Didactic Series International AIDS Society Paris, France July 2017 - PowerPoint PPT Presentation

Didactic Series International AIDS Society Paris, France July 2017 Geeta Gupta, MD UC Irvine Medical Center October 26, 2017 1

Learning Objectives 1) Review recent studies on antivirals presented at the IAS Conference 2) Discuss how the results of these antiviral studies may affect practice 2

New Antivirals ANTIVIRAL STUDIES

POLLING QUESTION In recent Phase III trials, when compared to Dolutegravir, Bictegravir showed virologic suppression that was: A) Superior B) Non- inferior (similar) C) Inferior D) Could not be assessed 4

POLLING QUESTION When compared to Dolutegravir, Bictegravir’s adverse event (AE) profile was: A) Superior B) Non- inferior (similar) C) Inferior D) Could not be assessed 5

Bictegravir INSTI – Integrase Inhibitor  unboosted INSTI  long half-life  high barrier to resistance  low drug–drug interaction potential 6

Study 1489: Bictegravir/FTC/TAF Versus Dolutegravir/ABC/3TC Phase 3 Double-blind Bictegravir/Emtricitabine/Tenofovir AF Treatment-naïve (n=314) HIV RNA ≥500 copies/mL eGFR: ≥50 mL/min Dolutegravir/Abacavir/Lamivudine HLA B*5701 negative (n=315) No HBV Week 0 48 96 144 Current Bictegravir: unboosted integrase inhibitor with high in vitro barrier to resistance and low potential for drug interactions. Analysis Primary outcome: HIV RNA <50 copies/mL. Non-inferiority margin: 12% (FDA snapshot algorithm). Stratified by HIV RNA level, CD4 count, geographic region. Baseline demographics: Male: 91%. Age: 31-32 years. Black: 36%. HCV RNA: 4.4-4.5 log10 copies/mL. CD4: 443-450 cells/µL. Asymptomatic HIV infection: 91%. eGFR: 123-126 mL/min. Gallant J, et al. J Int AIDS Soc . 2017;20(suppl 5):103-104. Abstract MOAB0105LB.

Study 1489: Bictegravir/FTC/TAF Versus Dolutegravir/ABC/3TC at Week 48 • Bictegravir group met non- HIV RNA <50 Copies/mL inferiority criteria 100 – Treatment difference: -0.6% (95% 93% 92% CI: -4.8, 3.6) 80 • No INSTI or NRTI resistance detected in either treatment arm Patients (%) 60 • CD4 cell increase was similar between the treatment arms (~230 40 cells/µL) 20 0 Bictegravir/ Dolutegravir/ FTC/TAF ABC/3TC (n=314) (n=315) Gallant J, et al. J Int AIDS Soc . 2017;20(suppl 5):103-104. Abstract MOAB0105LB.

Study 1489: Safety Outcomes Study 1489: Safety Outcomes Bic/FTC/TAF Versus Dol/ABC/3TC Bic/FTC/TAF Versus Dol/ABC/3TC • Both regimens were well tolerated Safety Results  No deaths Bictegravir/ Dolutegravir/ FTC/TAF ABC/3TC  No discontinuations due to adverse (n=314) (n=315) events in the bictegravir/C/F/TAF Discontinuations due to 0 1.3 arm adverse events (%) Adverse events (%)  Nausea was more common in the Diarrhea 13 13 dolutegravir arm Headache 12 14 Nausea 10 23* • No discontinuations due to renal Change in BMD (%) adverse events Spine -0.8 -0.6 Hip -0.8 -1.0 • Similar changes in eGFR: -11 Lipid changes (mg/dL) mL/min Total cholesterol 13 11 LDL-C 7 4 • Both treatment arms had similar HDL-C 5 5 Triglycerides 9 3 changes in BMD and lipid * P <0.001 versus bictegravir/FTC/TAF. parameters Gallant J, et al. J Int AIDS Soc . 2017;20(suppl 5):103-104. Abstract MOAB0105LB.

Study 1490: Bictegravir/FTC/TAF Versus Dolutegravir + FTC/TAF Phase 3 Double-blind Bictegravir/Emtricitabine/Tenofovir AF Treatment-naïve HIV RNA ≥500 (n=320) copies/mL eGFR: ≥30 mL/min Dolutegravir + Emtricitabine/Tenofovir AF HBV or HCV allowed (n=325) Week 0 48 96 144 Primary Endpoint Primary outcome: HIV RNA <50 copies/mL. HIV RNA <50 copies/mL Non-inferiority margin: 12% (FDA snapshot algorithm). Stratified by HIV RNA level, CD4 count, geographic region. Baseline demographics: Male: 89%. Age: 33-34 years. Black: 31%. HCV RNA: 4.4 log 10 copies/mL. CD4: 441 cells/µL. HBV/HCV infection: 2%/2%. eGFR: 120 mL/min. 10 Sax PE, et al. J Int AIDS Soc . 2017;20(suppl 5):121-122. Abstract TUPDB0201LB.

Study 1490: Safety Outcomes With Bictegravir/FTC/TAF Versus Dolutegravir/FTC/TAF Safety Results • Overall, both treatment arms were Bic/FTC/TAF Dolutegravir/ well tolerated (n=320) FTC/TAF (n=325)  Deaths (n=3, none related to study Discontinuations due 2 <1 drugs) to adverse events  Low rate of discontinuations due to (%) adverse events Adverse events (%) Headache 13 12 • Less decrease in eGFR in the Diarrhea 12 12 Nausea 8 9 bictegravir versus the dolutegravir Change in eGFR -7 -11* arm (mL/min)  No discontinuations due to renal Lipid changes (mg/dL) 12 15 adverse events and no cases of renal Total cholesterol 9 12 tubulopathy LDL-C 5 5 HDL-C 3 7 • Similar changes in lipid parameters Triglycerides in the bictegravir and dolutegravir * P =0.02 versus bictegravir/FTC/TAF. arms 11 Sax PE, et al. J Int AIDS Soc . 2017;20(suppl 5):121-122. Abstract TUPDB0201LB.

Study 1490: Treatment Outcomes With Bictegravir/FTC/TAF Versus Dolutegravir + FTC/TAF at Week 48 • Bictegravir group met non-inferiority HIV RNA <50 Copies/mL criteria 100 – Treatment difference: -3.5% (95% CI: - 93% 89% 7.9, 1.0) 80 • Similar increases in CD4 in the Patients (%) bictegravir and dolutegravir arms 60 (180 versus 201 cells/µL) • No resistance occurred in either 40 treatment group • No discontinuations due to lack of 20 efficacy 0 Bictegravir/ Dolutegravir/ FTC/TAF FTC/TAF (n=320) (n=325) 12 Sax PE, et al. J Int AIDS Soc . 2017;20(suppl 5):121-122. Abstract TUPDB0201LB.

DORAVIRINE: next generation NNRTI Doravirine: novel, next-generation NNRTI  Unique resistance profile confers activity against most prevalent NNRTI resistance mutations (K103N, Y181C, G190A, K103N/Y181C, E138K)  Dosed once daily with no food requirements  Low potential for drug–drug interactions, including with gastric acid– reducing agents  Demonstrated favorable efficacy and superior neuropsychiatric profile vs EFV in phase IIb trial  Demonstrated noninferior efficacy and more favorable lipid profile vs ritonavir-boosted darunavir in phase III DRIVE-FORWARD trial  Now under investigation as a fixed-dose combination with 3TC and TDF 13

DRIVE-AHEAD Study : Doravirine/Lamivudine/Tenofovir DF vs EFV/TDF/FTC in Treatment-Naïve Patients Phase 3 Double-blind Doravirine/Lamivudine/Tenofovir DF Treatment-naïve HIV RNA ≥1000 (n=364) copies/mL Stratified by HIV RNA Efavirenz/Emtricitabine/Tenofovir DF HCV or HBV allowed (n=364) Week 0 48 96 Primary Endpoint HIV RNA <50 copies/mL Primary outcome: HIV RNA <50 copies/mL (FDA snapshot algorithm). Non-inferiority: -10%. Baseline demographics: Male: 85%., Age: 30-32 years. White: 48%. History of AIDS: 14%. HIV RNA: 4.4-4.5 log 10 copies/mL. CD4: 416-435 cells/mm 3 . Squires KE, et al. J Int AIDS Soc . 2017;20(suppl 5):110-111. Abstract TUAB0104LB.

DRIVE-AHEAD Study: Treatment Outcomes With Doravirine/Lamivudine/Tenofovir DF vs Efavirenz/TDF/FTC in Treatment-Naïve Patients • Doravirine/3TC/TDF was non-inferior to HIV RNA <50 Copies/mL efavirenz/FTC/TDF at Week 48 Doravirine/3TC/TDF Efavirenz/FTC/TDF • HIV RNA >50 copies/mL: ~10% in each Difference (%): arm 100 3.5 (-2.0, 9.0) 91% 91% 84% 81% • Virologic failures in doravirine arm (6%) 81% 81% 80 • Primary NNRTI resistance: 1.6% Patients (%) 60 • Primary NRTI resistance: 1.4% • Doravirine arm was superior to efavirenz 40 – Lower incidence of neuropsychiatric adverse events 20 • Sleep disturbances (12% versus 26%) and dizziness (9% versus 37%) (both P <0.001) 0 ≤ 100K Overall >100K – More favorable change from baseline in ITT (n=277/258) (n=69/73) (n=364/364) lipids [ LDL-C (-2% versus 9%), non-HDL-C (-4% versus 13%) (both P <0.001)] HIV RNA (copies/mL) (Observed Failure Approach) Squires KE, et al. J Int AIDS Soc . 2017;20(suppl 5):110-111. Abstract TUAB0104LB.

EMERALD Study: Switch to Darunavir/Cobicistat/Emtricitabine/Tenofovir AF Phase 3 (n=1149) Extension Open-label, non- Treatment Phase Phase inferiority HIV RNA <50 copies/mL Darunavir/C/F/TAF for >2 months Previous ART virologic Darunavir/C/F/TAF failure allowed eGFR: ≥50 mL/min Continue bPI + F/TDF Absence of darunavir RAMs Week 0 24 48 96 Current Analysis Primary Endpoint C/F/TAF: cobicistat/emtricitabine/tenofovir AF. HIV RNA >50 copies/mL bPI: boosted PI. (cumulative) Non-inferiority margin: 4% (FDA snapshot algorithm). Baseline demographics: Male: 82%. Age: 45-46 years. CD4: 624-630 cells/mm 3 . Prior virologic failure: 15%. Molina JM, et al. J Int AIDS Soc . 2017;20(suppl 5):28. Abstract TUAB0101.