Doravirine (DOR) is an investigational NNRTI that currently is being developed in a coformulation with TDF and FTC. A Phase 3 comparison of DOR + 2 NRTIs (87% of study subjects were given TDF/FTC) and DRV/r + 2 NRTIs in initial therapy was presented at CROI earlier this year (DRIVE-FORWARD); the DOR arm was found to be noninferior to the DRV arm (see CROI 2017: Doravirine Noninferior to Darunavir + Ritonavir in Initial Treatment). At the 9th IAS Conference on HIV Science, another Phase 3 study of DOR was presented, this time a comparison of coformulated DOR/TDF/3TC with coformulated EFV/TDF/FTC in antiretroviral-naive individuals (DRIVE-AHEAD). This was a double-blind randomized placebo-controlled study, with 364 patients treated in each arm; about 85% were men. Baseline HIV RNA was >100,000 copies/mL in about 20% of patients. At week 48, by FDA snapshot analysis, HIV suppression to <50 copies/mL was seen in 84% of the DOR group and 81% of the EFV group, indicating noninferiority of DOR/TDF/FTC. Virologic failure was identified in 6% of the DOR group and 3.8% of the EFV group. NNRTI resistance mutations were detected in 6 of 23 DOR/TDF/3TC recipients and in 12 of 24 EFV/TDF/FTC recipients, and NRTI mutations were seen in 5 patients in each treatment group. The DOR recipients had much lower rates of adverse effects, particularly dizziness, sleep disturbance, and other neuropsychiatric symptoms. They also had decreases in total cholesterol, LDL, and triglycerides, and a slight increase in HDL, while the EFV recipients had increases in all lipid parameters (22 mg/dL in both total cholesterol and triglycerides).
Clinical Bottom Line
This study and the earlier study mentioned above, demonstrate that DOR + 2 NRTIs is as effective as EFV- and DRV/r-based regimens in initial therapy, and that it is tolerated better than EFV. DOR has not been compared head to head with integrase inhibitors, the anchor agents typically preferred for initial therapy, nor (despite its robust in vitro resistance profile) has it been studied in second-line therapy. Manufacturers of DOR reportedly plan to release it initially only in a coformulation with TDF and FTC; this is likely to limit its usefulness, particularly since most clinicians in the United States seek to avoid patient exposure to TDF if other options are possible.
Squires KE, Molina JM, Sax PE, et al; DRVIE-AHEAD Study Group. Fixed dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naive adults with HIV-1 infection: week 48 results of the Phase 3 DRIVE-AHEAD study. In: Program and abstracts of the 9th IAS Conference on HIV Science; July 24-26, 2017; Paris, France. Abstract TUAB0104LB.