National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013 1
Table of Contents
ChapterAcronyms and Abbreviations ............................................................................................. 3
Introduction and Preamble ................................................................................................ 5
Section I: Technical Guidelines ........................................................................................... 7
First Line & Second Line ART Regimen ................................................................ 7
Substitutionvs.Switch ......................................................................................... 7
AlternativeARV Drugs For Intolerance to ZDV/TDF and NVP/EFV: Substitution .................................................................................. 9
MonitoringPatientsonFirstLineART for Failure ................................................ 12
IdentifyingTreatmentFailure .............................................................................. 13
Protocol for determining ART failure (Protocol A1.1) at ART centers ............................................................................. 16
Management Protocol based on SACEP decision and Viral load test Results .......................................................................................... 19
InitiatingthestandardizedNACOSecond-LineRegimen ........................................... 21
DrugInteraction: ................................................................................................. 23
Second-LineARTandTBTreatment .................................................................... 25
LaboratorymonitoringofpatientsonSecondLineRegimen .............................. 27
AdherenceandSecond-LineART ......................................................................... 27
Section II: Operational Guidelines ...................................................................................... 31
StateAIDSClinicalExpertPanel(SACEP) ............................................................. 31
EligibilityandcriteriaforprovisionofSecondLineART ...................................... 34
ProtocolforSACEPreview ................................................................................... 34
TORofadditionalmanpower:SACEPcoordinator ............................................... 36
Section III: M & E Tools ....................................................................................................... 39
InstructionsforMonitoring/recordsKeepingforSecondLineART ..................... 39
Section IV: Laboratory Guidelines ...................................................................................... 45
Introduction: ........................................................................................................ 45
IntendedUseofHIV-1PVLAssayinACO’s SecondLineARTInitiative: .................................................................................. 45
TechniquesofHIV–1PVLAssay: ........................................................................ 48
PlasmaViralLoadAssayscurrentlyinuse inNACO’sSecond-LineRollOut: .......................................................................... 49
SpecimenCollection,Storage,andTransportation .............................................. 51
FactorstobeconsideredwhileInterpretingtheViralLoadResults: ................... 55
LimitationofViralLoadAssays: ........................................................................... 56
2 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
StandardizationofHIV-1PlasmaViralLoadReporting .............................................. 56
QualityAssuranceforHIV-1PlasmaViralLoadTesting: ............................................ 57
OperationalPlanforHIV-1ViralLoadTestingandEQAS ..................................... 59
PrecautionsandSpecificInstructionsforReagentsandEquipments .................. 61
Troubleshooting ................................................................................................... 63
DBScollectionforallpatientsundergoingViralLoadTesting ...................................63
Annexure
Annex I ........................................................................................................................ 67
Annex II ................................................................................................................ 71
Annex III ............................................................................................................... 73
Annex IV .............................................................................................................. 74
Annex V ............................................................................................................... 78
Annex VI .............................................................................................................. 79
AnnexVII(a)–ViralLoadTestRequisitionForm ................................................ 81
AnnexVII(b)–COBASAmplicorReportingFormat .............................................. 82
AnnexVII(c)–TaqmanReportingFormat ........................................................... 83
AnnexVII(d)–ViralLoadResultForm,AmplicorHIVMonitoring,v1.5 .............. 84
Annex VIII ............................................................................................................ 85
AnnexIX–SecondLineReporting ....................................................................... 88
1SL+AL:SACEPRegisterforAlternativeFirstLine& SecondLineART(AdultsandChildren) ...................................................... 88
2AL:AlternativeFirstLineFormatforSACEP Meeting(Adult&Children) ........................................................................ 90
2 SL: Second Line Format for SACEPMeeting(Adult&Children) ............................................................ 92
3AL+SLCombinedMonthlyReporting FormatforSecond&AlternativeFirstLineART ......................................... 94
4AL:ListofpatientsonAlternativeFirstLineART ..................................... 100
4SL:ListofPatientsonSecondLineART ................................................... 101
5SL:CentreWise(LinkedCentreInformation) breakupforPLHIVInitiatedonSecondLineART ................................... 102
Annexure X .......................................................................................................... 103
Acknowledgements ............................................................................................................. 105
3National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Acronyms and Abbreviations
3TC LamivudineABC AbacavirAIDS AcquiredImmunodeficiencySyndromeART AntiretroviralTherapyARV AntiretroviralATV AtazanavirAZT/ZDV ZidovudinebPI BoostedPICD4count CD4+T-LymphocyteCOE CentersofExcellenced4T StavudineddI DidanosineEC Enteric CoatedEFV EfavirenzFDC Fixed-DoseCombinationFTC EmtricitabineHb HemoglobinHIV HumanImmunodeficiencyVirusIDV IndinavirLPV LopinavirNACEP NationalAIDSClinicalExpertPanelNFV NelfinavirNNRTI Non-NucleosideReverseTranscriptaseInhibitorNRTI NucleosideReverseTranscriptaseInhibitorNVP NevirapinePI ProteaseInhibitorPLHIV PeopleLivingwithHIV/r Low-DoseRitonavirRTV RitonavirSACEP StateAIDSClinicalExpertPanelSQV SaquinavirTDF TenofovirDisoproxilFumarateVL Viral Load
4 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
5National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Introduction and Preamble
TheNationalARTprogrammelaunchedon1stApril2004ineightgovernmenthospitalsinsixhighprevalencestateshassincebeenscaledupto400ARTcentreswhereina total of around 16,00,000 patients have been registered inHIV care and nearly6,00,000patientsarecurrentlyonART.ThenationalprogrammeprovidesfreeFirstline,alternateFirstlineandSecondlineantiretroviraldrugstoadultsandchildrenaspertheireligibility.
ATechnicalResourceGroup(TRG)onARThasbeenconstitutedatNACOthatmeetsregularlytoupdateandformulatethetechnicalguidelinesforFirstlineandSecondlineART.AllARTcentersinthecountryhaveaccesstoSecondlineARTbutforinitiationofSecondlineARTaround41centershavebeenidentified.Theseinclude10CentresofExcellence,7PediatricCentresofExcellenceand20ARTPluscenters.ThisistoensurethatonlythosewhohaveconfirmedfailuretoFirstlineARTareinitiatedonSecondline treatment thereby minimizing unnecessary switches. Besides this, a specialtrainingofhealthcareprovidersatallARTcenters isdoneonmonitoringpatientsinitiatedonantiretroviraltherapyalongwithregulatorymechanismstominimizethechancesofresistanceduetoirrationalprescriptions.Inordertoensurehighqualityofcare,toensurethatonlyeligiblepatientsarestartedonSecondlineARTandmaintainuniformityintreatment,StateClinicalExpertPanels(SACEP)havebeenconstitutedatallCoEsandARTpluscenterswhereSecondlineARTisinitiated.EverypatientthatisreferredtothesecenterswithasuspectedfailuretoFirstlineARTisFirstreviewedbySACEPand,ifthesuspectedtreatmentfailureisconfirmedbyViralloadtesting,theneligiblepatientsareinitiatedonSecondlineARTafteradequatepreparedness.AfterthepatientsbecomestableonSecond lineART, theyare transferredback to theirreferringARTcentre.TheycontinuetogettheirSecondlinedrugsattheirownARTcenterthereafter.AlsocomplicatedcasesthatneedfurtherreviewandopinionarereferredtoNationalAIDSClinicalExpertPanel(NACEP)atNACO.
The initial roll out of Second line ART was done at 2 Centers of Excellence:GovernmentHospitalofThoracicMedicine(GHTM),TambaramandSirJJHospital,Mumbai.During thepilot phase,only thosepatientswhowereonARTat thesecentersforatleast6monthswereconsideredforSecondlineART.Theexperiencegainedatthesetwocentersduringthepilotphasewasusedforfurthermodificationandrefinementofprotocols.Currently,SecondlineARTis initiatedat10CentersofExcellence,7PediatricCentersofExcellenceand20ARTpluscenters.AllARTcentersinthecountryarelinkedtotheseCoE/ARTpluscentersandawell-definedreferralprocedureisinplace.
6 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
7National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Section I: TECHNICAL GUIDELINES
1.1 First LINE & Second LINE ART REGIMEN:
TheworkingdefinitionofFirstandSecondLineARTRegimenisasfollows:
First-line ART:
First-lineARTisthe initialregimenprescribedforanARTnaïvepatientwhenthepatientfulfillsnationalclinicalandlaboratorycriteriatobeinitiatedonART.
(Current NACO treatment guidelines for First-line ART recommend three drug combination therapy from two classes of ARV drugs for initial treatment i.e. 2 NRTI + 1 NNRTI)
Second-line ART:
Second-lineART is the subsequent regimenused in sequence immediately afterFirst-linetherapyhasfailed.
(Current NACO treatment guidelines recommend use of Ritonavir-boosted protease inhibitors (bPIs) supported by two agents from the NRTI class, of which at least one should be new.
1.2 SUBSTITUTION VS. SWITCH
ChangeofARVsprescribedshouldbecarefullydistinguishedbetweensubstitutingadrugwithinagivenregimenandswitchinganentireARTregimen:
• Treatment Failure refers to the loss of antiviral efficacy to current regimenand it triggerstheSWITCHof theentireregimenfromFirst toSecond line. Itisidentifiedbyclinicaland/orimmunologicalandconfirmedbythevirologicalcriteria.
• SingledrugreplacementofindividualARV(usuallywithinthesameclass)fortoxicity, drug-drug interactions, or intolerance refers to SUBSTITUTION of individual drug andwhich does not indicate a Second line regimen is beingused.
8 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ThefollowingARTregimenshavebeendesignatedas“National ART regimen”byNationalAIDSControlOrganization.(Table1)
Table 1: NACO Approved ART regimen
Regimen ARV Drug Combinations Indications
Regimen IZidovudine+Lamivudine+Nevirapine
FirstlineRegimenforpatientswithHb≥9gm/dlandnotonconcomitant ATT
Regimen I (a)Tenofovir+Lamivudine+Nevirapine
FirstlineRegimenforpatientswithHb<9gm/dlandnotonconcomitant ATT
Regimen IIZidovudine+Lamivudine+Efavirenz
FirstlineRegimenforpatientswithHb≥9gm/dlandonconcomitant ATT
Regimen II (a)Tenofovir+Lamivudine+Efavirenz
FirstlineRegimenforpatientswithHb<9gm/dlandonconcomitant ATT FirstlineforallpatientswithHepatitisBand/orHepatitisCco-infection FirstlineRegimenforpregnantwomen,withnoexposuretosd-NVPinthepast
Regimen IIIZidovudine+Lamivudine+Atazanavir/Ritonavir
RegimenforpatientsonAZTContainingFirstlineregimen,whodeveloptoxicitytobothNVPandEFV
AlsoSecondlineregimenforthosewhoareonTDFcontain-ingFirstlineregimenifHb≥9gm/dl
Regimen III (a)Zidovudine+Lamivudine+Lopinavir/Ritonavir
ForpatientsofRegimenIIIwhodevelopsevereAtazanavirtoxicity
FirstlineregimenforpatientswithHIV-2infectionwithHb≥9 gm/dl
Regimen IVTenofovir+Lamivudine+Atazanavir/Ritonavir
SecondlineregimenforthosewhoareonAZT/d4Tcontain-ingregimenintheFirstline
AlsoforpatientsonTDFcontainingFirstlineregimenwhodeveloptoxicitytobothNVPandEFV
Regimen IV (a)Tenofovir+Lamivudine+Lopinavir/Ritonavir
ForpatientsonRegimenIVwhodevelopsevereAtazanavirtoxicity
FirstlineRegimenforpatientwithHIV2infectionwithHb<9gm/dl
FirstlineRegimenforallwomenexposedtosd-NVPinthepast
Regimen VStavudine+Lamivudine+Atazanavir/Ritonavir
SecondlineforthosewhoareonTDFcontainingregimenintheFirstlineifHb<9gm/dl
Regimen V (a)Stavudine+Lamivudine+Lopinavir/Ritonavir
ForpatientsonRegimenVwhodevelopsevereAtazanavirtoxicity
9National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
• PatientsonEFVduetoconcomitantATTneedtobesubstitutedwithNVPtwoweeksaftercompletionofATTorinthenextclinicvisit.NoleadindoseforNVPrequiredinsuchpatients.
• IfNVPisdiscontinuedfor>2weeks,whilere-startingNVP,onehastousealead-indosefor2weeks.
• PatientsonAZTbasedregimentobesubstitutedwithTDF,iftheydevelopanaemia.
• ForpatientswithTDF toxicity,useAZTcontaining regimen ifnotanaemic,d4T ifanaemic(e-approvalfromSACEPrequiredford4Tassupplyofd4Tislimited).
• IfAZT,d4TandTDFcannotbeused,refertoSACEPatCoEonly.Forestablished3TCtoxicity,refertoSACEPatCoEonly.SACEPcantakeadecisiontoprovidealternativedrugandinformNACEPorcanaskNACEP,ifopinionisrequired.
• PatientswhohavedevelopedAZT inducedanaemia in thepast shouldnotbe rechallengedwithAZTagain.
• PatientswhodevelopedsevereNVPhypersensitivity(SJSandTEN)inthepastshouldnotbere-challengedwithNVPagain.
1.3 ALTERNATIVE ARV DRUGS FOR INTOLERANCE TO ZDV/TDF AND NVP/EFV: SUBSTITUTION
SubstitutionofARVdrugsforreasonsof intoleranceortoxicityordrug-druginteractionsmaybeneededinfollowingcases:
Intolerance to both ZDV and TDF:inthiscase,d4Tbasedtreatmentmaybeanalternative(e-approvalfromSACEPrequiredford4Tassupplyofd4Tislimited).
Intolerance to both NVP and EFV:inthiscase,ATV/rasasubstitutionARVwillbeprovideduponreviewandapprovalbytheSACEP.
As per NACO ART Guidelines for Adults and Adolescents, as a general principle, mildtoxicities (grade 1 and 2), do not require discontinuation of ART or drug substitution.Symptomatictreatmentmaybegiven.Moderateorseveretoxicities(grade3and4)mayrequiresubstitutionofthedrugwithanotherARVofthesameclass.(Table2)
10 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Table 2: Major Toxicities caused by First-line ARVs Regimen and recommended drug substitutions
Regimen Toxicity Drug substitution
ZDV/3TC/NVP
ZDVrelatedpersistentGIintoleranceorseverehematologicaltoxicity
NVPrelatedseverehepatotoxicity
NVPrelatedsevererash(butnot life-threatening)
NVP-relatedlifethreateningrash(StevensJohnsonSyndrome,angio-edema)
SubstitutewithTDF
SubstitutewithEFV(exceptinpreg-nancy. Inthissituation,switchtoLPV/r)
SubstitutewithbPIs
ZDV/3TC/EFV ZDVrelatedpersistentGIintoleranceorseverehematologicaltoxicity
EFVrelatedpersistentCNStoxicity
SubstitutewithTDF
SubstitutewithNVP,ifnotonconcom-itantATTorthereisnocontraindica-tiontoNVPuse.bPI(ATV/r)isrecom-mendedinsuchcircumstances
TDF +3TC+NVP/EFV
Usuallywelltolerated
Minor:weaknessandlackofenergy,headache,diarrhea,nausea,vomit-ingandintestinalgas
TDFcanreducebonemineraldensity
Renaldysfunction(Checkurineforroutine/microscopic,bloodurea,creatinineevery6months)
Renaldysfunctionisusuallymild,asymptomatic
Reverseswhenstopmedication
Acute renal failure (rare): reduce dosewhenrenalfailureorifseveretoxicity,substitute
Symptomaticmanagementofminorsideeffects
VitaminD3,Bisphosphonates,andCalciumsupplementsmaybeusedinpatientswithosteoporosis
asperNACOlabmonitoringprotocol
SubstitutewithAZT,ifHb≥9gm/dl;otherwise,substitutewithd4Tfollow-ingreview&e-approvalbySACEP
ATV Indirect hyperbilirubinaemia, clinicaljaundice,prolongedPRinterval-Firstdegree, symptomatic AV block insome patients, hyperglycemia, fatmal distribution, possible increasedbleeding episodes in people withhaemophilia,nephrolithiasis
Seek SACEP/NACEP guidance on substitutionwithLPV/r.
11National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Notes:
• The general principle is that single drug substitution for toxicity should be made within the same ARV class e.g. substitution of TDF with AZT or d4T (for renal toxicity or anemia) or EFV with NVP (for CNS toxicity or in pregnancy).
• d4T should not be a part of HAART for ART naive patients. Patients who are on d4T, substitution should be done with AZT or TDF depending on Hb. Substituting d4T may not reverse lipodystrophy but may slow its progression.
• If a life-threatening toxicity occurs, all ART should be stopped until the toxicity has resolved and a revised regimen commenced when the patient has recovered.
The ‘triple NRTI regimen’ has been shown to be inferior in its outcome and is not used in the National programme
Table 3: Substituting with alternative First Line ARV drugs
First line ARV causing the toxicity Alternative substitute Remarks
(a) Intolerance to both TDF and AZT
PatientshouldhavebeentriedonZDVand TDFwithdocumented intolerancetoboth.d4T+3TCwillbeprovidedafterreviewande-approvalbytheSACEP
TDF + 3TC d4T + 3TC ContinuethesameNNRTI
(eitherNVPorEFV)ZDV + 3TC
(b) For intolerance to both NVP and EFV
PatientshouldhavebeentriedonbothNVPandEFV(exceptforifhistoryofStevenJohn-sonSyndrome,exfoliativedermatitis,erythemamultiformortoxicepidermalnecrolysisispresent)anddocumentedasnottolerating,beforerequiringsubstitutionfortheNNRTIcomponent.NVP or EFV ATV/r ContinuewiththesameNRTIbackbonei.e.
ZDV/3TCorTDF/3TCifnoproblemsEssentially this moves the patient to the PI-based regimen. Counsel for good adherence. If this regimen fails, there is no other optimal alternative regimen at present in the National programme.
These patients should be referred to the SACEP for review, then COE shall manage and provide ATV/r as substitution for intolerance to NNRTI.
(c) Intolerance to TDF, d4T and AZT
RefersuchcasestoSACEPatCoEforreviewandABCbasedARV,ifrequired
See Annex I: Severity grading of clinical and laboratory toxicities of ARVs
12 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
1.4 MONITORING PATIENTS ON First LINE ART FOR FAILURE
TheprinciplesofmonitoringpatientonFirstlineARTare:
• Clinical monitoring and stagingateachvisitasperNACOguidelines.
o Doclinical stagingat each visit: use theT staging for clinical events. (seeTable4below)
• Immunological monitoring:Ensuringtheroutinemonitoring labtestsaredoneeg.CD4 countevery6months(orevenearlierdependingonCD4value/clinicaljudgment).
Adherence support and monitoringtoensure>95%adherence:
• Checkforprogressofimprovementateachvisitandweight.
• ScreenforTB:askforsymptomsandsignsofTBe.g.fever,weightloss,nightsweats,haemoptysis,lymphnodesinnecketc.
• Determine if Cotrimoxazole is required or not, based on CD4 counts andWHOClinical staging.
DevelopmentofaneworrecurrentWHOClinicalstage4conditionwhileonARTforatleast6monthsisconsideredfunctionalevidenceoftheprogression of HIV disease.However,certainWHO stage 3 conditions like pulmonary TB and severe bacterial infectionsmaysignify treatment failurewhereascertainWHOstage4conditions likeTB lymphadenitis,uncomplicatedpleuralTB,esophagealcandidiasisandrecurrentbacterialpneumoniasmaynot indicatetreatmentfailurewhichneedstobetaken intoconsideration. If thepatientdoesn’timprovefollowinginstitutionofappropriatetreatmentforthesestage4conditions,theyshouldbepromptlyreferredtoSACEP.(seebelow)
Table 4: Clinical staging events to guide decision making on switching
New or recurrent event on ARTa Recommendations Additional Management Options
Asymptomatic(T1)
DoNotswitch regimen
•Maintainschedulefollow-upvisits, includingCD4monitoring(ifavailable)
•Continuetoofferadherencesupport
Stage2event(T2) DoNotswitch regimenb
•Treatanddmanagestagingevent•Accessandofferadherencesupport•Checkifontreatmentforatleastsixmonths•AssesscontinuationofreintroductionofOIprophylaxis
•ScheduleearliervisitforclinicalreviewandconsiderCD-4(ifavailable)c
Good adherence is the key to maintaining the First line ART for longer duration.
Good adherence is required for Second line ART to ensure viral suppression and increase survival.
13National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
New or recurrent event on ARTa Recommendations Additional Management Options
Stage3event(T3) Considerswitching regimenbd
•Treatandmanagestagingeventand monitorresponse
•Assessandofferadherencesupport•Checkifontreatmentforatleastsixmonths•CheckCD4cellcount(ifavailable)cd
•AssesscontinuationofreintroductionofOIprophylaxis
Stage4event(T4) Switchingregimenbe •Treatandmanagestagingeventandmonitorresponse
•Checkifontreatmentforatleastsixmonths•AssesscontinuationofreintroductionofOIprophylaxis
•CheckCD4cellcount(ifavailable)c
•AssessandotheradherencesupportaReferstoclinicalstageswhileonARTforatleastsixmonths(termedT1,T2,T3,T4).
bDifferentiationofopportunisticinfectionsfromimmunereconstitutioninflammatorysyndromeisnecessary.
cTreatandmanagethestagingeventbeforemeasuringCD4cellcount.
dCertainWHOclinicalstage3conditions(e.gpulmonaryTB,severebacterialinfections)maybeindicatorsoftratmentfailureandthusrequireconsiderationofSecond-linetherapy;responsetoappropriatetherapyshouldbeusedtoevaluatetheneedforswitchingoftherapy.
eSomeWHOclinicalstage4conditions(lymphnodeTB,uncomplicatedTBpleuraldisease,oesophagealcandidiasis, recurrentbacterialpneumonia)maynotbeindicatorsoftreatmentfailureandthusdonotrequireconsiderationof Second-line-therapy,responsetoappropriateantimicrobialtherapyshouldbeusedtoevaluatetheneedtoswitchtherapy.
TBcanoccuratanyCD4levelanddoesnotnecessarilyindicateARTfailure.TheresponsetoTBtherapyshouldbeusedtoevaluatetheneedtoswitchARVdrugs.InthecaseofpulmonaryTBandsometypesofextrapulmonaryTB(e.gsimplelymphnodeTBoruncomplicatedpleuraldisease),theresponsetoTBtherapyisoftengoodandthedecisiontoswitchARVdrugscanbepostponedandmonitoringcanbesteppedup.Thisalsoappliesifsevereand/orrecurrentbacterialinfections(asstage3or4events)oroesophagealcandidiasisrespondwelltotherapy.
1.5 IDENTIFYING TREATMENT FAILURE
High index of suspicion is required
LookforthefollowingevidenceofsuspectedtreatmentfailureamongpatientsonFirstlineART(ensurepatienthasbeenonFirstlineARTforatleast6months):
• NewOIs/recurrence/clinicaleventsafter6monthsonFirstlineART(afterrulingoutIRIS).
• ProgressiveCD4countdecline.
• Slow/noclinicalimprovementover6-12months,associatedwithstationaryCD4,despite goodadherence.
• Clinicaldeteriorationinspiteofgoodadherencetotherapy.
* Even though one is less likely to develop IRIS after 6 months of therapy.
14 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
TheNACOdefinitionsofARTfailurearelistedintable5below:
Table 5: Definitions of Clinical, Immunological, and Virological treatment failure for First-line regimen.
Clinical failure (i) New or recurrent WHO stage 4 condition, after at least 6 months on ART (ii, iii)
Immunological failure FallofCD4counttopre-therapybaseline(orbelow) 50%fallfromtheon-treatmentpeakvalue(ifknown) PersistentCD4levelsbelow100cells/mm3 (iii,iV)
Virological failure Plasmaviralload>5,000copies/ml3(vi)
Notes:
i. CurrenteventmustbedifferentiatedfromIRIS.
ii. CertainWHOclinicalstage3conditions(egpulmonaryTB,severebacterial infections)mayindicatetreatmentfailureandthusrequireSecondlinetherapyto be considered.
iii. SomeWHOstage4conditions(lymphnodeTB,uncomplicatedTBpleural disease,oesophagealcandidiasis,recurrentbacterialpneumonia)maynot indicatetreatmentfailureandthusSecondlinetherapyneednotbeconsidered.
iv. SomeexpertsconsiderpersistentCD4countsofbelow50cells/mm3 after 12monthsofARTtobemoreappropriate.
v. Switchoftreatmentshouldbedoneonlywhentheviralcountismorethan5,000cells/mm3.
AttheARTcenter,suspicion of treatment failuredependsongoodclinicalassessmentbackedupbyuseofregularCD4counts.Beforelabelingapersonashaving‘failure’–ensurethatthefollowinghasbeendone:
• PatienthadareasonabletrialofFirstlineARTfor(atleast6months)
• Assessadherenceandsupportpatienttoimprovethis(reinforce)
• ScreenandtreatintercurrentOIs,excludeIRIS
• ProvideCotrimoxazolebasedonCD4orclinicalstageimmediately
• IfTBispresent:assessifthisisreinfectionorIRISoranewinfection.IftheresponsetoTBtherapyisgood,thenthedecisiontoswitchtherapycanbepostponedandthepatientre-evaluatedagain.
• CD4count(mostrecent)latestbyamonthaftertreatingtheintercurrentillness,ifany.
15National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
The Second line ART will be initiated only at CoE/pCoE/ART plus centers after SACEP review and patients will be transferred back to their referring center after 6 months viral load testing (except those having an OI at 6th month or toxicity to ART drugs).
In order to minimize the unnecessary referral to SACEP, the referring ART centre should follow the following guidelines before referring patients to SACEP:-
1) It is important to differentiate between complications of HIV disease and ARVtoxicitiesasthesemaypresentwithsimilarsignsandsymptoms.
2) The inter-current illnesses likeHepatitis-A,Malaria,etc.mustbekept inmindastheymayalsoleadtosymptomssimilartoARVdrugstoxicities.
3) Toxicitiesduetootherdrugsusedconcurrently likeCotrimoxazole,anti-TBdrugs,other antibiotics, herbalorothermedicationsetc.mustbe ruledoutbefore thetoxicitiesarethoughttobeduetoARV.
4) As a general principle, mild toxicities do not require discontinuation of ART orsubstitutionwithalternativeFirstlinedrugs.Symptomatictreatmentmaybegiveniftoxicityismildandpatientmonitoredclosely.
5) Moderate to severe toxicities require substitutionwith a different drug of sameclasswithadifferenttoxicityprofile.Agradingofcommonlabandclinicaltoxicitiesis at Annex I.
6) Severe life threatening toxicities e.g. Stevens – Johnson syndrome requirediscontinuationofallARVdrugsuntilpatientisstabilized.
7) HistoryandnatureoftoxicitiestoARVdrugsmustbeclearlydocumentedinthepatientrecord,andwherepossibleobjectivegradingoftoxicitiesshouldbedoneaccordingtoAnnexureI.Photodocumentationofskinrash&mucosallesions,lipodystrophyetc.shouldbedoneattheARTCentreandmustbesentduringSACEPreferral.
AllARTcentersshalluseprotocolA1.1listedbelowbeforereferringpatientstotheirlinkedCoE/ARTpluscentreasacaseof“suspectedtreatmentfailure”.
16 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
1.6 PROTOCOL FOR DETERMINING ART FAILURE (PROTOCOL A1.1) AT ART CENTERS
‘Suspecttreatmentfailure’duringthemedicalconsultationonfollowingground:
• Clinical:occurrenceofnewOIormalignancy,signifyingclinicaldiseaseprogression;recurrenceofpreviousOI,onsetorrecurrenceofWHOstageIV(&certainstageIII)conditions
• CD4:fallofCD4counttopre-therapybaselinewithoutotherconcomitantinfectiontoexplaintransientCD4countdecrease/50%fallfrom‘on-treatmentpeakvalue’/persistentCD4level<100cells/mm3
• ReviewneedforOIprophylaxis/treatmentespeciallyCPT
• ExplaintopatientaboutsuspicionoftreatmentfailureandneedtorefertoSACEPreview
• Continue1stlineARTwhilewaitingforSACEPreview.
• Refer to SACEP for appointment dates by email (given 2 alternate appointment dates)-informpatientofdateandtoattendSACEPinpersonwithallrecords.
• Sendallpatientinformation/recordstoSACEP/COE/ARTPlusCentre.
• DonotstopFirstlineARTtillvirologicalfailureconfirmedandSecondlineARTstarted.
Workwithpatienttoresolveissuescausingnon-adherence
Continue1stlineART,giveOIprophylaxisifnecessary.
Follow-upmonthly.Reassessclinically.
RepeatCD4after1month(toconfirmvalidityandexcludelabandphysiologicalvariability)
IfCD4notdeclining,continueadherencesupportandrepeatCD4in3months.Reassessanddetermineiftreatmentfailure.
DoesPatientadhereproperlyto1stlineART
SignsorsymptomsofOI
ManageIRISorOI,especiallyTB
Patienthasbeen on ART for at least6months
RepeatCD4immediately
Perform clinical staging
Giveprophylaxisand/ortreatmentforOI
Most recent CD4
within1monthofcurrentmedicalconsultation
available
Ruleoutothercausese.g.IRIS.
Continue1stlineARTandsupportadherence
DoesCD4valueindicate treatment failure?Asper3criteriaabove
YES
NO
NO
NO
NO
YES
YES
YES
YES
17National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Patients who are referred to SACEP for review should be accompanied with complete details of the history and all records, recent CD4 and other baseline tests, photographs of skin/mucosal lesions, if any. Incomplete records will delay decisions to be taken by SACEP. A referral format is enclosed at Annex II
Eligibility for enrollment into Second Line Treatment:
AllpatientswhorequireSecondlineARTshallbereviewedbySACEPatCOE/pCoE/ARTPluscentresasperlaiddownreferralprocedure,irrespectiveofthefactwhethertheystartedtreatmentinprivatesectororNACOcentres.
TheSACEPreviewwillbebasedonthereferralfromtheARTcentreprovidingFirstlineARTtothepatientsuspectedoftreatmentfailure.
Each COE/pCoE/ART Plus Centre will have defined ART centres linked to it and pa-tients fromthesecentres only will be reviewed by a particular CoE/pCoE/ART plus center after proper referral.
Whenapatientissuspectedtohavetreatmentfailure,theARTcentremustfollowtheNACOprotocol1.1)beforereferringtotheSACEP.Thisistoensurethatappropriatereferralsfor‘suspecttreatmentfailure’aremade:
• LaboratorytestsincludingHb,LFT,RFTandCD4andothersymptom-directedtestingshouldbedoneimmediatelyifsuspectedoftreatmentfailure.ThereshouldnotabiggapbetweenthesetestsandSACEPreferral
• MostrecentCD4count(within1month)ofthecurrentmedicalconsultationshouldbeavailable
• In themeanwhile, the patient is to be counseled for 100% adherence in a fewsessions (and/orbeoptionally linked to thenearestCareandsupportCentre foradherencesupport)
• EnsureuseofCotrimoxazoleprophylaxisifCD4<250cell/mm3orbasedonWHOClinical staging
• Continuewiththe1stlineARTregimenduringthistime.
• IfOIoranyintercurrentillnessispresent,treatforthespecificOIs.IftheOItreatmentisnotavailableintheinstitutionthenthesepatientscanbereferredtothenearestGovernmenthospitalorCOE/pCoE/ARTPlusCentreforfurthermanagement.
• CounselandsupportadherenceduringthisperiodofOItreatmentassomepatientsmaynotadheretotakingARTwhentheyfeelill.
18 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
• ForsuspectedTB,refertoRNTCPservicesfortreatmentandmonitortheresponsetoTBtherapy.IftheresponsetoTBtherapyisgood,thepatientshouldbeevaluatedagainforsuspicionoftreatmentfailure.RepeatCD4counts2weeksaftertheOIhasbeentreated,andforTB–aftertheintensivephase(i.e.8weeksofATTcompleted).Reviewthepatientforsuspectedtreatmentfailureasperprotocol.
If protocol 1.1 points towards a suspected treatment failure, following steps need to be taken:
• The referring ART centrewill inform and counsel the patient on the findings of‘suspected treatment failure’, support psychosocial needs, counsel to continue1st lineARTuntilotherwiseadvisedbytheARTSMO/MO;andwiththe informedconsentofthepatientforsharedconfidentialityinitiatetheprocessforreferraltotheSACEPforCOE/pCoE/ARTPlusCentres.
• During counseling/while referring, never tell the patient that his First line has failed until viral load report is available as failed. Counsel about suspicion of failure and that he is being referred for opinion and confirmation.
• TheARTcenterwill sendtherequest formwiththefilleddetails togetherwithaconfirmedcontactphoneofthepatient;andphotocopiesofthecasesheets/patienttreatmentrecordtotheCOE/ARTPlusCentrebye-mail.
• TheCoE/ARTplus centrewill enter thepatientdetails in the SACEP register andreviewthereferralformwithotherclinicaldetails.
• After review of patient records by the SACEP coordinator/research fellow/SMO,if the SACEP at CoE/pCoE/ART plus centre considers that the patient should bereviewedbySACEPthentwoalternativeappointmentdatesaregivenbye-mailtothereferringcentrewhowillinformthepatient.
• Afterreviewandothernecessary investigationsbytheSACEP,theCoE/pCoE/ARTplus centrewill send the feedback form (lower half of the referral form) to thereferringcentreandinformthemaboutthefinaldecisionoftheSACEP.
• Ifthepatientistobestartedon2ndlineART,theCoE/pCoE/ARTpluscentrewillaskthereferringcentretotransferoutthepatienttothatparticularCoE/pCoE/ARTpluscentreandpatientmaybesentbackbefore6month(maybeat3month)toNodalARTCentreonrequest,ifclinicallystableandimproving
19National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
1.7 MANAGEMENT PROTOCOL BASED ON SACEP DECISION AND VIRAL LOAD TEST RESULTS
OncepatienthasbeenreferredtoSACEPforevaluationaccordingtothetechnicalprotocol(A1.2),theSACEPwillreviewthepatientwithhisrecordanddocumentitsdecision,whichcan be
o Provide2nd line ART
o Not eligible for 2nd line ART
o ContinueFirstline,reinforceadherenceandre-evaluate
o EvaluateforHIV2
AfterthedecisionoftheSACEPtoprovide2nd lineARTtothepatient,theCOEstaffwillensurethenecessaryworktopreparethepatientforinitiationofSecondlineART.
TheSACEPcoordinator/DataManagershallcommunicatethedecisionoftheSACEPtothereferringARTcentrefortheirreference,andARTcentreto‘transferout’thepatienttoCOE/pCoE/ARTplusCentre.(SeeM&Esection).Thecentershallensurebaselinelaboratoryandclinicalscreening isdoneandrecordedbefore initiationofSecond lineART.AsapartofTreatmentpreparedness,thepatientshouldundergoaminimum of 3 counseling sessions. Treatment supporter should ideally be present. Consent form for 2nd line ART initiation shouldbesignedbythepatient–ANNEX III
The CoE/pCoE/ART plus center shall also ensure linkage with NGO/CBO/FBO/positivenetwork/CareandSupportCentre/ICTCforoutreachandcommunity/homebasedcare
Only the Programme Director/nodal officer of the COE/pCoE/ART plus Centre are authorized to prescribe Second-line ARVsafterapprovalofSACEP.ThedecisiontoswitchfromFirstlinetoSecondlinetherapyresidesonthedecisionoftheSACEPwhichwillmeeteveryTuesday(orthedesignateddayofthecentre),toreviewthecasehistory,ordertheViralloadtestingandapproveinitiationofSecondlineARTfortreatmentfailureanduseofalternativeregimens.
DetailsinthereportingandrecordingformatsshouldbecompletedbytheCOE/ARTplusCentre staff so that good documentation is present. Thiswill enable the COE/ART plusCentreandthenationalprogrammetolearnfromthenationalrolloutofSecondlineART.
Routinedrug resistance testing isnotpartof thenationalprotocol for Second-lineART,howeveritmaybedoneforresearch/surveillanceandmonitoringpurposes.Bloodsampleson dried blood spots (DBS)shallbecollectedandstoredforuseata laterdatefordrugresistancegenotyping.(SeeLaboratoryguidelinessectionbelow)
20 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Suspect treatment failure by clinical and/or CD4 criteria
(Exclude other factors: poor adherence, intercurrent illness, TB, OIs, IRIS etc.)
In 5-10% of the patients, there may be discordance between the Viral load and the clinical assessment/CD4.
Ithasbeennotedinsomecases,VL<400copies/mlorVLis400-5,000copies/mlbutthepatientshaveclinicaleventsandCD4isdecreasing.SuchcasesshouldbedocumentedandsenttoNACOforexpertopinion(NACEP).
Reviewpatientclinically.Continue1st line ART
InvestigateforothercausesforclinicalsignsorCD4fall.
EvaluateforOI/IRIS/non-HIVrelatedconditions
Reinforceadherenceto1st line ART.
“Transferout”fromreferringcentertoCoE/pCoE/ARTpluscenter
Counselpatientfor2nd line ART (minimum 3 sittings)preparednessandadherence.
ScreenforOIs/TB.
Givecotrimoxazoleifrequired.
Investigateandcorrectanaemia.
Initiate2ndlineARTwhenpatientisprepared.
VL<400
Transfer back to original (referring) ARTcenterwithtreatmentplan,oncase-to-casebasisdependingoncapacityofreferring ART centre
IfVL>400withnoOI,stilltransferthepatientbacktothereferring centre andcallthepatientbackforVLtestingafternext6monthsorelseretainthepatient,ifrequired
VL > 400
SACEPreferspatientbackto original ART center withappointmentdatefornext evaluation/VL test at 6 months withwrittentreatmentplanandfeedbackform.
Monthlyfollow-upatARTcentre.
Reinforceadherence
Strict CD4 follow-up3 monthly to monitor CD4 trend and if CD4 criteria forfailureisnotthereCD4followupisenough.
Counselpositiveprevention,condomuseandnutrition
ContinueARTatreferring (original) ART Centre
RepeatCD4andVLin3monthsthenSACEPreview
Counselpositiveprevention,condom usage and nutrition
VL < 400 copies/ml
VL >5,000 Copies/ml
VL 400 – 5,000 Copies/ml
FU at COE/pCoE/ART Plus Centre for at least 6 monthstostabilizepatientandadherenceto2nd lineART,reviewthe6-monthVL
Counselpositiveprevention,condomuseandnutrition
Protocol A1.2: SACEP Management according to viral load results
VLafter6months ofIIndlinetherapy
Nochangein1st line ART
Virologicallyconfirmedtreatmentfailure.Switchto2nd line ART regimen
Nochangein1st line ART
Viral load test
21National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
1.8 INITIATING THE STANDARDIZED NACO SECOND-LINE REGIMEN
AftertheSACEPhasapprovedSecondlineARTforthepatient,theclinicalmanagementshallbetheresponsibilityoftheCOE/pCoE/ARTPlusCentreandthepatientwillbe‘Transferredout’fromthereferringARTcentretotheCOE/pCoE/ARTPlusCentre.
TheobjectiveoftheSecond-lineis:
• ToprolongsurvivalofthePLHIV
The NACO standard Second line regimen (TDF + 3TC + ATV/r) (for those on AZT/d4T in First line regimen) aims to achieve viral suppression for as long as possible, so that survival can be prolonged.
Under thepublic health settings in India, theobjectiveof the Second-line is toprolongsurvivalofthePLHIVratherthanacompleteviralsuppressionas indevelopedcountrieswheremultipleSecondlineoptionsandsalvageregimenareavailableandearlyswitchingisthenorm.TheNACOtechnicalresourcegrouponARThadextensivediscussionsontheregimenwhichisoptimumforthenationalsettingandon‘early’vs‘late’switchingaswell.SincewehadonlyoneSecondlineregimenwithnosalvageregimen,itwasdecidedtogoforlateswitchingtogivethebenefitofFirstlineARTforaslongaspossible.
Table 6: NACO Second Line Regimen:
ARV drugs for 2nd line
Dosage Dosing schedule
TDF + 3TC Fixeddosecombinationof
Tenofovir300mg+Lamivudine 300 mg
oncedailyintabletform
Please advise thepatients toconsume all the three pillssimultaneously after meal(preferablydinner).(Keepthedruginteractionsinmind)
ATV/r Tab.Atazanavir300mg,Tab.Ritona-vir100mg
Eachtabtobetakenoncedailysimultaneously
The major side effects of Second line ART are described below in Table 7.
22 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Table 7: Side effects related to the NACO Second Line Regimen:
ARV drug Side effect/toxicity Management
TDF Usually well tolerated
Minor:weaknessandlackofenergy,headache,diarrhea,nausea,vomitingandintestinalgas.
Moreserioussideeffectsincludeliveror kidneyfailureandpancreasdisease.
TDFcanreducebonemineraldensity
Symptomaticmanagementof minorsideeffects
MonitorLiverandRenalfunctiontestasperNACOlabmonitoringprotocol
Calciumsupplementsmaybeusedinpatientswithosteoporosis
ATV* ApartfromthePI-classspecificside-effectslikehyperglycemia, fat maldistribution, hyperlipi-daemia(especiallywithRitonavirboosting),in-creasedbleedingepisodesinhemophiliacsetc.the unique side-effects of Atazanavir includeindirecthyperbilirubinaemia(producingyellowdiscoloration of eyes), skin rash and nephroli-thiasis(rare).
Unique drug interaction involving Atazanavir:
InadditiontoallthedruginteractionsinvolvingPIclass,Atazanavir hassignificantdruginterac-tionwithantacids,H2Receptorantagonistsandprotonpumpinhibitors*
Thepatientsneedtobecounselledthattheymayappeartobejaun-dicedwithyelloweyesbuttheyshouldnotbeafraidasitwillbeacosmeticproblemonly(likeGilbertdisease).Itshouldnotbetakenashepatotoxicity.However,LFThastobedoneshouldsomeoneappearstohavejaundice.Also,theyshouldbeadvisedtoconsumeplentyofwater.
Antacid:GiveAtazanaviratleast 2hoursbeforeor1hourafter antacidsoranybufferedmedications.
LPV/r Sideeffectsincludeabdominalpain,abnormalstoolsorbowlmovements,diarrhea,feelingweak/tired,headacheandnausea.Inaddition,patientstakingLopinavirshouldbemonitoredforpossibleliverproblems.Peopletakingthedrugwhohaveliverdisease,suchashepatitisBorhepatitisC,mayexperienceaworseningoftheirlivercondition.Asmallnumberofpa-tientshaveexperiencedsevereliverproblems.
Symptomaticmanagementofminorsideeffects.
SupportivecounselinganduseofotherdrugstomanageGIeffectsshouldbedone.Thesesymptomsimproveafterafewweeks.
MonitorLFTs,Lipidprofileandbloodsugarregularly
3TC Usually well tolerated
Sideeffectsmayincludecough,diarrhea, dizziness,headache,lossofappetite,mildstomachcrampsorpainandtroublesleeping.
Moreserioussideeffectsincludeburning,tingling,orpaininthehands,arms,feet,orlegs;chills;ear,nose,orthroatproblems;fever;muscleaches;nausea;paleskin;severestomachpain;skinrash;unusualtirednessorweakness;vomiting;andyelloweyesorskin.
Symptomaticmanagementof minorsideeffects
23National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
CAUTION : (WE SHOULD BE CAUTIOUS IN RECOMMENDING THE USE OF H2RA & PPIs WITH ATV/r AS MOST OF OUR PATIENTS ARE ARV-EXPERIENCED; THIS IS A BLACK BOX WARNING FOR ATV; ONLY SYSTEMIC ANTACIDS CAN BE CO-PRESCRIBED)
Side-effects of Atazanavir:ApartfromthePI-classspecificside-effectslikehyperglycaemia,fatmaldistribution,hyperlipidaemia(especiallywithRitonavirboosting);theuniqueside-effectsofAtazanavirincludeindirect hyperbilirubinaemia (producing yellow discolouration of eyes),skinrash,prolongationofPRintervalandnephrolithiasis.
1.9 DRUG INTERACTION:
Avoid concurrent use of the following drugs:
Astemizole, Cisapride, Fluticasone, Indinavir, Lovastatin, Simvastatin, Midazolam,Terfenadineetc
Unique drug interaction involving Atazanavir:
In addition toall thedrug interactions involvingPI class,Atazanavir has significantdruginteractionwithantacids,H2Receptorantagonistsandprotonpumpinhibitors.
S NoPatient on following drugs concomitantly
Recommendation/points to remember for ATV
1 Antacids GiveATVatleast2hoursbeforeor1hourafterantac-idsorbufferedmedications
2 H2ReceptorAntagonist 1. H2 receptor antagonist dose should not exceed adose equivalent to Famotidine 40mgBID inART-naïvepatientsor20mgBIDinART-experiencedpa-tients.
2. GiveATV300mg+RTV100mgsimultaneouslywithand/or>10hoursaftertheH2receptorantagonist.
Example: If a PLHIV on Zidovudine + Lamivudine + Ata-zanavir/Ritonavir (Regimen IV) requires to be treated with Famotidine 20 mg BID or Ranitidine 150 mg BID, S/he should be instructed to take Tab. Famotidine/Ra-nitidine with Zidovudine + Lamivudine at 8.00 AM and in evening give ZL and ATV/r at 8 p.m. and ensure that there is a gap of at least 2 hours before or 1 hour after Famotidine/Ranitidine evening dose.
24 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
S NoPatient on following drugs concomitantly
Recommendation/points to remember for ATV
3 ProtonpumpInhibitor 1. H2 receptor antagonist is not recommended with Tenofovir+Lamivudine+Atazanavir/Ritonavir
2. PPIs should not exceed the dose of Omeprazole20mg daily or equivalent dose of Esomeprazole20mg/Pantoprazole40mg/Rabeprazole20mg inPI-naïve patients, along with Ritonavir boostedAtazanavir.PPIsshouldbeadministeredatleast12hourspriorto Atazanavir/Ritonavir.
3. PPIs are not recommended in PI-experienced patients.
Example: If a PLHIV is on Tenofovir + Lamivudine + Atazanavir/Ritonavir requires to be treated with PPI, S/he should be instructed to take Tab. Omeprazole 20 mg/Esomeprazole 20mg/Pantoprazole 40 mg/Rabe-prazole 20 mg OD at 8 AM and Tenofovir + Lamivudine + Atazanavir/Ritonavir after 8 PM.
a. Prolongation of P-R and Q-Tc interval in the ECG can occur. So PR interval needs to be monitored in patients with known conduction defects or with concurrent use of other drugs that alter conduction abnormalities (like diltiazem, clarithromycin, cisapride, ketoconazole etc.). However, routine ECG before starting Atazanavir based ART is not mandatory.
b. Atazanavir induced urolithiasis is also reported; presumably due to precipitation of the drug resulting in crystalluria in a manner analogus to Indinavir.
c. If the serum total Bilirubin is > 7 mg/dl or the Child-Pugh Score is ≥ 7, then ATV/Ritonavir cannot be used and the details of such cases should be mailed to National AIDS Clinical Expert Panel (NACEP).
Counseling issues:
ThereisaneedforenhancedcounselingofthePLHIVontheseregimensparticularlyuniquesideeffectsofAtazanavir/Ritonavir.
So,thepatientsneedtobecounseledthattheymayappeartobejaundicedwithyelloweyesbuttheyshouldnotbeafraidasitisonlyacosmeticproblem.Itshouldnotbetakenashepatotoxicity.However,LFThastobedoneshouldsomeoneappearstohavejaundice.Also,theyshouldbeadvisedtoconsumeplentyofwater.
25National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
AsweareusingtheATVandRTVasseparatepills,duringcounselingweneedtoimpressupon thepatients to takeboth thepills togetherasourpatientsaregoing to takeATV,RTValongwithTDF,iftheymissRTV,thentherewillbedecreasedATVbloodlevelanditmayleadtotreatmentfailure.Soduringthecounselingsession,thesepointsneedtobestressedadequately.TheyshouldalsobecounselledthatATV/rshouldalwaysbetakenonafullstomachasotherwisetheabsorptionofATVgoesdown.
AlltheNodalOfficers,SMOs&MOsarerequestedtosensitizethecounselors,pharmacists,nurseandotherARTCentrestaffonuseofAtazanavir/Ritonavir.
Important consideration in pregnancy
RitonavirboosterLopinavir(notATV)istobeusedforpregnantwomenexposedtosd-NVPinthepast
1.10 SECOND-LINE ART AND TB TREATMENT
TuberculosisisthemostcommonlydetectedseriousopportunisticinfectionamongPLHIVsinIndia.Whiletuberculosishastobetreatedappropriatelyandonpriority,inthecontextof Second-line ART drug-drug interactionsmust to be considered. Rifampicin alters themetabolismofProteaseInhibitors,includingLopinavir,AtazanavirandRitonavir,andreduceseffectivenessof standarddoses.However,Rifamycin-classdrugsarehighlyefficacious intreatment of tuberculosis. Annex V
AnotherRifamycin,Rifabutin,canbeadministeredinthepresenceofPI-containingSecondlineARTregimenwithoutcompromisingtheefficacyofARTorAntiTBtreatment.ThereforeNACPandRNTCPhaverecommendedthesubstitutionofRifabutinforRifampicinforthedurationofTBtreatment.InthepresenceoftheboostingdruglikeRitonavir(PI),Rifabutinmetabolism is altered, and less Rifabutin is needed than would be without Ritonavir.Therefore, the dosage of Rifabutin during the administration of Second line regimencontainingLPV/rshallbe150mgthriceweeklyforallpatients,weighing>30kgweight.TheremainderoftheTBtreatmentregimens,includingdosingandduration,remainunchangedasperRNTCPguidelines.
Aswithallanti-TBtreatment,supervised treatment under DOTS is required.Thepatients’DOTSprovidershouldbeinformedandcounseledregardingthesubstitutionusingRifabutin,bythetreatingmedicalofficer.
Rifabutin dose: 150 mg OD, three times a week
SomeofthecommonsideeffectsofRifabutinincludeorange-browndiscolorationofskin,tears,saliva,sweat,urine,andstoolsandwillstopwhenyoufinishtakingRifabutin.TheARTcentreSMO/MOshouldbecontactedincaseofh/ochestpain,muscleaches,severeheadache, fatigue, sore throat, flu-like symptoms, vision changes, unusual bruising orbleeding,nausea/vomiting,yellowingoftheskinoreyes.
26 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Initiation of 2nd line ART in patient already on anti-TB treatment
Ifapatientisalreadyonanti-TBtreatment,andneedstobeinitiatedonSecond-lineART,thensubstitute Rifabutin for Rifampicin within the RNTCP regimen for 2 weeks prior to initiation of Second-line ART.Thisistoallowhepaticmetabolism(inducedbyRifampicin)tonormalizepriorto initiationofPI-containingregimens.Whilethepatient iscounseledandpreparedforinitiationof2ndlineregimen,thepatientshouldstillbegiventhe1st line ARTregimen.ThereisnoneedtoincreasethedoseofEFVwithRifabutincontainingATT
RNTCP recording and reporting:TBtreatmentcategorizationdoesnotchangewiththeuseofRifabutin,whichisasimplesubstitutionforRifampicin.ThesubstitutionofRifabutinforRifampicinshouldbenotedontheTBtreatmentcard,andintheTBregister“Remarks”column.
Initiation of Anti-TB treatment in patients already on 2nd line ART
Ifthepatientisalreadyon2ndlineART(Atazanavir/Ritonavircontainingtreatmentprotocol),anddetectedtohaveTB,subsitute Rifabutin for RifamipicinwithinthecategoryIorIIanti-TBregimenfromthestartofTBtreatment.
InregardstotheavailabiltyofRifabutinattheDOTScentresajointletterhasbeenissuedbyDDG(TB)andDDG(NACO)dated,19thFeb2013.TheletterisenclosedatAnnexX.
Initiation of Second line ART/Anti TB Treatment in the presence of TB co-infection (Protocol A 1. 3)
PLHIV on 1stlineARTreviewedbySACEP,hastreatment failure and eligible for 2nd line ART
SubstitutewithRifabutinforRifampicin,withintheanti-TBtreatmentregimen
•Treatmentpreparedness&counseling
•InitiateRifabutincontainingAnti-TBregimenonpriority
•Treatmentpreparedness&counseling
•InitiateRifabutincontainingAnti-TBregimenonpriority
•Initiate2nd line ART regimen whenpatientisstabilizedonTBtreatmentafter2weeks
•Treatmentpreparedness& counseling
•Initiate2nd line ART
AlreadyoncategoryIorIIAnti-TBtreatmentWithorwithoutEFV-basedARTregimen
Needtoinitiate2ndlineARTwithconcurrentdetectionofTBco-infection
Patientalreadyon2ndlineandthendetectedtohaveTBco-infection
After 2 weeks of Rifabutina
Note:
aThe2weekperiodallowshepaticfunctiontonormalizeafterinductionofP450cytochromeenzymes byRifampicin
bPatienttobecounseledwellforbothanti-TBand2ndlineART.Pillburdenishigh.Ifpatientisnotstartedon2nd lineARTimmediately,thencontinue1stlineregimentillpatientisswitchedtoswitchto2nd line ART occurs.
27National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
1.11 LABORATORY MONITORING OF PATIENTS ON SECOND LINE REGIMEN
TheprotocolforlaboratorymonitoringofpatientsonSecondlineARTisdescribedintable9below
Table 9: Protocol for laboratory monitoring of patients on Second line ART
TestsBase-line0
3 6 12 18 24
Hb, CBC Then annually
LFT
Renal function test Then every 6 -monthly
Fasting blood sugar Then annually
Fasting lipid profile
Viral Load (VL) Then no more VL unless indicated in protocol A1.2
CD4
More frequently if required.
Note: Resistance testing is for operational research/surveillance/monitoring only, undercurrentnationalprogramme.
Abaselineandannualcheckupoffastingbloodsugarandlipidprofileisrecommended.Thisistounderstandthebaselineandmonitorthepossiblemorbidities/sideeffectsofPIs.However,thenationalprogrammewillnotbeprovidingstatinsorfibratesfortreatmentofdyslipidemia.
1.12 ADHERENCE AND SECOND-LINE ART
NACO 2008 tools to support counseling and treatment adherenceforallpatientsandespeciallyforpatientswhohavedifficultywiththeirFirstlineARTandthosetakingSecond line ART:
1. Patientcounselingdiary(individual)
2. UsetheVisualAnalogueScale(VAS)tohelpunderstanddrugadherence
3. Patienteducationinformationleafletsfortheirprescribedregimens
4. Patientpill-takingmonthlycalendar
Long termadherence continues to be challenge to PLHIV taking lifelongART. Themostcommon reason for HIV drug resistance is due to non-adherence and missed doses.Adherenceapproaching100%isrequiredforoptimalviralsuppressionbothinFirstlineandSecond line ART.
28 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Theexperienceofthenationalprogrammetodateisthatingeneral,socio-demographiccharacteristicssuchasage,sex,socialclass,maritalstatusorpersonalitytraits,race,religionandeducationallevelsarepoorpredictorsofadherence.Patients’beliefs,knowledgeandexpectations (sometimes shared by friends and community), strongly influencemedicaldecision-making and willingness to begin and then adhere to prescribed treatments.Adherence is found to be greater when the person perceives the need for treatment,believes thetreatmentwillbehelpfulandunderstands thepurposeof themedications.Attitudesoffriends,trust inphysiciansandconfidenceinone’sownabilitytofollowtheagreed-upontreatmentsarealsoassociatedwithadherence.Lackofbeliefintheefficacyoftreatmentmayleadtoeithertreatmentrefusal,orinadequateadherenceonceinitiated.
Itisforthisreasonthatthe initial detailed counseling by the doctor about combination therapyiscrucialforlatersuccess.Simplytellingthepatientthatit’stimetobeginantiviraltherapy,writingoutprescriptionsandhandingthemtoapatientwhoasksnoquestionsandexpressesnoopinionsislikelytoleadtoadherenceproblemsandtreatmentfailure.Occasionally,well-meaningphysiciansurgereluctantpatientstostart treatment,despitethepatients’reservations.Themoreassertivepatientmaystatethatheorsheisnotreadytostart,butothersmayacquiescetoaregimenthattheyconsiderofdoubtfulvalueornotcompatiblewiththeirlifecircumstances.Do not start Second line ART if the patient is not ready to comply with adherence and follow up schedule.
HIV/AIDSisassociatedwithneurocognitive problemssuchasmemoryloss.Thiswillcauseadherence problems. Some patientsmay have trouble sorting their pills for the day ortheweek,whileothersmayhavetroublekeepingtrackofthetime,ormaysimplyforget.Evenamongasymptomaticpatients,memoryproblemsarepresent.Whenmemory isasignificantproblem,prescriptionofcomplexmedicalregimensisunlikelytosucceedunlesssocial(e.g.,familymember)orinstitutional(e.g.,homeattendant)resourcesareregularlyavailabletohelpwiththeschedulingandtakingofmedications.
Psychiatric disordersalsomayconstitutebarrierstoadherence.Evenmildconditionssuchasdepressedmood,aselicitedonself-reportratingscales,maybeassociatedwithmedicationnon-adherence,eitherbecauseofimpairedconcentration,whichisoneofthecriteriafordiagnosingmooddisorders, or becauseof feelings of hopelessness anddespair. Amongthose with chronic and severe psychiatric disorders, noncompliance with psychotropicmedication often contributes to relapse.When substance abuse is also present in HIV-infectedpatientswithseverementalillness,manyofwhomlivealoneinunstablehousing,theprobabilityofeffectivemanagementofcombinationtherapyispoor.
Two-waycommunicationbetweentheclinical teamandpatient iscritical to thesuccessofadherence.The patient has to believe that combination therapy will make a profound difference in extending life, or else the regimen’s burdens will outweigh the perceived rewards.Initiatingcombinationtherapyisnotusuallyregardedasanimmediateneed.Ifit takesextratime,oradditionalvisits, fortheclinical teamtoconvincethepatientthatcombination therapy shouldbe initiatednow,or for thepatient to convince thedoctorthathisorhercurrent lifecircumstancesaresimplynotconducivetostartingnow,thenextratimemustbeprovided.However,thereareafewurgentsituationswhenimmediateinitiation may be considered imperative. One example is a patient with an essentiallyuntreatableconditionsuchasPMLwho is rapidlygettingsicker. In thesecases,ARTcanleadtolife-savingremission.Inlessurgentsituations,treatmentcanbesafelyputoffwhiledoctor-patientdiscussionscontinue.
29National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Attheoutset,beforeevenbeginningcombinationtherapy,itishelpfultoreview anticipated problems and barriers to adherence, which then permits the patient to work out solutions on his or her own or with assistance.Forthispurpose,someprovidersgivetheirpatients1-2 weeks of cotrimoxazole and to use this time to reinforce adherence.Which dosesareproblematic?Whatarethecircumstances?What isthepatientthinkingwhenerrorsoccur?Whatisthepatient’sattitudeaboutmistakes?Doesheconsiderafifteen-minutedelayacatastrophesignifyingirremediablefailure?Alternatively,whatdotheythinkaboutmissingaweekend’sworthof“medications”?Suchrehearsalisoftenextremelyhelpfulinanticipatingandcorrectingpotentialpitfalls.
Somepatientsfindithelpfultohaveawritten treatment planthatshowsthenameofthemedication,timeofeachdose,numberofpillsorcapsulesperdoseandmealrestrictions,ifany,alongwithatelephonenumbertocallwithquestionsandforthenextappointmentdate.Bothdoctorandpatientshouldkeepacopyoftheplanforreviewatthenextvisit.Othertechniquesforpromotingadherenceincludeidentifyingdailyactivitiesthatcanbelinkedtopill-taking(e.g.,aregularTVshow),keepingamedicationdiaryorlog(preprintedformscanbeprepared),preparingpillsfortheweekatfixedtimes(e.g.,Sundayevening),andotherwiserelatingpill-takingtothenormalrhythmsofdaily life.Planningaheadforchangesinroutineorforweekendscanforestalllapsesatsuchtimes.
Mechanical aids are often useful. These range from pill boxes with dividers in whichmedicationscanbesortedbytheweekandtimeofdaytotimers,alarms,beepersthatcanbesettoringwhenitistimetotakepills,tosignsandchecklistspostedonrefrigerators.
Socialassistancecanmakeamajordifference,especiallyatthebeginningoftheregimen.Somepeoplehaveafamily member/treatment supporterwhoagreestoprovidereminderseverytimemedication isscheduled.Childrenremindtheirmothers;sometimesmothersremindtheiradultchildren.
Overtime,initialenthusiasmcandwindleastheincessantdemandsofschedulingpersist.Aspeoplefeelbetterandreturntowork,newproblemsarise.Amongthesearemaintainingconfidentiality, arranging schedules to accommodate pill-taking, frequent trips to thebathroom (if takingmedication that requires a high liquid intake), occasional dayswithsignificantsideeffectssuchasdiarrhoea,theconstantreminderofillnessandsimplytheongoingburdenoftheregimen.Itisimportanttoknowinmoredetailaboutthehurdles,questionsandworriesthatariseovertimewithART,andaccordinglytodevelopindividual interventionstomaintainadherenceoncetherapyisestablished.
ForpatientswhohavedifficultieswithadherencetoFirstlineARTorwhoaresuspectedoftreatmentfailure,orwhowillstartSecondlineART,the objectives of adherence counseling are:
• ToimprovetheadherencetomedicationssothatARTissuccessful
• To encourage self management of medications
• To foster honest communicationbetweenproviderandpatient
• To respect patient choices and decision-making related to their HIV relatedmedical care
Patients don’t want to disappoint their health care provider. The challenge is: how do you make it okay to say ‘no’ to doctors/counselors/nurses; or make it okay to say ‘I can’t do this’
30 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
31National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Section II: OPERATIONAL GUIDELINES
2.1 STATE AIDS CLINICAL EXPERT PANEL (SACEP)
a. StateAIDSClinicalExpertPanels(SACEP)havebeenconstitutedatallCOEsandARTpluscentretoreviewthepatientsreferredtothemwithneedforalternativeFirstlineandSecondlineART.EachCOE/ARTpluscentrehasARTcentreslinkedtoitandpatientfromthesecentersonlywillbereviewedbyaparticularCOE/ARTpluscentre.
b. TheSACEPwillreviewthepatientandhis/herrecordsandwillapprovetheCOE/ART plus to provide PI based Alternate First line drugs if the patient is foundtohaveseveretoxicitiestotheFirst lineARTorSecondlineARTasperclinicalprotocols.
c. OncethedecisionismadebySACEPtoprovidealternativeFirstlineARTtothepatientreviewed,patientswhoarerecommendedforPIbasedalternateFirstlineare‘transferredout’totheCoE/ARTpluscentrefromthereferringcentre.
d. ThepatientshallbestartedalternativeFirst/SecondlineARTonlyafteradherencecounselinghasbeendoneandpatienthasbeenassessedtobepreparedfor100%adherencetotheregimen.
e. Patients who have not been found eligible for Second line ART afterSACEP review a detailed follow up plan should be given to the referringARTcentreinthereplybackform.
State AIDS Clinical Expert Panel (SACEP) havebeenestablishedateachcentreofexcellence/pCoE/ARTpluscentre.Itconsistsof:
1. ProgramDirector/DeputyProgramDirectorofCOE/pCoE,NodalOfficerofARTpluscentre
2. OnemoreARTexpert(preferablynotfromthesameARTcentre)-PaneltobeformedbyNACO
3. RegionalCoordinator/JointDirector(CST)/Consultant(CST)atSACS/DPM.
Inadditiontotheabove,therewouldbeobserversfromcentral levelregularlyformonitoringpurposes.
32 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
The Terms of reference of SACEP/are:
• ReviewanddecideonallcasesreferredbythereferringARTcentreforPIbasedalternateFirstline/Second-lineARTprovision–bothforeligibilityforViralloadtestingandstartingSecondlineoralternativeFirst-lineARTregimen
• MeetattheCOE/ARTpluscentretoreviewcaseseveryTuesday(oraprefixedday)(nextworkingdayincaseofaholiday).Thisistoensurethatthereisnodelayinreviewandprocessingofthecasereferredforreviewofsuspectedtreatmentfailure.Amaximumof15-20patientsshallbereviewedateachmeeting(oldandnew).Howeverifthereare too fewpatients, themeetingmaybedeferredto thenextweek. If thenumberofpatientsonnextweekisagaintoosmall,themeetingstillshouldbeheldtoavoiddelay. It shouldbeensured that there isminimumtimetaken for reviewofpatientsandprovisionofdrugs.Alleffortsshouldbemadetoensurethatthisperioddoesnotexceedfourweeks.
• MentoringandensurehighqualitycasemanagementofthePLHAonSecond-lineARTbythereferringARTcentre
• DocumenttheregistrationandmonitorprogressofallpatientssuspectedoftreatmentfailuresentforSACEP/review
The SACEPwill follow the technical protocols as laid out byNACO in section I of theseguidelines.
Howeverforalltechnicalissues,theARTpluscentrescanreferdifficultcasestoSACEPoftheirCoE intheir region.Forpatientsrequiringanyfurthertechnical/operationalclarification,COE/ART plus centres can refer cases toNACEP (National AIDS Clinical Expert Panel) [email protected] and [email protected] coordinatedbyDrBBRewari,NPO (ART). Thispanel canhave representatives fromTRG,institutionsorindependentexpertsthatwouldbedeemedmostappropriateforthequeryunderconsideration.Hence,thecompositionoftheNACEPwillbedynamicanditscompositionwillvarydependingonthetypeoftechnicalquery.ThiswillensurethatmostappropriateresponseandguidanceisprovidedforthequerybythevarietyofexpertsandexpertiseonvariousareasundertreatmentandcareforHIV.
33National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Referral to SACEP
OnceapatientonART is suspected tohave toxicity toanyARVor is suspected tohavetreatmentfailure,theARTcentreSMO/MOshouldfollowthestepsmentionedbelow:
Step1 • The referringART centre should go through sectionon “Suspecting drugtoxicitiesamongpatientsonFirstlinetherapy”/Suspectedtreatmentfailure(Protocol A1.1).
• GothroughthetoxicitiesgradinginARTguidelines.
• ReferringARTcenterwillsendphotocopiesofpatient’srecordsandphotodocumentationfortypeoftoxicitiestoSACEPcoordinatoratCoE/ARTpluscentretogetherwithReferral/ReplyForm(Annex II) andconfirmthatSACEPcoordinatorhasreceivedit.
Step2 SACEPcoordinator/COEresearchassociatewillFirstenterthepatientdetailsintheSACEPregisterandthengetthepatientshistoryreviewedandifeligiblegiveappointmentdate/time(2alternativedates)tothereferringcentrebye-mail.
BeforegivingappointmenttheCoE/ARTpluscentremayrequestforanyotherpatienttreatmentrelateddocuments.
Step3 The referringARTcenterwill thencommunicate thedate/time topatientbyphone/personalcontactbyORW
Step4 OnlyaftertheSACEPhasreviewedthepatientandrecommendedinitiationofSecondline/AlternateFirstlineART(PIbased),initsreplyform,willthepatientbe‘transferredout’totheCoE/ARTpluscentre.
Note: For alternate First line ART:onlythosepatientswouldbe‘transferredout’toCoE/ARTplus centrewhoarebeing initiatedonPIbasedalternateFirst lineART. ForotherpatientsforwhomsubstitutionisbeingdonewithinNNRTIorNRTIclassofdrugsno‘transferout’isrequiredandtreatmentcanbechangedatthatARTcentreitselfafterSACEPrecommendations.SACEPreview isnotrequired forTDFbasedregimen.HowevereSACEPapprovalshallberequiredford4Tbasedregimenasonlylimitedquantitiesofd4Tshallbeprocuredinfuture
For Second line ART:allpatientsstartingSecondlineARTneedtobe‘transferredout’toCoE/ARTpluscentres.
34 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
2.2 ELIGIBILITY AND CRITERIA FOR PROVISION OF SECOND LINE ART
AllpatientswhorequireSecondlineARTshallbereviewedbySACEPasperlaiddownreferralprocedure,irrespectiveofthefactwhethertheystartedtreatmentinprivatesectororNACOcentres
TheSACEPreviewwillbebasedonthereferralfromtheARTcentreprovidingFirstlineARTtothepatientsuspectedoftreatmentfailure.Each COE/ART Plus Centre will have defined ART centres linked to it and patientsfromthesecentres only will be reviewed by a particular COE/ART Plus Centre.
CriteriaforprovisionofSecondlineART:• Referred by the NACO ART centre following the NACO protocol on determining
treatment failure (section 1.6)
• ReviewedbytheSACEPanddeterminedtobemedicallyeligibleaspertheNACOprotocolforSecondlineprovision
• Hasbeenassessedbycounselor/nurse/doctor foradherenceand isprepared forSecond line treatment
• Shouldhavefamilysupport/treatmentsupporter,andlinkedtoNGO/CBO/CSC/ICTCforoutreach/community/homebasedcareservicesandmonitoringofadherence
Furthermore, the patient to be provided Second line ART shall need to sign a consentform for informed consent (ANNEX III)forhomevisits/followedatthecommunitybylinkworker/NGO/positivenetwork/ICTCwhichwillsupporttheadherenceatcommunitylevelforSecondlineprovision.
The SACEP coordinator at COE/Data Manager at ART Plus Centre shall coordinate themeetingoftheSACEPtobeheldattheCOE/ARTPlusCentremeetingroom.TheCOE/ARTPlusCentrewillrequestthepatienttobephysicallypresentforthereviewpanel.TheSMOatARTcentreshouldalsobeinvolvedinthemeeting.
2.3 PROTOCOL FOR SACEP REVIEW
Step1
FollowProtocolA1.1for‘Suspectedtreatmentfailure’andthene-mailthedetails(briefART
history,clinicalstageandserialCD4values,reasonsforreferrals)ofpatienttoCoE/pCoE/
ARTpluscentretogetappointmentdates
Step2
CoE SACEP coordinator/ART plus centre’s datamanagerwill enter patient details intoSACEPregister(1SL+AL)CoESACEPcoordinator/CoEresearchassociate/ARTpluscentre’sdatamanagerwillreviewpatienthistorydetailssentbycentreandgiveappointmentdate(twoalternatives)andtimetothereferringcentrebye-mailforreviewbySACEP
Step3ThereferringARTcentrewillthencommunicatethedate/timetopatientbyphoneand
personalcontactbyORW/DLNvolunteer
35National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Step4
ReferringARTcentrewillsendphotocopiesofpatientrecordstogetherwithReferral/Reply
FormVI and confirm thatCoE SACEP coordinator/ARTplus centre’sdatamanagerhas receivedit.CoESACEPcoordinator/ARTpluscentre’sdatamanagerpreparesweeklySACEPmeetingformats(2SL)
Step5 TheSACEPwillreviewthecasenotesonlyinthepresenceofthepatientandguardian
Step6
TheSACEPwillorderaViralloadtestaccordingtoProtocolA1.2.
BloodsampletobetakentothelinkedViralLoadLabwillbeprocessedaccordingto
Laboratoryguidelinessection
Step7
TheSACEPwillreviewtheViralloadresultsinnextmeetinganddecideonmanagementofthepatientsandwilldocumentoneofthefollowingdecisions:
• ProvideSecondlineART
• Not eligible for Second line ART
• Re-evaluate/others
Step8
OncethedecisionismadebytheSACEPtoprovideSecondlineARTtothepatientreviewed,theclinicalmanagementofthepatientwillbedoneattheCoE/pCoE/ARTpluscentreitself.OnlytheProgramDirectororDeputyProgramDirectorofCoE/pCoEand/orNodalofficerofARTpluscentreprescribeSecondlineART
Step9
TheCoESACEPcoordinator/ARTpluscentre’sdatamanagershallinformthereferringARTcentreforthefollowingactions:
• ‘Transfer-out’thepatientintheM&Eformats,toCoE/pCoE/ARTpluscentre,
• SendthecompletedreplyformtothereferringARTcentre
Step10The patient must undergo 3 counseling sessions (minimum) to ensure treatment preparednessattheCoE/pCoE/ARTpluscentre
Step11 ThefollowupvisitsshallbemonthlyattheCoE/pCoE/ARTpluscentre
Step12
After6-monthsofSecondlineART,thefollowupViralloadtesthastobeperformed.TheresultwillbereviewedbyCoE/pCoE/ARTpluscentre.ThepatientswhohavesuppressedviralloadswithclinicalstabilitymaybetransferredbacktothereferringARTcentre,afterascertainingpatent’swillingness
Step13CoE SACEP coordinator/pCoE/ART plus centre’s datamanager to send SACEPMonthly reporttoNACObye-mailby4thofeverymonth([email protected])underoverallsupervisionofProgramDirector/DeputyProgramDirector&/orNodalofficer
TheCOEProgramDirector/DeputyProgramDirector&/orNodalofficerofARTPlusCentrewillbethephysicianresponsible;backedupbytheCOE/ARTPlusARTcentrestafftoensurehighqualityofcareforthepatienton2ndlineART.Prescriptionofthe2ndlineARTshallbedoneonlybytheProgramDirectororDeputyProgramDirectorofCoE/pCoEand/orNodalofficerofARTpluscentre.
Thepatientwhoisconfirmedtreatmentfailureandistobestarted2ndlinemaybeadmittedattheCOEfortreatmentofanyOIorforreinforcingadherence,ifrequired.TheCOEART
36 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
teamshallensurethatthepatienton2ndlineislinkedtoaNGO/CBO/ICTC/CSCforcareandsupportaswellasthepositivenetworkforothersupport.Condomuse,nutritionadviceandpositivepreventionaretobeemphasized.
DetailsinthereportingandrecordingformatsshouldbecompletedbytheCOEstaffsothatgooddocumentationispresent.
2.4 TOR OF ADDITIONAL MANPOWER: SACEP COORDINATOR
Forcarryingouttheseactivities,eachCOEshallbeprovidedwithanadditionalmanpowerinformofaSACEPcoordinator.TheTORsforSACEP Coordinator are:
1. ScreenandreviewallrecordsandcommunicationsofthereferralsmadetotheSACEP
2. MaintainingSACEP-schedulediary,scheduleandcommunicateappointmentdates
ofpatientstothereferringcentres
3. OrganizeSACEPmeetingsandcoordinatewithmembersoftheSACEP
4. EnsurelaboratorytestresultsofpatientsattendingareavailableforSACEPmeetings
5. Coordinatewithpharmacistforpatientdrugtransfers
6. Ensurefollow-upofpatientsattendingSACEP
7. Beresponsibleforpatients’registration,maintainingallformsandregistersrelated
to SACEP
8. PrepareandsendSACEPreportstoSACSandNACO.
9. CoordinatedactivitiesofintheregionlinkedtotheCoE
10. Beresponsible forreceivingandsendingcommunications fromandtothe linked
ART Centres
11. Beresponsibleforalldataentries,maintainingandupdatingallrecords,registers
andfilespertainingtotheCoE
12. AssisttheProgramDirectorandtheDeputyProgramDirectorofCoE inreceiving
andsendingallcommunicationsrelatedtotheCoE
13. Work in the ART centre and perform the duties of DataManager, if and when
required.
37National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
14. Responsibleforprocurements,maintainingaccounts,audits,handlingcontingency
pettycashoftheCoE
15. Assistthetrainingandmentoringcoordinatorincommunicationsandmaintaining
records
16. PerformanyotherjobasassignedbytheProgramDirector/DeputyProgramDirector
oftheCoE.
For SACEP meetings at the ART plus centres, the coordinator shall be one of the data managers at the centre and no additional staff shall be provided presently.
38 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
39National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Section III: M & E TOOLS
The soft copies of revised M&E tools have been sent to all COE and ART plus centres with instructions on how to use them and only those are to be used. The formats are enclosed at Annex IX.
ThemonitoringplanforSecond-lineARTfocusesontwomainaspectsofNationalART Programme namely – Clinical Monitoring of the Patients and ProgrammePerformance.Thesystemdeveloped;triestobuildontheexistingmonitoringsystemsexisting at ART centres. Refinements are added in current tools to record details of Secondlineandadditionaltoolsaredevelopedforcriticalareasofmonitoring.
Thesetoolswouldallow:
• Clinicianstoeffectivelymonitorthepatienton2ndlineclinically,and
• The ART programme to monitor the progress in implementation, identifyproblems, refine and adapt the implementation strategies; assess theeffectivenessoftheinterventions.
3.1 INSTRUCTIONS FOR MONITORING/RECORDS KEEPING FOR SECOND LINE ART
1. When the patient is referred from any ART centre to COE for evaluation, the patient is NOT ‘Transferred Out’ and would continue to receive the First line drugs from referring ART Centre till recommended otherwise.SACEP/COE(/ARTPlusCentre)willinformthereferringcentreoncedecisionismadeifpatientistobe transferred out or not.
2. Thepatientoncerecommendedfor2ndline;isthentransferredout(T/O)toCoE/ARTpluscentre.ThenormalprocedureofT/Oisfollowed.Therecordsarethustransferredaspertheusualprocedure,ifnotalreadydone.
3. AttheARTcentreofCOE/ARTPluscentres,thecurrentARTenrollmentregisterisusedforrecordingtheclinicaldetailsofthepatientonSecond-linebyfillingtheinformationonswitch
4. InthesameARTenrolmentregistera post fix to the ART registration–S(Secondline)canbeindicatedintheFirstblankcolumnbefore“ARTdateofstart”and“A”foralternativeFirstlineandregistrationnumberaregiveninasequentialorderincontinuationtothepatientsonFirstlineART.
40 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ThesummaryofSecondlineandalternativeFirstlineformatsisasbelow:
Monitoring and Evaluation tools for Second line and Alternative First line ART (Adults and Children)
(To be maintained at CoE/pCoE/ART plus centres)
Tool/Abbreviations M & E Tool- formats/Registers Directions
1
RRFSACEP Referral and Reply form
TobegeneratedatARTCentrewhenreferringthepatient.Thereplyportionto be sent back to referring centre bySACEPafter theevaluationof thepatient.(computerprintedformonly)
1SL*+AL**SACEP register (forallpatientsbeing referred to SACEP )
To bemaintained at CoE/pCoE/ARTplus Centre by SACEP coordinator/datamanager (Hard bound printedregistertobesuppliedbytheSACS).There should be no more than sixrowsperpageinordertoensurethatthere is adequate space forwritingthedetails.
2
2 AL
SACEP Meeting format (alternative First line) Thisformat should be preparedbeforeeverySACEPmeetingforallpatients(childrenandadults)tobereviewedinthatparticularmeeting for consultation forAlternativeFirstlineART
TobepreparedbeforeeverySACEPmeeting;giventoallmembersdur-ingthemeeting;andmaintainedatall CoE/pCoE/ART plus centres (infileringbinderandsoftcopy)
2 SL
SACEP Meeting format (Sec-ond line)
Thisformatshouldbepreparedbefore every SACEP meetingfor all patients (children andadults) to be reviewed inthat particular meeting forsuspectedtreatmentfailure.
TobepreparedbeforeeverySACEPmeeting,giventoallmembersdur-ing themeetingandmaintainedatall CoE/pCoE/ART plus centres (infileringbinderandsoftcopy)
3 3 AL+ SL
Monthly reporting format (Second line and alternative First line)
Combinedmonthly reportingformat for Second line and alternative First line ART foradultsandchildren
To be submitted to NACO byemail by 4th of every month at [email protected].
41National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Tools to be maintained at all CoE/pCoE/ART plus centres (in ring binder file and/or soft copy):
4
4 AL
Line list (alternative First line)
Cumulative list of patientsever initiated on alternativeFirst line ART
To bemaintained at all CoE/pCoE/ARTplusCentresinonecontinuousexcelsheet(softcopyonly)
4 SL
Line list (Second line)
Cumulative list of patientsever initiatedon Second lineART
To bemaintained at all CoE/pCoE/ARTpluscentresinonecontinuousexcel sheet (soft copy only). To bemaintained at referring ART centre also after transfer back of the pa-tientafter6months.
5 5 SL
Centre wise (linked centre information) break up for PL-HIV initiated on Second line ART
LinkedCentrewisecumulativeinformationaboutPLHIV.TobemaintainedatallCoE/pCoE/ARTpluscentresinonecontinuousexcelsheet(softcopyonly)
6 CFConsent form for Second line ART
To be obtained from each patientby SACEP coordinator/data man-agerwhenstartingSecondlineART(computerprintout,signedformtobekeptinringbinderform)
Note: Out of this only SACEP register is to be printed as hard bound register as per printing instructions sent to SACS.RestaretobeusedassoftcopiesandprintoutofsoftcopiestobekeptatCoE/pCoE/ARTpluscentresinseparateringbinderfilesyear-wise.
*SL-SecondlineART**AL-AlternativeFirstlineART
All Second line treatment related formats are enclosed at Annexure IX.
1. SACEP Register (1 SL + AL)wouldbemaintainedbyallCoEandARTPluscentersthatconduct SACEP meetings. The SACEP register is a clinic administration tool whichhelpstotrackpatientsfromreferraltooutcomes,provideinformationforweeklyandmonthlyreportingtoNACO.
• The SACEP coordinator (COE)/datamanager (ART Plus Centre) is responsible formaintainingandupdatingtheregister
• Tofillintheregister,pleasenotethat:
o IthastobeprintedintheformofaregisterandallpatientswhoarereferredtoCoE/ARTpluscentreforSACEP;shouldbeenteredinthisregister
42 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
o PatientistobeenteredonlyONCEinSACEP/registerwithdetailsinsamerow.Nomultipleentriesforsamepatientshouldexist(unique)butifthepatientwasnotfoundeligibleforrevieworafterreviewitwasdecidedbytheSACEPthatitisawrongreferralthenanewSACEPnumberwouldbegiventhenexttimethepatientisreferredtoSACEP.
2. SACEP Meeting format (2 SL & 2 AL)recordsthedetailsofeverymeetingandistobemaintainedatCOE/ARTpluscentre
3. Second line monthly ART centre report (3SL + AL) -thisreportistobesentonamonthlybasistoNACObyallCoE’sandARTpluscentres.ThisreportshouldbegeneratedaftercompilationoflinelistsfromallthelinkedARTcentres.
AllCOE/ARTpluscentrewillsentmonthlyreportforalternativeFirstlineandSecondlinecombinedformatsforadultsandchildrentoNACOatSecondline2008@gmail.com latest by 4th of every monthinprescribedformat.
4. Line Lists (4SL/4 AL):AllARTcentresshouldmaintainalistofpatientsonSecondlineandAlternativeFirstlineARTinprescribedformatandsendittotheirlinkedCoE/ARTpluscentre,sothatSecondlinemonthlyARTcentrereportcanbegenerated.
5. Centre wise information (5SL)-linkedcentrewisedetailedinformationonpatientsonSecondlineshouldbeavailablewithallCoEsandARTpluscentres.
Note: Electronic copies (excel) are available for the above formats fromNACO. [email protected]
43National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ARTcenterreferspatientstoSACEP(email).DonotstopFirstlineART
Patientforre-evaluation
SendpatientbacktooriginalARTcenterwithwrittentreatmentplanandSACEPadvice
Refer back to originalARTcenter,withtreatmentplan
“Transfer-Out”
VL>400
VL<400
IfnoOIsendthepatientbacktothereferringARTcentre or else retainthepatientandrepeatviralloadatanother 6months
PatientsentforVLtests
SACEPreviewsVLresults&decidestreatmentplan
2nd line ART initiatedandcontinuedfor 6monthsatCOE/ARTPlusCentre
COE/ARTPlusCentre
(1) Informs ART center to ‘transfer out’ patient
(2)EntryintoCOE/ARTPlusCentrePreART and ART enrollment register as ‘transfer–in’;
(3)Counseltreatmentpreparedness&usecounsellingdiary
SACEP Referral form (ANNEX II) &photocopyofrelevantdocuments(courier)
Replyform, (ANNEX II)
Informsappointmenttime(email)
Labrequestform(ANNEX VII)
Patientnoteligiblefor 2nd line ART
Patienteligiblefor 2nd line ART: Returns for 2nd LineARTinitiation
6month VL and CD4
DATA FLOW
SACEP coordinator:
–Vetsreferrals&ensuredocuments/testsready
–InformARTcenterappointmentdateforSACEP
–EnterspatientdetailsintoSACEPregister (SL-1)
SACEPmeeting:
–WeeklySACEPmeetingsheets(SL-2)
–Updatedetails/decisioninSACEPregister (SL-1)
44 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
45National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Section IV: LABORATORY GUIDELINES
4.1 INTRODUCTION:
HIVinfectionhasbecomeapandemicinthelast20years.ThedynamicsoftheHIV/AIDSepidemicinIndiawillhaveamajorimpactontheoveralldiseaseburdenofHIVintheAsia-Pacificregionandtheworld.NationalestimatesindicatethatIndiahas2.1to2.09millionpeoplelivingwithHIVinfection(2011).TheoverallaverageadultprevalenceinIndiais0.27%.
Theviralloadassay(estimationofcopiesofHIV-1ribonucleicacid(RNA)inplasmaofinfectedindividuals)iscriticalinmonitoringpatients’responsetoART(Antiretroviraltherapy)andprogressiontowardsAIDS.Hence,HIV-1viralloadassaywouldbeoneofthekeyparametersforassessmentofpatientswithsuspectedtreatmentfailureonFirstlineART(whomayberequiringSecondlineART).HIV-1viralloadassayresultswillhelptoinitiateSecondlineARTatdesignatedcentersasperNACOguidelines.
Viral loadassaysquantify theamountofHIV-1RNAcirculating in thebloodofaninfected individual. Although total quantification includes cell-free virus, virus ininfectedcells inall compartmentsof thebodyaswellas integratedprovirus, theeasiest measurement of viral load is of cell-free virus in an individual’s plasma.Currentlythereisnoclinicalindicationforviralloadtestingoftissues.HIV-1plasmaviralload(PVL)levelisbeingsuccessfullyusedtopredicttimetoprogressiontoAIDSand to assessefficacyofART.During treatment, thedecayof viral load in tissuestypically corresponds with virologic responses in plasma,making blood plasma ausefulsentinelforvirologicresponseingeneral.
4.2 INTENDED USE OF HIV-1 PVL ASSAY IN NACO’S SECOND LINE ART INITIATIVE:
TheHIV-1PVLassaywillbeperformedinHIVinfectedindividualsthatfailFirstlineARTatNACOdesignatedARTsites.TheresultsofPVLassaywillbeusedtodecidetheinitiation of Second line ART.
ThePVLassaywillbeperformed:
• BeforestartingSecondlineARTtogetthereferencevaluetodecideonfurthercourseofaction.APVLmeasurementwillbeperformedonpatientsreferredbySACEP.ThedecisiononwhethertoswitchARTornotwillbemadebasedontheviralloaddetectedasdetailedbelow:
- PVL < 400copies/ml:Nochangein1st line ART
46 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
- PVL 400-5,000 copies /ml:RepeatPVLafter3monthswithstringentmonitoringofpatientforadherencetoFirstlineARTregimen
- PVL >5000 copies/ml:StartpatientonSecondlineART.RepeatPVLafter6monthstoassesssuppressioninviralload
- RepeatPVLassayat12monthsif6monthsPVLismorethan400
• Repeat PVL on the same patient must be done at the same laboratory with the same technique/procedure, using the same platform
* This must be especially noted for laboratories which are initially linked to other laboratories and likely to have their own viral load assay set ups in the near future
If treatment failure is suspected based on immunological (Second confirmation of CD4T cell levels) and/or clinical criteria, theART centremust follow theNACOprotocol formanagementasdetailedinpages19(protocolA1.1).
TheARTcentrewillsuspecttreatmentfailureinpatientswhoareonFirstlineARTforatleast6monthsandhave:
AnewOI(clinicalfailure)
SlowriseofCD4cellsorfailureofCD4cellstoriseafter6-12monthsoftreatment
DeclineinCD4cellsby50%afteraninitialrise,asperNACO/WHOguidelines
PerformCD4cellestimationimmediatelyincasesofsuspectedclinicalfailureandrepeatafter4weeksforconfirmationoffailureasperprotocolA1.1
Simultaneouslyundertakethefollowing:
o EvaluatepatientforARTadherence
o RuleoutpresenceofOIsliketuberculosis,oesophagealcandidiasis,etc.
o Ensurepatienthasbeenoncotrimoxazoleprophylaxis.
o TreatandreviewOIsifpresent.
o TheARTcentretosendtherequestformwithcompletepatientdetailsalongwiththeconfirmedcontactphonenumbertothenodalofficer.
ThenodalofficerreferssuchapatienttoStateAIDSClinicalExpertPanel(SACEP)atCOEsand/orARTplusCentresfordecisiononHIV-1viralloadtesting.
Eligibility
AllHIVpositivepatientsshowingsignsoffailureonFirstlineARTwillbeeligibleforreviewbySACEPfollowingtheproperreferralproceduresfromtheARTcentres:
47National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
State-wiselistofCoEsandARTpluscentres
State COE*/ART Plus centre
Tamilnadu GovernmentGeneralChestHospital(GGCH),Tambaram*GovernmentMohan Kumaramangalam Medical College, Salem MaduraiMedicalCollege,MaduraiTirunelveliMedicalCollege,Tirunelveli
Maharashtra GrantGovt.MedicalcollegeandSirJJHospital,Mumbai*Govt.MedicalCollege,AurangabadGovernmentMedicalCollege,Sangli,MaharashtraB.J.MedicalCollege&SassoonHospital,PuneGovt.MedicalCollege,Nagpur
Gujarat B.J.MedicalCollege(BJMC),Ahmadabad*Govt.MedicalCollege,MajuraGate,SuratPanditDindayalUpadhyayHospital,Rajkot
Karnataka BowringandLadyCurzonHospital,Bangalore*KarnatakaInstituteofMedicalSciences,Hubli,KarnatakaVijayanagaraInstituteofMedicalSciences,Bellary,KarnatakaDistrictHospital,Gulbarga,KarnatakaDistrictHospital,Udupi,Karnataka
AndhraPradesh GandhiHospitalandMedicalCollege,Hyderabad*GovernmentGeneralHospital,Vijayawada,AndhraPradeshRajivGandhiInstituteofMedicalSciences,Kadappa,AndhraPradeshKingGeorgeHospital,Visakhapatnam,AndhraPradesh
WestBengal SchoolofTropicalMedicine(STM),Kolkata*
NewDelhi MaulanaAzadMedicalCollege(MAMC),NewDelhi*
Kerala Govt.MedicalCollege,Trichur
Assam MedicalCollegeandHospital,Guwahati
Manipur RegionalInstituteofMedicalSciences(RIMS),Imphal*
Bihar RajendraMemorialResearchInstituteofMedicalSciences,Patna
MadhyaPradesh GandhiMedicalCollege,Bhopal,MadhyaPradesh
Rajesthan SawaiManSinghMedicalCollegeandHospital,Jaipur
UttarPradesh KingGeorgeMedicalCollege,Lucknow
Mizoram CivilHospital,Aizwa
Punjab GovernmentMedicalCollege,Amritsar
Panjab/Haryana PostGraduateInstituteofMedicalEducationandResearch(PGI),Chandigarh*
UttarPradesh InstituteofMedicalSciences(BHU),Varanasi*
Uttaranchal DoonHospital,Dehradun
Jammu&Kashmir GovernmentMedicalCollege,Jammu
Orissa ShriramaChandraBhanjMedicalCollege,Cuttack
13moreARTpluscentreshavebeensanctionedsoastohaveatleastoneARTpluscentreineachstatetoprovideSecondlineART
48 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
NOTE:Bloodisnottobedrawnforaviralloadtestwithinfourweeksofanyinfectionorimmunization.
Protocol for the review panel
TheSACEPwillreviewthecasenotesalongwiththepatient.
Thepanelwillthenorderaviralloadtestifrequired.Specimens(wholebloodandDBS)willbecollectedfromthepatientattheCOEonadesignateddayandsenttotheidentifiedviralloadlabasdetailedbelowinthesectiononspecimencollection,storageandtransport.TheSACEPwillmeetonthefollowingdesignatedday(whichifhappenstobeaholidaythenonthenextworkingday)toreviewtheresultsofviralloadassayand,basedontheresultofPVL,decideonfurthermanagementofthecase.
4.3 TECHNIQUES OF HIV – 1 PVL ASSAY:
ViralloadassaysmeasuretheamountofHIV-1RNAinthecollectedplasmaspecimen.HIV-1RNAisresponsibleforHIVreplication.TheamountofHIV-1RNAinplasmacanbemeasuredbythefollowingdifferenttechniquesformeasurementofHIV-1RNA.
Quantitative PCR (polymerase chain reaction) is themost frequently used test.ForPCRtheviralRNAisextracted;anenzymeconvertstheextractedRNAtoDNA(cDNA);thisDNAisthenmultipliedmanyfoldsbythehelpofanenzymepolymerase;theproductisdetectedthroughchangesintheintensity/colorofcertainchemicalmarkers.ThisprocessmakesthedetectionofviralRNAeasier.TheoriginalnumberofRNAcopieswouldbethenquantifiedbasedonthefinalnumbersofcDNAobtained.TestresultsarereportedasHIV-1RNAcopies/ml.
The bDNA (branched DNA) isafairlyfrequentlyusedtest. Itmakesuseofsignalamplification (lightemittingmaterial). Thismaterialbindswith theHIVparticles.Theamountoflightismeasuredandconvertedtoaviralcount.
NASBA (Nucleic Acid Sequence Based Amplification Assay) is an in vitro nucleic acidamplificationtestforquantificationofamplifiedHIV-1RNAwhichismeasuredbymeansofelectrochemiluminescence.
The PCR test results are often different from the bDNA results for the same specimen. Because the tests are different, only one kind of test (PCR or bDNA) should be used to measure a person’s viral load over time.
ViralloadassayresultsarereportedascopiesofHIV-1RNAinonemilliliterofblood.ThebestviralloadassayresultinpatientsonARTis“undetectable”viralload.Thisdoesnotmeanthatthereisnovirusintheblood;itjustmeansthatthelevelisnotenoughtobedetectedthroughthetestused.“Undetectable”level(Noofcopies/mlofplasma)willdependonthesensitivityoftheassaysystemused.
49National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Some relevant terminologies
Sensitivity: Sensitivityisdefinedasthelowestviralloadlevelthatcanbedetectedinthespecimen95percentofthetime.Thestatisticalmethodofassessingsensitivityisgenerallyconsideredtobethestandardtodeterminethequantitative“limitofdetection”(LoD)forquantitativeHIV-1RNAassays
Precision: Theprecisionor reproducibility of an assay is definedby its ability toobtainthesamevaluewhentestedrepeatedly.Inviralloads,precisionismeasuredbytheabilitytodetect“foldchanges”inthelevelsoftheviralloads.
Dynamic Range: Thedynamicrangeofanassayisdefinedasthequantitativerangeoverwhichtheresultsarereliablyreported.
4.4 PLASMA VIRAL LOAD ASSAYS CURRENTLY IN USE IN NACO’S SECOND-LINE ROLL OUT:
4.4.1 AMPLICOR HIV-1 MONITOR TEST, VERSION 1.5
TheAmplicorHIV-1MonitorTest,version1.5(v1.5)isanin vitronucleicacidamplificationtestforthequantificationofHumanImmunodeficiencyVirusType1(HIV-1)RNAinhumanplasma.TheAmplicorHIV-1Test, version1.5usesPCR technology toachievemaximumsensitivity anddynamic range for thequantitativedetectionofHIV-1RNA inEDTAanti-coagulatedplasma.
TheAmplicorHIV-1Monitorversion1.5(v1.5)isprogrammedon,andapprovedforuseonAppliedBiosystemsGene-AmpPCR system9600/9700 thermal cycler. InAmplicorHIV-1monitorthespecimenpreparation ismanual, theamplification isautomatedontheABI9600/9700anddetectionisbymanualELISAorautomatedELISAreader.
The test can quantitateHIV-1 RNAover the range of 50-750,000 copies /ml by using acombination of two specimen preparation procedures, the Standard (dynamic range 400-750,000 copies /ml) and Ultra Sensitive (dynamic range 50-1,00,000 copies/ml)procedures.Testresultslessthan400arebelowthelowerlimitofdetectionoftheStandardtest. If quantitative results are desired for such specimens, original plasma specimensshouldberetestedusingtheUltrasensitivespecimenpreparationprocedure
This test is based on five major processes: specimenpreparation, reverse transcriptionoftargetRNAtogeneratecomplementaryDNA(cDNA);PCRamplificationoftargetcDNAusing HIV-1 specific complementary primers; hybridization of the amplified products tooligonucleotideprobesspecifictothetarget(s);anddetectionoftheprobeboundamplifiedproductsbycolorimetricdetermination.
TheAmplicorHIV-1MonitorTest,v1.5canbeusedwitheitheroftwospecimenpreparationprocedures, the Standard procedure or the Ultra Sensitive procedure. In the Standardspecimen preparation procedure,HIV-1 RNA is isolated directly fromplasmaby lysis ofvirusparticleswithachaotropicagentfollowedbyprecipitationoftheRNAwithalcohol.WiththeUltraSensitivespecimenpreparationprocedure,HIV-1viralparticles inplasma
50 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
areconcentratedbyhighspeedcentrifugation,followedbylysisofthevirusparticleswithachaotropicagentandprecipitationoftheHIV-1RNAwithalcohol.Aknownnumberofquantitation standard RNAmolecules are introduced into each specimenwith the lysisreagent. The HIV-1Quantitation Standard is carried through the specimen preparation,reversetranscription,amplificationanddetectionstepsandisusedforthequantitationofHIV-1RNAinthetestspecimen.
4.4.2 COBASAMPLICOR HIV-1 MONITORTM TEST, VERSION 1.5
The CobasAmplicor HIV-1 Monitor Test, version 1.5 (v1.5) is an in vitro nucleic acid amplification test for thequantitationofHuman ImmunodeficiencyVirusType1 (HIV-1)RNAinhumanplasmaontheCobasAmplicorTManalyzer.
InCobasAmplicorthespecimenpreparationismanualandtheamplificationanddetectionstepsareautomated.
The test can quantitate HIV-1 RNA over the range of 50-750,000 copies/mL by using acombinationoftwospecimenpreparationprocedures,theStandard(dynamicrange400-750,000copies/ml)andUltraSensitive(dynamicrange50-100,000copies/ml)procedures.Test results less than400arebelowthe lower limitofdetectionof theStandardtest. Ifquantitativeresultsaredesiredforsuchspecimens,originalplasmaspecimensshouldberetestedusingtheUltrasensitivespecimenpreparationprocedure.
This test is based on five major processes: specimenpreparation; reverse transcriptionoftargetRNAtogeneratecomplementaryDNA(cDNA);PCRamplificationoftargetcDNAusing HIV-1 specific complementary primers; hybridization of the amplified products tooligonucleotideprobesspecifictothetarget(s);anddetectionoftheprobeboundamplifiedproductsbycolorimetricdetermination.
The CobasAmplicor HIV-1Monitor Test, v1.5 can be usedwith either of two specimenpreparationprocedures,theStandardprocedureortheUltraSensitiveprocedure.IntheStandardspecimenpreparationprocedure,HIV-1RNAisisolateddirectlyfromplasmabylysisofvirusparticleswithachaotropicagentfollowedbyprecipitationoftheRNAwithalcohol.WiththeUltraSensitivespecimenpreparationprocedure,HIV-1viralparticlesinplasmaareconcentratedbyhighspeedcentrifugation,followedbylysisofthevirusparticleswithachaotropicagentandprecipitationoftheHIV-1RNAwithalcohol.AknownnumberofquantitationstandardRNAmoleculesareintroducedintoeachspecimenwiththelysisreagent. The HIV-1Quantitation Standard is carried through the specimen preparation,reversetranscription,amplificationanddetectionstepsandisusedforthequantitationofHIV-1RNAinthetestspecimen.
4.4.3 COBAS TAQMAN HIV-1 TEST
TheCOBASTaqManHIV-1Testisanin vitro nucleicacidamplificationtestforthequantitationofHumanImmunodeficiencyVirusType1(HIV-1)RNAinhumanplasmawithEDTA,usingtheHighPureSystemViralNucleicAcidKitformanualspecimenpreparationandtheCOBAS
51National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
TaqMananalyzerforautomatedamplificationanddetection.ThetestcanquantitateHIV-1RNAovertherangeof47-10,000,000copies/ml
The COBAS TaqMan HIV-1 Test utilizes real time PCR technology to achieve maximumsensitivity anddynamic range for thequantitativedetectionofHIV-1RNA inEDTAanti-coagulated plasma. The use of dual-labeled fluorescent probes provides for real-timedetection of PCR product accumulation by monitoring of the emission intensity offluorescentreporterdyesreleasedduringtheamplificationprocess.TheCOBASTaqManHIV-1Testaccuratelyprovidesquantitativeresultsoveraverywidedynamicrangesincethemonitoringofamplicon isperformedduringtheexponentialphaseofamplification.ThehighertheHIV-1titerofaspecimen,theearlierthefluorescenceofthereporterdyeoftheHIV-1proberisesabovethebaselinefluorescencelevel.
The COBAS TaqMan HIV-1 Test is based on four processes: Specimen preparationto obtain HIV-1 RNA; Automated reverse transcription of the target RNA to generatecomplementaryDNA(cDNA);SimultaneousPCRamplificationoftargetcDNAusingHIV-1specific complementary primers; and detection of cleaved dual fluorescent dye-labeledoligonucleotidedetectionprobes.
TheCOBASTaqManHIV-1TestprocessesEDTAcontainingplasmaspecimensandisolatesHIV-1 RNA through a generic manual specimen preparation (in case ampliprep is notavailable)basedonnucleicacidbindingtoglassfibers.TheHIV-1virusparticlesarelysedbyincubationatanelevatedtemperaturewithaproteaseandchaotropiclysis/bindingbufferthatreleasesnucleicacidsandprotectsthereleasedHIV-1RNAfromRNAs inplasma.AknownnumberofHIV-1‘QuantitationStandardArmored’RNAmoleculesareintroducedinto each specimenalongwith the lysis reagent. Subsequently, isopropanol is added tothe lysismixturewhich is then centrifuged through a columnwith a glass fiber insert.Duringcentrifugation,theHIV-1RNAandHIV-1QuantitationStandardRNAareboundtothesurfaceoftheglassfiberfilter.Unboundsubstances,suchassalts,proteinsandothercellularimpurities,areremovedbycentrifugation.Theadsorbednucleicacidsarewashedandelutedwithanaqueoussolution.Thedisposablesallowforaparallelprocessingof12specimensormultiplesthereof.Theprocessedspecimen,containingHIV-1RNAandHIV-1QuantitationStandardRNA,isaddedtotheamplification/detectionmixture.TheHIV-1targetRNAandtheHIV-1QuantitationStandardRNAarethenreversetranscribed,amplifiedanddetectedontheCOBASTaqMan-analyzerusingtheamplificationanddetectionreagentsprovidedinthetestkit.
4.5 SPECIMEN COLLECTION, STORAGE, AND TRANSPORTATION:
4.5.1 COLLECTION DAYS AND TIMINGS
Specimencollection is tobedonebetween11.00A.M to1:00PMonSACEPdayasdecidedbythecentre.
52 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Incasethespecimencollectiondayisaholiday,specimencollectionistobepostedonanalternatedaywithpriorarrangementwiththereceivinglaboratory.
Donot collect specimen if nextday to SACEP is aholiday (as specimenshave tobeprocessedforHIV-1PVLbythereceivinglaboratorywithin24hoursofcollection)
Previousarrangementwithtestingcentretobemadeincasethespecimenistobecollectedonadaynotscheduledforthepurpose(Collectionandtransportofspecimen)
4.5.2 SPECIMEN COLLECTION
Standardworkprecautionsaretobefollowedstringently
Page 1 of theVL-1 form (as perAnnex VII) is to be filledmandatorily induplicate/photocopy.(Specimensaccompaniedwithincompleteformswillberejected)
ConfirminformationonVL-1form(patient’sname,registration/accessionnumber,testneeded, date and time of collection, and physician’s/clinic’s name, etc)mandatorilybeforecollectionofspecimens
SterileEDTA(lavendertop)evacuatedbloodcollectiontubesaretobeused.
Thebloodcollectiontubesaretobelabeled (cryolabel)withpatient’sname,registration/accession number, test needed, date and time of collection, and physician’s/clinic’sname. The informationon the form shouldmatch the informationon the specimencollection tube
4ml blood is to be collected and placed in prescribed sterile tubes using EDTA(lavendertop)astheanticoagulant.Do not collect blood in heparin vials. (Thechoiceofanticoagulantusedinbloodcollectiontubescansignificantlyalterviralloadresults,byaffectingeithertheviriondecayrateex vivoorthedetectionbytheassaytypeused.PlasmatreatedwithsodiumheparinisnotappropriateforPCRassaysbecauseheparinisapotentinhibitorofPCR)
In case the linked HIV-1 PVL laboratory is in a different city, Dried Blood Spot (DBS) Preparation and Storage (as per Section 4.13) and then plasma separation (as per below) are to be performed by the ART Centre itself.
In case the linked laboratory is in the same city or same hospital, DBS Preparation and Storage (as per Section 4.13) and then plasma separation (as per below) are to be performed by the PVL laboratory within 6 hours of receipt of specimen.
4.5.3 PACKAGING AND TRANSPORTATION
All specimens will be transported by hand by lab technicians of the centre ofexcellence
53National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Thespecimenistobepackagedcarefullytoprotectfrombreakage,andleakageandinsulatedtoprotectfromextremetemperature.Coolpacksaretobeusedtomaintaintemperatureof2-80C.Ensurewholeblooddoesnotfreezeduringtransportation.
Forpackaging,thetubecontainingthespecimenisplacedinaleakproofcontainer(e.g.asealedplasticbag).
Thecoolpacksaretobeplacedaroundandthepackageistobeplacedinsideapunctureproof containerwith sufficientmaterial to absorb all the contents in case the tubebreaks or leaks.
Capthecontainertightly.
PlacetheVL-1forminanenvelopeandfastensecurelytotheoutsideofthecontainer.
Abiohazardlabelshouldbepastedonthevisibleoutersurfaceofthepackagecontainingthespecimens.
Incasethelaboratoryislocatedinthesamecity:TheLabtechnicianoftheARTcentreshouldtransportthespecimenwiththeVL-1forminduplicateandensuredeliverytothetestinglabofthewholebloodspecimenat2-8oCwithin3hoursofcollection(i.e.by2.00P.M.onMonday/Tuesdayafternoon).
Incasethelaboratoryislocatedinadifferentthecity:TheLabtechnicianoftheARTcentre should transport theplasma specimen (First having prepared, packaged andstoredDBS;andthenseparatedtheplasmaattheARTcentre)withtheVL-1forminduplicateandensuredeliverytothetestinglaboftheplasmaspecimenat2-8oCwithin24hoursaftercollection(i.e.by10AM.onTuesday/Wednesday).
ThetechnicianfromthecentreofexcellencecarryingthespecimensmustparticipatewiththetechniciansatthePVLlaboratoryintheprocessesofestimationofHIV-1PVLinordertolearnthetechniquesinvolved.
The DBS samples will be collected and stored as per section 4.13. It is recommended that the DBS samples be stored at 2-8oC for 20 days and then be couriered to NARI, Pune along with the consent forms. It is important to note that the consent form must be sent to the lab making DBS in case of intercity linkages for sending to NARI, Pune. The details on the envelope may be as follows:
For Second Line roll out
Dr R Paranjape
National AIDS Research Institute (NARI)
73 G Block, MIDC
Bhosari, Pune-411026
Maharashtra, India
54 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
4.5.4 RECEIVING SPECIMEN AT THE HIV-1 PVL TESTING LABORATORY
Receivinglabtoidentifythespecimenproperly.Ifthereisdiscrepancyinthetestrequisitionformversusthelabeledtube,DO NOT PROCEED.Takecorrectiveactiontoensurethatthepatient’snameandnumberontherequestformarecorrect.Incaseofanyconfusioncheckbackwiththecollectionsite.
Receiving lab to checkand therebyensureat the timeof specimen receipt that thetemperatureofthespecimenneverexceeded8°Candthewholebloodspecimenwasnotfrozen,duringstorageatthecollectionsiteandtransporttothetestingsite.Leakageisalsocheckedfor.
In case,of anydoubt sendback the specimenandVL-1 formback to theCOE,dulysignedbylabin-charge,withtheCOEtechnician.Anotherspecimenmustbecollectedfor PVL.
ThereceiptofthespecimenstobedulydocumentedonboththecopiesoftheVL-1.
Incasespecimenisrejected,onecopyoftheVL-1formwithsignaturesoflabinchargetobesentbackwiththecenterofexcellencetechnicianbyhandonthesameday.
Receivinglabtorecordthetime/dateofspecimenreceipt.
Do not freeze whole blood. Do not storewhole blood formore than 6 hours aftercollection-evenattemperaturerangeof2-25° C.Plasmaatthereceivinglabhastobeseparatedfromthewholebloodwithin2hoursofspecimenreceipt,within6hoursofspecimencollection(i.e.by4.00P.M.onthesamedayMonday/Tuesday).
4.5.5 PROCESSING OF THE WHOLE BLOOD SPECIMEN IN THE RECEIVING LAB:
AfterpreparationofDBS, theremainingwholebloodspecimen isbecentrifuged forseparationofplasmaasdetailedbelowandprocessedfurtherforestimationofHIV-1PVLaspertheinstructionsofthemanufacturerofthekitbeingused.
o Separationofplasmafromwholeblood:
• Centrifugewholebloodat800-1600xgfor10minutesatroomtemperature.
• Removetheplasmaandrecentrifugeat800xgforanother10minutes.
• Aliquot and store 800-900µl of plasma in a sterile 2 ml polypropylene screw-cappedtube.
• In caseof inadvertentdelay,plasmaspecimen tobeseparatedandstoredat2-8°Covernightandtransportedto thetestingsitenextmorningat2-8°C forperformanceof the teston thesameday (tobeprocessed forPVLwithin24hoursaftercollection).
• Plasmaspecimenistobekeptat2-8°Ctillprocessed.
55National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
• Receivinglabmustprocessthespecimenwithin24hoursafterspecimencollection.
• The plasma specimen must be brought to ambient temperature beforeperformingthetestasperthemanufacturer’sprotocol.
o PerformPVLassayaspermanufacturersprotocolontheavailableplatform
4.6 FACTORS TO BE CONSIDERED WHILE INTERPRETING THE VIRAL LOAD RESULTS:
TheHIV-1PVLquantificationassayisinfluencedbymanyfactors.Thustheinterpretationofabsoluteviralconcentrationmeasurementresultsisnotstraightforward.Oneimportantissue to consider iswhethermeasured change in viral loadactually reflects abiologicalevent,orwhether thechange iswithin thevariability limitof theassay.Repeat testsofthe sameblood specimencangive results that varybya factorof3. Thismeans thatameaningfulchangewouldbeadroptoless than 1/3 or an increase to more than 3 times thepreviousviralloadresult.Forexample,achangefrom200,000to600,000iswithinthenormalvariabilityofthetest.Adropfrom50,000to10,000wouldbesignificant.However,themost importantchange inapatientrespondingwell/optimallytoART isreachinganundetectableviralloadlevel.
There is a considerable variation in the results of various types of assays used inquantification of the same specimen but if performed proficiently, a commercial assayshows reproducibilitywithin approximately 0.2-0.5 log10, (varying in different regions oftheassays’dynamicrange).Dailyvariationinviralloadsamongclinicallystablepatientsisminimalatapproximately0.4log10.Thereforeachangeinviralload,greaterthan0.5log10 RNAcopies/ml (approximately3-fold),exceedsassayanddiurnalvariations,andmaybeconsideredtorepresenttruebiologicalevents,whilechangesoflessthan0.5log10 cannot be distinguished whether these are from random variability or a biological event. It isimportanttonotethatinthelowendofthedynamicrange,assayvariabilityhasgreaterimpactoninterpretationofabsoluteviralloadchange.
How are the changes in viral load measured?
Viralloadchangesareoftendescribedas“log”changes.Thisreferstoscientificnotation,whichusespowersof10.Forexample,a2-logdropisadropof102or100times.Adropfrom60,000to600wouldbea2-logdrop.Smallchangesof10,20,30copiesareoftennotconsideredtobeasignificantchangeinviralloadandcanreflectnormalviral“blips,”notachangeintreatmentresponse.
What do the numbers mean?
ItisnotknownhowlongaHIVpositivepatientwouldstayhealthywithanyparticularviralload.AllthatisknownsofaristhatlowerPVLisbetterandseemstomeanalonger,healthierlife.Theviralloadshoulddroptoreachlessthan50copieswithin6monthsofART.EvenwhentheHIV-1viralloadinaHIVpositiveisundetectable,theHIVviruscanbepassedon
56 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
toanotherperson,althoughtheriskislower.Thereisno“safe”levelofviralload.
4.7 LIMITATION OF VIRAL LOAD ASSAYS:
RNA assays used tomeasure PVL are perhapsmost heavily relied upon in themedicalmanagementofpeoplediagnosedwithAIDSandinpeoplewhotestpositiveontheHIV-1antibodytests.Asmanyimportantclinicaldecisionsarebasedonthesetests,thehigheststandardsofsensitivityandspecificityarerecommended.Therearehoweversomeconcernswiththeviralloadtestsasgivenbelow:
Intra-assayandbiologicvariabilitymayaffectthefindings.
Theviralloadtestresultscanbeunreliableifthebodyisfightinganinfection,orifthepatienthasjustreceivedanimmunization.Bloodshouldnotbetakenforaviralloadtestwithinfourweeksofanyinfectionorimmunization.Temporaryincreasesin viral load havebeen seen in these instances. Also, the physicianmust reviewthepatient’sadherencetotheARTregimenandshouldpostponetestingifrecentdosesofARThavebeenmissedthatmaycauserapidreplicationofHIV,in vivo.SuchpatientsmayalreadybeexperiencingviralreboundandtheirARTtherapycouldbeincorrectlyjudgedtobefailing.
AdrawbacktoPVLtestingisthehighcostofassaysandrequirementoftechnicalexpertise.
4.8 STANDARDIZATION OF HIV-1 PLASMA VIRAL LOAD REPORTING:
Laboratory reports of viral load assays should be standardized, accurate and adequatefor patient treatment and public health monitoring of the HIV infection and acquiredimmunodeficiencysyndrome(AIDS)epidemic.Toensuretestreportcomparabilityamonglaboratories,standardtestingandreportingmethodsareneeded;moreover,standardizedresults are needed for early detection of treatment failure and early access to patientcare.
Required items to report
ThelaboratoryshouldcompletelyfilloutthereportfoundinAnnexVII(atod),aspertestingplatform.
ItshouldbedulysignedintheVL-1reportingformat(SeeAnnexVII(atod))
ItshouldbesentfromthelabtotheARTcentrebycourierbySaturdaytoreachtheARTcentrelatestbyMonday.Thecourierwillbepaidfromthecontingencygrant.
Acopyofthereportshouldbee-mailedtoNACObySaturdayatdrbbrewari@yahoo.com and [email protected]
57National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
4.9 QUALITY ASSURANCE FOR HIV-1 PLASMA VIRAL LOAD TESTING:
Viral load testing is an integral part of themanagement ofHIV disease. It is absolutelyimperative to ensure the accuracy, precision and reproducibility of the test results byadheringtostringentQualityAssuranceandQualityControlmeasuresatalltimes.
QualityAssuranceisdefinedasasetofplannedandsystematicactivitiestoensureadequateconfidencethatrequirementsforqualitywillbemet.
InternalQualityControl refers tothosemeasuresthatmustbetakentoensurethat thetestisworking,thetechnicalaspectsofthetestprocedurehavebeenmet/followedandtheresultsproducedarevalidwithinthelimitationofthetestsystemused.LaboratoriesperformingHIV-1Viralloadquantificationneedtouseexternalqualitycontrolspecimensinadditiontothecontrolscontainedintestkitsforvalidationoftheresult.
Itisrecommendedthatahighpositivecontrol,lowpositivecontrolandanegativecontrolthatcomewiththetestkitsbeincludedwitheachrun.Thecopynumberpermlforeachpositiveresultshouldfallwithintherangeofvalues indicatedinthepackageinsert.Thenegative control should give a less than the lower detection limit result. If controls arenotasexpected, therun isnotvalidand is toberepeated.Thesecontrols shouldmeettheprescribed regulatory requirements for such controls. It is good tohave traceabilitytointernationalreferencestandards.Useofabovetestcontrols,thatareusedtovalidatea test runand toquantitateHIV-IRNA,wouldhowevernotvalidate theanalytic testingprocesswhichmayincludetestingproblemsrelatedtopipetting,inadequateincubationorwashingorvariabilityinkitlotsensitivity.
4.9.1 INVALID TEST RUNS
Wheninvalidpositiveornegativeresultsareobtainedonrunninginternalcontrols,therunisdeclaredinvalidandtheentiretestprocedureforallthespecimenshastoberepeatedinanotherrunbyprocessinganotheraliquotoftheoriginalplasmaspecimens.
Flagsandcommentsmaybegeneratedbytheanalyzerduringtherun.Theoperatormustchecktherunprintout(s)forflagsandcommentstoverifythattherunisvalid.
Withtheexceptionof instrument failuressubsequent to thedenaturationofamplicons,an instrument failure during a test run as indicated by the system errormessages alsoconstitutesaninvalidtestrun.
4.9.2 INTERNAL QUALITY CONTROL (ASSAY CONTROLS-PART OF THE SYSTEM)
Controls are supplied by the manufacturer and are to be processed like patientspecimens.Alowpositive,highpositiveandanegativecontrolaresuppliedwiththekit.Runcontrolstocheckaccuracyandreproducibility.
All quality control failures must be logged and corrective action completed beforespecimenanalysistakesplace.
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Allreagentsusedmustbeloggedontologsheetswiththedateopened,expirydateandsignature.Reagentsdiscardedduetocontamination,spillage,etc.mustbeloggedintheappropriatelogsheets.
Reagentsmustbestoredasrecommendedbythemanufactureranddailytemperaturelogsshouldbemaintained.
ResultsshouldbeenteredontoLevy-Jenningsplotstomonitoranytrends,shiftsorbiasin results.
4.9.3 EXTERNAL QUALITY ASSESSMENT
Every testing facility must be able to demonstrate and document its competence inperforming the tests. External quality assessment (EQA) is an evaluation by an outsideagency of the performance of a laboratory on specially supplied small panels of wellcharacterized specimens. The objective is to achieve between-laboratory and between-methodcomparability.
4.9.4 OBJECTIVES OF EQAS
Theprimaryobjectiveistocontinuallyimproveandmaintainthehighstandardofthelaboratory’sperformance,
Tocontinuallyinstituteaformalmonitoringandevaluationprogramme,
Tocontinuallypromotetheconceptofqualityassurance,qualitycontrol,andqualityassessmentinthelaboratory,
Toassessthequalityofserviceoftheparticipatinglaboratory,
Toidentifyproblemsandtakeappropriateinterventionsforcorrectiveactions,
Toencouragetheimplementationofgoodlaboratorypractices,and
Toprovideteachingandtrainingprograms.
Participationinexternalqualityassessment(EQA)isnotasubstitutetodaytodayinternalqualitycontrolpractices.EQAisdesignedtoassesstheintegrityoftheentirelabtestingprocess.Evenwhenallprecautionshavebeentakentoachieveaccuracyandprecisioninthelaboratory,errorsmayarisewhichmaybedetectedbyobjectiveexternalassessment.Theprincipleisthattheassessedmaterial(valuesareknown)issentfromaninternational,national or regional centre to a large number of participating laboratories at regulardesignatedintervals.Theresultsproducedbytheparticipatinglaboratoriesareassessedforaccuracy,precisionandreproducibilityinaconfidentialmannerbythelabconductingEQA.Thelabsproducinginaccurateresultsarerevampedthroughtrainingandtroubleshooting.
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TheEQASessentiallycontainsthefollowingcomponents:
Filling up questionnaire to understand the laboratory capabilities and additionalrequirements
TrainingforviralloadestimationprocedureandparticipationinEQAS
ProcessingofthespecimensreceivedunderEQASfollowingtheroutineprocedureofviralloadestimation
SubmissionofreporttotheEQAconductinglaboratory
Doinganalysisofresults,assessmentofperformanceandtroubleshooting
4.9.5 EQA FOR HIV-1 PLASMA VIRAL LOAD TESTING
TheNACOdesignatedlaboratoriesthatwillinitiate/performHIV-1PVLtestingforSecondlinerolloutaretoparticipateinEQAbeingconductedbythecentrelistedbelowforthetime being:
RCPA(RoyalCollegeofPathologistsAustralasia)QualityAssuranceProgramme
RCPA Quality Assurance Programmes Pvt Ltd was established by the Royal College ofPathologistsofAustralasiain1988andisprovidingtheEQAservicestoover40countriesand4,000programsaroundtheworld.RCPAQualityAssuranceProgramPvtLimitedisaNATA (National Associated Testing Authority, Australia) accredited Proficiency Testingprovider forHIV-I RNAViral load and complieswith the requirementsof ILACG13. ThedetailsforEQAaregivenatAnnex-VIII
4.10 OPERATIONAL PLAN FOR HIV-1 VIRAL LOAD TESTING AND EQAS
It is proposed that HIV-1 viral load testing facilities for the National HIV/AIDS care andtreatmentprogrammewouldinitiallybesetupatselectcenters.TheNACOlabsthathavebeenidentifiedtoinitiateandperformHIV-1PVLtestingforspecimensbeingsentbytheNACOidentifiedSecondlinecentresare:
KasturbaHospitalforInfectiousDiseases,Mumbai
TuberculosisResearchCentre(TRC),Chennai
InstituteofHumanBehaviorandAlliedSciences(IHBAS),NewDelhi
NationalInstituteofCholeraandEntericDiseases(NICED),Kolkata
GandhiHospitalandMedicalCollege,Hyderabad
60 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
StJohn’sHospital,Bangalore
PostGraduateInstituteofMedicalEducationandResearch(PGIMER),Chandigarh
InstituteofMedicalSciences(BHU),Varanasi
BiramjeeJeejeebhoyMedicalCollege(BJMC),Ahmedabad
RegionalInstituteofMedicalSciences(RIMS),Imphaland
NationalAIDSResearchInstitute(NARI),Pune
NACOhascreatedthefollowinginterimlinkagesuntilallthedesignatedHIV-1PVLtestingcentresbecomeoperational:
The above linked centres, both the COEs and the testing labs, should coordinate theircollectiondaysandtimessothatviral loadspecimensthatarebeingsentfromdifferentcentres to thesame labcanbecoordinated tobeprocessed togetheron thesameday,ensuringtheefficientuseofviralloadreagentsandlaboratorytime.
ItisproposedtoidentifytheeligiblepatientsafteradetailedexaminationbytheSACEP.TheSACEPmeetingwillbeheldonMonday/Tuesday(oranydesignatedday)morningbetween9:00AMto11:00AMdependingontheconvenienceoftheinstitution.EligiblecandidateswillbesubjectedtoHIV-1PVLtestingbeforeSACEPtakesthedecisiontoinitiateSecondline ART.
Bloodspecimen (4ml)willbecollected inanEDTAvacuumevacuated tube immediatelyafterSACEPmeetingandprocessedasgivenbelow:
• IncasethePVLtestinglabisinthesamecityastheCOE:wholebloodspecimenistobetransportedtothePVLtestinglabat2-8oCwithinamaximumof6hoursaftercollection
• IncasethePVLtestinglabisinadifferentcityastheCOE:thelaboratorytechnicianattheCOEwillprepare,package,andstoretheDBS(Section4.13)andseparatetheplasma (asdetailedabove)within2hoursafter specimencollection.Theplasmaspecimen will be stored at 2-8oC until transported by the COE technician. ThespecimenwillbehandcarriedbytheCOEtechnicianfromCOEtothePVLtestinglaboratoryasdetailedabove.TheCOEmustensurethatthelabtechniciancarryingthespecimensmustleavetheCOEthatsameday.
• FrequencyandprocessingofspecimenandtransportdetailswillbeasdetailedinTable1
• OncethespecimenshavebeenreceivedatthePVLtestinglab,estimationofHIV-1PVLmustbedonewithin24hoursafterthespecimenwascollected.
• ThePVLtestinglabmustcourierbackthetestreportstothecorrespondingCOEbytheweekend.Costofthesamewillbemetfromcontingencygrant.
To ensure the quality of the testing on a daily basis and to ensure that all labs meet
61National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
internationaltestingstandards,thesecenterswouldparticipateinEQASforHIV-1viralloadtesting.AnattemptisbeingmadetoprovideEQASspecimenstoalltheNACOidentifiedtestinglabsforHIV-1PVLtesting.Alllabsmustparticipateandprovidenecessarycooperationforimplementingthesame.
The details of the EQAS process flow have been annexed at the end of the laboratory guidelines for VL testing.
4.11 PRECAUTIONS AND SPECIFIC INSTRUCTIONS FOR REAGENTS AND EQUIPMENTS:
4.11.1 GENERAL
Viralloadassayisforin vitro measurement of plasma HIV-1 RNA copies and is not for diagnostic use
Treatall specimensaspotentially infectious.AdheretoStandardWorkPrecautionswhenperformingtheassay.
Onlypersonneltrainedinhandlinginfectiousmaterialshouldperformthisprocedure
Screwcappedtubesmustbeusedforprocessingspecimensandcontrolstopreventsplashing and potential cross-contamination of specimens or controls. Do not use snap-cap tubes.Handleallspecimensorcontrols inaccordancewiththeGoodLabPracticesinordertopreventcross-contamination
Donotpipettebymouth.
Donoteat,drinkorsmokeinlaboratoryworkareas.Wearprotectivedisposablegloves,laboratorycoatsandeyeprotectionwhenhandlingspecimensandkitreagents.Washhandsthoroughlyafterhandlingspecimensandkitreagents
Avoidcontactofthesematerialswiththeskin,eyesormucousmembranes.Ifcontactdoesoccur, immediatelywashwith largeamountsofwater.Burnscanoccur if leftuntreated.Ifspillsofthesereagentsoccur,dilutewithwaterbeforewipingdry.
Avoidcontaminatinggloveswhilemanipulatingspecimens
Specimensandcontrolsshouldalwaysbepreparedinthelaminarflow-failuretodosomayresultinspecimencontamination
HandleandmanipulatespecimensinaClassIIBiologicalSafetyCabinet
Thoroughlycleananddisinfectallworksurfaceswithafreshlypreparedsolutionof0.5%sodiumhypochloriteandfollowbywipingdownthesurfacewith70%ethanol.
Anydeviationsfromthespecifiedproceduresandguidelinesmayaffectoptimalassayperformance.
62 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ThistestisforusewithhumanplasmacollectedinEDTAanticoagulantsonly.Heparin has been shown to inhibit PCR and must not be used with this procedure.
4.11.2 REAGENTS STORAGE AND USE
Storereagentsstrictlyaspermanufacturersspecificreagentstoragerecommendations
Visuallyinspecteachreagentbottlebeforeusetoensurethattherearenosignsofleakage and or abnormal colour.
Donotuseakitafterexpirydate.DONOTinterchange,mixorcombinereagentsfromkitswithdifferentmasterlotnumbers.Ensurethatallreagentsusedareofthesame master lot of reagents.
Addallreagentsusingapipettecapableofaccuratelydeliveringspecifiedvolumes.
Regularlycalibratepipettesforaccuratedeliveryandmaintainlogs
Avoidmicrobialandribonucleasecontaminationofreagentswhenremovingaliquotsfromreagentbottles.TheuseofsteriledisposablepipettesandRNase-freepipettetipsisrecommended.
Donotfreezereagentsorcontrols
Donotpoolreagentsfromdifferentlotsorfromdifferentbottlesofthesamelot.
4.11.3 EQUIPMENT
Performmanufacturerrecommendedmaintenanceandcalibrationofallequipment,includingpipettestoensureproperfunctioning.
4.11.4 WORK AREAS
Tominimizethepossibilityoflabareasbecomingcontaminatedwiththeamplicon,thelabareashouldbeseparatedintoseveraldistinctareasorganizedaroundthepre-amplification(separatereagentandspecimenpreparationareas)andpost-amplification(AmplificationandDetection)areas.Personnel shoulduseproperanti-contamination safeguardswhenmovingbetweenareas.
Workflowinthelaboratorymustproceedinauni-directionalmanner,beginninginthePre-AmplificationAreaandmovingtothePost-Amplification(AmplificationandDetection) Area.
Pipettes and other supplies should be dedicated to a specific area. Specimens,equipmentandreagentsshouldnotbereturnedtotheareawhereapreviousstepwasbeingperformedandshouldnotbeusedforotheractivitiesormovedbetweenareas
63National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Pre-amplification activitiesmust beginwith reagent preparation and proceed tospecimenpreparation.
Suppliesandequipmentmustbededicatedtoeachpre-amplificationactivityandnotusedforotheractivitiesormovedbetweenareas.EquipmentandsuppliesusedforreagentpreparationmustnotbeusedforspecimenpreparationactivitiesorforpipettingorprocessingamplifiedDNAorothersourcesoftargetDNA
Glovesmustbewornseparatelyineachareaandmustbechangedbeforeleavingthatarea.
The pre-amplification area should have a template free area for preparation ofreagentsandanampliconfreeareaforspecimenandcontrolpreparation
Post-amplificationsuppliesandequipmentmustremain inthePost-AmplificationArea at all times
The post-amplification area should have analyzer(s) and Data station(s) withadditionalareaforpreparingWorkingAmplificationandDetectionreagents.
4.12 TROUBLE SHOOTING:
Whileperformingtheviralloadsinthelab,therewillbeoccasionswhenthingsmaygowrong.Theproblemscouldoccurbecauseofmechanical, chemicalorhumanerror. Staff should be trained to recognizewhen there is a problemand how tocorrectthemsothatthefinalpatientresultssentoutarenotaffected.Pleasefollowthemanufacturer’sinstructionsfortroubleshooting
Note: Adhere to standard work precautions and PEP as per NACO HIV testing. Keep eye splashers, body showers and supply of running tap water within vicinity of the working lab
4.13 DBS COLLECTION FOR ALL PATIENTS UNDERGOING VIRAL LOAD TESTING
The national programme will collect DBS samples from all patients who are sent for Viral load. The consent form is as annex IV (integrated consent for 2nd line ART as well as for collection of blood for storage)
The purpose of this collection and storage of blood on Dried Blood Spots (DBS) frompatientsundergoingevaluation for Second-lineART in India, is to subsequently conductHIVgenotypicresistancetestingonthesespecimenstoevaluatethepatternsofHIVdrugresistancethathavedevelopedamongpatientswhohavedevelopedtreatmentfailuretothestandardFirst-lineARTregimen.Clinicaland laboratorydatawillbeabstracted frompatientrecordstofurtheranalyzeandcorrelateHIVDRfindingswithvirologic,immunologic,andclinicaloutcomesofpatientsreceivingSecond-linetreatment.Overall,thefindingsoftheseanalysescanbeusedtoguidetheexpansionofARTservices,andspecificallySecond-lineARTservices,inIndia.
64 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
The objective of the analysis will be:
1. To determine the patterns of HIV-DR that are present among patients who havedevelopedtreatmentfailuretothestandardFirst-lineregimen,
2. TodetermineifHIV-DRpatternsattherapyswitchhaveanimpactonvirologicsuppressionat6monthsand/or12monthsamongpatientswhoreceiveSecond-linetherapy,and
3. Toevaluatetheclinical,immunologic,andsurvivaloutcomesofpatientswhodevelopedfailuretoFirst-lineARTat12and24months.ThisanalysiscanbestratifiedbyHIVRNAatthetimeofinitialSecond-lineevaluation(<400copies/mL,401-5,000copies/mL,>5,000copies/mL)
4.13.1 SPECIMEN COLLECTION, PROCESSING, AND STORAGE:
BloodisroutinelycollectedfrompatientsatthetimeofevaluationforSecond-lineARTattheSACEP (COE) forHIVRNA,chemistrypanel, liver function tests,andcompletebloodcount.Atthistime,adriedbloodspecimen(DBS)willalsobecollected.
Specimen collection:
DBS should only be made from patient’s blood tubes that have been specificallylabelled ormarked as eligible. Before the DBS ismade, the DBS-ID and ART-ID for theparticipant should be written on the filter paper card. Anti-coagulated blood shouldbe spotted onto filter paper within 24 hours of collection. The filter paper shouldbe handled only at the edge; the areas that will be used to collect specimens shouldnot be touched. A filter should only be spotted with the blood of a single patient. Forrecentlycollected,freshwholeblood,invertthebloodcollectiontube2-3timestomixthewholeblood.Carefullyopenthebloodcollectiontube.Useapipette(withdisposabletip)toaspirate100µlofwholebloodandapplyittothecentreofonepre-printedcircletofullysaturatethecircle.Repeatthisproceduretofilleachcircleonthecardwithblood.Foreachspecimenatleastfoursaturatedcirclesshouldbeobtained.Openingofthetubesandpipettingshouldbeperformedfollowingstandardlaboratorybiosafetyprecautions.
Specimen drying:
Avoidtouchingthepartofthecardwiththebloodspot..Dryallspecimencardsatleast4 hours at ambient temperature in a suspended horizontal position. Depending on theclimateitmightbenecessarytoallowspotstodryovernight.Donotuseoventofastenthedryingtimeofthecards.Whendry, thespotsshouldbeauniformdarkbrown.Theappearanceshouldbesimilartothatofadriedbloodstainandnoareasofredcolorationshouldbeseen.
65National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Specimen packaging:
MakesuretheDBSorDPSarecompletelydrybeforepacking.PackagingofeachDBScardintoaseparategas-impermeablezip-lockbagwith2-3desiccantpacks(toremoveanyresidualmoisture fromthecards)perbagandahumidity indicatorcard (to indicate therelativehumidity inside thebag) is recommended.Whenpacking,make sure that thehumidityindicatorcardsarefacedoutside.Placethefrontofthehumidityindicatorcardfacingoutsidesothatthemarkingsareclearlyvisible.Pressthebagwithbothhandstosqueezeouttheairfromthebagandthensealit.Place5-10oftheabovesmallbagsintoalargeplasticbag.Inthelargeplasticbag,alsoplaceaprintedmanifestwithspecimeninformation.Plasticorfoilbagsused for storage mustbegasimpermeabletokeepthecontentsofthebaghumidity-free.Bagsavailablefromgrocerystoresorotheroutletsthatdonotsellscientificsuppliesareinadequate.
Humidityindicatorcardsanddesiccantpackshaveacolorindicatorwhichchangesfrombluetopinkashumidityincreases.Allhumidityindicatoranddesiccantsshouldbereplacedwithfreshmaterialbeforetheyhaveallchangedtoapinkcolour.ToensureproperpackagingoftheDBScards,thehumidityindicatorcardshouldbeexaminedonceaweekifthesampleiskeptatroomtemperature.Beforeplacingdesiccantpacksintoazip-lockbagwithDBS,makesuredesiccantpackshaveremaineddryduringstorage(indicatorcardshouldshowbluecolor).Whenan indicator isbeginningtochange, it is timetochangethehumidityindicatoranddesiccantpacks.DesiccantpackscanbecomemoistafterusewithDBS,butalsoafterstorageinahumidenvironment.Storedesiccantpackswithhumidityindicatorcardstoevaluatewhethertheirmoisturelevelhasbecometoohigh.Humiditycardsanddesiccantpackscanbere-used.Moisthumidityindicatorcardsanddesiccantpacksshouldbedriedina65°Covenovernightuntilthecolourindicatorreturnstoblue.Removefromtheovenandstoreinasealedbagwithahumidityindicatorcarduntilreuseoruntiltheyonceagainneedtobedriedintheoven.
Specimen storage:
Forshort-termstorage(preferablytwoweeksmaximum,butnomorethan30days)atthecollectingsites,DBScanbekeptinthegasimpermeablezip-lockbagswithdesiccantsandstoredatroomtemperature.DBSheldatroomtemperatureshouldbestoredinaboxorcontainersothatdirectlightwillnotdamagethem.DBSshouldbeexaminedfrequently(e.g.,weekly)toevaluatewhetherthe30%circleinthehumidityindicatorcardhaschangedtoapinkcolor;whenitdoes,thedesiccantsmustbechangedimmediately.
DBScanbekeptatroomtemperatureorat4°Conly forshorttermstorage(<30days).DBSshouldnotbefrozenatthecollectionsiteunlessdefinitearrangementscanbeguaranteedtomaintaintheminafrozenstateuntiltheyreachthegenotypinglaboratory.Insettingswhereconstantrefrigerationmaynotbepossiblebecauseoffrequentelectricityoutages,orwherehighhumidityislikelywithintheavailablerefrigerator/freezer,itispreferabletoholdtheDBSatroomtemperature.Ifpossible,DBSshouldnotremainatacollectingsitewithlimitedstorageconditionsformorethan7daysbeforebeingtransportedtoalaboratorywithaconstantelectricitysupplyandarefrigeratororfreezerinwhichthehumidityhas
66 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
beenevaluatedandconfirmedassuitableforlong-termstorageofDBS.
For long termstorage (>30days),DBS shouldbe transported toa central facilitywherethereisaconstantelectricitysupplyinafreezerat20°C or belowthathasbeenevaluatedandconfirmedassuitableforlongtermstorageofDBS.Iffrozen,DBSshouldonlybetakenoutofcoldstoragewhentheyarebeingtransportedtoareferencelaboratoryortested.
Specimen Transport
DBS should be transported to the regional or national genotyping laboratory using thequickestandreliablearrangements.Unlesshumidityattheblooddrawsiteissubstantiallyhigherthanintheprocessinglaboratory,andprovidedsuitablestorageboxesareavailableatthesitetokeepDBSfromlightandcontamination,nospecialarrangementsneedbemadetotransportDBSmoreoftenthanweekly.
Forspecimensthathavebeenstoredatroomtemperature:Thedesiccantsinthespecimensbags shouldbe changedbefore transport forDBS specimens thathavebeen stored forlongerthan7daysatthecollectionsite.Thisshouldbedoneeveniftheindicatorremainsblue.Resealthebagandtransportspecimensbythefastestmeansusingcourierserviceorthroughthepostalsystem(preferablywithexpeditedserviceandaguaranteeddelivery)at roomtemperature.
For specimens that have been stored at 4oC: Remove the bagged specimens from therefrigeratorandallowthemtoreachroomtemperaturebeforeopeningthebag.Oncethesealedbaghasequilibrated,openitandremovetheolddesiccants.Addfreshdesiccantsand reseal the bag. Transport the bag by the fastestmeans. If a cooler is available fortransportthiswillprotectspecimensfromshortperiodsofhightemperature.
Forspecimenshavebeenfrozenat-20oCor-70oC:Thesespecimensshouldbetransportedondryiceorliquidnitrogen.ThawingoffrozenDBSspecimensshouldbeavoidedifpossible.Acoolerisnotsufficienttomaintaintheminafrozenstate.
AllDBS specimens shouldbe logged into the survey system (whether it is anotebookoracomputersoftwarepackage).Thelogshouldincludenotesonspecimenqualityandpackaging.
ThelogbookshouldincludearecordofeligiblespecimensforwhichthereisnoDBSmaterialavailabletobesenttothegenotyping laboratory,andthereason.Anacknowledgementor notification system should be set up involving the survey coordinator, the transportsystem,andthereceivinggenotypinglaboratory,toensureallDBSaredeliveredpromptlytogenotypinglabandarriveingoodcondition.Eitheremailorfaxnotificationusingtheshippingmanifestsmaybeusedforthispurpose.DBSshouldbere-examinedforpackagingandspecimenqualityonarrivalinthegenotypinglaboratoryandrecordedinthegenotypinglaboratory.
Every ART centre shall be linked to a VL lab for which instructions will be given by NACO to send the DBS filter paper to the corresponding HIV drug resistance genotyping national reference labs.
67National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEXURE
ANNEX I:
SEVERITY GRADING OF SELECTED CLINICAL AND LABORATORY TOXICITIES
(source:DivisionofAIDS,NationalInstituteofAllergyandInfectiousDiseases,USA–Modifies,)
ForabnormalitiesNOTfoundelsewhereinthetoxicitytableusethescaletoestimategradesoftoxicity.
GRADE 1Transientormilddiscomfort;nolimitationofactivity;nomedicalintervention/therapyrequired.
GRADE 2Mildtomoderatelimitationofactivity;someassistancemaybeneeded;noorminimalmedicalintervention/therapyrequired.
GRADE 3Markedlimitationofactivity;someassistanceusuallyrequired;medicalintervention/therapyrequired;hospitalizationpossible.
GRADE 4Extremelimitationofactivity;significantassistancerequired;significantmedicalintervention/therapyrequired;hospitalizationorhospicecare.
HAEMATOLOGY GRADE 1 GRADE 2 GRADE 3 GRADE 4
Haemoglobin 8.0–9.4g/dlOR80-94g/lOR4.93–5.83mmol/l
7.0–7.9g/dlOR70-79g/lOR4.31–4.92mmol/l
6.5–6.9g/dlOR65-69g/lOR4.03–4.30mmol/l
<6.5g/dlOR<65g/lOR<4.03mmol/l
Absoluteneutrophilcount
1000–1500/mm³OR1.0–1.5/G/1*
750–999/mm³OR0.75–.99/G/1*
500–749/mm³OR0.5–0.749/G/1*
<500/mm³OR<0.5/G/1*
Platelets 75000–99000/mm³OR75–99/G/1*
50000–74999/mm³OR50–74.9/G/1*
20000–49999/mm³OR20–49.9/G/1*
<20000/mm³OR<20/G/1*
68 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
CHEMISTRIES GRADE 1 GRADE 2 GRADE 3 GRADE 4
SODIUM
Hyponatraemia 130–135meq/IOR130–135mmol/l
123–129meq/IOR123–129mmol/l
116–122meq/IOR116–122mmol/l
<166meq/IOR<116mmol/l
Hypernatraemia 146–150meq/IOR146–150mmol/l
151–157meq/IOR151–157mmol/l
158–165meq/IOR158–165mmol/l
>165meq/IOR>165 mmol/l
POTASSIUM
Hyperkalaemia 5.6–6.0meq/IOR5.6–6.0mmol/l
6.1–6.5meq/IOR6.1–6.5mmol/l
6.6–7.0meq/IOR6.6–7.0mmol/l
>7.0meq/IOR>7.0 mmol/l
Hypernatraemia 3.0–3.4meq/IOR3.0–3.4mmol/l
2.5–2.9meq/IOR2.5–2.9mmol/l
2.0–2.4meq/IOR2.0–2.4mmol/l
<2.0meq/IOR<2.0mmol/l
BILIRUBIN
Hyperbilirubin-armia >1.0–1.5xULN >1.5–2.5xULN >2.5–5.0xULN >5.0 x ULN
GLUCOSE
Hypoglycaemia 55–64mg/dlOR3.01–3.55mmol/l
40–54mg/dlOR2.19–3.00mmol/l
30–39mg/dlOR1.67–2.18mmol/l
<30mg/dlOR<1.67mmol/l
Hyperglycaemia(nonfastingandnopriordiabetes)
116–160mg/dlOR6.44–8.90mmol/l
161–250mg/dlOR8.91–13.88mmol/l
251–500mg/dlOR13.89–27.76mmol/l
<500mg/dlOR<27.76mmol/l
Triglycerides 200–399mg/dlOR2.25–4.51mmol/l
400–750mg/dlOR4.52–8.47mmol/l
751–1200mg/dlOR8.48–13.55 mmol/l
<1200mg/dlOR<13.55mmol/l
creatinine >1.0–1.5xULN >1.5–3.0xULN >3.0–6.0xULN >6.0 x ULN
TRANSAMINASES
AST(SGOT) 1.25–2.5xULN >2.5–5.0xULN >5.0–10.0xULN
>10.0 x ULN
ALT(SGPT) 1.25–2.5xULN >2.5–5.0xULN >5.0–10.0xULN
>10.0 x ULN
GGT 1.25–2.5xULN >2.5–5.0xULN >5.0–10.0xULN
>10.0 x ULN
AlkalinePhosphatase 1.25–2.5xULN >2.5–5.0xULN >5.0–10.0xULN
>10.0 x ULN
Pancreaticenzymes
Amylase >1.0–1.5xULN >1.5–2.0xULN >2.0–5.0xULN >5.0 x ULN
Pancreaticamylase >1.0–1.5xULN >1.5–2.0xULN >2.0–5.0xULN >5.0 x ULN
69National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
CHEMISTRIES GRADE 1 GRADE 2 GRADE 3 GRADE 4
TRANSAMINASES
Lipase >1.0–1.5xULN >1.5–2.0xULN >2.0–5.0xULN >5.0 x ULN
Lactate <2.0xULNwith-out acidosis
>2.0xULNwith-out acidosis
Increased lactatewithpH<7.3withoutlife-threateningconsequences
Increased lactate withpH<7.3withlife-threat-ening conse-quences
GASTRO- INTESTINAL GRADE 1 GRADE 2 GRADE 3 GRADE 4
Nausea MildORtransient;reasonable intake maintained
Moderate discomfortORintake decreased for<3days
Severediscom-fortORminimalintake for >3 days
Hospitalizationrequired
Vomiting MildORtran-sient;2–3episodesperdayORmildvomitinglasting<1week
ModerateORpersistent;4–5episodesperdayORvomitinglast-ing >1week
Severevomit-ing of all foods/fluidsin24hoursORorthostatichypotensionORintravenousRxrequired
HypotensiveshockORhos-pitalizationforintravenousRxrequired
Diarrhoea MildORtran-sient;3-4loosestoolsperdayORmilddiarrhealasting<1week
ModerateORpersistent;5-7loosestoolsperdayORdiarrhealasting>1week
BloodydiarrheaORorthostatichypotensionOR>7 loose stools/dayORintrave-nousRxrequired
HypotensiveshocksORhospitalizationrequired
RESPIRATORY GRADE 1 GRADE 2 GRADE 3 GRADE 4
Dyspnoea Dyspnoeaonexertion
Dyspnoeawithnormalactivity
Dyspnoeaatrest Dyspnoearequir-ingO²therapy
URINALYSIS GRADE 1 GRADE 2 GRADE 3 GRADE 4
Proteinuria
Spoturine 1+ 2+ or 3+ 4+ Nephroticsyn-drome
24–hoursurine 200 mg to 1 gloss/dayOR<0.3%OR<3g/l
1 g to 2 g loss/dayOR0.3%to1.0%OR3gto10 g/l
2 g to 3.5 g loss/dayOR>1.0%OR>10 g/l
Nephroticsyn-dromeOR>3.5gloss/day
Grosshaematuria Microscopiconly Gross,noclots Grossplusclots Obstructive
70 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
MISCELLANEOUS GRADE 1 GRADE 2 GRADE 3 GRADE 4
Fever(oral,>12hours
37.7–38.5°COR100.0–101.5°F
38.6–39.5°COR101.6–102.9°F
39.6–40.5°COR103–105°F
>40.5°COR>105°Ffor>continu-oushours
Headache Mild;noRxre-quired
ModerateORnon-narcoticanalgesia Rx
ServereORre-spondstoinitialnarcoticRx
Intracable
Rashhypersesnitiv-ity
Erythema,prui-tus
Diffusemaculo-papularrashORdrydesquama-tion
VasiculationORmoistdesquama-tionORulcer-ation
ANYONEOF:muscous mem-braneinvolve-ment,suspectedStevens-Johnson(TEN),erythemamultiforme,ex-foliativederma-tistis
Fatigue Normalactivityreduceby<25%
Normalactivityreduceby<25–50%
Normalactivityreduceby>50%:cannotwork
Unable to care for self
71National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEX II:Request/Reply form to SACEP for review of patients suspected of treatment failure (to
be sent with patient records)
RRF: Request form to SACEP at COE /pCoE/ART plus Centre for Review
Dear Dr …………………………………………. Referral date……………………….
Centre of Excellence /ART plus Centre ………………………………
I would like to refer this patient for review by the SACEP for
Alternative First-line ARV ART drugs
Suspect Treatment Failure
Others (specify)…………………………………………….
Name……………………………………………………………......................................... Age-………… Sex…………................……..………
Name of the Care giver ..............................................................................................
Address & Phone no. …………………………………………………………………………………..…………..
………………………………………………………………………………………………………………………………...
........................…........................................................................................................
ART centre name & phone no. ….................................................................................
Contact person at ART centre&mobile no. …………………………………………………………………………........................................................Name & Contact no. of Linked NGO/CCC /DLN:The following are attached with this request form:
• PhotocopyofthePatienttreatmentrecord(WhiteCard)• PhotocopyofalllabtestsincludingCD4• Photocopyofallotherrelevantmaterial• Photodocumentationoftoxicity(Ifavailable)• Addressproofwithphoto
The following sections summarize the patient antiretroviral therapy history:
A: Summary of the case history of the patient (pre-ART; ART; suspected treatment failure/suspected ARV toxicity)…………………………………………………………………………………….............................................B. Summary of adherence history and other psycho-social issues…………………………………………………………………………………….............................................
C. Summary of relevant laboratory tests including CD4 (of last 1 month) /viral load (if available)
…………………………………………………………………………………................................................
Name and Signature of Nodal Officer of referring
ART centre with contact number & email
72 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Reply from SACEP at CoE/pCoE/ART plus Centre to Referring ART centre (After review)
Dear Dr ……………………………………………………… Date………………………...…….
ART centre…………………………………………………..
Patientname…………………………………………………..............…Gender/Age………….............….....…
Address……………………………………………………..................... SACEP registration no. …………………………………
Referred for………………………………………………..................…on Date……………………………................…………….
Findings/investigationresults:…………………………………………………………………….........................………………....................
……………………………………………………………………………………………………………….…………………….……
……………………………………………………………………………………………………………………………………………
Treatment/follow-upPlan:……………………………………………………………………………….…………………
……………………………………………………………………………………………………………………………………………
NameandSignatureofNodalOfficer
COE/ARTpluswithcontactnumber&e-mail
73National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEX III:
CF Consent form for patients starting Second line ART – at COE
Consent form for patients starting Second line ART
I, (name)…………………………………, (address) …………………………………................................. CONSENTtoshareall informationpertaining tomyhealthandHIV/AIDSstatuswith theserviceproviderswhowillbepartofthemanagementofmycondition.
And
I AGREEtoreceivetheSecondlineantiretroviraltherapy.
Ifullyunderstandtheinformationthathasbeenprovidedbythehealthcarestaffinthefollowing:
• ThatSecondlineARTisnotanemergencyandthuswillbestartedasperthedeci-sionofthedoctor.IshallattendtheARTcentreasperappointmentfortimelyinitia-tionofARTandregularfollowup
• ThatreceivingSecondlineARTinvolvessharedconfidentialitywithotherserviceproviderssuchasCBO/NGO/CCC/positivenetworkwhomayconductoutreachandhome-basedcareactivitiesathome
• ThatSecondlineARTrequires100%adherencetodrugsandIshallabidebythesame.
• ThatthereisnothirdlineARTavailableintheprogramme
• ThatIunderstandthesideeffectsofSecondlineART
• ThatIshallnotstopthedrugsonmyownandwillreturntothecentreifthereisanyproblem
• ThatthenationalprogrammeshallcollectandstoremybloodtofindoutiftheARTmedicinesareworkingagainsttheHIVatalaterdate(Drugresistancetestingetc).Thiswillnotaffectmycurrenttreatment.Thiswillhelpthedoctorstoimprovethecareandtreatmentofallpatientsundergoingtreatmentatthiscentre,andpossi-blyatothercentresinthecountry.
…………………. …………………
SignatureofwitnessSignatureofpatientwithdate
(Doctor/nurse/counselor)
(This should be translated in local language &/or explained for patient understanding before taking patients signature)
74 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Drug information on Second line ARVs
LPV/r drug-drug interactions
Class Proteaseinhibitor(PI)
NACO Formulation Heat stable tablet: 200 mg LPV + 50 mg RTV
Contraindication LPV/riscontraindicatedinpatientswithknownhypersensitivitytoLPV or RTV
Safety in pregnancy NodataonLPV/rinpregnantwomen.LPV/rshouldnotbeusedduringpregnancyandbreastfeeding.
Precautions Hepaticimpairment–avoidifsevererenalimpairment,pregnancy;breastfeeding.
Food Shouldbetakenwithfood
Interactions IfddIorantacidsareadministered,theyshouldbetakenatleast1hourapart
LPVshouldnotbetakenwiththesedrugs:amiodarone,astemizole,cisapride,ergotamineandsimilaralkaloids,flecanide,garlicsupplements,lovastatin,midazolam,pimozide,propadenone,rifamipicin,simvastatin,StJohn’swort,terfenadineandtriazolam
RifamipicinshouldnotbeusedincombinationwithLPV/rbecauseco-administrationmaycauselargedecreasesinLPVconcentrations.
LPVlevelsareincreasedbydelavirdineandRitonavir(RTV)
LPVlevelsaredecreasedbyamprenavir,carbamazepine,dexamethasone,Efavirenz,ketoconazole,nevirapine,Phenobarbital,StJohn’swort,phenytoin,rifamipicinandTDF.
LPVincreasesthelevelsofamiodaron,amprenavir,atorvastatin,bepridil,calciumchannelblockers,clarithromycin,ketoconazole,indinavir,itraconazole,lidocaine(systemic),quinidine,rifabutin,saquinavir,sildenafilandTDF.
LPVdecreasesthelevelsofamprenavir,atovaquoneandmethadone.
LPVhaspotentialinteractionswithanticonvulsants,statins,oralcontraceptives,tricyclicantidepressants,oralanticoagulantsandimmunosuppressants.
ANNEX IV:
75National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Adverse effects GI-related:diarrhoea,nausea,vomiting,colitis,abdominaldiscom-fort,asthenia,headache,insomnia,rash.
Less frequently: drug mouth, hepatic dysfunction, pancreatitis,dyspepsia, dysphagia, oesophagitis, influenza-like syndrome,appetite changes, hypertension, palpitations, thrombophlebitis,vascultitis,chestpain,dyspnoea,agitation,anxiety,ataxia,hypertonia,confusion,depression,dizziness,dyskinesia,parasthesia,peripheralneuritis, somnolence; Cushing syndrome, hypothyroidism, sexualdysfunction, anaemia, leucopenia, dehydration, oedema, lacticacidosis; arthralgia, myalgia, abnormal vision, otitismedia, tastedisturbances, tinnitus, acne, alopecia, drug skin, pruritis, skindiscoloration,naildisorders,sweating;Lipodystrophyandmetaboliceffects, raisedbilirubinand loweredsodium,lowplateletand lowneutrophilcountsalsoreportedinchildren.
Storage Roomtemperature(below30degrees)
Lamivudine (3TC)
Class Nucleosidereversetranscriptaseinhibitor(NsRTI)
NACO Formulation CombinedasfixeddosecombinationasTDF/3TCatdoseof300mgonceaday
Contraindication Knownsensitivityto3TC
Safety in pregnancy Limiteddataavailableonsafetyof3TCinhumanpregnancy
Precautions Renalimpairment
Hepaticimpairment:potentiallylife-threateninglacticacidosisandseverehepatomegalyreported,cautioninliverdisease.RecurrenthepatitismayoccurinpatientswithchronichepatitisBinfectionondiscontinuationof3TC
Food Canbetakenwithorwithoutfood
Interactions Rare
Adverse effects Nausea,vomiting,diarrhoea,abdominalpain,cough,headache,fatigue,insomnia,malaise,fever,rash,alopecia,muscledisorders,nasalsymptoms;peripheralneuropathyreported;rarelypancrea-titis;neutropenia,anaemia,thrombocytopenia;lacticacidosis/hepaticsteatosis;raisedliverenzymesandserumamylase
Storage Roomtemperature(15-30degreesC)
76 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ATV/r drug-drug interactions
Class Proteaseinhibitor(PI)
NACO Formulation Atazanavir300mgandritonavir100mg
Contraindication ATV/riscontraindicatedinpatientswithknownhypersensitivityto ATV or RTV
Safety in pregnancy NodataonATV/rinpregnantwomen.However,itsefficacyinpregnancyislessthanLPV/r.
Precautions Hepaticimpairment–avoidifsevererenalimpairment.
Food Shouldbetakenwithfood
Interactions In case of regimen IV/IVa1. H2receptorantagonistdoseshouldnotexceedadoseequiva-
lenttoFamotidine40mgBIDinART-naïvepatientsor20mgBIDinART-experiencedpatients.
2. GiveATV300mg+RTV100mgsimultaneouslywithand/or>10hoursaftertheH2receptorantagonist.
Example: If a PLHIV on Zidovudine + Lamivudine + Atazanavir/Rito-navir (Regimen IV) requires to be treated with Famotidine 20 mg BID or Ranitidine 150 mg BID, S/he should be instructed to take Tab. Famotidine/Ranitidine with Zidovudine + Lamivudine at 8.00 AM and in evening give ZL and ATV/r at 8 p.m. and ensure that there is a gap of at least 2 hours before or 1 hour after Famotidine/Ranitidine evening dose.In case of Second line Regimen V (Tenofovir + Lamivudine + Ata-zanavir/Ritonavir):
1. PPIs shouldnotexceedthedoseofOmeprazole20mgdailyorequivalentdoseofEsomeprazole20mg/Pantoprazole40mg/Rabeprazole20mg inPI-naïvepatients, alongwithRitonavirboosted Atazanavir. PPIs should be administered at least 12hourspriorto Atazanavir/Ritonavir.
2. PPIs are not recommended in PI-experienced patients.
Example: If a PLHIV is on Tenofovir + Lamivudine + Atazanavir/Ritonavir requires to be treated with PPI, S/he should be instruct-ed to take Tab. Omeprazole 20 mg/Esomeprazole 20mg/Panto-prazole 40 mg/Rabeprazole 20 mg OD at 8 AM and Tenofovir + Lamivudine + Atazanavir/Ritonavir after 8 PM.
H2 receptor antagonists are not recommended with Tenofovir+Lamivudine+Atazanavir/Ritonavircombination.
77National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Adverse effects Apart fromthePI-classspecificside-effects likehyperglycaemia,fat maldistribution, hyperlipidaemia (especially with Ritonavirboosting).Theuniqueside-effectsofAtazanavir include indirect hyperbilirubinaemia (producing yellow discolouration of eyes), skinrash,prolongationofPRintervalandnephrolithiasis.
Prolongation of P-R and Q-Tc interval in the ECG can occur.So PR interval need to be monitored in patients with knownconduction defects orwith concurrent use of other drugs thatalter conduction abnormalities (like diltiazem, clarithromycin,cisapride, ketoconazole etc.). However, routine ECG beforestartingAtazanavirbasedARTisnotrecommended.
Atazanavir inducedurolithiasis is also reported; presumablydueto precipitationof thedrug resulting in crystalluria in amanneranalogustoIndinavir.
Storage Roomtemperature(below30degrees)
Rifabutin
Class Anti-tuberculousagentNACO Formulation Tablet 150 mg
ConcurrentusewithATV/r(nochange),Rifabutindose150mgoncedaily3x/wk
RifabutinAUC↑by303%Contraindication AllergytorifampicinSafety in pregnancy Limiteddatainpregnancy.Notteratogenicinrats/rabbitsPrecautions AllergytorifamipicinFood noneInteractions Rifabutinreduceslevelsofwarfarin,barbiturates,benzodiazepines,
beta-blockers,chloramphenicol,clofibrate,oralcontraceptives,corticosteroids,cyclosporine,diazepam,dapsone,digitalis,doxycycline,haloperidol,oralhypoglycaemics,ketoconazole,methadone,phenytoin,quinidine,theophylline,trimethoprim,verapamil.
DrugsthatinihibitcytochromeP450andprolongsthehalflifeofRifabutin:PIsandDelavirdine,erythromycin,clarithromycin(56%increase),andazoles(fluconazole,itraconazole,ketoconazole).
Adverse effects Common:brown-orangediscolorationofsecretions:urine,tears,saliva,sweat,stool,skin.Infrequent:Rash,GIintolerance,neutropenia.Rare:flu-likeillness,hepatitis,hemolysis,headache,thrombocytopenia,myositis.
Uveitisisdose-related(usually>450mg/day)orwithstandard300mg/daycombinedwithdrugsthatincreaserifabutinlevels(mostPIs,clarithromycin,fluconazole)
Storage Roomtemperature(15-30degreesC).
78 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Recommendations for Co administering Antiretroviral Drugs with RIFABUTIN – 2007
Non-nucleoside reverse-transcriptase inhibitors
Antiretroviral dose change
Rifabutin dose change
Comments
Efavirenz Nochange___to450-600mg(dailyorin-termittent)
RifabutinAUC¯by38%.EffectofEfavirenz+proteaseinhibitor(s)onRifabutinconcentrationhasnotbeenstudied.Efavirenzshouldnotbeusedduringthe1st trimester of pregnancy.
Nevirapine NochangeNochange(300mgdailyorthrice-weekly)
RifabutinandNevirapineAUCnotsignificantlychanged.
Dual protease inhibitor combinations
Antiretroviral dose change
Rifabutin dose change
Comments
Lopinavir/ritonavir ä)
Nochange___ to 150 mg everyotherdayor3x/week
RifabutinAUCby303%;25-O-des-acetylRifabutinAUCby47.5fold.
Ritonavir (any dose) with saquinavir, indinavir, am-prenavir, fos-amprenavir, atazanavir, tipranavir or darunavir
Nochange____ to 150 mg everyotherdayor3x/week
RifabutinAUCand25-O-des-acetylrifabutinAUC,byvaryingdegrees.
ANNEX V:
79National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Treatment education information for Second line ART patients
REMEMBERTHAT
Ifyoumissdoses(even2doseinamonth)FURTHER DRUG RESISTANCEwilldevelop.ThisisbadforyouastheseSecondlinedrugswillstopworking.
Drugsmustbetakenasprescribedwithfood,anddonotmissanydose
Ifyouforgetadose,donottakeadoubledose.
IfyoustoptakingtheART,youwillbecomeillwithinmonths.
Donotshareanyofthedrugswithyourspouse,familyor friends.
Ifyoufinditdifficulttotakeyourpills,gobacktotheARTcenteranddiscussthiswiththedoctorandcounselor.Askforsupportfromyourtreatmentsupporter,family,friends,NGOandpositivenetwork.
Remember : Adherence is under your control
Note:Thecolor,shapeandsizeofARVdrugsmaybedifferentduetodifferentsuppliereachyear.
It is common to have side effects. They will usually go away in a few weeks. You can ask doctor to give you some medication to help you make it better. If you have side effects, do the following:
If you have Do the followingNausea TaketheARVpillswithfood.Diarrhoea Keepdrinkingandeating,donoteatspicy
food/chilies.Musclepain,fatigue Thesewillgoaway.
Inauseaordiarrheapersistsorgetsworse,reporttotheARTcenter.
Seekcareurgentlyif:
• Yelloweyeswithhighfever,headache,runningnoseandbodyache.
• Missedperiods/possibilityofpregnancy.
• Severeabdominalpains.
• Extremepalenessofface,handsoreyes.
• Fatigueandshortnessofbreath.
Note:Remembertotakeyourcotrimoxazoleprophylaxistableteveryday,ifthedoctorprescribesit. Alwaysusecondomduringsex. Donotstopanydrugsbyyourself.
ANNEX VI:
80 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Phone:CallARTcentreifyouhaveanyquestionsor problems.(9AM–4PM)
Phone:After4PM,ContactthehospitalEmergencynumber.
Phone:Callthelocalpositivenetworknumberforsupport.
NationalAIDSControlOrganisation MinistryofHealth&FamilyWelfare GovernmentofIndia,9thFloor,ChandralokBuilding 26,Janpath,NewDelhi–110001,India Tel:011-23325343,011-23731774,011-23731778,Fax:011-23731746 E-mail:[email protected]
81National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEX VII (A) – VIRAL LOAD TEST REQUISITION FORM
Annex VII (a)-Viral Load Test Requisition FormVL-1 National AIDS Control Organization Accession NumberPage-1 HIV-1 Plasma Viral Load Test Reauisition Form For Testing Lab Use Only
To be �lled out by the MO/Nurse/Lab technicion ART Center Information Patient SectionART Center Name : Name : _________________ Patient ID # : ___________________Address : _______________________ Patient Name : _________________District : _________ State : _________ Sex : M / FTelephone # : ____________________ Age : ____________ Previous HIV-1 Plasma Viral Load Test Results from ART CenterBaseline : 6 Months: Other (please Explain ): Relevant Clinical DetailsLatest CD4 Count,with date : _____________________________
Earlier HIV-1 PVL Test Performed ? Y / N Date Of Earlier HIV-1 PVL : ____ ____ _____ dd mm YY
Result of Earlier HIV-1 PVL Testing (If Performed ) : _____________________________________Manufacturer Of Previous HIV-1 PVL Test : __________ Assay/Kit used : ___________________
Any infection or immunization in the past 4 weeks ? Y / N HIV-1 PVL Specimen CollectionCollection Date : _______ ________ _______ Collection Time : _______________ Date Month YearName Of MO/Nurse?Lab Technician : _______________ Signature : ________________________
Signature Of ART Nodal Officer : ____________________ Stamp :__________________________To Be �lled out by the ART lab technician carrying the specimens For Lab Technician Couriering the SpecimenName of Lab Technician In-Charge : ___________________________________________________Name of ART Center : _______________________________________________________________
Date Of Specimen Transport to Lab : ______ _____ _____ Time Of Departure : ________ Day Month Year
Signature :To Be �lled out by laboratory - For Laboratory Use OnlyDate Specimen Received ( dd/mm/yy):________________ Time Received : _____________
Specimen received in the acceptable condition : Y / N (Please Circle )If No,list the state of specimen received :Unlabeled/Mislabeled/Insufficient/Inappropriate/Invalid/Other
Stamp:Name Of Lab In-Charge : ________________________Signature : ____________________________________
82 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEX VII (B) – COBASAMPLICOR REPORTING FORMAT
Annex VII(b) - Cobas Amplicor Reporting FormatVL-1 Lab NamePage 2 Address (Street ,District,State) Lab Phone Number
HIV-1 Plasma Viral Load Result Form Cobas Amplicor
Accession Number/Lab Registration Number : ________________________________
Patient ID Number : _______________________________________________________
Date Specimen Tested(dd/mm/yy):__________Date Of Report (dd/mm/yy):____________
Test Kit Name : Cobas Amplicor HIV-1 Monitor Test ,Version 1 Manufacturer : ____________Version : _______________________
ResultHIV-1 RNA Copies/ml
Log-Transformation :
Notes : HIV-1 Quantization by Cobas AmolicorHuman Immunodeficiency virus(HIV) is the etiologic agent of Acquired immunodefiency Syndrome(AIDS).
Quantitative measurements of HIV Viremia in the peripheral blood have shown that higher virus levels
may be correlated with increased risk of clinical progression of HIV Disease.
Interpretation : This procedure can detect virions associated HIV-1 RNA plasma at concentrations as 50
RNA copies/ml to 750,000 HIV-1 RNA copies/mL.Low viral load values may occur as "False positives"and
have been documented in the plasma of uninfected persons or persons infected with other RNA viruses
that resamble HIV(e.g.HTLV).Therefore,caution must be exercised when such a result is obtained on a
specimen of a patient not confirmed as being infected with HIV(through EIA,Western Blot,Or HIV DNA
Assays).
The minimum reliable and significant change in measurement(as compared to baseline value or
previous test value)is a 3-fold(0.5 log) change.
Recommendations:A positive viral load result must always be correlated with clinical hitory and HIV
status of the patient.The cobas Amplicor HIV-1 Monitor test 1.5 is not intended to be used as a diagnostic for HIV-1 infection.This test is not intended for HIV-2 Patients. It is recommended that the follow up viral load testsbe repeted at the same laboratory with the same technique/procedure in order to caompare changes in subsequent.
Name Of lab in-charge : ________________________ stamb of lab in-charge :
signature Of lab In-charge : __________________
Not valid for medical legal purposes
83National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEX VII (C)– TAQMAN REPORTING FORMAT
Annex VII(c) - Taqman Reporting FormatVL-1 Lab NamePage 2 Address (Street ,District,State) Lab Phone Number
HIV-1 Plasma Viral Load Result Form Cobas Taqman
Accession Number/Lab Registration Number : _________________________________________
Patient ID Number : ________________________________________________________________
Date Specimen Tested(dd/mm/yy):__________Date Of Report (dd/mm/yy):____________
Test Kit Name : Cobas Taqman HIV-1 Test Manufacturer : _____________Version : _______________________
ResultHIV-1 RNA Copies/ml
Log-Transformation :
Notes : COBAS TaqMan HIV-1 TestHuman Immunodeficiency virus(HIV) is the etiologic agent of Acquired immunodefiency Syndrome(AIDS).
Quantitative measurements of HIV Viremia in the peripheral blood have shown that higher virus levels
may be correlated with increased risk of clinical progression of HIV Disease.
Interpretation : This procedure can detect virions associated HIV-1 RNA plasma at concentrations low as 47
RNA copies/ml to 10,000,000 HIV-1 RNA copies/mL.Low viral load values may occur as "False positives"and
have been documented in the plasma of uninfected persons or persons infected with other RNA viruses
that resemble HIV(e.g.HTLV).Therefore,caution must be exercised when such a result is obtained on a
specimen of a patient not confirmed as being infected with HIV(through EIA,Western Blot,Or HIV DNA
Assays).
The minimum reliable and significant change in measurement(as compared to baseline value /
previous test value)is a 3-fold(0.5 log) change.
Recommendations:A positive viral load result must always be correlated with clinical hitory and HIV
status of the patient.The cobas Taqman HIV-1 test 1.5 is not intended to be used as a
dianostic test for hiv-1 infection.This test is not intended for HIV-2 Patients.
It is recommended that viral load tests be repeted at the same laboratory with the same
technique/procedure in order to caompare changes in subsequent viral load counts.Name Of lab in-charge : ________________________ stamb of lab in-charge :
signature Of lab In-charge : __________________
Not valid for medical legal purposes
84 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEX VII (D) – VIRAL LOAD RESULT FORM, AMPLICOR HIV MONITORING, V1.5
Annex VII(d) - Viral Load Result Form,Amplicor HIV Monitoring,V1.5VL-1 vvvv Lab NamePage 2 Address (Street ,District,State) Lab Phone Number
HIV-1 Plasma Viral Load Result Form Amplicor HIV Monitoring,version 1.5
Accession Number/Lab Registration Number : _________________________________________
Patient ID Number : ________________________________________________________________
Date Specimen Tested(dd/mm/yy):__________Date Of Report (dd/mm/yy):______________________
Test Kit Name : Amplicor HIV-1 Monitor Test ,Version 1.5 Manufacturer : ____________Version : _______________________
ResultHIV-1 RNA Copies/ml
Log-Transformation :
Notes : HIV-1 Quantization by amplicor HIV Monitor Test,Version 1.5Human Immunodeficiency virus(HIV) is the etiologic agent of Acquired immunodefiency Syndrome(AIDS).
Quantitative measurements of HIV Viremia in the peripheral blood have shown that higher virus levels
may be correlated with increased risk of clinical progression of HIV Disease.
Interpretation : This procedure can detect virions associated HIV-1 RNA plasma at concentrations low as 50
RNA copies/ml to 750,000 HIV-1 RNA copies/mL.Low viral load values may occur as "False positives"and
have been documented in the plasma of uninfected persons or persons infected with other RNA viruses
that resemble HIV(e.g.HTLV).Therefore,caution must be exercised when such a result is obtained on a
specimen of a patient not confirmed as being infected with HIV(through EIA,Western Blot,Or HIV DNA
Assays).
The minimum reliable and significant change in measurement(as compared to baseline value /
previous test value)is a 3-fold(0.5 log) change.
Recommendations:A positive viral load result must always be correlated with clinical hitory and HIV
status of the patient.The Amplicor HIV-1 Monitor test 1.5 is not intended to be used as a
dianostic test for hiv-1 infection.This test is not intended for HIV-2 Patients.
It is recommended that follow up viral load tests be repeted at the same laboratory with the same technique/procedure in order to caompare changes in subsequent viral load .
Name Of lab in-charge : ________________________ stamb of lab in-charge :
signature Of lab In-charge : __________________
Not valid for medical legal purposes
85National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEX VIII
Process for External Quality Assessment for the laboratories performingHIV-1 Viral Load Testing
Introduction
ProcessforExternalQualityAssessmentforthelaboratoriesperformingHIV-1ViralLoadTestingwillinclude4surveysinacalendaryeartotheNACOidentifiedcentresforperformingHIV-1ViralLoadTestingfortheSecondlineinitiative.
Thiswillserveasanimportanttool intheprocessofcontinuousqualityimprovementintheselaboratories.
Confidentiality
ParticipantswillbegivenaParticipantNumbertobeusedasareferenceinallcorrespondence.Atnotimeandundernocircumstancesistheidentityofaparticipatinglaboratoryrevealed.Reportreviewerswhoassessresultsandprovidecomments/discussionsandaneducationalcomponentforeachreportareunawareoftheidentityofparticipants.
Participating Laboratories:
NameofLaboratory&ContactPersonofeachparticipatinglabwouldbeprovidedtoRCPA
EQAS coordinating laboratory in India
NACOhasdesignatedNARItobetheEQAScoordinatinglaboratoryforVLEQASinIndia.
NARI, Pune would take on the responsibility for ensuring that the EQAS programmeis successfully and regularly implemented with active participation of testing labs bycoordinating,monitoring,supervising,training,andprovidingtroubleshootingsupportfortheVLEQASrunsheldatregularquarterly intervals.RocheIndiawouldsupportNARI inthisactivityandcoordinatewithRCPAAustraliaandtheparticipatingcentersforallrelatedactivitiesincludingbutnotlimitedtothedeliveryoftheEQASspecimenstotheselabsforproficiencytestingfourtimesayearatpredeterminedschedules.RocheIndiawouldalsoprovidecoordinationtrainingandtroubleshootingsupporttoNARIasandwhenrequiredfortheNACOVLlabsinthisentireactivity.NARIwouldsubmitformalquarterlyreportstoNACOontheperformanceoftheNACOVLlaboratoriesintheVLEQAS.
Testing
Participants should test specimens in the same manner as patient specimens.
(1)The specimens should be tested with the laboratory’s regular patient workload bypersonnelwhoroutinelyperformthetestinginthelaboratory.
(2)Theparticipantshouldtestspecimensthesamenumberoftimesthatitroutinelytestspatientspecimens.
(3)Theparticipantshouldmaintainacopyofallrecords,includingacopyofthecompletedquestionnaire,torecordproficiencytestingresults.
86 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
(4)The results sheet should be signed by the analyst and the laboratory manager,documenting that proficiency testing specimens were tested in the same manneras patient specimens, the report reviewed, results discussed and action taken (ifappropriate).Thisdocumentationshouldbekeptforaminimumofthreeyearsfromthedateoftheproficiencytestingevent.
Specimen Delivery
ThesurveypanelswillbesenttoRocheDiagnosticsIndiafromRCPAQualityProgramPvt.Limited,Australiainthefrozenconditions
UponarrivalthesepanelswouldcheckedfortheshippingconditionsbyanAuthorizedpersonofRocheandsupplementedwithadditionaldryice
4surveys(1surveyperquarter)eachconsistingof3specimenswillbesentouttoeachparticipatinglaboratoryeachcycleofsurveys.
ThespecimenswillbesentoutatthestartofthesurveyanddeliveredbyRocheDiagnosticspersonneltotheindividuallaboratoriestoensureeaseoflogisticsandthatthespecimenintegrityismaintained.
Upondelivery,thespecimensaretobefrozenat-70°Cor-80°Cuntiltheappropriatequestionnaireisreceivedviaemail.Itisessentialthatspecimensarefrozenimmediatelyuponreceiptandstoredinafreezerwhichisnot a frost free instrumentordoesnothaveadefrostcycle.
Specimensmaycontainvirulentpathogensandmustbetreatedwiththesamedegreeofcautionasroutinediagnosticspecimens.Specimensareissuedtoparticipantsontheunderstandingthattheywillbeusedforqualityassurancepurposesandthattheywillbetestedbystafftrainedtohandleequivalentclinicalspecimens.
Survey Process
ReceiveopensurveyemailalertfromNACO
ParticipanttoprintsurveyQuestionnaire
Testrelevantsurveyspecimens
SubmitresultsviaemaildirectlytoRCPAbythesurveyduedatewithacopymarkedtoNACO
RCPAwillsendtheassessmentreporttotherespectiveparticipatinglaboratorywithacopymarkedtoNACO
NARIPunewillsubmittoNACOformalreportsquarterlyontheEQASperformanceoftheNACOviralloadlabs
87National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Survey Questionnaires
Participantsaregiven18daystoperformtestingandsubmitsurveyresults.
Instructionsareoneachquestionnaireexplainingwhatisrequired.PleasecontacttheNARIifyoudonotunderstandanyaspectofthequestionnaire.
Feedback from participants is encouraged and a ‘Compliments, Concerns,Suggestions’ section is in each survey questionnaire, so that participants canimmediatelyprovidefeedbackforspecificsurveys,aswellastheoverallProgramme.
Disposal of Material
Anypartofspecimenswhichisnotusedbytheparticipantshallbedestroyedinthemannerrequiredbyanylaworregulatoryagencyforthedisposalofpotentiallybio-hazardouswaste.
Late Return of Completed Questionnaires (Results)
Lateresultswilldelayreportpreparation.Ifacompletedquestionnairearrivesafter all data hasbeenenteredandcollationofdatahascommenced,thereceivedquestionnairewillbemarked LATE andthefinalreporttoNARIfromRCPAwillnotbeamendedtoincludetheselate results.
Survey Reports
Surveyreportsarepresentedinthefollowingformat:-
•Section One willcontainaParticipantPerformanceTable.Thistableidentifiesparticipantsreturning results inconsistent with consensus of ≥80% of participating laboratories,omissionofkitdetails,useofexpiredkits,occurrenceoftranscriptionerrors,inconsistentorincompletedata,inappropriateinterpretativecommentselectionandnonidentificationof clerical errors.
•Section Two containsthecollatedreport,whichisasummaryofparticipantresults,andincludesdiscussion/commentfromascientist/pathologistwithHIVexpertise.
5.55.04.54.03.53.02.52.01.51.00.50.0
Valu
es (I
U/m
L Lo
g 10)
ParticipantResults ParticipantResults
MedianRange-0.25Range +0.25Specimen2A
MedianRange-0.25Range +0.25Specimen2B
Valu
es (I
U/m
L Lo
g 10)
HIV RNA Quantitation (n=11) - Specimen 2A HIV RNA Quantitation (n=8) - Specimen 2B6.56.05.55.04.54.03.53.02.52.01.51.00.50.0
88 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEXURE IX- SECOND LINE REPORTING
1 SL + AL: SACEP REGISTER FOR ALTERNATIVE FIRST LINE & SECOND LINE ART (ADULTS AND CHILDREN)(SACEP coordinator at CoE/pCoE and data manager at ART plus centre should maintain
this register)These columns should be on left half of register
Month: Year:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Sl. N
o (S
ACE
P re
gist
rati
on N
o) #
.
ART
Reg
istr
ation
Num
ber
Pati
ent N
ame
Age
Gen
der
Add
ress
Con
tact
Num
ber
Nam
e of
refe
rrin
g A
RT C
entr
e
Cont
act n
o. o
f ref
erri
ng A
RT C
entr
e
Nam
e &
Con
tact
Num
ber
of N
GO
s lin
ked
to re
ferr
ing
ART
Ce
ntre
(CCC
/DLN
/TI/
othe
r lo
cal N
GO
s)
Dat
e of
Ref
erra
l (Fi
rst e
lect
roni
c re
ferr
al fr
om A
RT c
entr
e se
ekin
g ap
poin
tmen
t)
App
oint
men
t Giv
en (
If Y
es-D
ates
/If N
o –
Reas
on )
Dat
e of
act
ual a
sses
smen
t by
SACE
P
Rea
son
For
Refe
rral
*
Late
st C
D4
(wit
h da
te) a
t the
tim
e of
SA
CEP
asse
ssm
ent
(not
mor
e th
an o
ne m
onth
old
))
Clin
ical
Sta
ging
at ti
me
of S
ACE
P as
sess
men
t
Func
tion
al S
tatu
s at
tim
e of
SA
CEP
asse
ssm
ent
(WA
B)
Whe
ther
VL
testi
ng re
com
men
ded
or n
ot b
y SA
CEP
(Y/N
)
If V
iral
Loa
d re
com
men
ded,
resu
lts
(wit
h da
te)/
Gra
de o
f to
xici
ty
Reco
mm
enda
tion
s of
SA
CEP
(fee
dbac
k to
be
sent
to th
e re
ferr
ing
ART
cen
tre&
SA
CS) *
*
Pati
ent
Care
giv
er
* 1.Suspectedtreatmentfailure2.Sideeffectsofdrugs3.OnSecondlineARTfromPrivate4.Others
**1.RecommendedforSecondlineART2.SubstitutionwithPIcontainingregimen3.SubstitutionofNRTIbackbone4.Substitutionwithotherregimen–(Specifyregimencode)5.Managementofcomplicatedcases/others6.ReferredbacktoARTcentreforreviewafter1/3/6months
***1.Ifviralload<400copies/ml,noOI,nosideeffects-transferoutthepatientbacktothereferringcentre2.ifviralload>400copies/mlat6monthafterSecondlineARTinitiationandnoOI/sideeffects,stilltransferthepatienttothereferringcentreandcallthepatientbackforviralloadafteranothersixmonths(12thmonthfromthetimeofinitiationofSecondlineART)
****Forpatientswithviralloadmorethan400copies/mlatSecondviralloadtesting(at6thmonthafterSecondlineARTinitiation)
89National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
These columns to be on the right side of the register
21 22 Follow up of patients on Second line 31
23 24 25 26 27 28 29 30
Dat
e of
initi
ation
of S
econ
d lin
e/A
lter
nati
ve
Firs
t lin
e A
RT
Reco
mm
ende
d re
gim
en (i
ndic
ate
regi
men
nu
mbe
r as
per
NA
CO A
RT G
uide
lines
)
Any
Maj
or O
I obs
erve
d w
hile
on
Seco
nd li
ne
ART
Dat
e of
vir
al lo
ad te
sting
at 6
mon
th a
fter
in
itiati
on o
f Sec
ond
line
ART
Resu
lt o
f vir
al lo
ad te
sting
at 6
mon
ths
Reco
mm
enda
tion
s of
the
SACE
P aft
er S
ec-
ond
vira
l loa
d **
*
Aft
er in
itiati
on o
f Sec
ond
line,
whe
ther
Pa-
tien
t ref
erre
d ba
ck to
the
refe
rrin
g A
RT c
entr
e as
per
gui
delin
es a
t six
th m
onth
(yes
/no)
Dat
e of
refe
rral
bac
k to
the
noda
l ART
cen
tre
Vir
al lo
ad te
sting
at 1
2 m
onth
( if r
ecom
-m
ende
d by
SA
CEP)
****
Reco
mm
enda
tion
s of
SA
CEP
at12
th m
onth
vi
ral l
oad,
if a
pplic
able
Repeat Viral loads (with date) for patients not eligible for Second line drugs at First SACEP review (As per guidelines, those whose VL is between 400- 5000 copies/ml)
1 2 3 4 5 6
90 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
2 AL: ALTERNATIVE FIRST LINE FORMAT FOR SACEP MEETING (ADULT & CHILDREN)
(To be prepared before SACEP meeting and given to all members during the meeting and to be kept at CoE/pCoE/ART plus centre)
Meeting date :
Alternative First line ART
1 2 3 4 5 6 7 8 9 10 11 12 13
Sl. N
o (S
ACE
P re
gis-
trati
on N
o).
ART
Reg
istr
ation
N
umbe
r
Nam
e of
pati
ent
Age
Gen
der
Add
ress
Nam
e an
d ad
dres
s of
re
ferr
ing
ART
cen
tre
ART
sta
rt d
ate
(wit
hin
the
prog
ram
)
ART
sta
rt d
ate
(out
-si
de t
he p
rogr
am)
% A
dher
ence
to F
irst
lin
e dr
ugs
Clin
ical
sta
ge a
t the
ti
me
of a
sses
smen
t
CD4 counts (with date) cells/Cmm
(expandable)
Type
of t
oxic
ity
/sid
e eff
ects
obs
erve
d
Summary -2AL Alternative First line ART Members Present
during the SACEP
Sl. No Name of the regimenNo of
patients1
1
TotalnumberofpatientsreviewedbySACEPforAlternativeFirstlinetreatment
TDF containing regimen (Adult) 2
ATV/r based regimen (Adult) 3
LPV/r based regimen (adult) 4
ABC/3TC+NVP 5
ABC/3TC+EFV
ABC/3TC+LPV/r
ZDV/3TC+LPV/r
d4T/3TC+LPV/r
TDF+3TC+ATV/r(HIV-2/dualtoxicity)
2TotalnumberofpatientsactuallyrecommendedonAlternativeFirstlineART
TDF containing regimen (Adult)
ATV/r based regimen (Adult)
LPV/r based regimen (Adult)
ABC/3TC+NVP
ABC/3TC+EFV
ABC/3TC+LPV/r
ZDV/3TC+LPV/r
d4T/3TC+LPV/r
91National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
14 15 16 17 18 19 20 21
Gra
de o
f tox
icit
y
Phot
o do
cum
enta
tion
(Y
es/n
oO
Any
OI’s
repo
rted
Nam
e of
dru
g (d
4t/A
ZT/
NV
P or
EFV
or
any
othe
r A
RV )
whi
ch (p
roba
bly)
ca
used
toxi
city
– s
peci
fy
Whe
ther
reco
mm
ende
d fo
r A
lt F
irst
line
? (Y
es/
No)
If recommended for Alt First line?
Rem
arks
Adult Regimen Paediatric Regimen
TDF
base
d Re
gim
en
ATV/
r ba
sed
Regi
men
Oth
er re
gi-
men
ABC
/3TC
+ N
VP
ABC
/ 3T
C+
EFV
ABC
/ 3T
C+
LPV/
r
ZDV/
3TC
+ LP
V/r
d4T/
3TC+
LP
V/r
92 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Second line ART
1 2 3 4 5 6 7 8 9 10 11 12
Sl. N
o (S
ACE
P re
gist
ratio
n N
o).
ART
Reg
istr
ation
no.
Nam
e of
pati
ent
Age
Gen
der
Add
ress
Nam
e , a
ddre
ss o
f ref
er-
ring
ART
cen
tre
ART
sta
rt d
ate
(wit
hin
the
prog
ram
me)
ART
sta
rt d
ate
(out
side
th
e pr
ogra
mm
e )
Adh
eren
ce to
Fir
st li
ne
drug
s
CD4 counts (with date)
Cells/cmm all values to be
given
Reco
mm
ende
d fo
r V
iral
Lo
ad T
est b
y SA
CEP
(Y/N
)
New cases
Follow up cases
NewCases:ThosePLHIVwhoarebeingreferredtoSACEPfortheFirsttimeandre-referredcaseswhowerepreviouslynotgivenappointmentorwerenotpreviouslyeligible(<400copies/ml).
Followupcasesincludes:
• ThosePLHIVwhohavecomeforreviewwiththeirFirstVLreportor
• RepeatVLresultsafterinitiationofSecondline(6th/12thmonth),or
• ThosePLHIVswhowerenoteligibleearlierandhavecomeforreviewofrepeatviralloadsresultsbySACEP(400-5000copies/ml)
13 14 15 16
Vira
l Loa
d re
sult
with
dat
e
Clin
ical
Sta
tus
(OI,
Clin
i-ca
l sta
ging
)
Whe
ther
reco
mm
ende
d fo
r Se
cond
line
ART
?
(Yes
/No)
Rem
arks
2 SL : SECOND LINE FORMAT FOR SACEP MEETING (ADULT & CHILDREN )
(To be prepared before every SACEP and given to members during the meeting &be kept at CoE/pCoE/ART plus Centres)
93National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
2SL Summary -Second Line ART Members Present during the SACEP
Sl. No No of
patients1
1Totalno.ofpatientsreferredtoSACEPforsuspectedtreatmentfailure
2
2Totalno.ofpatientssupposedtoattendSACEPforsuspectedtreatmentfailure
3
3TotalNumberofpatientsactuallyreviewedbySACEPforsuspectedtreatmentfailure
4
4TotalnumberofpatientsrecommendedforViral Load test
5
5TotalnumberofpatientsrecommendedforSecondLineART(AfterVL)
6
6TotalnumberofpatientsactuallyinitiatedonSecondLineART(Afterminimum2counsellingsessions)
94 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
3AL+
SL C
OM
BIN
ED M
ON
THLY
REP
OR
TIN
G F
OR
MAT
FO
R S
ECO
ND
& A
LTER
NAT
IVE
FIR
ST L
INE
AR
T(to
be
sent
to N
ACO
by
4th o
f eve
ry m
onth
to S
econ
dlin
e200
8@gm
ail.c
om)
(Pro
vide
d se
para
tely
in E
xcel
form
)
artdrugs@gm
ail.com
,Con
cerned
SAC
S(JD,C
ST),RC
&linked
CoE
/ART
plus/pC
oE)
1. N
ame
of A
RT C
entr
e
2. C
MIS
Cod
e of
ART
cen
tre
(sam
e as
cod
e fo
r Fi
rst l
ine)
3.Nam
eofth
eDistrict
4.Nam
eofth
eState
5.Nam
eofNod
alOfficer
6.Rep
ortforth
epe
riod
Mon
th Y
ear
Seco
nd li
ne A
RT
7. D
etai
ls o
f PLH
IV re
ferr
ed to
SA
CEP
for
susp
ecte
d tr
eatm
ent f
ailu
reA
dult
Child
ren
Tota
l
M
ale
Fem
ale
TS/T
GM
ale
Fem
ale
7.1Cu
mulati
venum
berofPLH
IVre
ferred
toSAC
EPfo
rassessmen
tatthe
be
ginn
ingofth
ism
onth
7.2Num
berofnew
PLH
IVre
ferred
toSAC
EPfo
rassessmen
tduringthis
mon
th
7.3
Cum
ulati
ve n
umbe
r of
PLH
IV re
ferr
ed to
SA
CEP
for
asse
ssm
ent a
t the
en
d of
this
mon
th =
7.1
+ 7
.2
7.4a
Cum
ulati
venum
berofpati
entsre
ferred
from
thisCoE
/ART
pluscentre
(The
repo
rting
cen
tre)(o
utof7
.3)
7.4b
Cum
ulati
venum
berofpati
entsre
ferred
from
referringART
cen
tres
linkedtoth
isCoE
/ART
plus(outof7
.3)
7.4cCum
ulati
venum
berofpati
entsgiven
app
ointmen
tforSAC
EPre
view
at
endofth
ism
onth(ou
tof7
.3)
7.4d
Cum
ulati
venum
berofpati
entsactua
llyre
view
edbySA
CEPatend
of
thism
onth(ou
tof7
.4c)
7.4e
Cum
ulati
venum
berofPLH
IVfo
undeligiblefo
rViralLoa
d(outof7
.4d)
95National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
7.4fCum
ulati
venum
berofPLH
IVactua
llyund
erwen
tVira
lLoa
d(outof
7.4e
)
8.1Cu
mulati
venum
berofPLH
IVfo
undeligiblefo
rSecond
line
atb
eginning
ofth
ism
onth
8.2Num
berofPLH
IVfo
undeligiblefo
rSecond
line
duringthism
onth
8.3
Cum
ulati
ve n
umbe
r of
PLH
A fo
und
elig
ible
for
Seco
nd li
ne a
t the
end
of
this
mon
th =
8.1
+ 8
.2
8.4Cu
mulati
venum
berofpati
entseverstartedon
Secon
dlin
eART
(Num
-be
ratth
ebe
ginn
ingofth
ism
onth)(8.7ofp
reviou
smon
th)
8.5Num
berofnew
pati
entsstarted
onSecond
line
ART
duringthism
onth
8.6Num
berofpati
ents“restarted“onSecond
line
ART
duringthism
onth
8.7
Cum
ulati
ve n
umbe
r of
pati
ents
eve
r st
arte
d on
Sec
ond
line
ART
(Num
-be
r at
the
end
of th
is m
onth
) = 8
.4+8
.5+8
.6
9.1Cu
mulati
venum
berofpati
entsonSecond
line
who
diedsincethe
beginn
ingofth
eprog
ramme
9.2a
Cum
ulati
venum
berofpati
entsonSecond
line
who
are“tran
sferred
out”to
otherCOE/ART
plus
9.2b
Cum
ulati
venum
berofpati
entsonSecond
line
who
are“tran
sferred
out”to
thereferringcentres(ART
cen
tres)
9.2cCum
ulati
venum
berofpati
entsonSecond
line
who
are“tran
sferred
in”(fromotherCOE/ART
plus)
9.3Num
berofallpa
tientson
Secon
dlin
etreatm
entw
hosetreatm
ent
statusin
thism
onthis“stop
pedtreatm
ent”
9.4Cu
mulati
veNum
berofpati
entsonSecond
line
who
arelo
stto
follo
w-up
(LFU
)
9.5Cu
mulati
veNum
berofpati
entsonSecond
line
treatm
entw
hodidnot
returnto
theART
cen
tre(Defau
lter)/w
hosetreatm
entstatusis“MIS”inth
is
mon
th
9.6
Tota
l num
ber
of p
atien
ts a
live
and
on S
econ
d lin
e A
RT (O
T) a
t the
end
of
this
mon
th =
8.7
+ 9.
2c -
(9.1
+9.2
a+9.
3+9.
4+9.
5)
9.7a
Outof9
.6,the
num
berofpati
entsonSecond
line
ART
initiated
on
DOTSth
ism
onth
96 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
9.7b
Outof9
.6,the
num
berofpati
entsonSecond
line
ART
initiated
on
non-DOTSanti
-tub
erculosistreatm
entthismon
th
9.7cOutof9
.6,the
totaln
umbe
rofpregn
antw
omen
onSecond
line
ART
thism
onth
Alt
erna
tive
Fir
st li
ne A
RT
10.1Cu
mulati
venum
berofPLH
IVre
ferred
toSAC
EPfo
rassessmen
tatthe
be
ginn
ingofth
ism
onth
10.2Num
berofnew
PLH
IVre
ferred
toSAC
EPfo
rassessmen
tduringthis
mon
th
10.3
Cum
ulati
ve n
umbe
r of
PLH
IV re
ferr
ed to
SA
CEP
for
asse
ssm
ent a
t the
en
d of
this
mon
th(1
0.1+
10.2
)
10.3aNum
berreferred
from
CoE
/ART
plus(The
repo
rting
cen
tre)(o
utof
10.3
)
10.3bNum
berreferred
from
otherART
cen
tres(o
utof1
0.3)
11.1Cum
ulati
venum
berofPLH
IVfo
undeligiblefo
rAlte
rnati
veFirstline
ART
atb
eginning
ofthismon
th(1
1.3ofpreviou
smon
th)
11.2Num
berofPLH
IVfo
undeligiblefo
rAlte
rnati
veFirstlineART
during
thism
onth
11.3Totalnum
berofPLH
IVfo
undeligiblefo
rAlte
rnati
veFirstlineART
till
theen
dofth
ism
onth(11.1+
11.2)
12.1Cum
ulati
venum
berofpati
entseverstartedon
Alte
rnati
veFirstline
ART
(Num
beratth
ebe
ginn
ingofth
ism
onth)
12.2Num
berofnew
pati
entsstarted
onalternati
veFirstlineART
during
thism
onth
12.3
Cum
ulati
ve n
umbe
r of
pati
ents
eve
r st
arte
d on
Alt
erna
tive
Fir
st li
ne
ART
(Num
ber
at th
e en
d of
thi
s m
onth
) =12
.1+1
2.2
13.1Cum
ulati
venum
berofpati
entsonalternateFirstlinewho
diedsince
thebe
ginn
ingofth
eprog
ramme
13.2aCu
mulati
venum
berofpati
entsonAlte
rnati
veFirstlinewho
are
“transferred
out”tootherCoE
/ART
PlusCe
ntres
13.2bCu
mulati
venum
berofpati
entsonAlte
rnati
veFirstlinewho
are
“transferred
out”toth
ereferringART
cen
tre
13.2cCu
mulati
venum
berofpati
entsonAlte
rnati
veFirstlinewho
are
“transferred
in”from
othercen
tres(C
oE/ART
plus)
97National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
13.3The
num
berofallpa
tientson
Alte
rnati
veFirstlinetreatm
entw
hose
treatm
entstatusinth
ism
onthis“stop
pedtreatm
ent”
13.4Cum
ulati
veNum
berofpati
entsre
ceivingAlte
rnati
veFirstlinewho
are
lostto
follo
w-up(LFU
)
13.5The
num
berofpati
entsonAlte
rnati
veFirstlinetreatm
entw
hodidnot
returnto
theART
cen
tre(Defau
lter)/,who
setreatm
entstatusis“MIS”in
thism
onth
13.6
Tot
al n
umbe
r of
pati
ents
aliv
e an
d on
Alt
erna
tive
Fir
st li
ne A
RT=
12.3
+13.
2c-(
13.1
+13.
2a+1
3.3+
13.4
+13.
5)
13.7Outof1
3.6,th
enu
mbe
rofpati
entsonAlte
rnati
veFirstlineART
initi-
ated
onDOTSth
ism
onth
13.8th
enu
mbe
rofpati
entsonAltFirstlineART
initiated
onno
n-DOTS
anti-tube
rculosistreatm
entthismon
th
13.9th
etotaln
umbe
rofpregn
antw
omen
onAlte
rnati
veFirstlineART
this
mon
th
14. T
reat
men
t A
dher
ence
N
umbe
r
14.1aOfa
llpa
tientswho
areonSecond
line
ART
thism
onth(9
.6),thenu
mbe
rwho
haveNOTbe
enassessedforad
herence
(ref
er g
uide
line)
14.1bOfa
llpa
tientson
Secon
dlin
eART
(9.6)thismon
thand
who
havebe
enassessedforad
herence,how
man
yha
d95
%
adhe
renceorbett
er(referguide
line)
14.2aOfa
llpa
tientswho
areonalternati
veFirstlineART
thism
onth(1
3.6)th
enu
mbe
rwho
haveNOTbe
enassessedfor
adhe
rence(referguide
line)
14.2bOfa
llpa
tientson
alte
rnati
veFirstlineART
(13.6)th
ism
onthand
who
havebe
enassessedforad
herence,how
man
yha
d95
%adh
eren
ceorbe
tter(referguide
line)
15 a
. Pri
mar
y Re
gim
en o
f PLH
IV s
tart
ed o
n Se
cond
line
/Alt
erna
tive
Fir
st li
ne A
RT a
t the
end
of t
he m
onth
Regi
men
Adu
lt
Pedi
atri
csTo
tal
Teno
fovir+Lam
ivud
ine+Nevira
pine
11
2
Teno
fovir+Lamivud
ine+Efavire
nz1
12
Zido
vudine
+Lam
ivud
ine+Atazan
avir/Rito
navir
11
2
Zido
vudine
+Lam
ivud
ine+Lopina
vir/Ritona
vir
11
2
Teno
fovir+Lamivud
ine+
Atazana
vir/Ritona
vir
11
2
98 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
Teno
fovir+Lamivud
ine+Lop
inavir/Rito
navir
11
2
Stavud
ine+Lamivud
ine+Lopina
vir/Ritona
vir
11
2
Stavud
ine+Lamivud
ine+Atazan
avir/Rito
navir
11
2
Aba
cavir+Lamivud
ine+Nevira
pine
11
2
Aba
cavir+Lamivud
ine+Efavire
nz1
12
Aba
cavir+Lamivud
ine+Lopina
vir/Ritona
vir
11
2
Zido
vudine
+Lam
ivud
ine+Lopina
vir/Ritnovir
11
2
Stavud
ine+Lamivud
ine+Lopina
vir/Ritona
vir
11
2
Aba
cavir+Lamivud
ine+Didan
osine+Lopina
vir/Ritona
vir
11
2
Others
11
2
Tota
l 15
1530
15.b
. Tot
al N
umbe
r of
Pati
ents
on
CPT
Prop
hyla
xis
Regi
men
Adu
ltsPe
diat
rics
Cotrim
oxazole(DS)
Cotrim
oxazole(SS)
Cotrim
oxazoleSu
spen
sion
Tota
l num
ber
of p
atien
ts
99National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
15.c
. Opp
ortu
nisti
c In
fecti
ons
OI’s
Num
ber
of e
piso
des
of O
Is th
is
mon
thO
I’sN
umbe
r of
epi
sode
s of
OIs
this
mon
th
Adu
lts P
edia
tric
sA
dults
Ped
iatr
ics
1(a)Tub
erculosis(Pulmon
ary)
8Toxoplasmosis
1(b)Tube
rculosis(E
xtra-Pulmo-
nary)
9CM
VRe
tinitis
2 Ca
ndid
iasi
s
10
Bacterial
Infecti
ons(skin)
3Diarrho
ea
11
Herpe
sSimplex
4 PC
P
12
Maligna
ncy
5Herpe
sZo
ster
13Others
6Ba
cterialInfectio
ns(R
espiratory)
14Others
7CryptococcalM
eningitis
100 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
4 A
L : L
IST
OF
PATI
ENTS
ON
ALT
ERN
ATIV
E FI
RST
LIN
E A
RT
12
34
56
78
910
1112
1314
1516
17
Sl. No (SACEP registration No).
ART Reg. No.
Name
Age
Sex
Address
Telephone
Date of ART start (1st line)
Current CD4 count
Type
of T
oxic
ity
Probable drug causing toxicity
SACEP recom-mendations
Date of ART start (alternative First line)
Alternative First line Regimen*
Status of patient (OT/MIS/LFU/TO/Death)
To b
e fil
led
by C
oE/P
CoE/
ART
plu
s ce
ntre
onl
y
Clin
ical
Symptom
sLabo
ratory
test
sPa
tien
t ref
erre
d ba
ck to
the
refe
rrin
g A
RT
cent
re (y
es/n
o?)
Dat
e of
refe
r-ra
l bac
k to
the
refe
rrin
g A
RT
cent
re
4 SL
: L
IST
OF
PATI
ENTS
ON
SEC
ON
D L
INE
AR
T
15.d
Wer
e th
ere
any
spec
ific
side
eff
ects
not
ed fo
r Se
cond
line
/Alt
erna
tive
Fir
st li
ne A
RT d
urin
g th
e m
onth
M
ale
Fem
ale
Parti
cula
rsA
dult
Pedi
atri
csA
dult
1. A
ZT In
duce
d A
naem
ia
2.Periphe
ralN
europa
thy
3.Hep
atitis
4.Lipod
ystrop
hy
5.Pancreati
tis
6.SkinRe
actio
n
7.CNSSide
Effe
cts
8. IR
IS
101National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
12
34
56
78
910
1112
1314
1516
17
Sr. No.( (SACEP Regn. No)
ART Reg. No.
Name
Age
Sex
Address
Telephone
Date of ART start (1st line)
Current regimen (at the time of SACEP Referral)
CD4
coun
tV
iral
load
at t
he ti
me
of S
ACE
P as
sess
men
t w
ith
date
SACE
P re
com
men
dati
ons
Date of ART start (Second line)
Second line ART regimen initiated
Status of patient (OT/MIS/LFU/TO/Death)
To b
e fil
led
by
CoE/
PCoE
/ART
pl
us c
entr
e on
ly
Baseline
At the time of At the time of referral to SACEP
Baseline
Aft
er 6
m
onth
s on
2nd
Li
ne
Aft
er 1
2 m
onth
s on
2nd
Li
ne
After Baseline VL
Aft
er 6
m
onth
s on
2nd
Li
ne
Aft
er
12
mon
ths
on 2
nd
Line
Pati
ent
re-
ferr
ed
back
to
the
refe
r-ri
ng
ART
ce
ntre
(y
es/
no?)
Dat
e of
re
ferr
al
back
to
the
refe
r-ri
ng A
RT
cent
re
1
2
3
4 5 6 7 8 9 10
Tota
l
102 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
5 SL
: CEN
TRE
WIS
E (L
INK
ED C
ENTR
E IN
FOR
MAT
ION
) BR
EAK
UP
FOR
PLH
IV IN
ITIA
TED
ON
SEC
ON
D L
INE
AR
TS.
No
Nam
es
of
Link
ed
ART
Ce
ntre
s
Cum
ula-
tiveno
of
patie
nts
Refe
rred
to
SAC
EP
(7.3
)
Cum
ula-
tiveno
of
patie
nts
givenap
-po
intm
ent
for
SACE
P review
(7
.4c)
Cum
ula-
tiveno
of
patie
nts
actually
review
ed
bySAC
EP
(7.4
d)
Cum
ula-
tiveno
of
patie
nts
elig
ible
for
viralloa
dte
st (7
.4e)
Cumulati
ve
num
ber
of
PLHIVactua
lly
unde
rwen
tVi
ral L
oad
(7.4
f)
Cum
u-lativ
enu
mbe
r of
PLH
A
foun
d el
igib
le fo
r Se
cond
lin
e (8
.3)
Cumulati
ve
num
ber
of
patie
ntsever
star
ted
on
Seco
nd li
ne
ART
(8.7
)
Cum
u-lativ
enu
mbe
r of
pa
tients
on S
econ
d lin
ewho
di
ed (9
.1)
Alivean
don
Secon
dlin
eART
(9.6)
At C
oE/
ART
plus
cent
re
At re
fer-
ring
cen
tre
Tota
l
1
2
3
4
5
6
7
8
9
10 To
tal
103National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ANNEX X
104 National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
105National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents May 2013
ACKNOWLEDGEMENTS
“The National AIDS Control organisation wishes to acknowledge contributions made by the guidelines team at NACO, Regional Coordinators, Joint Directors of SACS, Program Directors of CoEs, and other contributors in updating these guidelines.
We also acknowledge the technical support provided by World Health Organisation country office for India in developing and updating these 2013 guidelines.
The support of International Training and Education Centre for Health (I-TECH), India for printing these guidelines is also acknowledged”