Does Resistance Still Matter? Daniel R. Kuritzkes, M.D. Division of Infectious Diseases Brigham and Women s Hospital Harvard Medical School

Transcription

1 Does Resistance Still Matter? Daniel R. Kuritzkes, M.D. Division of Infectious Diseases Brigham and Women s Hospital Harvard Medical School

2 Disclosure The speaker serves as a consultant to, and has received honoraria and/or research support from the following companies: Gilead GlaxoSmithKline Janssen Merck ViiV DRK

3 The problem of drug resistance Emergence of drug resistance is a particular problem with RNA viruses, including retroviruses Virus populations comprise a quasispecies Genetically distinct variants evolve from an initial oligoclonal inoculum Variants are generated by error-prone RNAdependent polymerases

4 Drug-Resistant Mutants Preexist in Untreated Patients The HIV genome contains 10 4 nucleotides The mutation rate of HIV is ~3 x 10-5 nucleotides/ replication cycle ~10 10 virions are generated by rounds of replication each day DRK

5 The bad old days In the era of mono- and dual-therapy, failure to achieve full suppression of HIV replication invariably led to accumulation of drug resistance mutations (DRMs) Accumulation of DRMs led to increasing withinclass cross-resistance Addition of single active agents as new drugs were developed equated to serial monotherapy, generating multidrug-resistant (MDR) HIV Transmission of drug-resistant HIV, including MDR HIV, exacerbated the problem

6 % with resistance Long-term risk of developing drug resistance Risk of developing ARV drug resistance from UK CHIC Study (n=4306) Longitudinal cohort from 6 clinics in London Time to multiclass resistance 2 classes 3 classes Started ARV therapy with 2 NRTI plus third agent Overall risk of treatment failure was 38% over 6 yrs year 4 year 6 year Risk of accumulating resistance mutations to any drug 27% overall Phillips A. AIDS 2005;19: DRK IAS-USA SF_2007

7 CDC Survey: Drug-Resistant HIVAmong Newly Diagnosed Patients Resistance to: Any drug 1998 (n=257) Prevalence of Drug Resistance (%) 1999 (n=239) 2000 (n=299) (n=3130) 2007 (n=2480) (n=18,144) NRTI NNRTI PI >2 class Weinstock et al J Infect Dis 2004; 189:2174. Wheeler W et al. 14 th CROI, Los Angeles, 2007, Abstract 648 Kim D et al. 17 th CROI, San Francisco, 2010, Abstract 580. Kim et al 20 th CROI, Atlanta, 2013 DRK

8 Transmitted HIV-1 Drug Resistance among US MSM Bañez Ocfemia et al CROI 2014 DRK

9 Time to virologic failure (ITT) Kuritzkes et al J Infect Dis 2008 DRK

10 Proportion not achieving virologic failure Proportion of Patients without Virologic Failure by the Presence of Minority HIV-1 Drug-Resistant Variants P < Minority variants not detected Minority variants detected Days No. at risk MV not detected MV detected Li JZ et al JAMA 2011 DRK

11 Effect of Minority Variants and Antiretroviral Therapy Adherence on Virologic Failure Li JZ et al JAMA 2011; 305: DRK

12 Risk of triple-class resistance on newer ART regimens Phillips et al Lancet 2007; 370: DRK.ICAAC/IDSA.2008

13 ART resistance among ART-naïve patients at entry into clinical trials Margot et al CROI 2014 DRK

14 Resistant Samples (%) Decrease in Prevalence of MDR HIV in the US in Recent Era of HIV Treatment Assessment of phenotypic drug resistance patterns in US samples submitted to Monogram Biosciences for HIV resistance testing from (N = 62,397) 1-Class Resistance PI NRTI NNRTI Class Resistance PI and NRTI PI and NNRTI NRTI and NNRTI Class Resistance Paquet AC, et al. Antivir Ther. 2014;19: Slide credit: clinicaloptions.com

15 Incidence of virologic failure and ART resistance by year of ART initiation Scherrer et al Clin Infect Dis 2016

16 Emergence of resistance in darunavir trials Participants with emergent RAM, n PR RT Study Regimen N PDVF, n (%) Resistance testing Primary PI/DRV N(t)RTI NNRTI ARTEMIS DRV/r + FTC/TDF (16) GS-US GS-US D/C/F/TAF (4) DRV/c + FTC/TDF DRV+ cobi + 2NRTI 50 1 (2) (5) ODIN DRV + RTV (22) INROADS DRV/r +ETR 54 7 (13) MONET DRV + RTV (17) DRV/r +2NRTI (10) PROTEA DRV + RTV (1) DRV/r +2NRTI (1) TOTAL (11) Modified from Lathouwers et al CROI 2017

17 ACTG A5257: Resistance to Study Drugs 1809 Participants 295 Virologic Failures 1 Baseline Missing 56 VF Failed to Amplify ATV/r 75/94 VF Available 9 Any Resistance (1.5% of ATV/r) 5 isolated M184V 1 integrase mutation 2 T69D/T215AIT 1 K70N + M184V RAL 65/85 VF Available 18 Any Resistance (3% of RAL) 7 isolated M184V 1 isolated integrase mutation 7 integrase + M184V 3 integrase + M184V + K65R DRV/r 99/115 VF Available 4 Any Resistance (<1% of DRV/r) 3 isolated M184V 1 integrase mutation Lennox et al Ann Intern Med 2014

18 : Resistance at time of virologic failure through week 48 Sax et al Lancet 2012

19 Emergent Resistance in Patients with Virologic Failure through Week 48 Resistance Analysis Population % (n) Developed Any Primary Resistance % (n) Primary Resistance % (n) QUAD (n=701) ATR (n=352) ATV/r + TVD (n=355) 3.7% (26) 4.8% (17) 2.3% (8) 1.9% (13); 50% RAP 2.3% (8); 47% RAP 0 NRTI-R 1.7% (12) 0.6% (2) 0 M184V/I K65R 1.7% (12) 0.6% (2) 0 0.6% (4) 0.6% (2) 0 3rd agent Resistance to EVG (INSTI) Resistance to EFV (NNRTI) Resistance to ATV/r (PI/r) 1.6% (11) 2.3% (8) 0 T66I 0.3% (2) K101E 0.9% (3) I50L 0 E92Q 1.1% (8) K103N 2.0% (7) I84V 0 Q148R 0.4% (3) V108I 0.6% (2) N88S 0 N155H 0.4% (3) Y188Y/F/H/L 0.3% (1) G190G/A 0.3% (1) Primary PI-R White et al Intl Workshop on HIV & Hepatitis Drug Resistance, Sitges, 2012

20 SINGLE: Resistance at virologic failure Walmsley et al ICAAC 2012

21 Effect of transmitted TAMs on virologic response to ART Geretti et al CROI 2016 DRK

22 Gilead data showing TDR doesn t matter in contemporary regimens Margot et al J Infect Dis 2017

23 Pre-treatment resistance in TASP Derache et al CROI 2017

24 Viral suppression in TASP Derache et al CROI 2017

25 SELECT (ACTG A5273) La Rosa et al Lancet HIV 2016

26 Are INSTIs as good as boosted PIs in second-line ART? Second Line, EARNEST, and SELECT all show persistent activity of NRTIs despite resistence But few participants carried K65R Success of 2 nd -line regimens based largely on use of a boosted PI regimen Can an INSTI (e.g., dolutegravir) take the place of a boosted PI in second-line regimens if there is pre-existing NRTI resistance?

27 Dolutegravir resistance after failure of DTG monotherapy: Study design Blanco JL et al. CROI 2017, Seattle

28 Dolutegravir resistance after failure of DTG monotherapy: Results Blanco JL et al. CROI 2017, Seattle

29 Where does this leave us? Contemporary regimens less likely to result in virologic failure and drug resistance Dependent on monitoring plasma HIV-1 RNA Transmitted drug resistance (TDR) decreasing in many countries, but increasing in RLS Transmitted NRTI resistance has minimal impact on response to PI- or INSTI-based ART It may be time to re-examine the costeffectiveness of baseline resistance testing in countries where it has become standard of care