New NNRTI Doravirine Is Non-Inferior to Darunavir/Ritonavir in Phase 3 Treatment-Naive Study
A late-breaker oral presented results from a phase 3 study comparing the NNRTI doravirine to boosted darunavir, showing similar viral suppression and low rates of side effects at the 48-week primary endpoint.1
Doravirine is a once-daily NNRTI from Merck that can be taken with or without food and few drug-interactions and that retains activity against common first generation NNRTI mutations (K103N, Y181C, G190A and E138K). Last year at CROI, results from a phase 2b study reported non-inferiority compared to efavirenz.2 A fixed dose combination of doravirine/TDF/3TC (using generic NRTIs) is already in phase 3 studies and a long-acting formulation is in development.3,4
The current study, presented by Jean-Micheal Molina from Hôpital St Louis in Paris, randomised 769 treatment-naive adults to either doravirine (100 mg) or darunavir/r (800 mg/ 100 mg), both once-daily with investigator choice of TDF/FTC (87%) or ABC/3TC (13%) as background nukes.
Baseline characteristics include mean age 35 years (SD+/- 10.5), 84% male, 73% white/ 22% black with 10% having a clinical history of advanced stage HIV. Mean CD4 and viral load were approximately 420 cells/mm3 (+/- 215) and 4.4 log copies/mL (+/- 0.7 log), with 20% >100,000 copies/mL and 4% >500,00 copies/mL.
At week 48, viral load was <50 copies/mL in 83.8% (321/383) vs 79.9% (306/383), in the doravirine vs darunavir/r arms respectively, (difference 3.9%, 95% CI [-1.6, 9.4]), showing non-inferiority. Results of the stratified analysis of participants with baseline viral load >100,000 copies/mL, were 81.0% (64/79) vs 76.4% (55/72) respectively. Similar suppression was reported for the 17 participants in the doravirine arms with baseline viral load >500,000 copies/mL.
CD4 increases were similar at week 48: 193 vs +186 cells/mm3 (difference +7; 95%CI -21 to +35.
Discontinuations were similar in each arm although slightly less with doravirine than darunavir/r (n=56 (15%) vs n=71 (19%), respectively). Reasons included loss to follow up (4% vs 5%), lack of efficacy 3% vs 4%), withdrawn consent (3% each arm), side effects (1% vs 3%), non-complianse (2% vs 1%), doctor decision (1% in each), pregnancy(n=1 vs 0), protocol violation (<1% vs 2%) and death (n=1 vs 0).
Drug-related side effects were similar between arms. Drug-related side effects were reported in just over 30% of each arm, serious side effects in 5% vs 6% and discontinuations by 1.6% vs 3.1% (doaravirine vs darunavir/r respectively)
The most common were diarrhoea (6% vs 13%), nausea (7% vs 8%), and headache (6% vs 3%) for doravirine vs darunavir/r respectively. Fasting LDL-C and non-HDL-C were reduced in the doravirine arm and increased in the darunavir/r arm (-4.5 and -5.3 vs +9.9 and +13.8 mg/dL, p<0.0001).
Drug resistance test in 7/19 vs 8/24 people who were non-responders or rebounders, included one person with both NRTI and INI resitance at week 24. This person was non adherent and discontinued at week 24. No PI mutations were observed.
Two posters will also be presented at CROI 2017 later this week: (i) on increased doravirine levels from a drug interaction with ritonavir5 and (ii) on the use in severe renal impairment (eGFR < 30 mL/min/1.73 m2).6
Summary results from these posters with be added to this report once the embargos are on Wednesday and Thursday afternoons respectively.
- Molina J-M et al. Doravirine is non-inferior to darunavir/r in phase 3 treatment-naive trial at week 48. CROI 2017, 13-16 February 2017, Seattle. Late breaker oral abstract 45LB.
- Gatell JM et al. Doravirine 100mg QD vs efavirenz +TDF/FTC in ART-naive HIV+ patients: week 48 results. 23rd CROI, 22-25 February 2016, Boston. Poster abstract 470.
www.croiconference.org/sites/default/files/posters-2016/470.pdf (PDF poster)
- ClinicalTrials.gov [Internet]. Comparison of MK-1439A and ATRIPLATM in treatment-naive human immunodeficiency virus (HIV)-infected participants (MK-1439A-021). Identifier NCT02403674.
- ClinicalTrials.gov [Internet]. A rapid pharmacokinetic trial of the bioavailability of four MK-1439 nano formulations in healthy adults. Identifier NCT02549040.
- Khalilieh S et al Multiple-dose treatment with ritonavir increases the exposure of doravirine. CROI 2017, 13-16 February 2017, Seattle. Poster abstract 412.
- Ankrom W et al. Effect of severe renal impairment on doravirine pharmacokinetics. CROI 2017, 13-16 February 2017, Seattle. Poster abstract 430.