HIV Clinical Management: Antiretroviral Therapy and Drug Resistance

Transcription

1 HIV Clinical Management: Antiretroviral Therapy and Drug Resistance Judith S. Currier, MD, MSc Professor of Medicine University of California, Los Angeles

2 Disclosures: Research Grant from Theratechnologies to UCLA

3 Clinical Management Topics Initial Antiretroviral Therapy Efficacy and Tolerability Resistance Epidemiology Resistance Testing Second and Third Line ART Future priorities

4 ART Recommended for All People with HIV ART recommended for early HIV infection [1,2] DHHS and WHO guidance recommend ART for all HIV-infected pts worldwide, regardless of CD4+ cell count ART recommended for pregnant with early HIV infection [1] 1. DHHS Guidelines. January WHO. September 2015.

5 Number of people receiving antiretroviral treatment Source: UNAIDS/WHO estimates. The red shading shows future targets.

6 Antiretroviral Therapy : What to Start in 2017

7 Antiretroviral Therapy : What to Start in 2017

8 Efavirenz based ART as First Line Advantages Single tablet regimens available at low cost Over 15 million person years of treatment experience with efavirenz 600 mg/day Generally well tolerated Safely used in pregnancy and for patients with TB Challenges CNS side effects are common Drug interactions Low barrier to resistance

9 Alternative First Line ART Lower dose EFV 400 mg Better tolerated Lower cost Dolutegravir Superior virologic outcomes compared to EFV Fewer drug Interactions Very low risk of resistance at failure: no cases of resistance in first line clinical trials with DTG Limited data in children, pregnant women and TBcoinfection Will Immune Reconstitution Inflammatory Syndrome (IRIS) be a problem?

10 Using INSTI may enhance the risk of IRIS Pre-ART CD4 cell count ART with INSTI N= Pre-ART Viral Load IRIS Cases, N (%) 12 (3.0) 29 (1.5) M. tuberculosis 5 (42%) 7 (58%) Progressive Multifocal Leukoencephalopathy M. avium 2 (20%) 8 (80%) ART without INSTI N= (16.7%) 5 (83.3%) CMV 2 (40%) 3 (60%) Kaposi sarcoma 2 (50%) 2 (50%) Toxoplasmosis Patients Multi-center cohort study in France IRIS events requiring hospitalization, mainly related to mycobacterial infections, were rare but twice as frequent among patients with CD4 cells below 200/mm3 who initiated INSTI-based ART regimen compared those without an INSTI

11 Neuropsychiatric AEs in Dolutegravir Retrospective analysis on 2260 HIV+ patients in France Median age 50 CD4 591 DTG discontinuation for Neuropyschiatric (NP)-AEs was 5.4% Irritability and sleep disturbances were the most frequently observed NP-AEs >60 years old, female sex, and BMI were significantly associated with NP-Aes occurrences.

12 Ongoing International Trials with DTG, EFV and EFV 400 Pregnant women Dolphin- 1, Dophin-2, VESTED (DTG/FTC/TAF vs DTG/TDF/FTC vs EFV/TDF/FTC) TB Coinfection EFV rifampicin EFV +NRTI vs DTG + 2 NRT in TB TAF + rifampin Treatment Naïve ADVANCE (South Africa) DTG/TAF/FTC vs DTG/TDF/FTC vs EFV/TDF/FTC NAMSAL (Cameroun) DTG/3TC/TDF vs EFV 400 /3TC/TDF/ Second Line DAWNING 2NRTI +DTG s 2NRTI + PI/r D2EFT DTG/DRV/r vs 2NRTI + DRV/r Vitoria, Ford, Clayden, Pozniak and Hill. Curr Opin HIV AIDS 2017

13 HIV DRUG RESISTANCE The presence of transmitted drug resistance to NNRTI or NRT increases risk of virologic failure on first line ART with NNRTI s Image from Scientific American, 1998

14 HIV Drug Resistance : Context is Important Transmitted resistance in treatment naïve Resistance after first line failure Duration of failure and availability of VL monitoring Resistance after second line

15 HIVDR in ARV-naïve Individuals East Africa Southern Africa West & Central Africa Latin America & Caribbean

16 Pre-Rx Drug Resistance in Children in SSA

17 RV 329: African Cohort Study (AFRICOS) Prospective observational HIV-focused cohort executed by US Military HIV Research Program with PEPFAR and Department of Defense research support Enrolling adults aged 18+ at 11 HIV clinic sites in 4 countries Current enrollment over 2600 HIV infected and 500 HIV uninfected participants with 6 monthly visits HIV outcomes measured: CD4, viral load, genotype resistance testing at baseline and virologic failure Serum, plasma and cells stored Slide credit: Julie Ake

18 Drug Resistance ART Naïve Participants Uganda n=92 (%) Kenya n=35 (%) Tanzania n=59 (%) Nigeria n=35 (%) Total n=221 (%) Any SDRM 7 (8) 2 (6) 7 (12) 6 (17) 22 (10) Major NRTI Resistance 2 (2) 0 (0) 1 (2) 4 (11) 7 (3) L74V 2 (2) 0 (0) 1 (2) 1 (3) 4 (2) M41L 0 (0) 0 (0) 0 (0) 3 (9) 3 (1) M184V/I 0 (0) 0 (0) 0 (0) 1 (3) 1 (0.5) Major NNRTI Resistance 3 (3) 2 (6) 5 (8) 1 (3) 11 (5) K103N 3 (3) 2 (6) 4 (7) 0 (0) 9 (4) Y181C 1 (1) 0 (0) 1 (2) 0 (0) 2 (1) G190A 0 (0) 0 (0) 0 (0) 1 (3) 1 (0.5) Major PI Resistance 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

19 Impact of HIVDR between 2016 and 2030 in sub-saharan Africa (Low/Mid-Income countries) AIDS Deaths New Infections ART Costs With HIVDR (fast track projections) 5.6 million 5.1 million $ 83 billion Current level of PDR < 10% Amount attributable to HIVDR Current level of PDR 10% Amount (%) attributable to HIVDR 710,000 (13%) 380,000 (7%) $ 5.0 billion (6%) 890,000 (16%) 450,000 (9%) $ 6.5 billion (8%) J Infect Dis Feb 17

20 Resistance after First Line ART

21 Countries contributing data to resistance analysis and HIV-1 subtype distribution 1926 individuals from 36 countries Adapted from Lancet Infect Dis 2016; 16:

22 TDF and NNRTI resistance after first line failure of TDF containing ART CD4 < 100 risk strongest factor for TDF Resistance

23 Hosseinipour, M et al. JAIDS ;75 Suppl 2:S149-S155 HIV Drug Resistance in Option B + Malawi Prospective study of 1269 post-partum women randomized to different strategies for promoting uptake and retention of Option B+ At 6 months follow-up 75 % retained in care Of those retained 88 % had HIV RNA obtained and 84% were < 1000 copies ml Among the 55 with HIV RNA > 1000; 19(35%) had HIV drug resistance

24 Drug Resistance ART Experienced Participants Uganda n=10 (%) Kenya n=21 (%) Tanzania n=17 (%) Nigeria n=17 (%) Total n=65 (%) Major NRTI Resistance 2 (20) 11 (52) 10 (59) 9 (53) 32 (49) M184V/I 2 (20%) 11 (52) 10 (59) 9 (53) 32 (49) K70R 0 (0) 3 (14) 5 (29) 2 (12) 10 (15) D67N 0 (0) 2 (10) 4 (24) 3 (18) 9 (14) Major NNRTI Resistance 3 (30) 15 (71) 14 (82) 13 (76) 45 (69) K103N 1 (10) 7 (33) 7 (41) 10 (59) 25 (38) Y181C 0 (0) 5 (24) 5 (29) 3 (18) 13 (20) G190A 2 (20) 4 (19) 2 (12) 2 (12) 10 (15) V106A/M 0 (0) 1 (5) 4 (24) 0 (0) 5 (8) Major PI Resistance 0 (0) 0 (0) 0 (0) 1 (6) 1 (2)

25 High Prevalence of HIV DR among previously unmonitored patients with Virologic Failure in Malawi Examined rates of HIV Drug Resistance among 1498 patients in 5 district hospital programs on first line ART Viral load obtained if on treatment for at least 6 months, 24 months or longer or with clinical failure If VL > 5000 copies, adherence counseling done with repeat VL 3 months Sent samples for resistance testing if confirmed VL 88 (5.8%) had VF Among these patients with resistance testing (n=61) 95% had resistance to NRTI or NNRTI 50% had high level resistance to NRTI and 50% high level NNRTI Longer duration of ART associated with higher rates of resistance Patients in care for longer time with VL should be prioritized to shift to second line ART Rustein SE IDWeek2016;Abstract 1551.

26 Resistance at first failure and response to second line ART Second line ART after NNRTI first line Three major studies all compared LPV/r + 2 NRTI with RAL + LPV/r SECOND LINE 1 EARNEST 2 (2-3 NRTI +LPV/r vs LPV/r + RAL) (2-3 NRTI + LPV/r vs LPV/r + RAL vs LPV/r monotherapy SELECT (ACTG) 3 (2 NRTI + LPV/r vs LPV/r + RAL ) All 3 studies demonstrated non-inferiority of LPV/r + NRTI, no clear advantage of LPV/r + RAL Resistance testing was done in retrospect 1. Boyd M et al Lancet Jun 15;381(9883): Paton N, et al N Engl J Med 2014; 371: LaRosa A, CROI 2017

27 HIV Drug Resistance after First Line Failure in EARNEST Malawi, Uganda, Kenya and Zimbabwe 787 adults failing first line NNRTI treatment- median duration 4 years Viral subtype distribution A1 (40%; Uganda and Kenya) C (31%; Zimbabwe and Malawi) D (25%; Uganda and Kenya) DRM more common in subtype C Tenofovir resistance similar by subtype Subtype C resistance to ZDV, ABC, etravirine and ripivirine more common implications for second and third line Kityo C, et al JAIDS June 2017 Suppl

28 Paradox: Impact of Baseline Resistance on Risk of Virologic Failure No differences between arms, or after adjustment for baseline HIV-1 RNA, Wk 4 adherence, previous TDF use, country [1] ACTG 5273 overall results consistent with EARNEST, SECOND-LINE trials [2,3] Baseline NRTI Resistance K65R, 3 TAMs, Q151M or 69 ins/del Yes vs no (ref) IAS NRTI mutations 3 vs < 3 (ref) K65R and/or M184V/I No K65R but M184V/I vs no M184V/1 (ref) K65R and M184V/I vs no M184V/1 (ref) 1. La Rosa AM, et al. CROI Abstract Paton NI, et al. N Engl J Med. 2014;371: Amin J, et al. PLoS One. 2015;10:e HR for VF in Both Arms (95% CI) P Value 0.49 ( ) ( ) < ( ) 0.19 ( ) <.001 Slide credit: clinicaloptions.com

29 Resistance Testing and Clinical Practice: More Questions than Answers Identifying NNRTI resistance could inform the selection of first line ART How should surveillance data be used to inform local guidelines? Will first line DTG overcome this problem for first line? Cost effectiveness analyses suggest DTG cost effective when NNRTI resistance > 10% (Hill Abs 112, CROI 2017) Value of Resistance Testing in Third Line A5288/MULTI-OCTAVE: Management Using Latest Technologies to Optimize Combination Therapy evaluating use of resistance testing for 3 rd line due to report end of 2017

30 Prevention Surveillance Research Laboratory Capacity Governance ART Resistance Guidelines Group Meeting March 2017

31 Summary Clinical Management of ART is evolving Optimal uniform first line global regimen remains a goal- we are not there yet Earlier treatment expansion needs to be coupled with focus on long term adherence Newer treatment regimens offer promise for less resistance and toxicity, cost effectiveness studies are key to guide policy Viral load monitoring scale up critical for earlier detection of VF and prevention of resistance Clinical use of resistance testing may be most effective for third line ART

32 Zikomo