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CROI 2017: New NNRTI Doravirine Shows Good Efficacy in Phase 3 Study

Doravirine, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) from Merck, reduced HIV viral load as well as boosted darunavir in a Phase 3 clinical trial of people starting antiretroviral therapy (ART) for the first time, but it had a better lipid profile, according to a late-breaking presentation at the Conference on Retroviruses and Opportunistic Infections last week in Seattle.

Current first-line ART regimens are safe and highly effective, but having multiple potent and well-tolerated drugs available in multiple antiretroviral classes offers more options for constructing optimized regimens.

Doravirine (formerly MK-1439) is active against HIV with common NNRTI-resistance mutations including K103N. It can be taken once-daily with or without food and has low potential for drug-drug interactions. As previously reported, a Phase 2 trial showed that doravirine suppressed viral load as well as efavirenz (Sustiva), but with fewer neuropsychiatric side effects.

At CROI Kathleen Squires from Thomas Jefferson University in Philadelphiapresented results from DRIVE-FORWARD, a Phase 3 trial comparing doravirine against ritonavir-boosted darunavir for first-line therapy.

The study analysis included 769 previously untreated adults with HIV. Most (84%) were men, nearly 80% were white, and the average age was 35 years.At baseline the mean CD4 T-cell count was approximately 420 cells/mm³ and the mean viral load was 4.4 log copies/mL; 20% had high viral load above 100,000 copies/mL. At baseline they had no genotypic resistance to any study drugs.

Participants in this double-blind study were randomly assigned (1:1) to take either 100 mg doravirine or 800 mg darunavir (Prezista) plus 100 mg ritonavir. In addition they received 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), either tenofovir DF/emtricitabine (Truvada; 87%) or abacavir/lamivudine (Epzicom; 13%). In each arm patients received matching placebos for the drug not assigned, so they all took 4 pills a day.

Treatment continued for 96 weeks. The primary endpoint was the proportion of people with HIV RNA below 50 copies/mLat week 48.

Results

• At 48 weeks, 84% of participants in the doravirine arm and 80% of those assigned to boosted darunavir had undetectable HIV RNA below 50 copies/mL. The difference was not significant and doravirine was shown to be non-inferior to darunavir/ritonavir.
• Efficacy was comparable among patients who started with high viral load (81% for doravirine and 76% for darunavir/ritonavir), as well as among those who started with lower levels (90% vs 89%, respectively).
• The response rate was somewhat higher with doravirine among people who started with a CD4 count below 50 cells/mm³ (83% vs 67%, respectively), but the number of patients in this category was small.
• There was no difference based on whether they took tenofovir/emtricitabine or abacavir/lamivudine.
• Virological non-response rates were similar in the doravirine and darunavir/ritonavir arms (11% vs 13%, respectively).
• Among the 15 non-responders who underwent resistance testing, there were no genotypic or phenotypic NNRTI, NRTI, or protease inhibitor resistance mutations.
• Among 40 people who discontinued treatment early with detectable virus, 1 non-adherent individual developed doravirine resistance.
• CD4 cell gains were "robust" in both arms: 193 cells/mm³ for those on darunavir and 186 cells/mm³ for those on darunavir/ritonavir.
• Both regimens were generally safe and well-tolerated.
• The most common adverse events were diarrhea, nausea, nasopharyngitis (nose and throat inflammation), and headache.
• Rates of serious adverse events were similar in the doravirine and darunavir/ritonavir arms (5% vs 6%, respectively), as were events leading to treatment discontinuation (2% vs 3%).
• Side effects associated with other NNRTIs, such as rash and neuropsychiatric symptoms, were similar in both arms.
• Diarrhea was the only side effect with a notable difference, being more common in the darunavir/ritonavir arm.
• 3% in the doravirine arm and 4% in the darunavir/ritonavir arm withdrew consent, and 4% and 5%, respectively, were lost to follow-up.
• Fasting lipid levels decreased slightly in thedoravirine arm while increasing in the darunavir/ritonavir arm for LDL (-4.51 vs + 9.92 mg/dl), non-HDL (-5.3% vs +13.75 mg/dl), total cholesterol (-1.37 vs +17.9 mg/dl) and triglycerides (-3.14 vs +21.97 mg/dl). HDL levels rose by about 4.0 mg/ml in both arms.

"Doravirine is a novel once-daily NNRTI for first-line treatment with consistent efficacy regardless of baseline viral load and very good tolerability," the researchers concluded. The major advantage of doravirine over darunavir/ritonavir was its favorable effect on lipid levels.

While rates of discontinuation due to adverse events were low, most people who did not complete the study were either lost to follow-up or voluntarily withdrew consent -- 7% in the doravirine arm and 9% in the darunavir/ritonavir arm. Squires said that the large pill burden was commonly mentioned as a reason for withdrawal.

In order to be competitive in today's market, antiretrovirals must be easy to take as well as safe and effective, as a majority of people starting first-line treatment can now take 1 pill once daily.

Merck has developed a fixed-dose coformulation of doravirine, tenofovir DF, and lamivudine, which is being evaluated in ongoing studies. The Phase 3 DRIVE-AHEAD trial is comparing doravirine/tenofovir DF/lamivudine to efavirenz/tenofovir DF/emtricitabine (Atripla) for initial treatment, while DRIVE-SHIFT is evaluating a switch from another suppressive regimen to the doravirine coformulation, according to a Merck press release.

2/20/17

Sources

JM Molina, K Squires, PE Sax, et al.Doravirine is non-inferior to darunavir/r in phase 3 treatment-naive trial at week 48.Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 45LB.

Merck. Merck’s Doravirine, an Investigational Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) for the Treatment of HIV-1 Infection, Met Primary Efficacy Endpoint in Pivotal Phase 3 Trial. Press release. February 14, 2017.