After 96 weeks, more people achieved viral suppression on a doravirine-based antiretroviral drug regimen compared with a darunavir (Prezista)-based one, Kathleen Squires, M.D., reported at the recent 22nd International AIDS Conference. This phase 3 double-blind clinical trial is sponsored by Merck, the manufacturer of doravirine. Squires is Merck's global director of scientific affairs.
In 2017, 48-week results from the same trial, the DRIVE-FORWARD study, were presented at the Conference on Retroviruses and Opportunistic Infections. At that time, doravirine was shown to be non-inferior and to have a better lipid profile than darunavir. In laboratory tests, doravirine also worked against HIV that had developed mutations that made the virus resistant to some non-nucleoside reverse transcriptase inhibitors (NNRTIs). Doravirine is an NNRTI, while darunavir is a protease inhibitor. In vivo, two participants in the doravirine arm developed resistance against the study drug.
All 766 study participants included in the 96-week analysis were antiretroviral naive. They had been randomized 1:1 to receive doravirine or ritonavir (Norvir)-boosted darunavir once a day, plus one of two nucleoside reverse transcriptase inhibitors (NRTIs): emtricitabine/tenofovir disoproxil fumarate or TDF (Truvada) or abacavir/lamivudine (Epzicom, Kivexa). Investigators selected these background regimens individually, choosing emtricitabine/TDF for 87% of participants in either arm. The study was conducted at 125 clinical centers in 15 countries, including Chile, Argentina, and South Africa, as well as some in North America and Western and Eastern Europe, according to Squires. Nonetheless, the study population was mostly male (84%) and white (73%).
At the 96-week mark, 73.1% in the doravirine arm had achieved viral suppression compared with 66.0% in the darunavir group. Viral suppression was defined as HIV-1 RNA of less than 50 copies/mL. However, there was no difference in viral suppression rates between the two arms among those with high viral loads (> 100,000 copies/mL) at treatment start. Twenty percent of participants were described as having high viral loads. CD4 cell counts increased slightly more in the doravirine group, at an average of 224 cells/mm3 compared with 207 cells/mm3 in the darunavir group.
As was the case at 48 weeks, lipid profiles continued to be better in the doravirine group compared with the darunavir arm at 96 weeks, with total cholesterol rising by 4.1 mg/dL in the study drug group compared with 21.9 mg/dL in the comparator group. Similarly, low-density lipoprotein cholesterol (LDL) and non-high-density lipoprotein cholesterol (non-HDL) fell in the doravirine arm (by 0.44 mg/dL and 0.48 mg/dL, respectively) while rising in the darunavir arm (by 14.0 mg/dL and 17.7 mg/dL, respectively). An earlier phase 3 trial of the study drug, called DRIVE-AHEAD, had also shown better lipid results in the doravirine and lamivudine (3TC, Epivir) arm compared with the efavirenz (Sustiva, Stocrin) and emtricitabine (FTC, Emtriva) arm. Participants in both groups also took TDF (Viread), which is known to lower lipid levels. The results of DRIVE-AHEAD were presented at the 2017 International AIDS Conference.
Among people living with HIV in the U.S., strokes are more common among African Americans and women than among white men. While the current study included few women or people of color, cholesterol levels -- which are linked to cardiovascular problems, including stroke -- were better in the doravirine arm than the darunavir arm.
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"The lipid profile of doravirine as demonstrated by the Phase 3 DRIVE-FORWARD and DRIVE-AHEAD trials suggests that doravirine could be an option for those that may need to consider cardiovascular health issues," Squires concluded.
Drug-related adverse events were common, but mild. Mostly, participants developed diarrhea, nausea, headache, and upper respiratory tract infections. More people in the study drug arm than the comparator arm experienced headaches and upper respiratory infections, while the reverse was true for diarrhea and nausea. Fewer people in the study drug arm than in the comparator group dropped out because of adverse events (1.6% versus 3.4%).
Applications for U.S. Food and Drug Administration approval of doravirine alone, as well as a fixed-dose combination of doravirine/lamivudine/TDF, are pending, a Merck press release noted. It listed a target date of October 2018 for approval of these drugs.