3 Structure of Talk Basis of resistance Resistance in treated: prevalence and predictorsResistance in untreated: prevalence, risk groups, persistence, minority populations and consequencesPotential for resistance in developing world
4 Replication Cycle of HIV maturation inhibitorreversetranscriptaseinhibitorsintegrase inhibitorsDS dna COMPLEXproteaseinhibitorsCD4 attachment inhibitorsfusion inhibitorchemokine receptor inhibitorsHIV entry inhibitors
6 Question: Drug resistance emerges during antiretroviral therapy Because the drug interacts with the virus to cause resistance mutationsBecause pre-existing variants of virus preferentially replicate in the presence of drugRegardless of the level of viral suppression achieved
7 Virological Response to Antiretroviral Therapy rebound10510410310210110010-110-210-3assay limitof detectionCopies/mLSuppression
8 Selective Pressure of Therapy Drug-susceptible quasispeciesDrug-resistant quasispeciesViral loadTime
9 Selective Pressure of Therapy Treatment beginsDrug-susceptible quasispeciesDrug-resistant quasispeciesViral loadTime
10 Selective Pressure of Therapy Treatment beginsDrug-susceptible quasispeciesDrug-resistant quasispeciesSelection of resistant quasispeciesViral loadIncomplete suppressionInadequate potencyInadequate drug levelsInadequate adherencePre-existing resistanceTime
11 Resistance Accumulates MutationsFold ChangeSusceptible ResistantDetermine clinical relevance for each drug
12 How Much Resistance in ARV Treated Individuals?
13 Prevalence of Resistance as a Proportion of Treated Patients important to place resistance in context of all TREATED patientsPillay et al. JID 2005;192:
14 Predictors of Resistance in ARV-treated Patients
15 Prevalence of Triple-class Drug Failure Over Calendar Time Treatment experienced at start of HAARTTreatment naïve at start of HAART1/97 1/98 1/99 1/00 1/01 1/02 1/03 1/97 1/98 1/99 1/00 1/01 1/02 1/03Follow-up (n)Triple-class treatment failure (n)Mocroft et al. JID 2004;190:1947–56.
16 Years from start of ART (≥3 drugs) Cumulative Risk of Triple-class Virologic Failure (incl boosted PIs) in 10,603 PatientsYears from start of ART (≥3 drugs)246810Extensive failure of:Nucleosides4%9%15%21%28%PIs2%8%11%16%NNRTI13%20%26%31%35%TCF5%Extensive TCF0%1%3%PI failure = boosted PIs; TCF = triple class failurePhillips et al. CROI Abst 532.
17 Resistance in Treated Individuals is… Decreasing since initiation of triple therapyLow in those using RTV boosted PIsManaged by new drugs within existing classes and new classes
18 Transmission of Resistance ARV treated individuals living longerIncident infections continue to increase worldwideTransmitted resistance well recognised in countries with wide ARV coverage
19 Transmission of Resistance in Europe (17 countries) SPREADRoute of Infection p-value OR CIIDU 6.8% /Origin / infect. in HPC 5.2% 10/Heterosexual 12.0% 30/MSM (reference) 10.0% 47/Origin / infect. in HPC* 5.2% 10/*HPC = high prevalence countriesn=989; 22% recent infectionsWensing et al. JID 2005;192:
20 Samples with IAS mutation(s) (%) In resource rich world, transmitted resistance appears to be stabilising or even reducing14Chronic infection12108Samples with IAS mutation(s) (%)64Acute infection2199719981999200020012002200320042005Year of sampleUK Collaborative Group on HIV Drug Resistance.AIDS 2007;21:
21 Persistence of Transmitted Resistance in Primary HIV Infection Persistent resistancen=11Primary resistancen=2Reversion to wild typeUS; F/U median 9 monthsn=14Persistent resistancen=16Primary resistancen=2Reversion to wild typeUK; F/U up to 3 yearsVariable persistence according to mutations: TAMs persist, K103N persists, PI persist, MDR persistLittle et al. 11th CROI 2004, San Francisco, CA. Abs 36LB.Pao et al. JAIDS 2004;37:
22 In resource rich world...Rates of transmitted resistance stabilising or reducingTransmitted resistant species persist prior to initiating treatment, and represents a risk for onward transmission
23 Implications of ARV Rollout in Resource Poor World for Resistance
24 Implications of HAART Without Virological Monitoring: Therapy Failure? Increasing ResistanceImplications of HAART Without Virological Monitoring: Therapy Failure?Treatment onsetVirological failure (>1000c/mL)Clinical failure (AIDS events)VL 1000MonthsYearsCD4 countVL
26 DART TRIAL ZDV/3TC/TDF (n=300) Prevalence of mutations at 24 and 48 weeks in absence of virological monitoringMutationWeek 24 (n=24)Week 48 (n=41*)M184V15 (62%)32 (78%)K65R3 (12%)6 (15%)M41L7 (29%)17 41%)D67NG9 (38%)23 (56%)K70R8 (33%)L210W0 (0%)3 (7%)T215FY17 (41%)K219QEN1 (4%)9 (22%)Total TAMs: 01–34–610 (42%)13 (54%)11 (27%)18 (44%)12 (39%)TAM Group** IIII and II5 (36%)4 (11%)2 (7%)11 (37%)17 (57%)Pillay et al. CROI Abstr. 642.
27 Summary Resistance develops following failure of therapy Resistance can be transmittedImprovements in ARV use reduces emergence and transmission of resistanceExtensive resistance may develop in absence of monitoring of ARV use
28 Question: Risk of resistance is increased by: Mono and/or dual therapy prior to HAARTUse of ritonavir boosted PIsInitiation of HAART at CD4 counts >200/L