Optimizing Clinical Utility of Integrase Inhibitors. Anton Pozniak MD FRCP

Transcription

1 Optimizing Clinical Utility of Integrase Inhibitors Anton Pozniak MD FRCP

2 INSTIs-Characteristics Rapid viral load decline Low rates resistance/ Transmitted Resistance Less chance of side effects Less pills, some are formulated as an STR Few drug interactions with unboosted INSTIS

3 3 Drug therapy is Standard of Care in ART Naive Regimen EACS IAS-USA DHHS RPV/TDF/FTC Recommended or use TAF Alternative Alternative DRV/r or/ c + TDF/FTC Recommended or use TAF Alternative Recommended or use TAF ATV/r + TDF/FTC Alternative Alternative Alternative EVG/c +TDF/FTC Recommended or use TAF Recommended* Use TAF Recommended or use TAF RAL + TDF/FTC Recommended or use TAF Recommended* Use TAF Recommended or use TAF DTG + TDF/3TC Recommended or use TAF Recommended* Use TAF Recommended or use TAF DTG + ABC/3TC Recommended Recommended Recommended DHHS ART Guidelines. July Günthard HF, et al. JAMA. 2016;316: EACS ART Guidelines. October 2016.

4 WHO Guidelines Programs in Botswana and Brazil and more coming Regimen EFV 600mg TDF/XTC EFV 400mg TDF/XTC WHO Recommended- Alternative DRV/r or ATV/r + TDF/FTC - EVG/c +TDF/FTC - RAL + TDF/FTC - DTG + TDF/3TC Alternative DTG + ABC/3TC - WHO 2016

5 Naïve Patients The Future is Integrase? Summary of Primary endpoint Efficacy Data: ARV Naïve at 48 weeks VL< 50/ml 85-90% Raltegravir non-inferior to atripla at 48 weeks, superior at 5 years (Startmrk) Equivalent to atazanavir/r and darunavir/r at 96 weeks (ARDENT- ACTG 5257) Elvitegravir Non- inferior to atripla or to atazanavir/r at 48 weeks ( Gilead 102 and 103) Superior to atazanavir/r in women (WAVES) Dolutegravir Non inferior to raltegravir at 48 weeks (Spring-2) Superior to atripla at 48 and 96 weeks (Single) Superior to darunavir/r at 48 and 96 weeks (Flamingo) Superior to atazanavir/r in women (ARIA) Rockstroh, JAIDS, 2013; Landowitz, CROI 2014; Elion CROI 2013; De Jesus, CROI; 2013; Raffi, Lancet, 2013; Walmsley NEJM, 2013, Clotet, Lancet, 2014 ; Squires IAS 2015

6 In ART Naïve What about 4 Drug Therapy with an INSTI Are the Outcomes Better especially in Late presenters Try and get VL down fast and CD4 higher quickly 6

7 REALITY Study: raltegravir-intensified quadruple therapy in first-line antiretroviral therapy Design Randomisation 1 : 1 Open label W48 Adults, adolescents and children > 5 years ARV-naïve CD4 < 100/mm 3 N = 902 N = NRTI + NNRTI + 12 weeks of RAL 2 NRTI + NNRTI Two other factorial randomisations: 12 weeks enhanced prophylaxis, 12 weeks supplementary food Objective Primary endpoint: 24-week mortality REALITY Kityo C. AIDS 2016, Durban, Abs. FRAB0102LB

8 REALITY Study: raltegravir-intensified quadruple therapy in first-line antiretroviral therapy Mortality HIV RNA < 50 copies/ml (95% CI) Additional RAL Standard ART % 10.9% 10.2% 13.0% 12.4% % 42.8% 74.1% 77.2% 54.6% 76.0% 82.9% 79.5% 5 0 W24: HR =1.09 (95% CI: ) ; p = N at risk Weeks % Weeks Mean change in CD4/mm 3 at W48: vs (p = 0.04) REALITY Kityo C. AIDS 2016, Durban, Abs. FRAB0102LB

9 Warning in Late presenters? INSTIs and IRIS ATHENA cohort study 2.7 times higher risk of IRIS for Integrase inhibitors vs Non INSTI

10 Can we use this data to advantage? Elvitegravir:Raltegravir and Dolutegravir Emergent Resistance Through Weeks n(%) EVG/c/FTC /TDF (n=701) W96 Population Analyzed 36 (5.1%) Emergent Resistance 16 (1.9%) Primary INSTI-R 14 (2.0%) or NNRTI-R or PI-R E92Q N155H Q148R T66I T97A Primary NRTI-R M184V/I K65R (2.1%) 15 5 RAL 65/85 VF Available 18 Any Resistance (3%) 0 TDF 7 FTC 0 TDF+FTC 1 RAL 7 RAL+FTC 3 RAL+FTC+TDF DTG 50 mg OD DRV/r 800/100 mg OD PDVF, n (%) 2 (<1) 2 (<1) INI mutations, n NRTI mutations, n PI mutations, n * 0 Clumeck N, et al. 14th EACS; Brussels, Belgium; October 16-19, Abst. LBPS7/2.

11 Plus..Rate of Transmitted resistance to INSTIs low so Lets start with DTG regimen (as high genetic barrier) before we have resistance tests back A consequence-viral load reduction much earlier as not waiting for tests and renders patient undetectable and non-transmitter and Patients engaged in care immediately

12 Standard pathway U&E LFT FBC Hep A/B/CCD4 VL Syphilis HLA-B5701 glucose VRT lipids RITA

13 New pathway 48 h U&E LFT FBC Hep A/B/CCD4 VL Syphilis HLA-B5701 glucose VRT lipids RITA

14 San Francisco RAPID programme Antiretroviral Regimens Truvada + Dolutegravir 26 (67%) STRIBILD 7 (18%) Truvada + Darunavir/r 4 (10%) Truvada+Raltegravir 1 ( 2%) Triumeq 1 ( 2%)

15 Time to VL suppression by ART initiation strategy: SFGH RAPID Universal ART CD4-guided ART Proportion <200 copies RAPID vs. universal ART P<0.001

16 And if transmitted resistance increases can we still use an INSTI in this way? Data on file, Gilead Sciences 2.5-fold > 2.5 to 5-fold > 5 to 10-fold > 10-fold a Primary and other integrase strand transfer inhibitor resistance (INSTI-R) mutations are listed. Primary INSTI-R mutations are T66I/A/K, E92Q/G, T97A, Y143C/H/R, S147G, Q148H/K/R, N155H, and other INSTI-R mutations are H51Y, L68I/V, V72A/N/T, L74M, Q95K/R, F121C/Y, A128T, E138A/K, G140A/C/S, P145S, Q146I/K/L/P/R, V151L/A, S153A/F/Y, E157K/Q, G163K/R, E170A, and R263K in IN. b Susceptibility was determined as the fold-change in EC 50 vs. NL4-3 wild-type vector by Monogram Biosciences, Inc. The biological or lower clinical cut-offs for reduced susceptibility in this assay are 4.0 for DTG, 1.5 for RAL, and 2.5 for EVG. No cut-off has been determined for BIC. Confidential GS-9883/F/TAF Virology Ad Board, Rome, May 27, 2016

17 Switching Therapy in Virologically Suppressed Pts

18 Switching Therapy in Virologically Suppressed Pts: When and Why? To manage adverse events To manage or prevent drug toxicity To simplify regimen (number of doses or pills) To address food restrictions To address drug interactions To plan for pregnancy To reduce cost

19 Switch Studies with INSTIS in Virologically Suppressed Pts Trial From To Outcome vs Suppressive ART GS-123 TDF/FTC + RAL EVG/COBI/FTC/TDF Virologic suppression maintained Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF Noninferior or superior Strategy-PI TDF/FTC + PI/RTV EVG/COBI/FTC/TDF Noninferior or superior SPIRAL 2 NRTI + PI/RTV (experienced pts) RAL + 2 NRTIs Noninferior or superior GS-109 TDF-based ART EVG/COBI/FTC/TAF Noninferior or superior STRIIVING Suppressive ART DTG/ABC/3TC Noninferior or superior GS-119 DRV/RTV-containing salvage regimen EVG/COBI/FTC/TAF + DRV Noninferior or superior LATTE CAB or EFV + 2 NRTIs CAB + RPV (PO) Noninferior or superior LATTE-1 CAB + ABC/3TC CAB + RPV (IM) Noninferior or superior SWORD-1 & 2 3-drug regimen DTG + RPV Noninferior or superior

20 A lesson: If you switch with Background resistance More Virological failures SWITCHMRK -1 and -2: Switch from stable LPV/RTV to RAL-based HAART Virologic outcomes at Wk 24, NC = F Median previous antiretroviral drugs, n (range) RAL 5.0 ( ) LOP/r 5.0 ( ) RAL 5.5 ( ) LOP/r 6.0 ( ) RAL + ARVs, n LPV/RTV + ARVs, n Eron J, et al. CROI Abstract 70aLB. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. Copyright 2009 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

21 Switching can cause problems! STRIIVING: Switch From Suppressive ART to Fixed- Dose DTG/ABC/3TC Ongoing randomized, open-label phase IIIB study Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 24 Wk 24 Wk 48 HIV-1 RNA < 50 copies/ml on stable ART 6 mos; no previous virologic failure; HLA-B*5701 negative (N = 551) Baseline ART* (n = 277) DTG/ABC/3TC (n = 274) DTG/ABC/3TC (n = 277) *Containing 2 NRTIs plus NNRTI, PI, or INSTI. PI NNRTI INSTI TDF/FTC BL ART use, % Trottier B, et al. ICAAC 2015.

22 HIV-1 RNA < 50 c/ml (%) STRIIVING: Virologic Outcomes at Wk 24 Switch to DTG/ABC/3TC noninferior to maintaining baseline ART Primary Efficacy Analysis: ITT-Exposed and Per Protocol Populations DTG/ABC/3TC (ITT-E, n = 274) Baseline ART (ITT-E, n = 277) DTG/ABC/3TC (PP, n = 220) Baseline ART (PP, n = 215) 20 0 Virologic Success 1 1 < 1 2 Virologic Nonresponse No Virologic Data Trottier B, et al. ICAAC

23 But Switching had a Price! STRIIVING: Adverse Events 10 pts discontinued for AEs in DTG/ABC/3TC arm vs 0 in baseline ART arm AEs in 10 Pts Who Withdrew* Grade Insomnia 2 Diarrhea, flatulence, rash Abdominal pain, anxiety, nausea, body ache Euphoric mood Headache Abdominal cramps, chills, diarrhea, dizziness, headache 2 Pruritus 2 Abdominal pain, diarrhea, flulike syndrome, profuse sweating, change in body odor Fatigue, malaise, depression Nasal congestion Worsening fatigue Nausea Alopecia 1 Fatigue 1 Trottier B, et al. ICAAC Homicide N/A *None serious AEs except homicide. Not drug related.

24 Switching with history of resistance GS-119: Immediate vs Delayed Switch to EVG/COBI/FTC/TAF + DRV for Tx-Experienced Pts Multicenter, open-label phase III trial Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 24 (FDA Snapshot) Secondary endpoints: HIV-1 RNA < 50 c/ml at Wk 48, CD4+ cell count change, safety Randomized 2:1 Wk 24 Wk 48 Wk 144 Tx-experienced pts, HIV-1 RNA < 50 c/ml for 4 mos on DRV/RTVcontaining ART, with history of drug resistance* and egfr > 50 ml/min (N = 135) Switch to EVG/COBI/FTC/TAF + DRV 800 mg QD (n = 89) Baseline ART (n = 46) EVG/COBI/FTC/TAF + DRV 800 mg QD (n = 46) *Resistance to 2 ARV classes, including 3 thymidine analogue mutations and/or K65R, but not integrase inhibitors, unless currently suppressed on RAL, EVG, or DTG (50 mg QD only), and no DRV resistance. Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:

25 GS-119: Virologic Suppression After Switch to EVG/COBI/FTC/TAF + DRV (2 pills) At Wk 48, virologic efficacy of switch to EVG/COBI/FTC/TAF + DRV was noninferior and statistically superior to continuing baseline regimen (P =.004) [1] No emergent resistance in EVG/COBI/FTC/TAF + DRV arm; 1 pt in baseline ART arm with viral rebound (Wk 36) developed resistance (M184V + K65R) [1] No impact of genotypic susceptibility score on the efficacy of the switch regimen [2] HIV-1 RNA < 50 c/ml EVG/COBI/FTC/TAF + DRV (n = 89) Baseline ART (n = 46) Treatment difference: 18.3% (95% CI: 3.5% to 33.0%; P =.004) 11 2 Virologi c Failure Wk No Data 1. Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74: Margot N, et al. HIV Glasgow Abstract O123.

26 Can INSTIS be used in Dual therapy? Less cost Why optimise dosing? Less drug to be manufactured and stored Less chance of side effects Less pills (though cant get less than STR!) Also useful in Nuke limiting Strategies Abacavir-HLA and CVS risk Tenofovir Renal and Bone toxicity Now we have TAF but no clinical TB or Pregnancy data

27 2 drugs without TDF or TAF Health Warning! Not in Hepatitis B co-infected 1-5% in Eastern european region? Pregnancy?TB

28 Analysing the efficacy of 2-drug versus 3-drug treatments PI/r + raltegravir-no benefit DTG + 3TC- low VL experimental DTG + RPV-non inferior CTV + RPV-experimental for LA injectable PI/r + maraviroc-no benefit PI/r + NRTI (mainly 3TC) -non inferior

29 Pts (%) Switch From Suppressive ART to DTG + RPV Noninferior to Continued Baseline ART at Wk HIV-1 RNA < 50 c/ml Virologic No Data Nonresponse Wk 48 Llibre JM, et al. CROI Abstract 44LB. DTG + RPV (n =513) Baseline ART (n = 511) Treatment difference: -0.2% (95% CI: -3.0% to 2.5%) < AE rates generally similar between treatment arms through Wk 52 Numerically higher rate of drug-related grade 1/2 AEs with switch: 17% vs 2% Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1%

30 Switch to DTG + RPV in Suppressed Pts With Multiple Previous Treatment Failures Open-label cohort study based in clinical practice setting (N = 38) DTG 50 mg/day + RPV 25 mg/day for pts with long-term virologic suppression but virologic failure on > 1 previous ART regimens Baseline Characteristic, % Switch to DTG + RPV (N = 38) Regimen at time of switch Reasons for switch to DTG + RPV Pre-existing resistance mutations NRTI + NNRTI + PI NRTI + NNRTI + PI + INSTI Drug drug interaction Toxicity Simplification NRTI: 65; NNRTI: 37; PI: 32; INSTI: NA HIV-1 RNA suppressed to < 35 copies/ml in 92% (35/38) at Wk 48 No virologic failures; 3 pts d/c (GI toxicity, DDI, physician decision, n = 1) DTG + RPV associated with improved liver function tests, improved lipid profile, and stable kidney function at Wk 48 Díaz A, et al. AIDS Abstract TUPDB0106.

31 Has PI/r plus integrase a role in Treatment experience? EARNEST and SECOND-LINE studies In treatment-experienced patients, RAL+LPV/r was non-inferior to 2NRTI+LPV/r No efficacy advantage No significant difference in number of Grade 3 or 4 adverse events Costs of RAL+LPV/r significantly higher than 2NRTI+LPV/r in most countries

32 Percent with VL<400 copies/ml Ernest 2 nd Line treatment study VL responses by randomized arm PI mono PI/NRTI PI/RAL Global p< PI/RAL vs PI/NRTI global p< PI-mono vs PI/NRTI global p< Weeks from switch to second-line Week 96 outcomes: Paton, NEJM 2014; 371; ; Week 144 outcomes: Hakim, Poster 552, CROI

33 Simple Start Integrase plus 3TC PADDLE: Dolutegravir + Lamivudine in Treatment-Naive Pts Open-label, single-arm phase IV exploratory trial Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 (ITT-e, FDA snapshot analysis) First Cohort Second Cohort Treatment-naive pts with HIV-1 RNA ,000 copies/ml; CD4+ cell count 200 cells/mm 3 ; HBsAg negative (N = 20) DTG 50 mg QD + Lamivudine 300 mg QD (n = 10) Second cohort to be enrolled following confirmation of first cohort success at Wk 8 Dolutegravir 50 mg QD + Lamivudine 300 mg QD (n = 10) Figueroa MI, et al. EACS Abstract 1066.

34 PADDLE Study: Efficacy-DTG and 3TC in Naïve patients Experimental Study # SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < Not done 105 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 SAE <50 <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 < <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < < <50 <50 <50 <50 <50 < <50 <50 <50 Not done <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 PDVF <50 <50 <50 <50 <50 <50 <50 <50 <50 SAE = serious adverse event PDVF = protocol defined virologic failure Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB.

35 % <50 Week 40 ANRS 167 LamiDol Study DTG/3TC Maintenance Subjects No Hx of failure, No Hep B 8 week Switch to 2NRTI+DTG Then to DTG/3TC-40 Weeks FU DTG+3TC 97% (101/104) pts maintained therapeutic success through 40 wks of dual therapy (study Wk 48) [1] No INSTI resistance in 3 pts with virologic failure 7 pts with serious AEs, only 2 related to dual therapy Joly V, et al. 24th CROI; Seattle, WA; February 13-16, Abst. 458.

36 LATTE-2: Maintenance Therapy With Cabotegravir IM + RPV IM (ITT-ME Population) HIV-1 RNA <50 c/ml at Week 48: ITT-ME (Snapshot) Both Q8W and Q4W comparable to Oral CAB at Week 48 a a Met prespecified threshold for concluding IM regimen is comparable to oral regimen (Bayesian Posterior Probability >90% that true IM response rate is no worse than -10% compared to the oral regimen). Observed Bayesian Probabilities: Q8W vs Oral = 99.7%; Q4W vs Oral = 99.4%. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

37 Protocol-Defined Virologic Failure (PDVF) Maintenance period a Q8W IM (n=115) Q4W IM (n=115) Oral CAB (n=56) Subjects with PDVF 2 (1%) b 0 1 (2%) INI-r mutations 1 c 0 0 NRTI-r mutations NNRTI-r mutations 1 c 0 0 NNRTI K103N, E138G, and K238T (FC RPV=3.3; Etravirine=1.9); INI Q148R (FC CAB=5.1; Dolutegravir=1.38) c No additional PDVFs beyond W48 on any arm (all subjects through W72) d PDVF: <1.0 log 10 c/ml decrease in plasma HIV-1 RNA by Week 4, OR confirmed HIV-1 RNA 200 c/ml after prior suppression to <200 c/ml, OR >0.5 log 10 c/ml increase from nadir HIV-1 RNA value 200 c/ml. a One additional PDVF without treatment-emergent resistance occurred during oral Induction Period due to oral medication non-adherence. b One PDVF at Week 4: no detectable RPV at Week 4 and Week 8, suggesting maladministration. c One PDVF at Week 48 at HIV- 1 RNA 463 c/ml (confirmed at 205 c/ml). d Contains data beyond W48. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

38 Monotherapy Simplest of all! But perhaps the most risky?

39 Emergent INSTI Resistance After Switch to DTG Monotherapy International, multicenter retrospective study Evaluated virologically suppressed pts switched to DTG 50 mg QD monotherapy Pts with history of VF on INSTI and INSTI resistance excluded 11 of 122 pts switched to DTG monotherapy experienced VF 9 of 11 had genotypic INSTI resistance at VF INSTI resistance pathways varied INSTI Resistance at VF 92Q/155H (n = 1) 97A/155H (n = 1) 155H/148R (n = 1) 118R (n = 2) 148K (n = 1) 148H (n = 2) 148R (n = 1) Blanco JL, et al. CROI Abstract 42.

40 Conclusions 1. No clinical advantage of 4 (with INSTI) drugs-even in low CD4 and high VL. 2. Need RT inhibitors plus high barrier to resistance in 2 drug Rx 3. Dual therapy Regimen in naïve or switch-some data evolving 4. Utility in Long acting injectables 5. Monotherapy is a niche area but only with boosted Pis not InSTIs 6. Stay with the data use triple therapy and wait for trials to report.