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Conference Call Line: 1-800 -920-7487 Participant Code: 9982883

Learn about the results of the PROUD and ANRS IPERGAY trials, which evaluated the effectiveness of PrEP in high-risk MSM. This presentation is brought to you by the NCATEC AETC.

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Conference Call Line: 1-800 -920-7487 Participant Code: 9982883

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  1. Conference Call Line: 1-800-920-7487 Participant Code: 9982883 Please type your name into the chat box to confirm your attendance.

  2. Visit us at www.med.unc.edu/ncaidstraining This presentation was made possible by AETC grant award # H4AHA00067 from the HIV/AIDS Bureau of the Health Resources Services Administration (HRSA), U.S. Department of Health and Human Services (HHS). NCATEC operates an AIDS Education and Training Center (AETC) that strengthens the capacity of health care professionals to care for people living with HIV/AIDS through training and technical assistance. The information presented here is the consensus of HIV/AIDS specialists in NCATEC and does not necessarily represent the official views of HRSA/HAB.

  3. CROI 2015Joe Eron & David Wohl UNC – Chapel Hill

  4. HIV Prevention

  5. PROUD: Immediate vs Deferred PrEP in High-Risk MSM in “Real World” Trial • Randomized, open-label trial of daily oral TDF/FTC PrEP in HIV neg MSM in 13 clinics in London reporting unprotected anal intercourse in last 90 days: • Immediate TruvadaPrEP(n = 267) vs • Defer TruvadaPrEP for 12 mos(n = 256) • Primary endpoint: HIV infection in first 12 mos • 86% reduction in risk seen over 60 wks with immediate PrEP (90% CI: 58% to 96%, P = .0002) • Rate difference: 7.6 (90% CI: 4.1-11.2) • Number needed to treat to prevent 1 infection: 13 (90% CI: 9-25) • M184V/I observed in 3/6 patients who seroconverted • No K65R observed • High rate of STIs seen in both groups • DMSB interrupted this trial in October 2014 and recommended that all participants be offered PrEP McCormack S, et al. CROI 2015. Abstract 22LB.

  6. PROUD: Immediate vs Deferred PrEP in High-Risk MSM in “Real World” Trial McCormack S, et al. CROI 2015. Abstract 22LB.

  7. ANRS IPERGAY: On-Demand Oral PrEP in High-Risk MSM • Randomized double-blind trial of HIV neg MSM with unprotected anal sex with 2 or more partners w/in 6 months: Event-driven oral TDF/FTC (n = 199) vsPlacebo (n = 201) (both with prevention services) in France. • Primary endpoint: HIV seroconversion Molina JM, et al. CROI 2015. Abstract 23LB.

  8. ANRS IPERGAY: On-Demand Oral PrEP in High-Risk MSM Kaplan-Meier Estimate of Time to HIV Infection 0.20 • 86% reduction in risk seen in PrEP arm (95% CI: 40% to 99%, P = .002) • Number needed to treat for 1 yr to prevent 1 infection: 18 • In pts with infection no TFV found in serum in last 2 visits • 4 cases of acute HCV infection noted among lab abnormalities • More GI side effects in TDF/FTC arm • Trial stopped early by DSMB who recommended that all participants start PrEP 0.16 Placebo 14 infections; incidence 6.6/100 PY 0.12 Probability of HIV-1 Infection 0.08 P = .002 TDF/FTC 2 infections; incidence 0.94/100 PY 0.04 0.00 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Mos n at risk:PlaceboTDF/FTC 201199 141140 7482 5558 4143 Molina JM, et al. CROI 2015. Abstract 23LB.

  9. ANRS IPERGAY: On-Demand Oral PrEP in High-Risk MSM Molina JM, et al. CROI 2015. Abstract 23LB.

  10. NCATEC: www.med.unc.edu/ncaidstraining

  11. Antiretroviral Therapy

  12. TenofovirAlafenamide (TAF, GS-7340)Novel Prodrug of Tenofovir Tenofovir(TFV) • Gut • Plasma • Lymphoid Cell X TFV Tenofovirdisoproxilfumarate(TDF) TFV TFV TAF TFV-MP TFV TDF Tenofoviralafenamide (TAF) TFV-DP

  13. Study Design: Studies 104 and 111 • Two Phase 3 randomized, double-blind, double-dummy, active-controlled studies • Study 104 (North America, EU, Asia), Study 111 (North America, EU, Latin America) • Stratified by HIV-1 RNA, CD4 cell count, geographic region • Primary endpoint: proportion of patients with HIV-1 RNA <50 copies/mL (Taqman 2.0) • Non-inferiority (12% margin) based on Week 48 FDA snapshot analysis • Combined efficacy analysis pre-specified • Pre-specified Week 48 safety endpoints: serum creatinine, proteinuria, hip BMD, spine BMD E/C/F/TAF QD n=866 Primary Endpoint Tx-Naïve Adults HIV-1 RNA ≥1000 c/mL eGFR ≥50 mL/min Week 0 48 96 144 1:1 E/C/F/TDF QD (Stribild, STB) n=867 Wohl DA, et al. CROI 2015. Abstract 113LB.

  14. Studies 104/111: TAF Noninferior to TDF at Wk 48 Δ +2.0%(95% CI: -0.7% to +4.7) • TAF also noninferior to TDF at Week 48 in each study (104 and 111) • Results similar across all baseline virologic and demographic subgroups • 7 pts in TAF arm and 5 pts in TDF arm with NRTI resistance at virologic failure • 1 in TAF arm and 2 in TDF arm with combined M184V/I + K65R • 5 pts in TAF arm and 3 pts in TDF arm with INSTI resistance at VF • 0.9% in TAF arm and 1.5% in TDF arm discontinued due to AE • CD4+ increases greater in TAF arm: 211 vs 181 (P = .024) 100 92 90 TAF/FTC/EVG/COBI (n = 866) 80 TDF/FTC/EVG/COBI(n = 867) 60 Patients (%) 40 20 6 4 4 4 800 784 n = 0 Virologic Success* Virologic Failure No Data *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Wohl DA, et al. CROI 2015. Abstract 113LB.

  15. Renal Markers With TAF and TDF at Wk 48 • Smaller decreases in eGFR with TAF[1] • Significantly less proteinuria, albuminuria, tubular proteinuria with TAF[1] • In separate single-arm trial of virologically suppressed pts with eGFR 30-69 mL/min switched to open-label TAF/FTC/EVG/COBI[2] • At Wk 48 after switch: • 92% maintained virologic suppression • No change in eGFR • Reduction in proteinuria and markers of renal tubular function • Improvement in hip and spine BMD Change in eGFR (Crockroft-Gault) TAF/FTC/EVG/COBITDF/FTC/EVG/COBI P < .001 20 10 Mean Δ From BL in eGFR, mL/min* -6.6 0 -11.2 -10 -20 0 12 24 36 48 Time (Wks) 1. Sax P, et al. CROI 2015. Abstract 143. 2. Pozniak A, et al. CROI 2015. Abstract 795.

  16. Changes in Spine and Hip BMD Through Week 48Studies 104 and 111: Week 48 Combined Analysis Spine Hip p <0.001 p <0.001 ‒0.66 ‒1.30 Mean (SD) % Change from Baseline ‒2.86 ‒2.95 0 0 24 24 48 48 Week Week Sax P, et al. CROI 2015. Abstract 143.

  17. LATTE: Carbotegravir (GSK1265744) + RPV as Maintenance ART: Wk 96 Results • Carbotegravir (CAB), DTG analogue with long half-life, oral or injectable formulations • Randomized, dose-ranging phase IIb study of oral formulation • Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 Wk 48primary analysis ART-naive pts, HIV-1 RNA > 1000 c/mL(N = 243) Wk 96 *Pts with HIV-1 RNA < 50 c/mL at Wk 24 continued to maintenance phase. TDF/FTC or ABC/3TC. Margolis D, et al. CROI 2015. Abstract 554LB.

  18. LATTE: Virologic Success Through Maintenance Week 96 • 6 pts in CAB arms with PDVF at Wk 96; 4 additional pts since Wk 48 Wks *Carbotegravir 30 mg selected for future development Margolis D, et al. CROI 2015. Abstract 554LB.

  19. BMS-955176: Investigational Second-Generation Maturation Inhibitor Comorbidity

  20. BMS-955176: Investigational Second-Generation Maturation Inhibitor • BMS-955176 binds tightly and reversibly to HIV-1 Gag with greater potency and coverage of Gag polymorphs than first-generation maturation inhibitors • Low-dose with half-life supportive of once-daily dosing • Low serum binding • No significant safety issues in early clinical studies • Antiviral activity measured over 10 d in placebo-controlled study • HIV-infected treatment-naive and experienced pts with HIV-1 RNA ≥ 5000 and CD4+ count ≥ 200 • All doses ≥ 10 mg associated with HIV-1 RNA declines over dosing period • Median change in HIV-1 RNA from BL to Day 11: 1.4 log10 c/mL • No serious AEs, no discontinuations due to AEs over study period BMS-955176: Median Δ in HIV-1 RNA Over Time 1 Dosing period Placebo5 mg10 mg20 mg40 mg80 mg120 mg 0 Median Δ in HIV-1 RNA From BL, log10 c/mL -1 10 11 13 1 2 3 4 5 6 7 8 9 25 -1.8 Study Days Hwang C, et al. CROI 2015. Abstract 114LB.

  21. TEMPRANO: Early ART and IPT in HIV-Infected African Adults With High CD4 Count Primary Endpoint for Patients with >500 CD4 - 44% reduction in risk with early ART Danel , C, et al. CROI 2015.

  22. Co-Morbidities

  23. NA-ACCORD: Abacavir Use and Risk of MI Adjusted HRs for MI in Those With Recent (prescribed within past 6m) ABC Use D:A:DReplication • Retrospective analysis of pts in the cohort to explore ABC use and MI • Data on MI collected from 1/1/1995 to 12/31/2010 • Three analyses: • FULL population (n=16,733): All ART users EXCEPT those on ABC at study entry • RESTRICTED population (n=6,485): Only ART naive on entry who initiated ART thereafter • D:A:D Replication: Simulates D:A:D analysis • Endpoint of incident MIs: Presence of clinical diagnosis or elevation of cardiac enzymes • 301 MIs in Full, 93 in Restricted • ABC initiators more likely to be black, IDU, heterosexual risk, HCV, HTN, renal impairment, high total cholesterol, a CD4 <200, and history of AIDS • Recent ABC use associated with MI in adjusted analyses of D:A:D Replication and Restricted population but not the Full population. • Significant independent risk factors for MI • Both: Age 60+, HTN, eGFR < 30, AIDS • Full: Smoking, DM 1.33 Full Study 1.95 Restricted Study 0.00 1.00 2.00 3.00 4.00 Palella F, et al. CROI 2015. Abstract 749LB.

  24. A5260: Changes in Limb and Trunk Fat With INSTI vs bPI First-line Regimens • Metabolic substudy of A5257, comparison of first-line TDF/FTC + • RAL (n = 106) • ATV/RTV (n = 109) • DRV/RTV (n = 113) • Endpoints: change from BL to Wk 96 in peripheral fat, central adiposity, lean mass • ATV/RTV vs DRV/RTV • Combined PIs vs RAL • Similar changes in limb and trunk fat (SAT and VAT) among regimens • Greater gains in VAT and SAT in BL VL stratum HIV-1 RNA ≥ 100,000 c/mL vs < 100,000 c/mL, regardless of regimen 50 40 30 20 10 0 Baseline Wk 96 McComsey G, et al. CROI 2015. Abstract 140.

  25. Rosuvastatin affects on Carotid Intimal Thickness and Coronary Calcium Score Longenecker T, et al. CROI 2015. Abstract 137.

  26. Rosuvastatin affects on Carotid Intimal Thickness and Coronary Calcium Score • As expected, LDL-C drop was greater ROS arm. • 3 (2 on statin) with premature study drug DC Mean Change in CIMT Mean Change in CCA in those with BL calcification Longenecker T, et al. CROI 2015. Abstract 137.

  27. Randomized Trial of Statin Therapy and Coronary Plaque Progression • Randomized 12-mo trial in HIV+ pts on stable ART with LDL-c < 130 and ≥ 1 coronary plaque by CTA • Atorvastatin 20 mg ( to 40 mg at 3 mos) (n = 19) vs • Placebo (n = 21) • Statin therapy reduced progression of coronary plaques over a year • Reduced overall plaque volume, including lipid-laden plaques • Plaque volume decreased 4.7% with atorva; increased 18.0% in the placebo arm • Reduced high-risk morphology plaques by 19% in atorva arm (20% increase in placebo arm. • Statin therapy safe and well tolerated Lo J, et al. CROI 2015. Abstract 136.

  28. HCV Coinfection

  29. ION-4: LDV/SOF for 12 Wks in GT1/4 HCV/HIV-Coinfected Pts • Phase III open-label, single arm study in HIV virologically suppressed HIV/HCV coinfected pts (N = 335) • 20% with compensated cirrhosis • n = 4 with HCV GT4 • ART regimens • TDF/FTC/EFV (n = 160) • TDF/FTC + RAL (n = 146) • TDF/FTC/RPV (n = 29) • HCV treatment naive or experienced • Previous HCV PI therapy: 29% • Previous SOF + RBV: 13% • Very high rate of SVR12 • No difference in SVR rates based on HCV treatment experience or cirrhosis status SVR Rates According to BL Characteristics 96 97 96 95 94 100 80 60 SVR12, % 40 20 321/ 335 142/ 150 179/ 185 258/ 268 63/ 67 n/N = 0 Yes No Overall Yes No Previous HCV Tx Cirrhosis Naggie S, et al. CROI 2015. Abstract 152LB.

  30. ION-4: LDV/SOF Drug-Drug Interactions With bPIs • In drug-drug interaction studies with LDV/SOF and boosted PIs and TFV[2] • LDV/SOF increases ATV, RTV, and TFV exposure • ATV/RTV + TDF/FTC increases LDV • DRV/RTV + TDF/FTC decreases SOF • Staggered administration did not mitigate interactions but interactions not deemed clinically relevant German P, et al. CROI 2015. Abstract 82.

  31. ALLY-2: SOF + DCV in GT 1-6 HCV/HIV-Coinfected Pts • Phase III open-label study • Non GT1 < 20% in each cohort; compensated cirrhosis < 50% overall; HIV-1 RNA < 50 c/mL and CD4+ ≥ 100 in pts on ART; CD4 ≥ 350 in pts not on ART • ART allowed: PI/RTV, NRTIs, NNRTIs, INSTIs, MVC, ENF • Primary endpoint: SVR12 in GT1 naive pts treated for 12 wks Wk 8 Wk 12 SOF 400 mg QD + DCV 30/60/90* mg QD (n = 101) Treatment-naive pts (N = 151) Pts followed to Wk 36 • SOF 400 mg QD + • DCV 30/60/90* mg QD • (n = 50) Treatment-experienced pts (N = 52) SOF 400 mg QD + DCV 30/60/90* mg QD(n = 52) *Standard dose of 60 mg adjusted for ART: 30 mg with RTV; 90 mg with NNRTIs except RPV. Wyles DL, et al. CROI 2015. Abstract 151.

  32. ALLY-2: Virologic Outcomes With SOF + DCV • High SVR12 rates with 12 wks SOF + DCV • Large decline in SVR rate with shortening to 8 wks • In 12-wk groups analyzed by GT, 100% with SVR12 except GT1a • GT1a naive: 96%; Exp’d: 97% • Similar SVR12 rates in pts with or without baseline NS5A RAVs • 12 pts with relapse, 10 in 8-wk arm • 1 relapse in 8-wk arm had emergent NS5A RAVs • No NS5B RAVs at BL or time of failure • No discontinuation of therapy due to AEs • 10 pts with HIV-1 RNA > 50 at EOT • 8 with repeat testing; 7 with suppression without change in ART; 1 with HIV-1 RNA of 59; 2 LTFU • 2 with HIV VF = HIV-1 RNA ≥ 400 c/mL GT1 Overall 98 98 96 97 100 76 76 80 60 SVR12, % 40 20 80/83 31/41 43/44 98/101 38/50 51/52 n/N = 0 12-Wk 8-Wk 12-Wk 12-Wk 8-Wk 12-Wk Naive Exp’d Naive Exp’d Wyles DL, et al. CROI 2015. Abstract 151.

  33. Thanks to: Joe Eron Michele Bailey Megan Katsaounis IT People www.med.unc.edu/ncaidstraining

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