalsoincreasessusceptibilitytoZDV(96).

4.�.2. Considerations for PI component

• Withafirst-lineregimencontainingaNNRTI,second-lineARTshouldincludeaPI.• InthePIclass,themajorityofdrugsareboostedwithalowdoseofRTV,itselfaPI,100mg

BID–exceptnelfinavir(NFV),whichisboostednotchemicallybutwithfood.Themeansofboostingisritonavir’sinhibitionofthecytochromeP450(CYP)3A4isoenzyme.Subsequently,thedruglevelsofthemainPIs(exceptNFV)areincreased(98).RTVisusedonlyforboostingotherPIsandisnoteffectiveasastand-aloneARV.

• ThedifferencesamongthePIslieinthenumberofmutationsneededtodevelopresistanceandintheprofileoftheirside-effects.

• OneofthehighestgeneticbarriersforresistanceisdocumentedforLPV/r(99).• Theresistanceprofilesofritonavir-boostedatazanavir(ATV/r),fosamprenavir(FPV/r),indina-

vir(IDV/r)andSQV/rshowslightdifferencesthathavelittleornoclinicalimpact.

aLPV/rislistedasthepreferredRTV-boostedPIinthistable,butotherboostedPIscanbesubstituted,basedonindividualpro-grammepriorities.ATV/r,SQV/r,FPV/randIDV/rareallpossibilities.Intheabsenceofacoldchain,NFVcanbeemployedasthePIcomponent,butitisconsideredlesspotentthananRTV-boostedPI.bZDV+3TCarelistedhereforstrategicusesinceresistancetobothispredictedfollowingfailureofthelistedfirst-lineregi-men.ZDVmaypreventordelaytheemergenceoftheK65Rmutation;3TCwillmaintaintheM184Vmutation,whichmaydecreaseviralreplicativecapacityaswellasinducesomedegreeofviralresensitizationtoZDV.Itmustbestressedthattheclinicalefficacyofthisstrategyhasnotbeenproven.

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• NFVseemstobeinferiortotheotherPIs,butitiswelldocumentedinpregnantwomen.Incaseoffailure, theD30Nmutationisusuallyselected; itdoesnotencodeforcross-resistanceforotherPIs(100, 101).

• LPV/risthePIofchoiceduetoitswell-documentedpotency(102),availabilityasaFDCandrelativelylowpillburdenandgoodtolerance.AnewtabletformulationofLPV/rhasbeenap-provedinEuroperequiringtwopillsBIDandnorefrigeration(103).

• Recentstudies(104, 105)showedsimilarefficacyofSQV/randFPV/rtoLPV/r,butinARVnaivepatients.Thepro-drugformulationofamprenavir(APV)intheformofFPV,theonce-dailyPIATVandthenewformulationofSQV(500mgtablets)havenotbeendirectlytestedagainstLPV/r.Therefore,only indirectdataareavailable.Further studieswithhead toheadcomparisonsamongboostedPIsinARVexperiencedindividualsareneeded.

• Possiblesideeffects,comorbidities,druginteractionsandindividualpreferencesshouldinflu-encethechoiceofPI.

• If first-lineARTregimenscontainingPIsfail, thechoiceofasecond-lineregimenismainlybasedonresistanceprofiles.Ifresistanceprofilesarenotavailable,thenresistancetothePIscontainedinthefirst-lineregimenmustbeassumedtobethecauseoftheregimen’sfailure(seesectionII.4.4aboveforsuccessandfailurecriteria).

• Possibleoptionsintheeventafirst-lineregimenwithaPIfails: ° ZDV+3TC+PI/r→ ABC+ddI+NNRTI ° oroneofthesalvageoptions(seesectionII.4.6below).

4.�. Salvage regimensIncaseofconfirmedsecond-lineARVtreatmentfailure(usingvirological,immunologicalorclini-calcriteria),asalvageregimenshouldbeconsidered.Salvageregimensarecombinationsofdrugsthatwillprobablyworkevenagainstvirusesthatarepartlydrugresistant.Everyregimenaftersec-ond-linetreatmentiscomplicatedandrequiresahighlevelofARTknowledgeandskillonthepartofthehealthcareprovider.Performingaresistancetestinthesecircumstancesishighlydesirable.Itisattimesbettertowaitseveralmonthsbeforeinitiatingsalvagetreatment,althoughthisstrategycanbedangerous,particularlyiftheCD4cellcountislow.

• Ifpossibletwoeffectivedrugsshouldbeadded,forexamplethefusioninhibitorenfuviztide(ENF) (106),which is administered twicedailywith subcutaneousapplication, and thenewboostedPIsTPV/r(107, 108)orboosteddarunavir(DRV/r)(108–112).

• ThegeneticbarrierofTPV/rseemstobeevenhigherthanthatofLPV/r,anddatashowitseffi-cacytobecomparableorbetterthanthelatter’s(113).ThisPIispresentlyusedonlyforsalvageregimens.

• AnotheroptionisacombinationoftwoPIs(114–117),exceptboostedtipranavir(TPV/r),whichisnottobecombinedwithanyotherPIs.

(Forrecommendeddosages,pleaserefertoAnnex4.)

4.�. Structured treatment interruptionMostARTprovidersareopposedtoplannedinterruptions,butthereareconditionsthatmayjustifythem.Forexample,constantCD4count>500cells/mm3withcompletelysuppressedvirusforyearsmayoffersuchanopportunity.Althoughitisnotnecessarytointerrupt,itisbettertodosothantofacepooradherencefollowedbythedevelopmentofresistantstrains.Duringstructuredtreat-mentinterruption,theCD4cellcountnormallyfallsrapidlytopre-ARTlevels;thus,itisimpera-tivetomonitormonthlycountsduringthefirstthreemonths,thenonceeverythreemonths.SomepatientscontinuetomaintainsatisfactoryCD4cellcount(usually>350cells/mm3)withalowVL(1000–5000copies/ml)formonthsandyears.Thescientificinvestigationofthisissueiscontinuing(118–122),andinvolvesdiscussionsparticularlyamongtheself-helpgroupsandARTproviders.However,arecentmulticentrictrialconductedintheUnitedStatesdemonstratedthatthisstrategycanbeassociatedwithanincreasedriskofHIVdiseaseprogression,occurrenceofnon-AIDSre-

21


latedcomplications(kidney,liverandcardiovasculardisease)anddeath(123),whichmotivatedtheinterruptionofthespecificarmstudyusingthestructuredtreatmentinterruptionstrategy.Becauseoftheseresultsandthelackofdefinitiveevidenceofthebenefitsofstructuredtreatmentinterrup-tionsstrategiesinotherstudies,WHOdoesnotrecommendthisapproachoutsideclinicaltrials.

�. Clinical monitoring of patients with HIVOnceapersonhasbeendiagnosedwithHIVinfection,acontinuumofcareandmonitoringshouldbeensured.

�.1. Monitoring of laboratory indicators before ART• CD4cellcount ° Repeateverysixmonths,unlessthereareunexpectedresults(rapidfallofCD4cellscount

ordiagnosisofopportunisticinfection). ° IfstartingARTisunderdiscussion(CD4countis350cells/mm3orless),repeatCD4count

everythreemonths.Statistically,everypatienthasamedianaveragelossof50CD4cells/mm3peryear,buttheycanalsodropveryquickly,especiallywithconcomitantinfection.

• Viralload ° Althoughviral load testing isexpensive, thecostsofunmonitoredARTaremuchhigher

(uselessdrugs,hospitaladmissionincaseoffailure),aswellasbringingamuchhigherriskforfurthertransmissionofHIVduetohigherinfectivityfromanelevatedviralload.

° Ifpossible,viralloadshouldbemonitoredinthesameintervalasCD4cellcount.Theresultgivesahintabouttheintensityofviralreplication;lowviralload(1000–5000copies/ml)indicatesslowprogression,highviralload(>100000copies/ml)indicatesahighriskforrapidprogression.

• Thegenerallaboratorytestingpanel(seeTable3above)shouldberepeatedeverysixmonthsiftherearenochangeswithregardtoinitiationofARTorothercircumstances(comorbidities,pregnancy,etc.).

�.2. Monitoring of laboratory indicators in ART patientsSuccessfulARTisfirstreflectedbythedecreaseofviralload;immunologicalresponseisaresultofviralload,andthusoccurslater.ARTmonitoringisbestdonewithviralloadandCD4countboth.• Viralload ° VLshouldbemeasuredafter4–8weeksforassessmentofwhethertheregimenissuccess-

ful.Viralloadusuallyfallsbelowtheassay’slimitsofdetectionwithin16–24weeks. ° Subsequentmonitoringofviralloadshouldbedoneinintervalsofthreetofourmonths. ° Onceviralloadisbelowthetestingthresholdwhichis<50copies/ml(or60or70copies/ml,

dependingontheavailabletest),itshouldremainthere.• CD4cellcountshouldberepeatedeverysixmonths,exceptincaseofclinicalfailure.• Thegenerallaboratorytestingpanel(seeTable3above)shouldberepeatedeverysixmonthsif

therearenochangesinARTorothercircumstances.• DependingonspecificARVsused,thefrequencyforlaboratorytestingmightdiffer.SeeTable10.

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Table 10. Frequency of laboratory testing, generally and with specific ARV use

Baseline Week 2 Week 4 Week 8 Week 16 Week 24 Week 36 Week 48Viral load X X X X XCD4 count X X X (X) XComplete blood count X X X X(ZDV) X (X) X

Liver Function Test (LFT)

X X(NVP) X X(NVP,ZDV,PIs)

X(NVP,PIs) X (X) X

Cholesterol triglycerides X(PIs) X(PIs) X(PIs)

Renal function test X X(TDF) X(TDF,

IDV) X (X) X

X:laboratoryteststobeperformedirrespectiveoftheARVsbeingadministered;X (ARV):laboratoryteststobeperformedifanARVinparenthesesisbeingadministered;(X):optionaltest.

�.3. Immune reconstitution inflammatory syndromeIRIShappensafterinitiatingART,moreoftenwithCD4counts<100cells/mm3.Ifadormantop-portunisticinfectionisnotdiagnosedbecauseofmissingclinicalsymptoms,theremaybeanin-flammatoryreactionafterinitiatingART,duetoanimprovedandactivatedimmunesystem,leadingtodiagnosisoftheOI(124, 125).ThismayoccurinuptoathirdofpersonswithTBwhoiniti-ateART(85)(forfurtherinformationonIRISinTB/HIVcoinfectedpatients,refertoProtocol4,Management of tuberculosis and HIV coinfection).TheOIoftenpresentsdifferentlythanusual,forexample, in abscesseswithMycobacterium avium-intracellulare (MAI)or curious chestX-rayswithPCP.TheincidenceofIRISisprobablyabout10%.MAIandCMVarethemostcommonOIs,butworseningofatreatedPCPmayalsooccur(126).Inprinciple,ARTshouldbecontinuedalongwithtreatmentof theOI.Low-doseprednisoneorprednisolone(20–60mg/day)mayhelp.ARTshouldbediscontinuedifirregularlytakenduetoside-effectsofOItreatmentorifthereispainwithoesophagitis(CMV,herpes,candidiasis).

�.4. Monitoring adherenceEverypatient’sadherencetoARTshouldbemeasuredandrecordedduringroutineclinicalvisits.Whiletherearetoolsformonitoringadherence(seeAnnex5),thepreferredmethodisastandard-izedquestionnairefor14daysoronemonth.

Viralloadreboundshouldalwayspromptphysicianstodiscussadherencebehaviorwiththeirpa-tients.Theuseofopenquestionsthatacknowledgecustomarylowadherenceismorelikelytoelicitfullresponses.

Optimizingadherenceinthefirstfourtosixmonthsoftreatmentiscrucialtoensuringlong-termimmunovirologicalsuccess(127).Severalinterventionsarepossible,butpriorityshouldbegiventointerventionsaimedatimprovingadherenceintheearlymonthsofART (127–131).

Staff shouldprovide individualized support to adherence,basedon theneedsof eachpatient atanytimeduringtreatment.Ateverypatientvisit,healthcareprovidershavetoensurethateverypatient:• hasemotionalandpracticallivingsupport• fitsthedrugregimenintoadailyroutine• understandsthatnon-adherenceleadstoresistance• recognizesthatalldosesmustbetaken• feelscomfortabletakingdrugsinfrontofothers• keepsclinicalappointments

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• understandsARVinteractionsandside-effects• knowsalarmsignalsandwhentoseeadoctoraboutthem(132, 133).

OnceapatientisalreadyonART,additionalissuesmayarisewhichalsoneedtobeaddressedinatimelyfashion:• treatingdepressiontoenhanceadherenceandimprovelong-termoutcomes(134);and• managementofdruginteractionsanddosages.

�.�. Management of ARV toxicity and side-effectsSide-effectsarecommonwithARVs,especiallyPIs.SeeTable11.• LPV/randNFVcancauseseverediarrhoea.• LPV/risassociatedwithhyperlipidaemia(especiallyhightriglycerides).• ProblemswithlipidmetabolismcanoccurwithnearlyallPIs.• Long-termstudiesofside-effectsandincreasedriskforcardiovascularcomplicationsareneeded.

ToxicitymightbeareasonforsubstitutionofprescribedARVtoanotherARVdrugwithinthesameregimen.Switchingtoanothertreatmentregimenduetotoxicityisnotrecommended.

Table 11. Documented toxicity of ARVs and suggestions for management

ARV Toxicity ManagementHepatic necrosis (life-threatening)NVP • Fever,rash(50%),nausea,vomiting,

eosinophilia,elevationofALT/AST• Usuallyinfirst6–18weeks,rareafter

48weeks• 1–2%ofallNVPtreatedindividuals,

higherifCD4count>250infemalesand>400inmales

• MonitorLFTatweeks2,4,8and16,andtheneverythreemonths.

• Treatmentissymptomatic.• Hepaticnecrosisislifethreatening;in

severeclinicalsituations,stopdrugsatonce.

Lactic acidosis (life-threatening)Fromhighesttolowestrisk:• d4TwithddI• ddI• d4T• ZDV

• Nausea,vomiting,wasting,fatigue,pancreatitis,multiorganfailure,acuterespiratorydistresssyndrome(ARDS)

• 1–10per1000patients/yearforddIandd4T

• Monitorlacticacidclinically.Ifsuspected,lookforearlyindicators(creatinekinase(CK),HCO3).

• Thesymptomatictreatmentisbicar-bonateagainstacidosis.

• ChangetoABC,TDF,3TC,FTC.Hypersensitivity (life threatening in case of re-exposure: anaphylactic shock)ABC • Nearlyalwaysfeverandrash,also

fatigueandnausea• 5%,rareaftersixweeks

• Monitorskin,donotstarttogetherwithotherrash-producingdrugs.

• StopABC,donotuseagainifdiagno-sisisfirmlysuspected.

• ChangetoZDV,TDFord4T.Stevens–Johnson syndrome, toxic epidermal necrolysisNVPLesswithEFV

• Fever,rashwithblistering,myalgia• NVP:0.3%,EFV:0.1%

• Monitorskin.• Administerantibioticsandintensive

careofwounds,perhapsinaburnscentre.

PancreatitisFromhighesttolowestrisk:• d4TwithddI• ddI• d4T

• Pain,highlevelsoflipase• ddI1–7%,lesswithdoseadjustment

• Monitorlipaselevel.• Thesymptomatictreatmentispain

medication,parenteralnutrition,drugstoppage.

• ChangetoZDVorTDForABC.

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ARV Toxicity ManagementNephrotoxicityTDF • RenalfailureandFanconisyndrome

• Morefrequentinindividualswithbaselinerenaldysfunction(135)

• Monitorcreatinine,historyofrenalfailure.

• Treatmentissymptomatic.• Eventuallytryagainwithdoseadjust-

mentofTDF(creatinineclearanceisneeded:TDFeverysecondday).

• ChangeTDFtoZDV,ABCord4T.AnaemiaZDV • Anaemiaandneutropenia

(slightdecreaseisnormalwithZDV)• 1–4%,dosedependent

• Monitorbloodcountafter2,4,8and12weeks.Macrocytosiswithlightanaemia(haemoglobinupto10g/dlor100g/litre)iscommon.

• Treatmentisatransfusionoferythro-poetin(veryexpensive)orchangingZDVtoanotherNRTI(TDF,ABCord4T).

Peripheral neuropathyd-drugs:ddI,d4T • Pain/paraesthesiaofextremities

• 10–30%,alsoafteryears• Monitorperipheralnerves,warn

patient.• Treatmentispainmanagement,

changeofART.Stopd-drug,changetoanotherNRTI(ZDV,TDF,ABC).

Fat atrophyd4TandotherNRTIs • Reducedbuccalfatandextremityfat

• Commonwithlonguse(mitochon-drialtoxicity)

• Monitorandcomparetopreviouspictures.

• Changed4TtoTDForABC.Ifatro-phyisirreversible,plasticsurgeryisindicated.

Fat accumulationPIs • Increasedabdominalfat(“crixi

belly”),breastsize,buffalohump• 20–80%

• Measureandcomparetopreviouspictures.

• ChangetoNNRTIiflipodystrophy/lipoatrophyisnottolerable.Plasticsurgerymaybeindicated.

RashNNRTI>APV/FPV>ABC • Maculopapularitching

• 15%NNRTI,APV~20%,ABC5%• Monitorfever,LFT,CKinclosevis-

its.• Thinkofotherallergenicdrugs

(sulfamethoxazole/trimethoprimandotherantibiotics,prophylaxis).RashessometimesresolvespontaneouslywithcontinuedART.

• ChangeNVPtoEFVorviceversa.Ifnoimprovement,tryanewregimen.

Elevation of transaminaseNNRTIs(all)andPIs(all) • Otherwiseunexplainedelevationof

LFT• 8–15%withPIandNNRTI• Morefrequentinpatientswithchronic

HBVorHCV

• MonitorALTeverythreemonths,lookforotherreasons(drugs,hepatitis).

• Elevationoftenresolveswithcontinu-ationofNNRTIorPI.

• DiscontinueNNRTIorPI.Gastrointestinal intolerancePIs(all),ZDV,ddI • Nauseaandvomiting,diarrhoea

• Common• Ruleoutotherreasons(IRISwith

CMVcolitis,cryptosporidiosis,microsporidiosis,alsoweeksafterinitiatingART).

• Treatmentisloperamideifthereisnootherreasonfordiarrhoea;meto-clopramide,Zofranefornauseaandvomiting.

2�


ARV Toxicity ManagementCentral nervous system (CNS) toxicityEFV • Nightmares,impairedconcentration,

depression(riskofsuicide)• 50%

• Warnpatient,takepsychiatrichistory,refertopsychiatricconsultation.

• Treatmentusuallynotnecessary,resolvesin5–21days.

Insulin resistancePIs(allbutATV),espe-ciallyIDV

• Elevatedglucosetolerance,elevatedglucosewithmorningfasting

• 5%

• Monitorfastingbloodglucose.• Treatmentisviadietandexercise,

metforminorGlitazone.• ChangePItoNNRTI.

Hyperlipidaemiad4T>PIs(allbutATV) • Increasedlipids,increasedLDL,cho-

lesterol,triglycerides(forthelast,d4Tisparticularlyprominent)

• %varies

• Monitorfastinglipidlevelsatinitia-tionofARTandeverysixmonths.

• Treatmentisperlipid,cholesterolandtriglycerideguidelines.

• Usestatinsandfibrates.Becarefulwithinteractions(nosimvastatin,nolovastatin).

HyperbilirubaemiaATV>IDV • Elevationofbilirubin(harmless;

possibleitching,noprolongedliverdamage,reversible)

• Frequencyvaries

• Monitorbilirubinandclinicalsymp-toms.

• Stopdrugonlyifnottolerated.ChangePI.

NephrolithiasisIDV • Abdominalpain,haematuria,renal

colic• 10–20%peryear,lesswith>3litre

fluid/day

• Monitorurinalysis,creatinine.• Treatmentisthesameasfornephroli-

thiasis.

Source: Bartlett (136).

�.�. Drug interactionsDrug interactioncanbeasevereprobleminART.PLHIVneed to takeagooddealofdifferentagentsduetoconcomitantdiseasesormanifestationofHIVandAIDS.

Thoughsomedrugsaregenuinelycontraindicated,mostdrugsthatshowinteractionscanstillbegivenincombination;however,theprobabilityofside-effectsisthengreater,andtheyshouldbecloselymonitored.Theeffectivenessofcontraceptivescouldalsobejeopardized.(SeealsoProtocol9,Support for sexual and reproductive health of people living with HIV.)Tables12and13illustrateinteractionsofdrugswithNNRTIsandwithPIs.

2�


Table 12. NNRTI interaction with selected drugs

NNRTI (drug A)a With … (drug B) Effect Significance b

EFV NVP+ Ergotamine ↑ levelofB ++(avoid)

+ Antiarrhythmics:lidocaine,amiodarone,others ↑ and↓levelofB ++(caution)+ + Anticonsulvants:carbamazepine,phenytoin,

phenobarbital↓ levelofBand/orA;usegabapentininstead

++

(+)c + Itraconazole,ketoconazole (–)clevelofB ++ Cyclosporine,tarolimus,Rapamycin ↑ levelofB +++ Calciumchannelblockers ↑ levelofB ++

+ + Sildenafil,vardenafil,tadalafil ↑ levelofB +++ Fentanyl ↑ levelofA ++

+ + Methadone ↓ levelofB +++ + Contraceptives ↑ and↓ levelofB +++ + Rifampin,rifabutin ↑ and↓ levelof

B,↓ levelofA(caution)

++

+ + StJohn’swort ↓ levelofB +++ + Warfarin ↑ levelofB ++

a+or++underdrugAshowsthedrugstrengthinchangingthelevelofdrugB.bSignificance:+probableimportance,++definiteclinicalimportance.c(+)or(−)indicatesinconsistentresults.Sources:Sande&Eliopoulos;Gilbert,Moellering&Eliopoulos;Antoniu&Tseng(137–139).

Examplesofhowthetablesshouldbereadareasfollows.1.InTable12line6:EFVstronglyincreasesthelevelsofmidazolam,alprazolamandtriazolamwhileNVPdoessolessstrongly.Thesignificanceofthisisthatthereisadefiniteclinicalimpor-tance;however,thesedrugscanstillbecoadministered.2.InTable13line4:APV,IDVLPV,NFV,RTVandSQVallincreasethelevelsofcarbamazepine,clonazepam,phenytoinandphenobartialwhilethesedrugsinturndecreasethelevelsofthethosePIs.Thesignificanceofthisisthatthereisdefiniteclinicalimportance.Thecombinationofanyoftheseshouldbeavoided.

Table 13. Protease inhibitors interactions with selected drugs

Protease inhibitor (drug A) a With … (drug B) Effect Significance b

APV ATV IDV LPV NFV RTV SQV

+ Fentanyl,tramadol,hydroco-don

↑ levelofdrugB +

+ + Codeine,morphine,metha-done

↓ levelofdrugB +

+ + + + + + + Amiodaron,lidocaine,flecainide

↑ levelofdrugB +

+ + + + + + Carbamazepine,clonazepam,phenytoin,phenobarbital

↑ levelofdrugB↓ levelofdrugA

++(avoid)

+ + + + Tricyclicantidepressants ↑ levelofdrugB ++ + Allotherantidepressants ↑levelofdrugB +

+ Loratadine ↑ levelofdrugB ++

2�


Protease inhibitor (drug A) a With … (drug B) Effect Significance b

APV ATV IDV LPV NFV RTV SQV+ Atovaquone ↓ levelofdrugB +

+ + + ++ + + ++ Benzodiazepine ↑ levelofdrugB +++ Betablockers ↑ levelofdrugB +

+ + + + + + + Calciumchannelblockers ↑ levelofdrugB ++

+ + + Clarithromycin,erythromy-cininrenalimpairment

↑ levelofdrugB +(caution)

+ + + + + Clarithromycin,erythromy-cin

↑ levelofdrugBanddrugA

+

+ + + + Contraceptives ↑ levelofdrugB ++

+ + + + Corticosteroids ↑ levelofdrugB↓ levelofdrugA

+

+ + + + + + + Cyclosporine ↑ levelofdrugB ++ + + + + + + Ergotderivatives ↑ levelofdrugB ++(avoid)

+ ++ + + + + + Protonpumpinhibitors(PPIs)

↓ levelofdrugA +(caution)(++,ATV-

avoid)

+ ++ + + + + + H2antagonists↓ levelofdrugA ++(caution)

(++,ATV-avoid)

+ + + + + + + Lovastatin,simvastatin ↑ levelofdrugB ++(avoid)+ Irinotecan ↑ levelofdrugB ++(avoid)

+ + + + + Ketoconazole,itraconazole ↑ levelofdrugB↑ levelofdrugA

+

+ + + + + + + Pimozide ↑ levelofdrugB ++(avoid)

+ + + + + + + Rifampin ↑ levelofdrugB↓ levelofdrugA

++(avoid)

+ + + + + + + Rifabutin↑ levelofdrugB↓ levelofdrugA

+(caution,doseadjust-

ment)

+ + + + + + + Sildenafil Some↑,some↑ levelofdrugB

++

+ + + + + + + StJohn’swort ↓ levelofdrugA ++(avoid)+ Tenofovir ↓ levelofdrugA ++(addRTV)

+ + + Theophyline ↓ levelofdrugB +

+ + + + Warfarin ↑ levelofdrugB +a+or++underdrugAshowsthedrugstrengthinchangingthelevelofdrugB.bSignificance:+probableimportance;++definiteclinicalimportance.Sources:Sande&Eliopoulos,Gilbert,Moellering&Eliopoulos,Antoniu&Tseng(137–139).

2�


III. Suggested minimum data to be collected at the clinical level

Thesuggestedminimumdatatobecollectedareimportantinthedevelopmentofkeyindicatorsonaccesstotreatmentanditssuccess.Suchindicatorsassistmanagersindecision-makingonwaystostrengthenandexpandtheseservicestoallwhoneedthem.

Thefollowingdatashouldbecollectedateachclinical facilityonaregularbasis (e.g.monthly,quarterlyorsemi-annually):• numberofHIVpatients“seenforcare”(seenatleastonceintheprevious12months);• numberofHIVpatientsseenforcarewhoareeligibleforART(CD4<350cells/mm3);• numberofHIVpatientsseenforcareinitiatingHAART;• numberofHIVpatientsseenforcarereceivingfirst-lineHAART;• numberofHIVpatientsonHAARTchangingfromfirst-lineHAARTtosecond-lineHAART;• numberofHIVpatientsonHAARTchangingfromsecond-lineHAARTtosalvageHAART;• numberofHIVpatientsinterruptingARTtreatment,includingthereason(e.g.death,toxicity/

sideeffects,losstofollow-up,ARVsnotavailable,etc.);• numberofpatientswhodiedwhileonHAART,includingcauseofdeath(e.g.HIV/AIDSrelated

mortalityornon-HIV/AIDSrelatedmortalitysuchasaccident,overdoseorsuicide);• numberofHIVpatientswhodiedwithinthefirst12monthsofinitiatingHAART;and• numberofdeathsamongallHIVpatientsincludingcauseofdeath(e.g.HIV/AIDSrelatedmor-

talityornon-HIV/AIDSrelatedmortalitysuchasaccident,overdoseorsuicide).

2�


Annex 1. Essential information on personal history of HIV/AIDS treatment

Table 14. Essential information on personal history of HIV/AIDS treatment

DateCD4cells/mm3

% VLcopies/ml

CurrentART

Resistance(genotypeorphenotype)

PreviousARTregimens,reasonsforchanging

30


Annex 2. Revised WHO clinical staging of HIV/AIDS for adults and adolescents

(InterimEuropeanRegionversionforpeopleaged≥15yearswithpositiveHIVantibodytestorotherlaboratoryevidenceofHIVinfection)

Acute HIV infection• Asymptomatic• Acuteretroviralsyndrome

Clinical Stage 1• Asymptomatic• Persistentgeneralizedlymphadenopathy(PGL)

Clinical Stage 2• Seborrhoeicdermatitis• Angularcheilitis• Recurrentoralulcerations(twoormoreepisodesinsixmonths)• Herpeszoster(extensivezosteracrossonedermatome)• Recurrentrespiratorytractinfections(twoormoreepisodesinanysix-monthperiodofsinusitis,otitismedia,

bronchitis,pharyngitis,tracheitis)• Fungalnailinfections• Papularpruriticeruptions

Clinical Stage 3• Oralhairyleukoplakia• Unexplainedchronicdiarrhoeaforlongerthanonemonth• Recurrentoralcandidiasis(twoormoreepisodesinsixmonths)• Severepresumedbacterialinfections(e.g.pneumonia,empyema,pyomyositis,boneorjointinfection,menin-

gitis,bacteraemia)• Acutenecrotizingulcerativestomatitis,gingivitisorperiodontitis

Clinical Stage 4a• Pulmonarytuberculosis• Extrapulmonarytuberculosis(excludinglymphadenopathy)• Unexplainedweightloss(morethan10%withinsixmonths)• HIVwastingsyndrome• Pneumocystispneumonia• Recurrentsevereorradiologicalbacterialpneumonia(twoormoreepisodeswithinoneyear)• CMVretinitis(±colitis)• Herpessimplexvirus(HSV)(chronicorpersistentforatleastonemonth)• HIV-associatedencephalopathy• HIV-associatedcardiomyopathy• HIV-associatednephropathy• Progressivemultifocalleukoencephalopathy(PML)• KaposisarcomaandHIV-relatedmalignancies• Toxoplasmosis• Disseminatedfungalinfection(e.g.candida,coccidomycosis,histoplasmosis)• Cryptosporidiosis• Cryptoccocalmeningitis• Non-tuberculousmycobacterialinfectionordisseminatedmycobacteriaotherthantuberclebacilli(MOTT)

aPossiblytobeincludedinStage4ifsupportedbysufficientevidence:analcancerandlymphoma(T-cellHodgkinlymphoma).Source:WHORegionalOfficeforEurope(140).

31


Annex 3. Resistance testsResistancetestingneedsaminimumof500–1000copies/ml;itisnotpossiblewithcompletelysuppressedvirus.

Genotypic resistance testing is based on the analysis of RNA mutations.The amplified genome is se-quenced.Knownmutationsareencodedforchangedsusceptibilityofthevirus.Itisanindirectproofofdrugresistance.Theresistantviruspopulationhastobehigherthan20%ofthewholepopulation.

Virtual phenotypic resistance testingusescomputer-basedalgorithmsofgenotypictestsconnectedwithlargedatabanksforinterpretingresults.

Phenotypic resistance testing, likemicrobiologicalsusceptibility testing,examines theabilityofvirusestoreplicateincellcultureinthepresenceofdifferentagents.Itiscomparedtothesameabilityofwild-typevirus.The50%inhibitoryconcentration(IC50)isamarkerofdrugpotency.Theresultsofthetestshowdif-ferentgradesofsusceptibility.

Which resistance test to useAlltestsarepresentlyveryexpensive.Genotypictestscost€400,phenotypictestscost€800(2005).Thetimebetweentakingthesampleandachievingresultscanbeweeks.Basicgenotypictestingshouldshowenoughevidenceforfurtherplanningofregimens.First-andsecond-lineregimensdonotrequirethemoreexpensivephenotypictest.WhenthereisaconfusedARThistory,withalotofalreadyknownmutationsoraninexplicabletreatmentfailure,aphenotypictestmightbejustified.Foralltests,theindividualhastocon-tinuetakingthefailingregimen;otherwise,wild-typeviruswillovergrowtheresistantstrains.Therearenostandardizedrecommendationsfortheuseofeitherphenotypicorgenotypicresistancetesting.

32


Anne

x 4.

Ess

entia

l inf

orm

atio

n ab

out A

RVs

Tabl

e 1�

.Es

sen

tial

ARV

dru

g in

form

atio

n

AR

VA

bbr.

Size

Dos

age

Rem

arks

Maj

or si

de-e

ffect

s(c

f. Ta

ble

11)

Res

istan

ce p

rofil

e

(maj

or a

nd m

inor

)N

RTIs

Aba

cavi

rA

BC

300

mg

300

mg

tabl

etB

ID

or

600

mg

OD

No

re-e

xpos

ure

ifhi

stor

yof

hyp

er-

sens

itivi

tyre

actio

n.H

yper

sens

itivi

tyre

actio

n(fever,rash,andinfluenza-

like

sym

ptom

ssuc

has

GIa

nd

pulm

onar

ysy

mpt

oms)

65R

,74V

,115

F,1

84V

/I

Did

anos

ine

ddI

250

mg

400

mg

Patients≥

60kg:400mg

tabl

etO

D

Patie

nts<

60k

g:2

50m

gta

blet

OD

Two

hour

safte

rmea

l,do

sere

duc-

tion

with

TD

F;n

otin

com

bina

tion

with

riba

varin

.

Perip

hera

lpol

yneu

ropa

thy,

pa

ncre

atiti

s,la

ctic

aci

dosi

s65

R,7

4V

Emtr

icita

bine

FTC

200

mg

200

mg

caps

ule

OD

Sam

eas

3TC

65R

,184

V/I

Lam

ivud

ine

3TC

300

mg

150

mg

300

mg

tabl

etO

D

or

150

mg

tabl

etB

ID

Rar

edi

arrh

oea

65R

,184

V/I

Stav

udin

ed4

T30

mg

30m

gca

psul

eB

IDN

otw

ithZ

DV.

Perip

hera

lneu

ropa

thy,

lip

odys

troph

y,e

leva

tion

of

ALT

/AST

41L,

67N

,70R

,75T

/M/S

/A,

210W

,215

Y/F

,219

Q/E

Teno

fovi

rTD

F30

0m

g30

0m

gta

blet

OD

Dos

ere

duct

ion

ofd

dI,n

otin

co

mbi

natio

nw

ithd

4T;c

aref

ulw

ith

renalinsufficiency(dosereduction).

Renalinsufficiency

41L,

65R

,210

W

Zido

vudi

neZD

V30

0m

g30

0m

gta

blet

BID

Not

with

d4T

;bet

ters

usce

ptib

ility

w

hen

65R

and

184

V.A

naem

ia,G

I,he

adac

he41

L,6

7N,7

0R,2

10W

,215

Y/

F,2

19Q

/EA

BC +

3TC

KV

X60

0 m

gA

BC

,30

0m

g3T

C1

tabl

etO

D

TDF

+ FT

CTV

D30

0m

gTD

F,

200

mg

FTC

1ta

blet

OD

ZDV

+ 3

TCC

BV

300

mg

ZDV,

15

0m

g3T

C1

tabl

etB

IDH

ighe

r(hi

stor

ical

)dos

eof

ZD

V

(hig

herr

isk

ofsi

de-e

ffect

s).

ZDV

+ 3

TC +

ABC

TZV

300

mg

ZDV,

15

0m

g3T

C,

300

mg

AB

C

1ta

blet

BID

Not

onc

eda

ily.

33


AR

VA

bbr.

Size

Dos

age

Rem

arks

Maj

or si

de-e

ffect

s(c

f. Ta

ble

11)

Res

istan

ce p

rofil

e

(maj

or a

nd m

inor

)N

NRT

IsEf

avir

enz

EFV

600

mg

600

mg

tabl

etO

DSt

arti

nth

eev

enin

g.D

izzi

ness

,sle

epin

gdi

sord

ers,

psyc

hiat

ricd

isor

ders

(dep

res-

sion

,ris

kof

suic

ide)

100I

,101

E,1

03N

,106

A/M

,10

8I,1

81C

,188

L,1

90A

/S,

225H

,230

LN

evir

apin

eN

VP

200

mg

200

mg

tabl

etB

IDFi

rst1

4da

ys2

00m

gO

D,t

hen

20

0m

gB

ID.

Ras

h,li

vere

nzym

eel

evat

ion

100I

,101

E,1

03N

,106

A/M

,10

8I,1

79D

/E,1

81C

/I,1

88C

/H

,190

A/S

,230

LD

elav

erdi

neD

LV20

0m

g10

0m

g20

0m

g×

2ta

blet

sTID

or

10

0m

g×

4ta

blet

sTID

Not

use

din

Eur

ope.

Ras

h,G

Isym

ptom

s,di

arrh

oea

K10

3N/S

,Y18

1C/l,

P23

6L,

G19

0A/S

/E/Q

/C,Y

188L

/H

/C,V

106A

/M,K

101E

/P,

M23

0L,K

238T

/N,F

318L

,V

179D

/EPI

sA

taza

navi

rAT

V30

0m

g30

0m

gca

psul

esO

D

plus

100

mg

caps

ules

RTV

OD

Dos

age

fort

reat

men

texp

erie

nced

pa

tient

s.U

sew

ithR

TV.

Bili

rubi

nel

evat

ion

(har

mle

ss)

24I,

33F/

I/V,3

6I/L

/V,4

6I/L

,50

L,5

4V/L

/M/T

,82A

/F/T

/S,

84V,

88S

,90M

Fosa

mpr

enav

irFP

V70

0m

g70

0m

gta

blet

BID

pl

us10

0m

gca

psul

eRT

VB

ID

Dos

age

fort

reat

men

texp

erie

nced

pa

tient

s.U

sew

ithR

TV.

Ras

h,h

eada

che,

dia

rrho

ea,

dysl

ipid

aem

ia32

I,47V

,50V

,54L

/M,8

2A/F

/T/

S,8

4V

Indi

navi

rID

V40

0m

g40

0m

gca

psul

esB

ID

plus

10

0m

gca

psul

eRT

VB

ID

Use

with

RTV

.K

idne

yst

ones

,dys

lipid

aem

ia24

I,32

I,36

I,46

I/L,5

4V,

82A

/F/T

/S,8

4V,9

0M

Lopi

navi

r/ri

tona

vir

fixed

com

bina

tion

LPV

/r13

3m

g/33

mg

200

mg/

50m

g(1

33m

g/33

mg)

×3

cap

-su

lesB

ID

or

(200

mg/

50m

g)×

2ta

blet

sB

ID

Old

form

ulat

ion

requ

ired

refr

ig-

erat

ion;

new

form

ulat

ion

does

not

;on

ced

aily

und

erd

iscu

ssio

n.

Dia

rrho

ea,m

eteo

rism

,dys

lipi-

daem

ia10

I/R/V

,20M

/R,2

4I,3

2I,

33I/F

/V,4

6I/L

,53L

,54V

/L,

63P,

71V

,82A

/F/T

,84V

,90M

Nel

finav

irN

FV25

0m

g62

5m

g62

5m

g×

2ta

blet

sBID

or 250

mg

×5

tabl

etsB

ID

With

mea

l,re

sorp

tion

incr

ease

s270%

;noboosterw

ithRTV

.D

iarr

hoea

,met

eoris

m30

N,3

6I,4

6I/L

,54V

/L/M

/T,

82A

/F/T

/S,8

4V,8

8D/S

,90M

Rito

navi

rRT

V10

0m

gO

nly

asa

boo

ster

Dys

lipid

aem

ia,l

iver

enz

yme

elev

atio

n,d

iarr

hoea

Saqu

inav

irSQ

V50

0m

g50

0m

g×

2ca

psul

esB

ID

plus

10

0m

gca

psul

eRT

VB

ID

New

500

mg

tabl

ets;

was

in2

00m

gta

blet

sunt

il20

04.U

sew

ithR

TV.

Dia

rrho

eaa

ndo

ther

GIs

ymp-

tom

s, dy

slip

idae

mia

48V,

53L

,54V

/L,8

2A/F

/T,

84V,

90M

Tipr

anav

irTP

V25

0m

g25

0m

g×

2ca

psul

esB

ID

plus

10

0m

g×

2ca

psul

esR

TV

BID

Dos

age

fort

reat

men

texp

erie

nced

pa

tient

s.D

ono

tcom

bine

with

oth

er

PIs.

Use

with

RTV

.

Dys

lipid

aem

ia(s

ever

e),l

iver

en

zym

eel

evat

ion,

dia

rrho

ea13

L/V,

20M

/R/V

,33F

/I,

35D

/N,3

6I,4

5R,4

6I/L

,47V

,54

A/M

/T/V

,58E

,66F

,69K

,71

I/K,7

4P,8

2F/L

/T,8

4C/V

,90

M,9

1S

34


AR

VA

bbr.

Size

Dos

age

Rem

arks

Maj

or si

de-e

ffect

s(c

f. Ta

ble

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Annex 5. Tools for adherence monitoring

Self-reporting isagoodadherencemarker,butit isnotperfect.ItseemstooverestimateARTadherencemorethanothermethods(142).Tobeeffective,thepatientmustbewillingtodiscloseproblems,particularlyfacetoface.Thismethodmaybeimportantinreinforcingthecentralroleofpatientsinmanagingtheirownadherence,asopposedtoprovider-controlledmethods.

Provider estimatesofadherencehavebeendemonstratedtobepoor(143)andarenotadvisable.

Drug-level monitoringisexpensiveandnotyetpossibleforallARVs.Itisnotamethodforroutinecontrolofadherence,andcanonlyrevealasnapshotofthetimethesampleistaken(144).Incaseoflowplasmadruglevels,adherencehastobediscussed.LaboratorymarkerslikemeancorpuscularvolumeoferythrocytesmightshowadherencetoZDVandtoalesserextentd4T.

Medication Event Monitoring System (MEMS)isfrequentlyusedinresearchsettings.Anelectronicde-vicefittedtopillboxesrecordstheremovalofthecap.ItisassociatedwithpredictablevirologicalresponsetoART(145).Itisnotpossiblewithblisterpacks.

Pill counts and pharmacy recordsmaybeseenasanunwelcomeattemptofhealthcareproviderstopoliceadherence.Theyaretime-consumingandrequirepatientstobringtheirmedicationwiththem.

Pill identification test (PIT)isanovelmethodthatcorrelateswithvalidatedself-reportingmeasures(146).Patientsareinvitedtodistinguishthepillsof theirregimenfromadisplayofARVs,includingtwo“twinpills”,whicharesimilarbutnotidenticaltotheirown.

Theuseofsurrogate markersisreliablebuttoolatewhenpooradherenceisrevealed.Individualswithviro-logicalfailureonaPI-containingregimenhadlowPIbloodlevels,lowadherencelevelsbypillcountandanabsenceofgenotypicresistancetoPIs,suggestingtheirtreatmentfailurehadbeencausedbylowadherence(147, 148).Providershavetobecarefulwithinterpretationofthesemarkers,however,becauseofotherpos-siblereasonsforlowdruglevels(145).

3�


Annex 6. List of antiretroviral drugs5

Table 1�. Antiretroviral drug list

International non-proprietary name(INN)

Proprietary name Pharmaceutical company

NRTIsAbacavir (ABC) EpzicomUS,KivexaUnited Kingdom (lamivudine/

abacavir)TrizivirEurope,United Kingdom, US(zidovudine/lamivudine/abacavir)ZiagenUnited Kingdom, United States

GlaxoSmithKline

Abavir Genixpharma

VirolVirolLZ(abacavir/lamivudine/zidovudine)

Ranbaxy

Didanosine (ddI) Videx,VidexEC Bristol-Myers Squibb

DinexECOdivirKit(didanosine/lamivudine/efavirenz)

Cipla

Aviro-ZVirosineViro-Z

Ranbaxy (India)

Divir Thai Government

Emtricitabine (FTC) ATRIPLA(efavirenz/emtricitabine/tenofovir) Bristol-Myers Squibb and Gilead Sciences

EmtrivaTruvada(tenovovir/emtricitabine)

Gilead Sciences

Lamivudine (3TC) CombivirUnited Kingdom, United States (lamivudine/zidovudine)EpivirUnited Kingdom, United States,ZeffixUnited Kingdom EpzicomUnited States,KivexaUnited Kingdom (lamivudine/abacavir)TrizivirUnited Kingdom, United States (zidovudine/lamivudine/abacavir)

GlaxoSmithKline

LamivoxStavex-L(lamivudine/stavudine)Stavex-LN(lamivudine/nevirapine/stavudine)Zidovex-L(lamivudine/zidovudine)Zidovex-LN(lamivudine/nevirapine/zidovudine)

Aurobindo

Duovir(lamivudine/zidovudine)Duovir-N(lamivudine/nevirapine/zidovudine)LamivirOdivirKit(didanosine/lamivudine/efavirenz)Triomune(lamivudine/nevirapine/stavudine)

Cipla

HeptavirLamistar30,Lamistar40(lamivudine/stavudine)Nevilast(lamivudine/nevirapine/stavudine)Zidolam(lamivudine/zidovudine)

Genixpharma

VirolamVirocomb(lamivudine/zidovudine)Virolans(lamivudine/nevirapine/stavudine)Virolis(lamivudine/stavudine)VirolLZ,Abac-ALZ(abacavir/lamivudine/zidovudine)

Ranbaxy

5ThislistisacompilationofthoseARVsthatarewidelyused,andshouldnotbeconstruedtobeexhaustive.Itwasaccurateasof31July2006.Disclaimer:Thementionofspecificcompaniesorofcertainmanufacturers’productsdoesnotimplythattheyareendorsedorrecommendedbytheWorldHealthOrganizationinpreferencetoothersofasimilarnaturethatarenotmentioned.

3�




Stavudine (d4T) Zerit,ZeritXR Bristol-Myers Squibb

StavexStavex-L(lamivudine/stavudine)Stavex-LN(lamivudine/nevirapine/stavudine)

Aurobindo

StavirLamivir-S(lamivudine/stavudine)Triomune(lamivudine/nevirapine/stavudine)

Cipla

Lamistar(lamivudine/stavudine)Nevilast(lamivudine/nevirapine/stavudine)Stag

Genixpharma

Stavir GPO (Thailand)

AvostavTriviro-LNS(lamivudine/nevirapine/stavudine)Virolans(lamivudine/nevirapine/stavudine)Virolis,Coviro(lamivudine/stavudine)Virostav

Ranbaxy

Tenofovir (TDF) Truvada(tenofovir/emtricitabine)Viread(tenofovir)

Gilead Sciences

ATRIPLA(efavirenz/emtricitabine/tenofovir) Bristol-Myers Squibb

Triple nuceoside (TRZ) TrizivirUnited Kingdom, United States (zidovudine/lamivudine/abacavir)

GlaxoSmithKline

Zidovudine (ZDV or AZT) CombivirUnited Kingdom, United States (lamivudine/zidovudine)RetrovirUnited Kingdom, United States TrizivirUnited Kingdom, United States (zidovudine/lamivudine/abacavir)

GlaxoSmithKline

Zidovex Auribindo

ZidovirDuovir(lamivudine/zidovudine)

Cipla

Zido-H(zidovudine) Genixpharma

Antivir GPO (Thailand)

Aviro-ZVirocomb(lamivudine/zidovudine)VirolLZ(abacavir/lamivudine/zidovudine)Viro-Z

Ranbaxy

NNRTIsDelavirdine (DLV) Rescriptor Pfizer, Inc.

Efavirenz (EFV) SustivaEurope, United Kingdom,StocrinAustralia, Europe, Latin America, South Africa

ATRIPLA(efavirenz/emtricitabine/tenofovir)

Bristol-Myers Squibb

Viranz Aurobindo

Efavir Cipla

Estiva Genixpharma

Efferven Ranbaxy

3�




Nevirapine (NVP) Viramune Boehringer Ingelheim

NevirexStavexLN(lamivudine/nevirapine/stavudine)

Aurobindo

Duovir-N(lamivudine/nevirapine/zidovudine)NevimuneTriomune(lamivudine/nevirapine/stavudine)

Cipla

Nevilast(lamivudine/nevirapine/stavudine) Genixpharma

GPOVir GPO (Thailand)

NevipanTriviroLNS(lamivudine/nevirapine/stavudine)Virolans(lamivudine/nevirapine/stavudine)Zidovex-LN(lamivudine/nevirapine/zidovudine)

Ranbaxy

Fusion inhibitorsEnfuvirtide, T-20 FuzeonUnited Kingdom, United States Roche Pharmaceuticals &

Trimeris, Inc.

Protease inhibitorsAmprenavir (APV) AgeneraseUnited Kingdom, United States GlaxoSmithKline

Atazanavir (ATV) ReyatazEurope, United States Bristol-Myers Squibb

Fosamprenavir (FPV) LexivaUnited States,TelzirUnited Kingdom GlaxoSmithKline and Vertex

Indinavir (IDV) Crixivan Merck & Co.

Indivex Aurobinda

Indivir Cipla

Indivir Genixpharma

Virodin Ranbaxy

Lopinavir/ritonavir combination (LPV/r)

Kaletra Abbott Laboratories

Nelfinavir (NFV) Viracept Pfizer, Inc., Roche Pharmaceuticals

Nelvex Aurobinda

Nelvir Cipla

Nelfin Genixpharma

Nefavir Ranbaxy

Ritonavir (RTV) Norvir Abbott Laboratories

Ritovir Hetero/Genix

Saquinavir (SQV) FortovaseEurope, United Kingdom, United StatesInviraseUnited Kingdom, United States

Roche Pharmaceuticals

3�


Annex 7. Glossary

AdherenceispatientabilitytotakeARVdrugsasprescribedatspecifictime.Highadherenceisdefinedastakingover95%ofdoses;lowadherenceisanythingunderthislevel.

BackboneisthepartofARVtreatment,usuallyconsistingoftwoNRTIswhichareusedincombinationwithanNNRTIoraPIoraPIandfusioninhibitor.“Optimizedbackbone”meansanadjustedcombinationofprobableworkingNRTIsbasedonresultsofresistancetesting.

Genetic barrierisadescriptionofthenumberofmutationsneededforthevirustoberesistanttoadrug.Re-sistancewith1mutationmeansalowgeneticbarrier;resistancewith10mutationsmeansaveryhighgeneticbarrier,thoughthischaracterizationissubjecttochange.

Major mutationsarethechangesinviralRNAthatencodeforresistancetoparticularARTdrugsorARTclasses.

Minor mutationsworkincombinationandcanleadtoresistanceorcounteractdisadvantagesofothermajororminormutations.

Nucleosideanalogue mutations(NAMs)revealcross-resistanceformostNRTIs.

Apoint mutationisonechangeintheRNAcoderesultinginresistancetoadrugorclassofdrugs.Forex-ample,inARTtreatmentmutation103meansaresistancetoallNNRTIs,resultingfromchangesinvirusatspecificpoint.

ResistanceistheresultofchangingaminoacidsintheRNAstrainofthevirus.ThishappensduetothepoorreplicationabilitiesofHIV.Mostchangesleadtothedeathofthevirus;otherchangesareviable,andtheresultantvirushastheabilitytosurvivethemechanismsofART.Inmostcases,resistanceleadstopoorerviralfitness,meaningaslowerHIVreplicationrate.Thoughabenefitforthepatientatthebeginning,itwillresultintotalresistanceandhighreplicationratesofthelessfitviruses.However,severalcombinationsofresistancepatternscanbalancethisdisadvantage,sothatsomeresistancepatternsresultinafittervirusintheend.

Thymidine analogue mutations(TAMs)areusuallyaresultofZDVtreatment.

40


Annex 8. Beyond the horizon

ResearchonARTcontinues.Newviralmutationsanddrugresistanceoccurregularly–asdonewunder-standingsoftheinteractionsbetweendrugsandthevirus.ThefollowingaresomeofthelatestARVstobeapprovedortobependingapproval,alongwithnewcombinationsofolderdrugs.

• Aonce-dailyfixed-dosecombinationofTDF+FTC+EFVhasbeenrecentlydevelopedandappearstobeslightlymoreeffectivethanthestandardZDV+3TC+EFVcombination(42).

• TMC125(etravirine)isanewNNRTIthathaspotenciesdespiteexistingmutationswhichencodeforNNRTIclassresistance(149).

• DRV(darunavir)isanewPIwithanevenhighergeneticbarrierthanLPV/r.DevelopmentofresistanceisslowerthanwithNFV,APVorLPV/rinvitro.TMC114isavailablethroughanexpandedaccesspro-gramme(EAP)(150).IthasbeenrecentlyapprovedbytheUSFederalDrugAdministration(FDA).

• AG1549 (capravirin) isalsoa second-generationNNRTI,which iseffectivedespiteclassicalNNRTImutations.

• Newcoreceptorinhibitorsinthefusionsmoleculearecoming.CXCR4-andCCR5-expressingvirusesarebeingfoughtwithdrugsthatcaninhibitoneorbothofthem.Newtestsforthecoreceptorexpressionofthevirusareneededforthistreatment.Side-effectsarelimitedfornow,thoughinitialexperiencewiththisnewclasshasrevealedcardiotoxiceffects.OnAugust6,2007,FDAgrantedacceleratedapprovaltoSelzentry(maraviroc)forcombinationantiretroviraltreatmentofadultsinfectedwithonlyCCR5-tropicHIV-1detectable,whohaveevidenceofviralReplicationandhaveHIV-1strainsresistanttomultipleantiretroviralagents.

41


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1 patient evaluation and antiretroviral treatment for adults and

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