Efficacy and Safety of Doravirine 1mg QD vs Efavirenz 6mg QD with TDF/FTC in ART-Naive HIV-Infected Patients: Week 24 Results Jose M. Gatell, Francois Raffi, Andreas Plettenberg, Don Smith, Joaquin Portilla, Christian Hoffmann, Keikawus Arasteh, Melanie Thompson, Debbie P. Hagins, Javier O. Morales-Ramirez, Xia Xu, Hedy Teppler Abstract TUAB4 TDF/FTC + Doravirine vs EFV: Study Design Patients: HIV-1+ ART-naïve HIV RNA 1, c/ml CD4 count 1 cells/µl Part 1 Dose Ranging Phase (N=21) DOR 25 mg DOR 5 mg DOR 1 mg (n=42) DOR 2 mg EFC mg (n=42) DOR 1 mg Continue EFV Part 1 Extension Phase Week 24 Week 48 Week 96 DOR 1 mg (n=66) EFC 6 mg (n=66) Part 2 Additional Patients (N=132) Week 24 Week 48 Week 96 Note: blinding maintained through Week 96 study visit Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4.
TDF/FTC + Doravirine vs EFV: Baseline Characteristics Doravirine 1 mg (N=18) Efavirenz 6 mg (N=18) % Male 91.7 93.5 Age (years), median (range) 35 (19 67) 34 (2 57) % White 79.6 79.6 % with AIDS 3.7 6.5 HIV RNA (log 1 c/ml), median (range) 4.6 (2.6 6.5) 4.6 (3. 6.7) % with HIV RNA >1, c/ml, at screening 35.2 37. CD4 Count (cells/µl), median (range) 42 (92 111) 43 (118 1121) % with CD4 count 2 cells/µl 6.5 9.3 % with Clade B viral subtype 69.4 79.6 Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4. TDF/FTC + Doravirine vs EFV: Primary Endpoint 1 9 8 7 6 5 4 3 2 1 3.7 15.7 6.5 12 Percentage < 4 cop/ml at 24 weeks Doravirine 1mg Efavirenz 27.8 26.9 47.2 42.1 63.6 72.2 4 8 12 16 2 24 57.5 73.1 Δ(95% CI): -1.2 (-13., 1.5) Treatment Week Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4.
Patients with HIV RNA <2 c/ml, % (95% CI) Non-completer = Failure Approach 1 9 8 79.4 84.1 83. 88.9 87. 7 6 65.7 65.7 75. Δ(95% CI): 1.9 (-7., 11.) 5 4 39.8 3 27.8 33.3 2 21.3 1 4 8 12 16 2 24 Treatment Week Doravirine 1mg Efavirenz Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4. TDF/FTC + Doravirine vs EFV: Results by Baseline HIV RNA 1 1, c/ml >1, c/ml 8 6 4 2 83.3 85.7 92.4 92.1 6.5 65.8 92.1 94.7 n/n: 55/66 54/63 25: 51/66 58/63 11: 23/38 25/38 35/38 36/38 % <4 c/ml % <2 c/ml % <4 c/ml % <2 c/ml Doravirine 1 mg q.d. Efavirenz 6 mg q.d. Virologic failures: DRV 17, EFV 11 -- mostly due to low-level viremia at week 24 (no resistance detected) 1 or more CNS adverse events: DRV 27%, EFV 46% -- difference -19.4% (95% CI -31.7, -6.6) Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4.
Protocol-defined Virologic Failures by Week 24 Doravirine 1 mg (N=18) Efavirenz 6 mg (N=18) Virologic failure 4 c/ml, n (%) Non-response 17 (15.7) 1 (9.3) Rebound 1 (.9) Virologic failure 2 c/ml, n (%) Non-response 4 (3.7) Rebound 1 (.9) Resistance testing performed* 1 1 NNRTI mutations detected NRTI mutations detected Non-response: patient did not achieve vrna <4 (or <2) c/ml by Week 24. Rebound: after initial response of vrna <4 (or <2) c/ml, patient had 2 consecutive measurements 4 (or 2) c/ml at least 1 week apart, at or after Week 24. (Rebound after Week 24 not included here.) * vrna > 5 copies/ml required for resistance testing. Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4. Number of Protocol-defined Virologic Failures by Week 24 ( 4 c/ml, confirmed) vrna (copies/ml) at time of Virologic Failure Type of VF 4-5 >5-1 >1-2 >2 Total Rebound Doravirine Efavirenz 1 1 Non-Response Doravirine 4 7 2 4 17 Efavirenz 4 6 1 Rebound: after initial response of vrna <4 (or <2) c/ml, patient had 2 consecutive measurements 4 (or 2) c/ml at least 1 week apart, at or after Week 24. (Rebound after Week 24 not included here.) Non-response: patient did not achieve vrna <4 (or <2) c/ml by Week 24. Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4.
Primary Safety Comparison: CNS Events, All Causality Significantly fewer patients on DOR had 1 CNS event by week 24 (p<.1) Suicidal ideation Somnolence Depressive symptom Hallucination Attention disturbance Depression Nightmares Abnormal dreams Insomnia Dizziness 1.9.9.9 2.8.9 3.7.9 2.8 2.8 5.6 6.5 6.5 7.4 8.3 9.3 % of Patients with 1 CNS Event DOR 1 mg (N=18) 17.6 EFV (N=18) Δ (95% CI) 26.9% 46.3% -19.4 (-31.7, -6.6) Efavirenz 6 mg Doravirine 1 mg 27.8 5 1 15 2 25 3 % of patients with at least one CNS event by week 24 Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB4. Second-Generation HIV-1 Maturation Inhibitor : Antiviral Activity and Safety with Atazanavir ± Ritonavir Carey Hwang, Dirk Schürmann, Christian Sobotha, Marta Boffito, Heather Sevinsky, Neelanjana Ray, Palanikumar Ravindran, Hong Xiao, Mark Krystal, Ira Dicker, Dennis Grasela, and Max Lataillade Abstract TUAB16LB
HIV-1 Life Cycle Maturation Maturation inhibitor Release Assembly/ cleavage Budding Lataillade et al. CROI 215, Abstract 114LB. Attachment Inhibitor: Study Design TDF/FTC 3/2 mg + ATV 3 mg + RTV 1 mg N=4 4 mg + ATV 3 mg + RTV 1 mg N=8 4 mg + ATV 4 mg N=8 8 mg + ATV 4 mg N=8 Days 1 28 Day 3 Days 35 Day 42 Inpatient days: Day -1 to Day 3 Objectives Change in plasma HIV-1 RNA levels from baseline to Day 28 Safety and tolerability of during combination therapy Dosing period Furloughed Outpatient visits Discharge Key Inclusion Criteria HIV-1 subtype B-infected subjects Treatment-naïve (<1 week of antiretroviral treatment) or -experienced (PI naïve) subjects Plasma HIV-1 RNA 5, c/ml CD4+ T-cell count 2 cells/µl Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB
Attachment Inhibitor: Median Change in HIV-1 RNA Median change in HIV-1 RNA at Day 29 was between -1.66 and -2.18 log 1 c/ml for the arms and was -2.22 log 1 c/ml for the standard of care arm Median Change in HIV-1 RNA (log 1 c/ml) from Baseline 1.5.5 1 1.5 2 2.5 5 Dosing Period 1 15 2 25 3 35 4 45 5 Study Day TDF/FTC 3 mg/2 mg + ATV 3 mg + RTV 1 mg 4 mg + ATV 3 mg + RTV 1 mg 4 mg + ATV 4 mg 8 mg + ATV 4 mg Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB Attachment Inhibitor: Maximum Median Decline in HIV-1 RNA from Baseline Maximum median change in HIV-1 RNA (log 1 copies/ml) -.5-1 -1.5-2 -2.5 TDF/FTC 3/2 mg + ATV 3 mg + RTV 1 mg (n=4) -2.39 4 mg + ATV 3 mg + RTV 1 mg (n=8) -2.2 4 mg + ATV 4 mg (n=8) -1.86 8 mg + ATV 4 mg (n=8) -2.23 8 mg + ATV and 4 mg + ATV + RTV had similar maximum median changes in HIV-1 RNA compared with the standard of care arm Greatest elevations in bilirubin seen in maturation inhibitor plus boosted ATV (arm 2) Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB
AI4682: Median Change in Bilirubin at Day 28 from Baseline 7 Median change in total bilirubin at Day 28 from Baseline, (μmol/l, SI Units) 6 5 4 3 2 1 41.8 TDF/FTC 3/2 mg + ATV 3 mg + RTV 1 mg* 6. 4 mg + ATV 3 mg + RTV 1 mg 11.8 4 mg + ATV 4 mg 7.7 8 mg + ATV 4 mg Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB Conclusions is a potent, once-daily, second-generation MI 8 mg + ATV and 4 mg + ATV + RTV demonstrated similar antiviral activity (~2.2 log 1 c/ml median decline) compared to the standard of care control over the 28-day treatment period was generally well tolerated There were no SAEs or AEs leading to discontinuation + unboosted ATV was associated with lower median changes from baseline in bilirubin levels compared to the arms with boosted ATV A Phase IIb study investigating + ATV in a booster-sparing and nucleot(s)ide-sparing regimen in treatment-experienced patients initiated July 215 Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 215; Abst. TUAB16LB