1 Patient Evaluation and Antiretroviral Treatment for Adults and ...
Transcript of 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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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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HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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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HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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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PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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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HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
• 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-
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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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HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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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PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
• 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.
24
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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�
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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�
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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�
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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�
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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�
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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
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34
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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3�
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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�
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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�
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
International non-proprietary name(INN)
Proprietary name Pharmaceutical company
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�
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
International non-proprietary name(INN)
Proprietary name Pharmaceutical company
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�
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
PATIENT EVALUATION AND ANTIRETROVIRAL TREATMENT FOR ADULTS AND ADOLESCENTS
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