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.
Recommend
More recommend
