WHEN TO START? CROI 2015: Focus on ART

Transcription

1 CROI 215: Focus on ART FORMATTED: Washington, DC: May 13, 215 Roy M. Gulick, MD, MPH Gladys and Roland Harriman Professor of Medicine Chief, Division of Infectious Diseases Weill Cornell Medical College New York, New York Slide 3 of 38 Learning Objectives After attending this presentation, participants will be able to: Learn about the latest findings from CROI regarding treatment. Learn about the latest findings from CROI regarding prevention. WHEN TO START? Slide 5 of 38 Washington, DC: May 13, 215 1

2 WHEN TO START? TEMPRANO: Design Slide 6 of 38 2X2 factorial design in Cote D Ivoire Eligible patients: HIV+, CD4 <8, not eligible for ART by WHO GL (N=276) Randomization: Start ART according to WHO GL Start ART according to WHO GL + INH X 6 months Start ART immediately Start ART immediately + INH X 6 months Primary ART was TDF/FTC/EFV (LPV/r or 3 NRTIs in certain cases) Primary endpoint = death, AIDS, serious bacterial infx, non-aids cancer Danel CROI 215 #115LB WHEN TO START? TEMPRANO: Results Baseline: 78% women, average age 35 yo, average CD4 465 (41% CD4 >5); 35% +Quantiferon; 9% on T/S Results: Primary endpoint (average f/u 3 months) 2.6% LTFU 24 clinical events ART: WHO (11.4%) vs. immediate (6.6%) 44% (P=.3) For subgroup with CD4 >5 WHO (1%) vs. immediate (6%) INH: yes (7%) vs. no (11%) 39% (P=.6) Sensitivity analyses (M=F, adjusted CD4, as treated) similar Slide 7 of 38 Danel CROI 215 #115LB Slide 8 of 38 WHAT TO START? Washington, DC: May 13, 215 2

3 Study Schema A5257: Phase III, prospective, multi-center, randomized, open-label trial (N=189) ART-naïve, HIV+ subjects 18 yr, VL 1 c/ml McComsey CROI 215 #14 Abstract WEAB16LB Randomized 1:1:1 to three NNRTI-sparing ARV regimens Stratified by screening HIV-1 RNA level ( or <1, copies/ml), Framingham 1-year CHD risk score (<6% vs 6% risk), and A526s participation A526s Substudy (N=328) No known CVD, diabetes mellitus, or use of lipid-lowering medications Participants followed for 96 weeks after enrollment of last subject FTC/TDF + ATV/r (N=19) A526s FTC/TDF + RAL (N=16) At baseline and week 96 DXA scan (limb fat, trunk fat and lean mass) CT abdomen (visceral and subcutaneous abdominal fat) At baseline Leptin, adiponectin, IL-6, hs-crp, D-dimer, scd14, scd163 FTC/TDF + DRV/r (N=113) Slide 9 of 38 Fat Changes: Peripheral and Central Slide 1 of 38 RAL 2% RAL 25% DRV/r 14% ATV/r 23% ATV/r 11% DRV/r 2% RAL 29% RAL 33% DRV/r 21% ATV/r 31% ATV/r 16% DRV/r 29% McComsey CROI 215 #14 Abacavir Use and Risk for Myocardial Infarction in the NA-ACCORD (N=16733 with 31 MI) Adjusted hazard ratios of MI among persons with recent ABC use (vs. no recent ABC use): Unadjusted risk: 1.88 (95% CI: 1.35, 2.6) Adjusted D:A:D model Model adjusted for cardiac risk factors Rx-naïve starting ABC Adjusted Hazard Ratio Palella CROI 215 #749 Slide 11 of 38 Washington, DC: May 13, 215 3

4 Abacavir Use and Risk for Myocardial Infarction in the NA-ACCORD Adjusted hazard ratios of select established CVD risk factors that remained significantly associated with MI in the Restricted study population Full study population Recent ABC use Age <4 (vs. 5 59) years Age 4-49 (vs. 5 59) years Age 6 (vs. 5 59) years Hypertension Diabetes egfr 3-59 (vs. 6) ml/min/1.73m 2 egfr <3 (vs. 6) ml/min/1.73m 2 High ( 24 vs. <24 mg/dl) total cholesterol High ( 3 vs. <3 mg/dl) triglycerides Statin use Slide 12 of Adusted hazard ratio for MI Palella CROI 215 #749 Slide 13 of 38 WHEN TO CHANGE & WHAT TO CHANGE TO Abstract 69, Vavro CL Integrase Resistance Correlates of Response to Dolutegravir (DTG) Through 48 Weeks: VIKING 3 and 4 Rx-experienced patients (including integrase inhibitors) Baseline IN Resistance and Response at Day 8 (DTG monotherapy) Slide 14 of 38 Vavro CLet al, Abstract 69, CROI Seattle 215 Washington, DC: May 13, 215 4

5 Integrase Resistance Correlates of Response to Dolutegravir (DTG) Through 48 Weeks (VIKING 3 and 4) Study Population: VL >5K; virologic failure on RAL or EVG; optimized background at 7 days DTG 5 mg BID (ITT-E, Snapshot Algorithm) Baseline IN Mutation Group Week 24 <5 c/ml Week 48 <5 c/ml N N (%) N (%) All (66%) 128 (6%) No Q (78%) 98 (7%) Q * (52%) 23 (48%) Q * 25 6 (24%) 7 (28%) *L74I, E138A/K/T, G14A/C/S Slide 15 of 38 Vavro CROI 215 Abstract #69 Phase 3 Phase 2 Phase 1/2 TAF Newer ART Agents (partial list) NRTI NNRTI PI Entry Inh apricitabine BILR 355 dexelvucitabine doravirine festinavir (MK-1439) elvucitabine TMC Phase 1 CMX157 RDEA 86 CTP-298 CTP-518 PPL-1 SPI-256 cenicriviroc BMS ibalizumab PF HGS4 SCH53276 VIR-576 II cabotegravir (GSK 744) BI INH-11 MI BMS GSK Slide 16 of 38 Drug Delivery: TDF vs. Tenofovir Alafenamide Fumarate (TAF) Slide 17 of 38 Washington, DC: May 13, 215 5

6 Mean (SD) Change from Baseline egfr* HIV-1 RNA <5 c/ml, % TAF: Phase 3 Study Design: Studies 14 and 111 Tx-Naïve Adults (N=1733) HIV-1 RNA 1 c/ml egfr 5 ml/min 1:1 n=866 n=867 E/C/F/TAF QD E/C/F/TDF QD Two Phase 3 randomized, double-blind, double-dummy, active-controlled studies Study 14 (North America, EU, Asia), Study 111 (North America, EU, Latin America) Primary endpoint: proportion of patients with HIV-1 RNA <5 copies/ml Non-inferiority (12% margin) based on Week 48 FDA snapshot analysis Combined efficacy analysis pre-specified Week Primary Endpoint Slide 18 of 38 Wohl CROI 215 #113LB TAF Phase 3: VL <5 copies/ml at Week 48 Studies 14 and 111: Week 48 Combined Analysis Virologic Outcome E/C/F/TAF (n=866) E/C/F/TDF (n=867) Success Failure No Data Treatment Difference (95% CI) Favors E/C/F/TDF.7% E/C/F/TAF non-inferior to E/C/F/TDF at Week 48 Comparable responses by baseline VL and CD4 Favors E/C/F/TAF 2.% 4.7% 12% +12% Wohl CROI 215 #113LB Slide 19 of 38 *Cockroft-Gault (ml/min). TAF: Phase 3 Change in egfr (Cockcroft-Gault) Studies 14 and 111: Week 48 Combined Analysis Mean (SD) change from baseline egfr Cockroft-Gault (ml/min) Time (Weeks) Time (Weeks) No cases of proximal renal tubular dysfunction (Fanconi s syndrome) E/C/F/TAF E/C/F/TDF p <.1 Slide 2 of 38 Sax CROI 215 #143LB Washington, DC: May 13, 215 6

7 Mean (SD) % Change from Baseline Slide 21 of 38 Changes in Spine and Hip BMD Through Week 48 Studies 14 and 111: Week 48 Combined Analysis Spine Hip p < p < Week Week E/C/F/TAF, n E/C/F/TDF, n Sax CROI 215 #143LB Cabotegravir (CAB, GSK ) Integrase inhibitor similar to DTG; similar resistance Potent in HIV+ individuals (5, 1, 3, 6 mg oral) Margolis EACS 213; Spreen HIV Clin Trials 213;14:192 Nanotechnology formulation; SC + IM injections T ½ 21-5 days! Supports monthly or quarterly dosing Safety: ISR (all mild) and nodules with SC dosing Spreen JAIDS 214;67:481 Slide 22 of 38 LATTE 1: CAB and RPV as 2-Drug Oral Maintenance Therapy Study Design Slide 23 of 38 HIV ART-naïve HIV-1 RNA 1 c/ml CD4 2 cells/mm 3 1:1:1:1 Randomization Stratified by VL and NRTI Blinded to CAB dose N=243 Oral Induction Phase Oral Maintenance Phase CAB 1 mg + 2 NRTIs* CAB 1 mg + RPV 25 mg CAB 3 mg + 2 NRTIs CAB 3 mg + RPV 25 mg CAB 6 mg + 2 NRTIs CAB 6 mg + RPV 25 mg EFV 6 mg + 2 NRTIs *ABC/3TC or TDF/FTC D Margolis CROI 215, #554LB Washington, DC: May 13, 215 7

8 LATTE 1: Week 96 results CAB and RPV Oral Maintenance Therapy Virologic Success: HIV-1 RNA <5 c/ml by FDA Snapshot (ITT-E) Proportion, % (95% CI) 1 BL Median CD4+ cell count (IQR) CAB total n=16 EFV 6 mg n=47* Baseline 412. (333., 548.) (34., 651.) Change from Baseline at W96 CAB 1 mg (n=6) (137., 355.) (158., 415.) CAB 6 mg (n=61) CAB 3 mg (n=6) EFV 6 mg (n=62) Slide 24 of 38 Margolis CROI 215, #554LB BMS-66368: Oral HIV Attachment Inhibitor Prodrug of BMS Inhibits CD4 binding by binding to gp12 PK suggest QD or BID dosing without boosting baseline susceptibility in some pts due to envelope polymorphisms; screened by baseline IC 5 Slide 25 of 38 Study pop: CD4 >2, VL >5 off ART X >8 wks or ART-naive (N=5) Nettles JID 212;26:12 BMS-66368: Phase 2b Randomized, partially blinded (to 68 dose) Rx-experienced pts (>1 wk on >1 ART) with IC5<1nM for 529 (N=251) Randomized to TDF + RAL + 68 [4 or 8 bid; 6 or 12 qd] or ATV/r Results: 8d monotherapy: up to 1.5 log with 12 mg qd Wk 48 VL < % vs. ATV/r 71%; no difference by BL VL or CD4 68: no SAE or rx d/c 6 mg bid selected for phase 3 Thompson CROI 215 #545 Landry CROI 215 #59 Slide 26 of 38 Washington, DC: May 13, 215 8

9 Maturation Inhibitors Slide 27 of 38 Lataillade CROI 215, #114LB Study population: HIV+, VL >5K, CD4 >2, PI and MI naive No serious adverse events, grade 3/4 events, no d/c due to adverse events Plans for phase 2b Slide 28 of 38 Lataillade CROI 215, #114LB PREVENTION Slide 29 of 38 Washington, DC: May 13, 215 9

10 PROUD Pilot GMSM reporting UAI last/next 9days; 18+; and willing to take a pill every day Randomize HIV negative MSM (N=545) (exclude if treatment for HBV/TDF + FTC contra-indicated) Risk reduction includes TDF + FTC NOW Risk reduction includes TDF + FTC AFTER 12M Follow 3 monthly for up to 24 months Main endpoints in Pilot: recruitment and retention From April 214: HIV infection in first 12 months McCormack CROI 215 #22LB Slide 3 of 38 HIV Incidence Group No. of Followup (PY) (per 1 Incidence infections PY) 9% CI Overall Immediate Deferred Efficacy =86% (9% CI: 58 96%) P value =.2 Rate Difference =7.6 (9% CI: ) Number Needed to Treat =13 (9% CI: 9 25) McCormack CROI 215 #22LB Slide 31 of 38 N=414 n=26 n=28 Molina CROI 215 #23LB Slide 32 of 38 Washington, DC: May 13, 215 1

11 Molina CROI 215 #23LB Slide 33 of 38 Slide 34 of new infections 2 new infections Molina CROI 215 #23LB FACTS 1 Phase III RCT 18-3 years, HIV negative, sexually active women Not pregnant, Willing to use effective contraception and condoms No renal, hepatic, pelvic or bone disease Enrolled irrespective of HSV-2, Hepatitis B or breastfeeding status Randomised to pericoital use (BAT 24) (N=259) Vaginal TFV 1% gel Monthly visits 1-27 months HIV testing, safety assessment, product resupply and quarterly CVL Placebo gel Comprehensive HIV prevention counselling, provision of condoms and contraception, treatment for symptomatic STIs Primary endpoint = HIV infection Rees CROI 215 #26LB Slide 35 of 38 Washington, DC: May 13,

12 Cumulative proportion of HIV endpoints Primary outcome: cumulative HIV incidence by trial arm (mitt) Time from randomisation (months) Placebo TFV gel TFV gel: 61 Log-rank test stratified by site, p=.95 placebo: 62 HIV incidence 4%/year overall No difference in HIV incidence between TFV gel vs placebo Rees CROI 215 #26LB Slide 36 of 38 Acknowledgments Cornell HIV Clinical Trials Unit (CCTU) Division of Infectious Diseases Weill Cornell Medical College AIDS Clinical Trials Group (ACTG) HIV Prevention Trials Network (HPTN) Division of AIDS, NIAID, NIH Multiple colleagues for slides The patient volunteers! Slide 38 of 38 Washington, DC: May 13,