Doravirine is an investigational NNRTI that is active in vitro against many common NNRTI resistance mutations (including K103N, Y181C, and E138K). It is given once daily, has no food restrictions, and can be given with acid-blocking medications. In a Phase 2 study of treatment-naive individuals, rates of virologic suppression were equivalent to those seen with efavirenz (both treatment groups also were given TDF/FTC), with fewer adverse effects, including fewer neuropsychiatric adverse effects.
At CROI this year, researchers presented results of a large (n = 769) randomized, placebo-controlled Phase 3 comparison of doravirine and darunavir/ritonavir, each given with 2 NRTIs. Study subjects were treatment naive, and 87% were given TDF/FTC. At week 48, by FDA snapshot, 84% of the doravirine group and 80% of the darunavir/ritonavir group had HIV RNA levels <40 copies/mL; this result met criteria for noninferiority. In the patients with virologic failure, no HIV resistance developed in either group, though 1 patient in the doravirine group who discontinued (and was not counted as a virologic failure) was found to have significant NRTI and NNRTI resistance. Fewer patients in the doravirine treatment group developed diarrhea but, otherwise, adverse effects occurred at about the same rates in the two groups. Lipid levels decreased slightly in the doravirine group (perhaps attributable to the effect of coadministered TDF), while they increased by 10-20 mg/dL in the darunavir/ritonavir group.
Clinical Bottom Line
In studies thus far, doravirine has been as effective as efavirenz and darunavir/ritonavir in terms of viral suppression, and it appears to be more tolerable than those agents. It has yet to be compared with integrase inhibitors, which currently are our typical anchor agents for first-line therapy, and it seems no such studies are planned. Despite its robust resistance profile, doravirine also has not been evaluated in advanced lines of treatment. Studies evaluating a fixed-dose combination of doravirine/TDF/3TC are under way, in both first-line therapy and as a switch strategy. Doravirine appears likely to be the next ARV to receive FDA approval, and data from these studies will give us a better idea of how we might best use doravirine, if it becomes available.
- Molina JM, Squires K, Sax PE, et al. Doravirine is non-inferior to darunavir/r in Phase 3 treatment-naïve trial at week 48. In: Program and abstracts of the 2017 Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle. Abstract 45LB.