HIV Drug resistanceimplications

Transcription

1 HIV Drug resistanceimplications for therapy Deenan Pillay Africa Centre for Health and Population Studies, UKZN University College London

2 Potential implications of HAART without virological monitoring: Therapy failure? CD4 count VL Months Years VL 1 Treatment onset Virological failure (>1c/mL) Clinical failure (AIDS events) increasing resistance

3 All viruses are archived and can re-emerge Drug pressure Resistance testing only detects the majority virus population in plasma wild type drug-resistant virus

4 IMPACT OF VIRAL VARIATION/QUASISPECIES Potency Durability Viral load total majority susceptible strain minority resistant strain time -FIRST PHASE VIRAL DECLINE AS AN IN VIVO PHENOTYPE

5 HOW TO DEFINE RESISTANCE? Genotype- mutations, collections of mutations In vitro phenotype fold resistance, gene of choice Clinical response- complexity of multiple drugs

6 Phenotyping Inhibition of viral replication (%) 1 Susceptible strain Wild type Resistant strain 5 Resistance IC 5 IC 5 IC 5 Drug concentration

7 ZDV/3TC/ABC: Example of Slow Stepwise Appearance of Mutations in Subjects With Virologic Failure Plasma HIV-1 RNA Log WT 5 c/ml 4 c/ml 5 c/ml M184V D67N/D, K7R/K, M184V M184V, T215T/Y M41L/M, M184V, T215Y M41L, M184V, T215Y M41L, M184V, L21L/W, T215Y 28 weeks of M184V only ABC=5.9, ZDV=4.1fold Study week ABC=6.2, ZDV=12.2 fold

8 The intensity of virological monitoring is associated with resistance to 1 st line HAART 7% 6% 5.9% 6.1% 5% 4% 3% 2.7% 2% 1.7% 2.1% 1% %.7%.1%.3% Any TAMS M184V/I 3rd Agent K65R Any TAMS M184V/I 3rd Agent K65R Frequent viral load monitoring Infrequent/no viral load monitoring Gupta et al CID 29

9 INCIDENCE OF RESISTANCE IN VIROLOGICAL FAILURES ON 1ST LINE NNRTI- OR bpi- CONTAINING REGIMENS: A META ANALYSIS 6% 53.% 5% 4% 35.3% 3% 21.% 2% 1% 5.3% %.3% Major NNRTI.6%.9%.% M184V/I Any TAMS Major PI K65R Major NNRTI 1.5%.% M184V/I Any TAMS Major PI K65R PI Studies NNRTI Studies Gupta et al, LID 29

10 Antiviral dynamics determines HIV evolution and predicts therapy outcome Rosenbloom et al, Nat Med 212

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12 Virological response

13 Emerging resistance

14 High rates of re-suppression after virological failure on first line therapy in the absence of routine monitoring: 96 week data from the DART NORA substudy Gupta et al Clin Inf Dis 214

15 Evidence on HIV drug resistance testing Dunn et a, 27

16 Population impact of drug resistance - will spread of HIV drug resistance require change of 1 st line therapy?

17 TDR and time since roll out East Africa: Estimated proportion with NNRTI TDR 8 years after start of roll out = 7.4% Gupta et al, Lancet, 212 Also: Frenz et al; AIDS rev 212

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19 POPART intervention; modelling outcome Christophe Fraser

20 Will ART expansion in SA lead to a relative increase in HIV drug resistance? Cambiano, Bertagnolio, Jordon, Pillay, Perriens,Ventner, Lungren, Phillips. AIDS, 214

21 Meta-analysis demonstrates importance of M184V minority assays Continuity Ratio of new Study Year Standard AS-PCR N correction detections (95% CI) K13N Metzner (1., 1.94) Metzner (1., ) Metzner (1., 91.11) Johnson Pillay Buckton Coovadia (1.16, 25.2) 3. (1., 28.84) 1.2 (1., 1.55) 3. (1.19, 7.56) K13N Hauser (1., 59.66) Metzner (1., ) Metzner (1., 28.84) Paredes (1.4, 4.2) Toni (1., 91.11) D+L Subtotal (I-squared = 54.4%, p=.12) 2.21 (1.49, 3.29) I-V Subtotal 1.44 (1.22, 1.7). M184V Metzner (1., 35.91) Metzner (1.53, ) Metzner Johnson Buckton Metzner (1., ) 3. (1., 28.84) 13. (1.98, 85.46) 23. (1.53, ) M184V Metzner (1., ) Toni (1., ) Vignoles (2.3, ) D+L Subtotal (I-squared =.%, p=.878) 9.32 (4.46, 19.44) I-V Subtotal 9.32 (4.46, 19.44). NOTE: Weights are from random effects analysis

22 Objective To assess the impact of transmitted drug resistance mutations on virological and immunological response up to 16 months after starting a combination antiretroviral therapy (cart) Specific analyses: Transmitted drug resistance and fully active treatment 2NRTI + 1NNRTI or 2NRTI + 1boosted PI regimen Study population HIV infected patients regardless of age Start of cart after sample taken before antiretroviral treatment for genotypic testing 22

23 Methods Virologic endpoint: time to first of two consecutive viral load>5 copies/ml after six months of therapy Definition TDR (two steps): WHO list 29 1 Patients having at least one mutation Stanford 2 version 6..5 Group Patients with no detected mutation (used as a reference group) Group 1 show no drug resistance to their prescribed drug (classified as susceptible or as potential low level resistance ) Group 2 resistant to at least one of their prescribed drugs (classified as Low-level resistance, Intermediate' or as High level resistance ) 1 Bennett PlosOne 29, 2 Liu CID 26 23

24 Characteristics at the time of starting cart 1,56 patients from 25 cohorts 76% male Median age 38 years 56% of European origin 69% harboured a subtype B virus Pre-treatment viral load and CD4 counts were 5 log1 cp/ml and 218 cells/μl Transmission risk groups: 5% homosexual, 32% heterosexual, 8% IDUs and 2.1% perinatal 9.5% (n=954) patients harboured a virus with 1 mutation 49.8% (n=475) received a fully active treatment 5.2% (n=479) harboured a virus predicted to have at 24 least low level resistance for 1 prescribed drug

25 Virological failure according to TDR In adjusted analysis*: Patients with resistance to 1 drug: - significant higher risk of VF compared to patients without mutations - HR: 3.3 (2.5; 4.4) P<1-4 % VF patients receiving a fully active cart and patients with no mutation: - risk of VF was not significantly different - HR: 1.4 (.9; 2.3) P= Time after start of therapy (month) *All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin 25

26 Impact of TDR according to treatment strata HR* No TDR TDR TDR No TDR TDR TDR No TDR No TDR TDR and TDR and No TDR TDR and TDR and No TDR and and and and fullyactive fully resistant fullyactive resistant resistant fully resistant active active cart cart TDR TDR and and fullyactive fully active cart ALL 2NRTIs + 1NNRTI 2NRTIs + PI/rtv ALL 2NRTI+1NNRTI 2NRTI+1PI/rtv TDR TDR and and resistant resistant *All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin 26

27 From: Efficacy and Tolerability of 3 Nonnucleoside Reverse Transcriptase Inhibitor Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1: A Randomized, Controlled Equivalence TrialNNRTI-Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1 Ann Intern Med. 214;161(7): doi:1.7326/m Figure Legend: Outcomes at week 96, according to the FDA snapshot definition. ART = antiretroviral therapy; ATV/r = atazanavir plus ritonavir; DRV/r = darunavir plus ritonavir; FDA = U.S. Food and Drug Administration; RAL = raltegravir. Date of download: 1/9/214 Copyright American College of Physicians. All rights reserved.

28 Conclusion Differential resistance on 1 st line therapy Impact of resistance is a function of therapeutic availability increase transmission of resistance likely with extended roll out