Investigational Approaches to Antiretroviral Therapy

Transcription

1 Investigational Approaches to Antiretroviral Therapy Rajesh T. Gandhi, MD Massachusetts General Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Learning Objectives After attending this presentation, learners will be able to: Discuss the appropriate use of novel antiretroviral agents Identify new approaches for treating people with HIV infection Slide 4 of 40 Investigational Approaches to Antiretroviral Therapy Are there any new options for initial treatment of HIV? Are two antiretrovirals as good as (or better than) three? Updates on 2- drug therapy What are the options in someone who has difficulty taking daily drugs? Long-acting agents in development What are new medicines for treating someone with multi-drug resistant HIV? What s on the horizon?

2 Case Scenario What to Start? 29 yo M with positive HIV Ag/Ab and confirmatory test HIV RNA, HIV genotype, CD4 count, BUN/Cr, other labs pending You decide to initiate same-day ART Which regimen would you choose? 1. Efavirenz/TDF/FTC 2. Rilpivirine/FTC/TAF 3. EVG/c/FTC/TAF 4. DTG/ABC/3TC 5. DTG + FTC/TAF 6. BIC/TAF/FTC Case Scenario What to Start? 29 yo M with positive HIV Ag/Ab and confirmatory test HIV RNA, HIV genotype, CD4 count, BUN/Cr, other labs pending You decide to initiate same-day ART 1. Efavirenz/TDF/FTC risk of non-response if transmitted NNRTI resistance 2. Rilpivirine/FTC/TAF less effective if VL >100 K, CD4 < EVG/c/FTC/TAF lower barrier to resistance than DTG 4. DTG/ABC/3TC need HLA-B701 first 5. DTG + FTC/TAF 6. BIC/TAF/FTC New Antiretroviral Drugs New medications in current classes Bictegravir (INSTI) (approved Feb 2018) Doravirine (NNRTI)

3 Bictegravir (BIC) Unboosted integrase inhibitor; high barrier to resistance; low potential for drug interactions Phase 3 trials in treatment naïve people: BIC/FTC/TAF vs DTG/ABC/3TC; BIC/FTC/TAF vs. DTG + FTC/TAF BIC non inferior to DTG in terms of virologic suppression; no resistance 1,2 As compared to DTG/ABC/3TC, similar changes in estimated GFR, tubular proteinuria, bone mineral density and lipids Randomized switch studies in virologically suppressed persons: Switching to BIC/FTC/TAF non-inferior to continuing boosted PI 3 or a DTG, ABC, 3TC-containing regimen 4 1 Gallant J et al, Lancet 2017; 2 Sax P et al Lancet 2017; 3 Daar E et al IDWeek Molina J-M et al, CROI 2018 abstract 22 Bictegravir/FTC/TAF: Treatment Naïve Trials Study ,2 Study ,4* -0.6% -3.5% (-4.8 to 3.6%) (-7.9 to 1.0%) Proportion of Participants, % HIV-1 RNA < 50 c/ml 100 B/F/TAF (n=314) ABC/3TC/DTG (n=315) HIV-1 RNA No HIV-1 RNA 50 c/ml Data HIV-1 RNA < 50 c/ml B/F/TAF (n=320) DTG + FTC/TAF (n=315) HIV-1 RNA No HIV-1 RNA 50 c/ml Data Bictegravir/FTC/TAF has non-inferior efficacy vs DTG-containing regimens in treatment-naïve populations at Week 48 Gallant J et al, Lancet 2017; Sax P et al Lancet 2017 Indications: Initial treatment of adults with HIV Replacement for regimen in persons who are virologically suppressed and have no history of treatment failure or known resistance to its components Pharmacology and dosing: One-pill, once a day, with or without food. Not recommended if estimated CrCL <30 ml/minute Drug resistance: Bictegravir/FTC/TAF Active in vitro against HIV isolates that carry some integrase resistance mutations Efficacy in people with prior INSTI failure or resistance is unknown

4 Bictegravir/FTC/TAF Drug interactions: Rifampin contraindicated 1 ; other rifamycins not recommended. Metformin AUC increased 39%; no effect on glucose 2 ; assess benefit/risk BIC chelated by polyvalent cations; time doses according to label Pregnancy: Not recommended -- insufficient safety data Side effects: Diarrhea, nausea and headache Increase in serum creatinine (median 0.1 mg/dl) because of inhibition of tubular secretion 1 Custodio JM et al CROI 2018, #34; 2 Custodio J et al ID Week 2017, 1386 Doravirine (DOR): Investigational NNRTI Active in vitro against HIV that is resistant to first-generation NNRTI (isolates with K103N, Y181C, G190A, E101K, E138K, K103N/Y181C) 1 Once daily without regard to food Low potential for drug interactions In phase 3 clinical trial (DRIVE- FORWARD) 2, DOR non-inferior to darunavir/r in terms of virologic suppression with superior lipid profile 1 Lai AAC 2014;58: Molina JM, et al, CROI 2017, Abstract 45LB DRIVE-AHEAD: Doravirine/3TC/TDF in Treatment-Naïve Persons With HIV Infection Phase 3 Double-blind Doravirine/3TC/Tenofovir DF (n=364) Treatment-naïve Efavirenz/FTC/Tenofovir DF HIV RNA 1000 copies/ml (n=364) Stratified by HIV RNA HCV or HBV allowed Week Primary Endpoint Primary outcome: HIV RNA <50 copies/ml (FDA snapshot algorithm). HIV RNA <50 copies/ml Non-inferiority: -10%. Baseline demographics: Male: 85%. Age: years. White: 48%. History of AIDS: 14%. HIV RNA: log 10 copies/ml. CD4: cells/mm 3. Squires KE, et al. J Int AIDS Soc. 2017;20(suppl 4): Abstract TUAB0104LB

5 DRIVE-AHEAD: Doravirine/3TC/TDF in Treatment-Naïve Persons With HIV Infection DOR/3TC/TDF non-inferior to EFV/FTC/TDF at Wk 48 in terms of virologic suppression HIV RNA >50: ~10% in each arm Virologic failures in DOR arm (6%) Primary NNRTI resistance: 1.6% Primary NRTI resistance: 1.4% DOR superior to EFV in terms of lower incidence of neuropsychiatric adverse events; more favorable changes in lipids New drug applications for DOR/TDF/3TC and for DOR alone submitted to FDA in Jan 2018; PDUFA date: Oct 2018 Patients (%) HIV RNA <50 Copies/mL Doravirine/3TC/TDF Difference (%): 3.5 (-2.0, 9.0) % 91% 84% 81% Overall ITT (n=364/364) 100K (n=277/258) Efavirenz/FTC/TDF 81% 81% >100K (n=69/73) HIV RNA (copies/ml) (Observed Failure Approach) Squires KE, et al. J Int AIDS Soc. 2017;20(suppl 4): Abstract TUAB0104LB; Orkin C et al, CROI 2018, abstract 491 Case Scenario 50 yo HIV+ M with diabetes, hypertension, chronic renal insufficiency (creatinine clearance of 25) HIV RNA 30,000, CD4 cell count 450 HLA-B5701 positive You want to choose a regimen that avoids TAF, TDF, ABC 1. Darunavir/cobicistat + FTC 2. Darunavir/ritonavir + raltegravir 3. Darunavir/ritonavir + dolutegravir 4. Darunavir/ritonavir + 3TC 5. Dolutegravir + 3TC 6. Dolutegravir + rilpivirine OR FEW

6 Current NRTI-limiting Regimens for Initial Therapy LPV/r + 3TC (GARDEL) 1 Non-inferior to LPV/r + 2 NRTI Disadvantages: high pill burden, toxicities DRV/r + RAL (NEAT001) 2,3 Non-inferior to DRV/r + TDF/FTC CD4 <200: DRV/r + RAL inferior to DRV/r + 2 NRTI VL >100 K: more failures with DRV/r + RAL 1 Cahn P et al, Lancet ID 2014; 2 Raffi F et al, Lancet, 2014; 3 Lambert-Niclot S et al, J Antimicrob Chemother, 2016; 4 Figueroa MI et al, 15 th EACS, 2015 Dolutegravir + 3TC for Initial Therapy PADDLE: single arm study 20 pts with VL <100K: HIV RNA <50 in 90% at wk 48 ACTG A5353: Phase 2 single-arm study HIV RNA 1000 to <500, participants enrolled Week 24, HIV RNA <50 in 90% Virologic failure (n=3); suboptimal adherence 1 person: R263RK and M184V GEMINI-1 and -2: ongoing phase 3 trials; results anticipated this year ACTG A5353 Wk 24 Virologic Outcomes Baseline HIV RNA >100K 100K (n=37) (n=83) <50 (%) VL Virologic non-success (%) HIV RNA >50 copies/ml 8 0 Other reasons 0 2 Figueroa MI et al, 15 th EACS, Taiwo BO et al, Clin Infect Dis, DRV/r + 3TC for Initial Therapy Randomized trial (ANDES) DRV/r + 3TC (n=75) DRV/r + 3TC/TDF (n=70) VL <50 at wk 48: 93 94% Baseline VL >100K: high response rate Dual therapy non-inferior to triple therapy at wk 48 Promising results; larger trial ongoing Patients (%) HIV RNA <50 (ITT) Darunavir/r +: 3TC 3TC + tenofovir DF Difference (%): -1.0% (-7.5 ; 5.6%) 93% 94% % 92% Overall (n=70/66) Baseline HIV RNA >100K Copies/mL (n=20/12) Figueroa et al, CROI 2018, Abstract 489

7 Switching to NRTI-limiting regimens after virologic suppression (maintenance) LPV/r + 3TC/FTC (OLE) 1 ATV/r + 3TC (SALT, ATLAS-M) 2-3 DRV/r + 3TC (DUAL) 4 DRV/r + RPV (small trial, n=60) 5 DRV/r + DTG (DUALIS) being studied DTG + 3TC (LAMIDOL, ASPIRE favorable results 6,7 ; TANGO large RCT just launched 8 ) 1 Arribas JR et al, Lancet ID, 2015; 2 Perez-Molina JA et al, Lancet ID, 2015; 3 Di Giambenedetto S et al, J Antimicrob Chemother 2017; 4 Pulido T HIV Drug Therapy 2016 Glasgow, O331; 5 Maggiolo F, JAIDS, 2016; 6 Joly V et al CROI 2017, abstract 458; 7 Taiwo B et al CID, 2017 ; 8 Switching to DTG + RPV in Virologically Suppressed Patients: SWORD-1 and -2 Pts on stable 1 st or 2 nd ART (no change due to VF) and VL <50 for >12 mo. Randomized 1:1 to continue antiretroviral regimen (CAR) or switch to DTG + RPV DTG + RPV non-inferior to CAR DTG/RPV single pill regimen available Food, acid lowering therapy, cation considerations HIV RNA <50, % Virologic outcomes at wk DTG + RPV (n=513) CAR (n=511) 5 4 <1 1 <1 1 Virologic Virologic No virologic success non-response data Llibre JM et al. CROI 2017; Abstract 44LB.; Llibre JM et al, Lance 2018 Long-acting Antiretrovirals 55 yo M with HIV, achalasia, dysphagia Long-standing difficulty swallowing pills Virologically suppressed on dolutegravir and rilpivirine He asks whether there are long-acting HIV medicines that he can take intermittently instead of having to take a daily oral regimen 1. Yes 2. No 3. Not yet 4. I don t know 25

8 LATTE-2: Long-Acting Cabotegravir + Rilpivirine as Maintenance Therapy Cabotegravir (integrase inhibitor) and rilpivirine (NNRTI): long-acting formulations 1,2 LATTE-2: Phase 2a 3 Open-label 18 years of age ART-naïve CD4 200 Creatinine clearance 50 No HBV or ALT 5x ULN *In virologically suppressed patients, oral RPV added during last 4 weeks of induction phase. Qualification for maintenance phase: HIV RNA <50 between wk -4 and day 1. Baseline characteristics: Median age: 35 years. Male: 92%. Median HIV RNA: 4.4 log 10 copies/ml. HIV RNA >100K copies/ml: 18%. Median CD4: 489 cells/mm Spreen HIV Clin Trials 2013;14: Spreen JAIDS 2014;67: Margolis DA, et al. Lancet. 2017Jul 21. [Epub ahead of print]. LATTE-2: Virologic Outcomes With LA Cabotegravir + Rilpivirine as Maintenance Therapy HIV RNA <50 Copies/mL (%) % 87% 94% Week 96 Results Oral cabotegravir + 3TC/ABC daily (n=56) IM cabotegravir + IM rilpivirine Every 4 weeks (n=115) Every 8 weeks (n=115) 2% 4% 0% 2% Success Failure No Protocol-defined virologic failure: q8 weeks (n=2 at weeks 4 and 48 [INI + NRTI resistance]) and oral cabotegravir (n=1 at week 8 [no resistance]) 14% Injection site reactions: mild/moderate; transient High participant satisfaction Ongoing phase 3 trials (FLAIR, ATLAS): every 4-wk dosing; results in 2018 ATLAS-2M: every 8-wk dosing; results in % Virologic Data Eron J, et al. J Int AIDS Soc. 2017;20(suppl 4): Abstract MOAX0205LB. Margolis DA, et al. Lancet. 2017Jul 21. [Epub ahead of print]. Long-acting NRTTI: MK-8591 (EFdA) Nucleoside RT translocation inhibitor (NRTTI) Half life of active anabolite: hr Humans: single oral dose as low as 0.5 mg suppressed HIV RNA for >7 day Study in healthy volunteers: multiple daily doses as low as 0.25 mg expected to lead to HIV suppression Phase 2b trial in people with HIV, in combination with DOR and 3TC, has started (DRIVE2Simplify) Daily dosing Phase 1b, single-dose, monotherapy study Study population: ART naïve (N=30) Grobler et al CROI 2017 #435 Matthews et al IAS 2017 #TUPDB0202LB Matthews RP et al CROI 2018 #26

9 Long-acting NRTTI: MK-8591 (EFdA) Animals: drug accumulates in lymph nodes, vagina, rectum Oral MK-8591, even at low doses, protects monkeys from rectal SHIV challenge Parenteral dosing: 6-12 months Supports possible role in PrEP, long-acting implantable therapy Grobler et al CROI 2016 #98 Friedman et al CROI 2016 #437LB Grobler et al CROI 2017 #435 Markowitz M et al IAS 2017 #MOAX0203LB Markowitz M et al CROI 2018, #89LB Adapted from slide by Trip Gulick, MD Case Scenario 60 yo F diagnosed with HIV in Multiple previous regimens HIV RNA 20,000; CD4 cell count 150 HIV phenotype: resistance to NRTI, NNRTI, PIs. Sensitive to INSTI Which of the following classes of drugs are in/have completed phase 3 clinical trials? 1. Entry/attachment inhibitors 2. Maturation inhibitors 3. Capsid inhibitors 4. Broadly neutralizing antibodies New Medications for Multi-drug Resistant HIV in Phase 3 trials Ibalizumab Fostemsavir

10 A Approved HIV Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion fostemsavir ibalizumab gp41 gp120 V3 loop CCR5 Inhibitors maraviroc* enfuvirtide* CD4 Cell Membrane * = FDA approved CCR5/CXCR4 (R5/X4) Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 2003;100: Humanized monoclonal Ab: binds CD4 on host cells; blocks HIV entry (post attachment inhibitor) 1 Active against CCR5 and CXCR4 tropic HIV No cross resistance with other ARVs 2 IV infusion: 2,000 mg loading dose then 800 mg every 2 wks Duration of infusion: min Ibalizumab 1 Emu B et al, Abstract 1686, IDWeek 2017; 2 Weinheimer S et al, CROI Ibalizumab in Persons with Multi-Drug Resistant HIV Phase 3 trial: 40 heavily treatment experienced pts with 3-class ARV resistance, 1 active drug Primary endpt: VL drop >0.5 log 10 c/ml: 3% during control period 83% after loading dose After loading dose, regimen optimized at day 14 Wk 24: VL <200 in 50% Expanded access: viral suppression to wk 48 March 6, 2018 Emu B et al, Abstract 1686, IDWeek 2017; Weinheimer S et al, CROI 2018, #561 36

11 Fostemsavir (FTR): Oral HIV Attachment Inhibitor Prodrug of temsavir: binds to gp120, inhibits HIV attachment to CD4 Phase 3 trial in heavily treatment experienced patients with virologic failure (BRIGHTE) Kozal M et al, 16th EACS, 2017 Fostemsavir (FTR): Phase 3 Trial (BRIGHTE) Adjusted Mean (95% CI) Mean VL Change at day 8 N=69 N=201 Placebo FTR 600mg BID Difference (95% CI) = (-0.810, ) P< Virologic response through wk 24 (observed analysis) Kozal M et al, 16th EACS, 2017 Regulatory submissions are currently anticipated to take place in the 2019/2020 timeframe At wk 24, 54% of randomized and 36% of non-randomized ppts who received FTR + OBR achieved VL <40 HIV Maturation Inhibitors (MI) Slide courtesy of Trip Gulick, MD Treated with maturation inhibitor Immature virus Morales-Ramirez IAS 2017 #MOAB0103:BMS /GSK development halted due to GI toxicity

12 40 On the Horizon Broadly neutralizing antibodies Other novel agents Broadly Neutralizing Antibodies against HIV Slide courtesy of Pablo Tebas, MD Scheid J et al, Nature, 2016 Similar results with VRC01. Bar K et al, NEJM 2016 Combination bnab, long-acting bnab being studied for treatment, prevention

13 Selected other investigational drugs in the pipeline: Investigational Approaches to Antiretroviral Therapy New options for initial treatment: Bictegravir/FTC/TAF approved; Doravirine (NNRTI) under FDA review Two-drug therapy advancing: DTG + 3TC and DRV/r + 3TC being studied for initial therapy; DTG/RPV approved for maintenance What are the options in someone who has difficulty taking daily drugs? Long-acting agents in development: LA-CAB/LA-RPV in phase 3 trials; MK-8591 (EFdA); others What do you give to someone with highly drug resistant HIV? Ibalizumab approved; fostemsavir completed phase 3; other agents being developed What s on the horizon? broadly neutralizing antibodies, and many others!! Extra slides

14 DTG + 3TC switch LAMIDOL 1 : Single-arm study of switching participants (n~ 100) with virologic suppression on 3-drug ART to DTG + 3TC 97% therapeutic success LAMIDOL: % therapeutic success ASPIRE 2 : participants (n=89) with virologic suppression randomized to continue 3-drug ART or to switch to DTG + 3TC DTG + 3TC non-inferior to continuation of 3-drug ART TANGO 3 : large (n=550) RCT launched in Joly V et al CROI 2017, abstract 458; 2 Taiwo B et al CID, 2017 ; 3 HPTN 083: PrEP with IM CAB vs. oral TDF/FTC Study population: MSM and TGW, at high-risk for HIV acquisition (N=4500) Study regimen: CAB every 2 months injections (after loading dose) vs oral TDF/FTC daily Design: non-inferiority, efficacy study Currently enrolling Monoclonal Antibody against CCR5: PRO 140 Weekly subcutaneous injection Single drug maintenance of suppression study 1 : 10 pts had virologic suppression for 2 yr (out of 31 who entered) One week randomized placebo controlled phase 2b/3 trial in combination with existing ART in people failing current ART 2 N=52; CCR5 tropic HIV Resistance to 3 ARV classes or 2 or more classes with limited treatment options At 1 week, statistically significant reduction in HIV RNA of > 0.5 log 10 c/ml with PR0 140 vs placebo Participants continuing for additional 24 weeks with weekly PRO 140/optimized ART 1 Lalezari J et al, CROI 2017, abstract 437; 2