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Two new HIV drugs, Doravirine and Bictegravir, suppress viral loads in studies and proceed to Phase 3 testing

, by Liz Highleyman

A pair of new drugs—Merck’s doravirine and Gilead Sciences’ bictegravir—showed potent activity against HIV in clinical trials, researchers reported at the Conference on Retroviruses and Opportunistic Infections (CROI) last week in Seattle. Doravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), worked as well to suppress viral loads as a boosted protease inhibitor and had a more favorable effect on blood lipid levels. Bictegravir, an integrase inhibitor, also proved non-inferior at suppressing viral loads compared to a different integrase inhibitor.

Current first-line antiretroviral medications are highly effective, easy to take, and have few side effects. But having more potent and well-tolerated drugs available from multiple antiretroviral classes offers more options for putting together optimized regimens, and competition can help bring down the cost of treatment.

Doravirine: A New NNRTI

Doravirine (formerly MK-1439) is an experimental next-generation NNRTI. It can be taken once daily with or without food and has low potential for drug-drug interactions. A previous study showed that it suppressed viral load as well as the widely used NNRTI efavirenz (Sustiva), but with fewer central nervous side effects.

Kathleen Squires, MD

Kathleen Squires, MD

Kathleen Squires, MD, from Thomas Jefferson University in Philadelphia presented late-breaking results from the Phase 3 DRIVE-FORWARD trial, which compared doravirine against the boosted protease inhibitor darunavir (Prezista) for first-time therapy (abstract 45LB).

This study included 769 adults with HIV being treated for the first time. Most were white men and the average age was 35 years. At baseline the average CD4 count was approximately 420 cells/mm3, one in five had HIV viral load above 100,000 copies/mL, and no participants had evidence of resistance to any study drugs.

Participants were randomly assigned to take either 100 mg doravirine or 800 mg darunavir boosted with 100 mg ritonavir once daily for 96 weeks. To complete their regimen, they also took tenofovir disoproxil fumarate/emtricitabine (Truvada) or abacavir/lamivudine (Epzicom).

All of the participants received matching placebos for the drug they were not assigned to, so everyone took four pills a day. With one-pill, once-daily antiretroviral coformulations now being the standard of care, this is considered to be a high pill burden.

After 48 weeks on treatment, 84% of people taking doravirine and 80% of those taking boosted darunavir had undetectable HIV RNA (below 50 copies/mL), showing that doravirine was non-inferior to darunavir/ritonavir. The two drugs had similar effectiveness for people who started with either a low or high viral load, and for those who took tenofovir/emtricitabine or abacavir/lamivudine.

Squires reported that CD4 cell gains were “robust” in both arms: 193 cells/mm3 with darunavir and 186 cells/mm3 with darunavir/ritonavir.

Both treatment regimens were generally safe and well tolerated. The most common adverse events were diarrhea, nausea, nose and throat inflammation, and headache. Side effects associated with other NNRTIs—such as rash and neuropsychiatric symptoms—were uncommon and similar in both arms. Diarrhea was reported more often in the darunavir/ritonavir arm compared to the doravirine arm (22% vs 14%).

The major advantage of doravirine over darunavir/ritonavir was its favorable effect on blood lipid levels. Low-density lipoprotein (LDL), total cholesterol, and triglyceride levels fell slightly in the doravirine arm while rising in the darunavir/ritonavir arm.

Only a small number of people in both groups stopped treatment early due to adverse events: 2% in the doravirine arm and 3% in the darunavir/ritonavir arm. But an additional 7% of participants taking doravirine and 9% taking darunavir/ritonavir quit voluntarily or were lost to follow-up. Squires noted that the large number of pills was commonly mentioned as a reason for quitting early.

Joseph Eron, MD, from the University of North Carolina at Chapel Hill, who moderated a CROI press conference on new antiretroviral drugs, said this was a “tough study” due to its high pill burden. If everyone who dropped out voluntarily or stopped attending follow-up visits had responded as well as those who stuck with treatment, the regimen’s success rate would be similar to that of current first-line regimens.

In today’s competitive market, antiretrovirals for first-time treatment can probably only succeed if they are coformulated into a once-daily single tablet-regimen. Merck is working on a fixed-dose coformulation of doravirine, tenofovir disoproxil fumarate, and lamivudine, which is now being tested in Phase 3 studies for treatment-experienced and treatment-experienced people.

Bictegravir: A Novel Integrase Inhibitor 

Bictegravir (formerly GS-9883) is an investigational integrase inhibitor that can be taken once daily and does not require a booster, unlike Gilead’s older integrase inhibitor elvitegravir (Vitekta, also in Stribild and Genvoya). Elvitegravir and ViiV Healthcare’s dolutegravir (Tivicay, also in Triumeq) are recommended for first-time therapy in current U.S. treatment guidelines and are available in single-tablet coformulations.

Early studies showed that bictegravir has potent activity against both wild-type (non-mutated) and drug-resistant HIV, and it has low potential to be either a “victim” or “perpetrator” of drug-drug interactions, according to Joseph Custodio, PhD, from Gilead (abstract 40).

Paul Sax, MD

Paul Sax, MD (Photo: Liz Highleyman)

Paul Sax, MD, from Brigham and Women’s Hospital in Boston reported findings from a Phase 2 trial comparing bictegravir to dolutegravir for initial HIV treatment (abstract 41). This study included 98 previously untreated adults, mostly men, with a median age of about 32 years and a median CD4 count of approximately 450 cells/mm3.

Participants were randomly assigned to take 75 mg bictegravir or 50 mg dolutegravir. Both drugs were combined with 25 mg tenofovir alafenamide and 200 mg emtricitabine (the drugs in Descovy), taken once daily with or without food for 48 weeks.

Both treatments were highly effective, with 97% of people taking bictegravir achieving viral suppression at both 24 and 48 weeks, compared to 94% at 24 weeks and 91% at 48 weeks for those taking dolutegravir. One person in the bictegravir arm and two in the dolutegravir arm had HIV RNA above 50 copies/mL, and none of them showed evidence of drug resistance.

Here too, CD4 counts rose rapidly after starting treatment, by 258 cells/mm3 in the bictegravir arm and by 192 cells/mm3 in the dolutegravir arm.

Again, both regimens were safe and well tolerated, with no treatment-related serious adverse events. The most frequent adverse events were diarrhea and nausea. Kidney function biomarkers declined a bit in both treatment groups, but there were no serious kidney problems reported.

These results were promising enough to proceed to Phase 3 trials using a newly developed single-tablet regimen containing bictegravir, tenofovir alafenamide, and emtricitabine.

Sax said that four Phase 3 studies—using once-daily single-tablet coformulation of bictegravir, TAF, and emtricitabine instead of separate pills—are now underway and fully enrolled.

Liz Highleyman is a freelance medical writer and editor of HIVandHepatitis.com.

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