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SEATTLE -- The investigational agent doravirine was as likely to suppress HIV below the limit of detection as a commonly used boosted protease inhibitor, researchers said here.
At 48 weeks, 84% of patients randomized to receive the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), and 80% taking boosted darunavir (Prezista), had HIV RNA below 50 c/mL, showing that the investigational drug was non-inferior, reported , of Thomas Jefferson University in Philadelphia, and colleagues.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- The investigational agent doravirine was as likely to suppress HIV below the limit of detection as a commonly used boosted protease inhibitor in a late-stage clinical trial.
- Note that the major advantage of doravirine over boosted darunavir was its favorable effect on lipid levels, and levels of fasting LDL, non-HDL, total cholesterol, and triglycerides fell slightly in the doravirine arm.
But doravirine caused fewer undesirable changes in blood lipid levels, Squires noted in a late-breaking report at the annual Conference on Retroviruses and Opportunistic Infections.
Virological response rates in this trial were lower than those seen in some other studies of modern antiretrovirals, but its placebo-controlled design required participants to take multiple pills, which led some to drop out early.
"It's a tough study because they had four pills, and they had 10% of people drop out, mostly for pill reasons," commented , of the University of North Carolina at Chapel Hill to MedPage Today.
"If you add 10% to their success rate, it looks pretty similar to integrase [inhibitors]," noted Eron, who was not involved in the study.
Study Details
NNRTIs have long been a mainstay of first-line HIV treatment. In recent years they have been supplanted by integrase inhibitors, but having potent and well tolerated drugs available in multiple antiretroviral classes offers patients and providers more options for constructing optimal regimens.
Early studies showed that doravirine remains active against HIV with common NNRTI-resistance mutations. It can be taken once daily with or without food and has low potential for drug-drug interactions. A showed that doravirine was associated with fewer neuropsychiatric side effects than efavirenz (Sustiva).
Squires presented results from the phase III DRIVE-FORWARD trial, which compared doravirine against the ritonavir-boosted protease inhibitor darunavir for initial HIV therapy.
The placebo-controlled, double-blind, non-inferiority study included 769 treatment-naive adults. Most participants (84%) were men and the average age was 35. The mean CD4 cell count was approximately 420 cells/mm3 and 20% had viral load over 100,000 copies of HIV RNA/mL at the start of the study. At baseline, participants had no resistance to any study drugs.
Participants were randomly assigned on a 1:1 basis to take 100 mg doravirine or 800 mg darunavir boosted with 100 mg ritonavir, along with two coformulated nucleoside/nucleotide reverse transcriptase inhibitors chosen by the study investigators. All were taken once daily. Most (87%) took tenofovir DF/emtricitabine (Truvada) while 13% used abacavir/lamivudine (Epzicom).
In each arm, patients received matching placebos for the opposite drugs, so everyone took a total of four pills daily. With once-daily, single-tablet regimens now the standard of care for initial HIV treatment, this was considered a high pill burden.
Results
The study's primary endpoint was the proportion of people with HIV RNA below 50 c/mL at 48 weeks. Ongoing follow-up is continuing through 96 weeks.
The proportion of patients achieving undetectable viral load was similar in both arms: 84% with doravirine and 80% with darunavir/ritonavir, meeting the predefined non-inferiority margin of 10%.
Efficacy was comparable regardless of baseline viral load. Among patients who started with viral levels below 100,000 c/mL, viral suppression rates were 90% in the doravirine arm and 89% in the darunavir/ritonavir arm. Among those with higher viral load, the corresponding rates were 81% and 76%. There was also no difference based on whether participants were taking tenofovir/emtricitabine or abacavir/lamivudine.
A "robust rise in CD4 cells" was seen in both the doravirine and darunavir/ritonavir arms, Squires said, with gains of 193 and 186 cells/mm3, respectively.
Nineteen patients (5%) in the doravirine arm and 24 patients (6%) in the darunavir/ritonavir arm met the study criteria for virological failure, which included both non-responders and rebounders, Squires reported. She noted that most viral rebound was "very low," but the protocol required these patients to come off the study.
Among the 15 individuals who underwent resistance testing, "no genotypic or phenotypic resistance mutations were observed," she said.
In addition, 40 people (10%) taking doravirine and 53 (14%) taking darunavir/ritonavir had detectable virus at time of treatment discontinuation. Of these, five underwent resistance testing, which found that one non-adherent patient developed doravirine and emtricitabine resistance.
Both treatment regimens were generally safe and well tolerated, with similar overall frequency of adverse events in the doravirine and darunavir/ritonavir arms. Rates of serious adverse events (5% versus 6%) and drug-related adverse events (31% versus 32%) were also comparable in the two groups.
The most commonly reported adverse events were diarrhea, nausea, headache, and nasopharyngitis. Side effects associated with NNRTIs, such as rash and neuropsychiatric symptoms, were similar in both arms, but diarrhea occurred more often with darunavir/ritonavir, Squires said.
Squires reported "very low rates" of study discontinuation due to adverse events: 2% in the doravirine arm and 3% in the darunavir/ritonavir group. Most participants who did not complete the study were either lost to follow-up or voluntarily withdrew consent. She noted that the high pill burden was a commonly cited as a reason for stopping the study.
Lipid Benefits?
The major advantage of doravirine over boosted darunavir was its favorable effect on lipid levels. Lipid abnormalities are a known side effect of the protease inhibitor drug class.
Levels of fasting LDL, non-HDL, total cholesterol, and triglycerides fell slightly in the doravirine arm, but rose in the darunavir/ritonavir arm. Total cholesterol, for instance, decreased by 1.37 mg/dL with doravirine and increased by 17.9 mg/dL with darunavir/ritonavir. HDL showed similar small increases in both arms.
In order to be considered a marketable first-line HIV treatment option today, antiretrovirals must be coformulated to reduce pill burden, ideally to one pill once daily.
Merck has developed a fixed-dose coformulation of doravirine, tenofovir DF, and lamivudine that is now being evaluated in phase III studies, according to a company press release. DRIVE-AHEAD is comparing doravirine/tenofovir DF/lamivudine to efavirenz/tenofovir DF/emtricitabine (Atripla) for initial treatment, while is evaluating a switch from another suppressive regimen to the doravirine coformulation.
Disclosures
The study was funded by Merck.
Squires disclosed relevant relationships with Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck, and ViiV Healthcare.
Eron disclosed no relevant relationships with industry.
Primary Source
Conference on Retroviruses and Opportunistic Infections
Molina JM, et al "Doravirine is non-inferior to darunavir/r in phase 3 treatment-naïve trial at week 48" CROI 2017; Abstract 45LB.