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HIV resistance: First Line Failures

HIV resistance: First Line Failures. Jesi Ramone, M.D. Clinical Assistant Professor STAR Health Center SUNY Downstate. Case Vignette.

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HIV resistance: First Line Failures

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  1. HIV resistance:First Line Failures Jesi Ramone, M.D. Clinical Assistant Professor STAR Health Center SUNY Downstate

  2. Case Vignette • 25yr homosexual male diagnosed with AIDS 2012 during evaluation for Syphilis. DOH PNAP had contacted patient after a former partner had tested positive for Syphilis. • VL 150,000, CD4 180 • No other cormobidities • After H&P, what do you recommend?

  3. When to Start: Evolution of DHHS Treatment Initiation Guidelines “ART is recommended for all individuals with HIV… Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner; therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners” –2012 DHHS Guidelines HIVAN, HIV-associated nephropathy. Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 1998-2012. 3

  4. DHHS and IAS-USA Guidelines: What to Start *In HLA-B*5701–negative patients with baseline HIV-1 RNA < 100,000 copies/mL. †Avoiding the use of ABC or LPV/RTV might be considered for patients with or at high risk of cardiovascular disease. 1. DHHS Guidelines. February 2013. 2. Thompson MA, et al. JAMA. 2012;308:387-402.

  5. maturation inhibitors reverse transcriptase inhibitors integrase inhibitors protease inhibitors CD4 attachment inhibitors fusion inhibitors chemokine receptor inhibitors HIV entry inhibitors Life Cycle of HIV DS dna COMPLEX

  6. Any additional testing indicated prior to initiating therapy?

  7. Resistance Tests: When to use them and which test to use • Initial therapy • Failure to respond • Rebound following a response • Is testing necessary if resistance can be predicted? • Information can be used now or later • Immediately relevant information may be obtained • Which test? • Reflex Testing • If genotype is complex send phenotype or obtain virtual phenotype

  8. Resistance Tests: When to use them and which test to use • Two or more treatment regimens and measurable HIV RNA level (or 3-class experienced) • First Question – do you switch therapy? • Resistance testing is essential information for this decision • What are the treatment option? • Additional information includes: • Clinical status, CD4 cell count, previous treatments including tolerability and toxicity, adherence, social situation • If changing therapy resistance testing guides choices • Resistance testing does not dictate therapy • Even in highly resistant patients information may help avoid toxicity, cost and further resistance evolution • Which test? Phenotypic information may have its greatest utility when resistance level is high

  9. Evolution of Guidelines for Treatment Experienced Patients Extensive Treatment Experience/Resistance • March 2004 • Preservation of immune function and prevention of clinical progression • May 2006 • Re-suppress HIV RNA levels maximally and prevent further selection of resistance mutations Use New Agents to Fully Suppress HIV RNA

  10. Management of Highly treatment Experienced Patients • Detectable plasma HIV RNA on therapy • Obtain resistance testing • The greater the resistance the more useful phenotype or virtual phenotype • Assess clinical situation • Adherence • Previous treatment history – ARV tolerability and toxicity • Balance clinical urgency with availability of active agents including new drugs and expanded access • New agents – especially those in a new class are likely to have the most activity

  11. Patient started on Atripla (EFZ/FTC/TDF) • VL declined to <50 in 6 weeks, CD4 250 • However, rebound to 10,000 3 months later

  12. Genotype done and reveals K103N • What do you switch to?

  13. Second generation NNRTI Etravirine (Intelence)

  14. TMC125-C223: Virologic Response to Etravirine at Week 48 • N = 199 HIV-infected patients with NNRTI resistance and ≥ 3 primary PI mutations • Median BL fold resistance • Nevirapine: 61.3 • Efavirenz: 41.4 • Etravirine: 1.6 • Patients randomized to • Etravirine (400 mg BID) + NRTIs + LPV/r ± ENF • Etravirine (800 mg BID) + NRTIs + LPV/r ± ENF • Active control: best available regimen from licensed agents (NNRTIs excluded) 25 23% 22% 20 15 Pts With VL < 50 c/mL at Wk 48 (%) 10 5 0% 0 CPI Etravirine400 mg BID Etravirine800 mg BID Cohen C, et al IAC 2006. Abstract TUPE0061.

  15. Each of the following mutations, always in combination with up to 4 other mutations was associated with a mean FC > 10 K101P, V179E, V179F, Y181I, Y181V, G190S, M230L For 179E, G190S, or M230L, the additional mutations always included Y181C when FC > 10 TMC125-C223: B/L NNRTI Mutations and Virologic Response at Week 48 Response to ETV 800 BID by # of B/L NNRTI mutations Activecontrol ETV800 BID 0* 1 2 ≥ 3 0 n = 79 n = 40 n = 14 n = 19 n = 16 n = 30 -0.14 -0.5 -0.54 -1.0 -0.9 Mean Change in log10 VL -1.01 -1.5 -1.38 -1.67 ITT, NC=F delta VL = 0 -2.0 *All patients had NNRTI mutations from prior genotyping Cohen C, et al IAC 2006. Abstract TUPE0061.

  16. Pooled ECHO and THRIVEStudy Design Randomized, double-blind, double-dummy, multicenter, 96-week study RPV 25mg QD + FTC/TDF (N=346) + EFV placebo QD ECHO N=690 patients EFV 600mg QD + FTC/TDF (N=344) + RPV placebo QD ARV-naïve HIV RNA ≥ 5,000 c/mL No NNRTI RAMs Sensitivity to the NRTIs RPV 25mg QD + 2NRTIs* (N=340) + EFV placebo QD THRIVE N=678 patients EFV 600mg QD + 2NRTIs* (N=338) + RPV placebo QD *Investigator’s choice: TDF/FTC (60%); ZDV/3TC (30%); ABC/3TC (10%) • Primary objective: non-inferiority (12% margin) vs. EFV in confirmed virologic response (viral load <50 copies/mL, ITT-TLOVR) at Week 48 • RPV demonstrated non-inferior virologic efficacy (< 50 c/mL) vs. EFV in a broad and diverse patient population ITT-TLOVR 84% vs. 82% (pooled data)2 ITT = intent-to-treat; TLOVR = time-to-loss of virologic response Pooled analyses were pre-planned 16 1. Rashbaum B, et al. ICAAC 2011. Chicago. #H2-805 2. Cohen C, et al. HIV10 2010. Glasgow. Oral #432

  17. Pooled ECHO and THRIVE: Wk 96 FTC/TDF DatasetVirologic Failure in the Resistance Analysis at Week 96 14.2% 11.5% 6.8% 4.2% 2.7%*† 2.6%* Overall Year 1 Year 2 *In Year 2, both treatment groups had 0.2% of subjects characterized as “never suppressed” †One VF occurred after Week 96 in the RPV group • Overall, there were a greater number of VFs with RPV+FTC/TDF vs EFV+FTC/TDF • In Year 1 (up to Week 48) VFs were greater with RPV+FTC/TDF. The rates of VFs and rebounders in Year 2 (Week 48 to 96) were low and similar for RPV+FTC/TDF and EFV+FTC/TDF 17 Nelson M, et al. EACS 2011. Belgrade, Serbia. #LBPE7.3/7

  18. Monogram Analysis of RPV Phenotypic testing of more than 8500 clinical specimens demonstrated that, with the exception of H221Y, the established RPV mutations are strongly associated with reduced phenotypic susceptibility with OR‡ > 20 and % of samples > BCO†> 40% Monogram BCO for RPV is 2.0 Median FC* of K103N is < BCO† and the % of samples > BCO† is low These findings provide confirmation of the contribution of these individual genotypic mutations on phenotypic susceptibility to RPV *FC- fold change in IC50 ; †BCO- biological cutoff; ‡OR- odds ratio 18 Napolitano LA, et al. ICAAC 2011. Chicago. Oral #H1-371

  19. Studies 102 and 103: Study Design N=348 STRIBILD QD N=700 patients Randomized 1:1 Study 102: EFV/FTC/TDF placebo QHS EFV/FTC/TDFa QHS N=352 STRIBILD placebo QD N=353 STRIBILD QD N=708 patients Randomized 1:1 Study 103: ATV + RTV + FTC/TDF placebos QD ATVb + RTVc + FTC/TDF QD N=355 STRIBILD placebo QD a EFV/FTC/TDF is a coformulated single-tablet regimen QHS; EFV dose, 600 mg; FTC dose, 200 mg; TDF dose, 300 mg. b ATV dose, 300 mg QD; c RTV dose, 100 mg QD. ATV, atazanavir; EFV, efavirenz; QD, once daily; QHS, once daily at bedtime; RTV, ritonavir. 19 STRIBILD Prescribing Information. Gilead Sciences, Inc. 2012.

  20. Noninferior Efficacy and Comparable Virologic Failure to EFV/FTC/TDF and ATV + RTV + FTC/TDF at Week 48a Virologic Success and Failure by FDA Snapshot Analysis(Primary Study Endpoints) STRIBILD EFV/FTC/TDF Study 102 Study 103 ATV + RTV + FTC/TDF 3.6 (-1.6 to 8.8)b 3.0 (-1.9 to 7.8)b c d c d a Week 48 window is between Day 309 and 378 (inclusive). b Difference in response rate, % (95% CI). c Subjects with HIV-1 RNA <50 copies/mL at Week 48. d Includes subjects who had ≥50 copies/mL in the Week 48 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, and at the time of discontinuation had a viral value of ≥50 copies/mL. 20 STRIBILD Prescribing Information. Gilead Sciences, Inc. 2012.

  21. Resistance-Associated Mutations Through Week 48 • Virus samples from STRIBILD-treatment failure subjects who were viremic with HIV-1 RNA >400 copies/mL at virologic failure, at Week 48, or at the time of early study drug discontinuation were evaluated for STRIBILD resistance. Genotypic and phenotypic data were available for 23 subjects (3%, 23/669) • The development of one or more mutations associated with resistance to EVG, FTC, and/or TDF was observed in 13 of 23 (57%) STRIBILD subjects with viremia who had evaluable genotypic data NNRTI, non-nucleos(t)ide reverse transcriptase inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor; PI, protease inhibitor. 1 Sax PE, et al. Lancet. 2012;379:2439-2448; 2 DeJesus E, et al. Lancet. 2012;379:2429-2438. 21

  22. Resistance Patterns

  23. NRTI resistance pattern

  24. Three Pathways to NRTI Cross-Resistance • TAMs • 41L, 44D, 67N, 70R, 118I, 210W, 215Y/F, 219Q/E • Selected by ZDV and d4T in sequential fashion • Associated with cross resistance to all NRTIs • ABC/ddI/TDF cross-resistance • 65R: ddI, ABC, TDF • 74V: ddI, ABC • Multinucleoside resistance • Q151M complex: all NRTIs • T69 insertion: all NRTIs + TDF Johnson VA, et al. Topics HIV Med. 2003;11:215-221. Hirsch MS, et al. Clin Infect Dis. 2003;37:113-128.

  25. Dichotomous Pathways in the Evolution of TAMs Zidovudine or Stavudine 70R 215Y 41L 215Y 210W 67N 70R 219Q/E Lower-level AZT and d4T resistance Less NRTI cross-resistance Common with AZT monotherapy Higher-level AZT and d4T resistance More NRTI cross-resistance Common with dual-NRTI therapy (ie, AZT/ddC or AZT/ddI)

  26. Summary of Effects of Common Mutational Patterns

  27. V118I and E44D/A • Confers moderate-level resistance to lamivudine in absence of M184V • Not selected by 3TC • Generally seen only in treatment-experienced patients • Selection is strongly correlated with • Prior exposure to ddI • Concomitant presence of specific clusters of TAMs, including M41L with T215Y/F or D67N with L210W • Prevalence increases as a function of the number of NRTIs used in prior therapy

  28. PI resistance patterns

  29. PI Cross-Resistance • Primary PI mutations • Cross-resistance: 46, 82, 84, 90 • Drug specific: D30N (NFV); I50V (AMP), I50L (ATV) • However • Alternate resistance pathways occur • Example: L90M (NFV) • Secondary mutations accumulate with ongoing replication and increase cross-resistance • Initial failure of some PI-based regimens may not be associated with PI mutations • Example: LPV/r, boosted fosamprenavir • Sequencing among PIs is limited by lack of additional drugs Johnson VA, et al. Topics HIV Med. 2003;11:215-221. Hirsch MS, et al. Clin Infect Dis. 2003;37:113-128.

  30. ATV1 Naïve Experienced I50L Atazanavir Amprenavir Indinavir Ritonavir Saquinavir Nelfinavir I84V Atazanavir Amprenavir Indinavir Ritonavir Saquinavir Nelfinavir Susceptible Reduced phenotypic susceptibility Resistant Resistance and cross-resistance associated with ATV Coverage of resistant isolates2 % ATV susceptible (FC <3.1-fold) Number of approved PIs showing resistance • 950 clinical isolates from PI-experienced (ATV-naïve) patients • Isolates with 5/14 key protease amino acid substitutions* exhibited reduced susceptibility (FC >3) * 10, 20, 24, 33, 36, 46, 48, 54, 63, 71, 73, 82, 84, 90 1. Colonno RJ, et al.Antiviral Therapy 2002;7:S4; 2. Colonno RJ, et al.42nd ICAAC, San Diego 2002. #H-2049

  31. Integrase Resistance • Raltegravir • Elvitegravir – only available within Stribild • Dolutegravir – approved 8/2013 All are indicated in naïve patients but RAL only ‘preferred’ INSTI on DHHS guidelines for initial therapy Genetic barrier to resistance lower than PI/r

  32. Integrase RAMs • E92Q, E138A/D/K/T, E157Q, G163E/K/Q/R/S G193E/R, G140A/S • L74I/M, N155H, Q148H/R, T66I, Y140A/S, Y143C/H/R , • Most common pathway with Q148 + >2 INSTI-resistance substitutions is Q148 + G140+ E138 (in VIKING)

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