Update on HIV-1 Drug Resistance and Tropism Testing

Transcription

1 Update on HIV-1 Drug Resistance and Tropism Testing Daniel R. Kuritzkes, MD Section of Retroviral Therapeutics Brigham and Women s Hospital Harvard Medical School ACTHIV 2011: A State-of-the-Science Conference for Frontline Health Professionals

2 Learning Objectives Upon completion of this presentation, learners should be better able to: Identify patterns of resistance and crossresistance among newer antiretroviral drugs including 2nd-generation NNRTI, integrase inhibitors and CCR5 antagonists which may impact your patients Select among phenotypic and genotypic tests of viral tropism based on their advantages and limitations

3 Etravirine TMC125 identified through screening for activity against NNRTI-resistant viruses In vitro passage experiments suggested high genetic barrier to resistance Known and novel NNRTI resistance mutations identified through in vitro passage experiments L100I, Y181C, G190E, Y318F V179I/F Data from DUET and phase 2 trials identified 17 clinically significant ETV resistance mutations 1. Vingerhoets J, et al. AIDS 2010 [epub ahead of print]; 2. Etravirine [package insert]. Raritan, NJ: Tibotec Therapeutics; 2008.

4 DUET-1 and -2: Etravirine resistanceassociated mutations ETR mutations (n=17) weighted based upon impact on response (weight factor) 1: 3.0: Y181I/V 2.5: L100I, K101P, Y181C, M230L 1.5: V106I, V179F, E138A, G190S 1.0: V90I, A98G, K101E/H, V179D/T, G190A Most common resistance mutations emerging at ETR failure in DUET trials: V179F/I and Y181C/I 2 1. Vingerhoets J, et al. AIDS 2010 [epub ahead of print]; 2. Etravirine [package insert]. Raritan, NJ: Tibotec Therapeutics; 2008.

5 DUET-1 and -2: Predictors of ETR Response and Resistance at Failure Vingerhoets J et al. AIDS 2010 [epub ahead of print]

6 Integrase inhibitor resistance Integrase strand-transfer inhibitors (INSTI) select for specific resistance mutations in HIV-1 IN Three pathways identified for raltegravir: N155H Q148K/R/H Y143C/R Extensive cross-resistance between raltegravir and elvitegravir

7 Raltegravir Resistance at Failure (%) BENCHMRK Combined Analysis: Raltegravir Resistance at Virologic Failure Nonresponse (n=13) Viral rebound (n=81) 62% 67% Week % % 23% 30% % 10% 0 155, 148, or Percent With Mutation at Integrase Codons 155, 148 or Includes only patients with virologic failure for whom integrase genotypic data were available (n=89). Cooper DA, et al. N Engl J Med. 2008;359:

8 Raltegravir Resistance Evolution N155H N155H + Q148H Q148H + others N155H + Q148H Q148H Q148H + others Q148H + others Fransen S, et al. J Virol 2009

9 % population % population Fitness of INSTI-resistant mutants in presence of raltegravir Q148H N155H G140S/Q148H E92Q/N155H Days post-infection INSTI = integrase strand transfer inhibitor Hu et al JAIDS 2010

10 Mechanism of HIV-1 entry CD4 Binding Co-receptor Binding Virus-Cell Fusion CD4 gp41 gp120 V3 loop Cell Membrane CCR5/CXCR4 (R5/X4) Adapted from Doms et al. Genes Dev. 2000;14:

11 HIV-1 co-receptor usage R5 viruses use CCR5 exclusively X4 viruses use CXCR4 exclusively Dual/mixed viruses (D/M) can use either CCR5 or CXCR4 (or represent mixed R5 and X4 viruses) V3 loop of gp120 is the major determinant of co-receptor usage

12 CCR5 antagonists are allosteric inhibitors of HIV-1 infection Free receptor wt gp120 gp120 binding site on CCR5 High affinity Drug ( ) bound to CCR5 Binding site disrupted by drug Very low affinity Adapted from Mosley M et al. 13th CROI 2006; abstract 598.

13 % inhibition % inhibition Inhibition curves for competitive versus non-competitive inhibitors of HIV-1 Competitive inhibitor Non-competitive inhibitor Log drug concentration Log drug concentration DR Kuritzkes

14 Subject 07J Bulk VCV Susceptibilities Baseline Week 2 Week 8 R R R Week 19 failure confirmation Week 24 Week 28 DM DM DM Tsibris et al J Virol 2009

15 CCR5 antagonist resistance STUDY MOTIVATE (MVC treatmentexperienced) MERIT (MVC treatment-naïve) ACTG A5211 (VCV treatmentexperienced) P03802 (VCV treatment-naïve) N Resistant/ N tested (%) Number exposed 15/36 (42%) 840 4/29 (14%) 360 (BID arm) 4/29 (14%) 90 4/26 (15%) 68 Mori et al, 6 th European Workshop on HIV Drug Resistance, 2008, Budapest Tsibris et al J Virol 2008; Wilkin et al JAIDS 2010 (in press) Strizki et al 7 th Ann Symp on Antiviral Drug Resistance, 2006, Chantilly, VA Craig C et al. 17 th CROI, San Francisco, 2010, Abstract 536.

16 Coreceptor Changes on CCR5 Antagonists Represents the dominant pathway to failure 57% of subjects in MOTIVATE-1 and -2 35% of subjects in A % of subjects in MERIT Origin of CXCR4-using viruses: Emergence from pre-existing minority population Tropism assay misclassifications (1 st gen) ~10% of A5211 subjects ~8% of MOTIVATE subjects Fätkenheuer et al NEJM 2008 Gulick et al J Infect Dis 2007 Heera et al 15 th CROI 2008

17 Coreceptor Tropism by the Standard and Enhanced Tropism Assays Standard assay Enhanced assay Screen (n) Entry on study Screen (n, %) R5 (12) DM DM/X4* DM (7/12, 58%) R5 (18) R5 DM/X4 DM (9/18, 50%) R5 (88) R5 R5 DM (9/84, 11%) Total 118 *n=10 Total 25/114 (22%) Enhanced tropism assay reclassified 25 individuals with R5 virus at screen 15/25 were VCV recipients 12/15 had early emergence of X4 virus on study (week 2-8) by standard tropism assay Su et al J Infect Dis 2009;200:

18 Genotypic tests of HIV tropism Based on V3 loop sequence analysis Several algorithms to predict coreceptor usage PSSM Geno2pheno Overall, high specificity but low sensitivity Newer approaches incorporate heteroduplex mobility shift in addition to sequence analysis Recent data suggest genotype may be as good as phenotype in predicting maraviroc response

19 Population V3 sequencing to predict virologic response to maraviroc MOTIVATE-1 MOTIVATE-2 A McGovern et al AIDS 2010

20 Sensitivity of phenotypic and genotypic tropism testing compared to ultra-deep sequencing Swenson et al J Infect Dis 2011

21 Median change in plasma VL in patients receiving maraviroc Swenson et al J Infect Dis 2011

22 Proportion of MVC-treated patients with VL <50 copies/ml Swenson et al J Infect Dis 2011

23 Can genotype replace phenotype for determining coreceptor usage? Genotyping performs well, particularly with deep sequencing approaches Validation studies all compared to Trofile, not enhanced-sensitivity Trofile assay Maraviroc recipients all pre-screened with Trofile Genotype and phenotype both miss presence of minority CXCR4-using variants in some patients Genotype can be used cautiously in some clinical settings, but phenotype still preferred Kuritzkes DR J Infect Dis 2011

24 Minority HIV-1 Drug Resistance Mutations and the Risk of Initial Antiretroviral Treatment Failure: A Systematic Review and Pooled Analysis Jonathan Li, Roger Paredes, Heather Ribaudo, Daniel Kuritzkes for the Minority Resistant Variants Working Group

25 Inclusion/Exclusion Criteria (study-level) Inclusion criteria Clinical trials (case-control or cohort studies) Adults (>18 yrs) Use of a sensitive assay to determine minority drug resistance mutations Treatment naïve patients on initial HAART (2 NRTI + another class) Data on both virologically suppressed and failing patients Treatment failure data available Exclusion criteria Pediatrics HIV-2 patients Reviews, cross-sectional studies, single case-reports Li JZ et al JAMA 2011

26 Inclusion Criteria (patient level) Initial HAART regimen of 2 NRTI + NNRTI No pre-existing NNRTI or NRTI, resistance mutations by standard genotyping Stanford DB mutation scoring <10 for all drugs Data available on either minority NNRTI or NRTI mutations Li JZ et al JAMA 2011

27 Study Selection Flow Diagram Abstracts from CROI and Resistance Workshop ( ) 2 Research groups contacted 1 eligible study 302 Citations from Pubmed 18 Full-text articles obtained for full review 9 eligible studies 270 Citations from EMBASE 256 Duplicates 298 Excluded after review of abstract 10 Excluded after review: 2 No control group 2 Treatment experienced 2 Cross-sectional study only 1 Boosted PI regimen only 1 Pediatrics 1 Integrase inhibitor regimen only 1 No virologic failure data Li JZ et al JAMA 2011

28 Studies Design Method Limit of Detection MV n/n Balduin, J Clin Virol, 2009 Cohort AS-PCR K103N 0.2% 13/56 Geretti, JAIDS, 2009 Case control AS-PCR All % a 3/89 b Goodman, Resistance Workshop (abs), 2009 Cohort from RCT AS-PCR K103N 0.5% 14/423 Jakobsen, CID, 2010 Cohort SNaPshot All 2% a 2/20 Johnson, PLoS Med, 2008 Case control from RCT AS-PCR K103N 0.9%, Y181C 1% M184V 0.5% a Metzner, CID, 2009 Case control AS-PCR K103N 0.01%, Y181C 0.2% M184V 0.2%, K65R 0.4% Metzner, J Clin Virol, 2011 Cohort AS-PCR K103N 0.01% M184V 0.2%, K65R 0.4% Paredes, JID, 2010 Case cohort from RCT Peuchant, AIDS, 2008 Cohort AS-PCR K103N 0.4% M184V 0.3% Simen, JID 2009 Cohort from RCT 9/240 b 3/18 b 7/56 AS-PCR K103N 0.003%, Y181C 0.03% 134/280 c 5/ All 1% 4/70 Total 194/1265 Li JZ et al JAMA 2011

29 Patient characteristics Median MV no MV Baseline log 10 pvl (N) 4.79 (117) CD4+ count (N) 208 (116) 4.95 (693) 234 (692) P = 0.14 P = 0.07 Li JZ et al JAMA 2011

30 Kaplan-Meier Curves for the Proportion of Patients without Virologic Failure by the Presence of Minority HIV-1 Drug-Resistant Variants Li JZ et al JAMA 2011

31 Effect of Minority Variants and Antiretroviral Therapy Adherence on Virologic Failure Group vs. no MV HR 95% CI N Any MV Any MV (multivariate) a MV Type NRTI MV NNRTI MV EFV NVP MV / Adherence 769 No MV / Any Adh ref ref MV / Adh 95% MV / Adh <95% MV / Adherence 769 No MV / Adh 95% ref ref No MV / Adh <95% MV / Adh 95% MV / Adh <95% MV % 965 <1% % MV % 829 <0.5% % MV copy # copies copies copies copies Li JZ et al JAMA 2011 Hazard Ratio (95% CI)

32 Conclusions MVs significantly increase rates of virologic failure Driven by NNRTI MVs Increase in VF with MVs occurs even in pts with high levels of adherence No significant difference in rates of VF between patients with MVs above and below 1% Li JZ et al JAMA 2011