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PARIS -- A new once-daily combination pill offered good HIV suppression regardless of starting viral load, with a more favorable side effects profile than older first-line drugs, a researcher reported here.

After 48 week of treatment, 84% of study participants taking doravirine as part of a three-drug combo (along with tenofovir disoproxil fumarate and lamivudine) reached an undetectable viral load, compared with 81% of those taking an efavirenz-based regimen, according to Kathleen Squires, MD, of Thomas Jefferson University in Philadelphia, and colleagues, in a presentation at the International AIDS Society (IAS) Conference on HIV Science.

Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs have long been a mainstay of initial HIV treatment. In recent years they have been supplanted by integrase inhibitors, but having potent and well-tolerated drugs available from multiple antiretroviral classes offers patients and providers more options for individualized treatment.

The investigational doravirine has a unique resistance profile, remaining active against HIV with resistance to other drugs in its class, and it has a low potential for interactions with other drugs, according to preclinical studies.

In a phase II clinical trial, doravirine demonstrated good antiviral efficacy and caused fewer neuropsychiatric side effects than efavirenz (Sustiva). Data from the phase III DRIVE-FORWARD trial, which Squires presented earlier this year, showed that doravirine worked as well as ritonavir-boosted darunavir (Prezista), but had a more favorable lipid profile.

DRIVE-FORWARD showed that similar proportions of patients receiving doravirine and darunavir/ritonavir, both combined with two nucleoside/nucleotide reverse transcriptase inhibitors chosen by their physicians, reached a viral load level below 50 copies of HIV RNA per mL (84% and 80%, respectively).

Drug maker Merck then moved on to evaluate a once-daily fixed-dose coformulation of doravirine, tenofovir disoproxil fumarate (TDF), and lamivudine.

Squires presented findings from the phase III DRIVE-AHEAD trial comparing the doravirine combination pill against the Atripla coformulation (efavirenz/TDF/emtricitabine).

DRIVE-AHEAD enrolled 728 participants who were starting HIV treatment for the first time. About 85% were men and the median age was 31 years. The mean baseline CD4 count was approximately 420 cells/mm³, 14% had a clinical history of AIDS, and about 22% had a high viral load above 100,000 copies/mL.

Participants were randomly assigned to receive the doravirine combination pill or the efavirenz coformulation for 48 weeks. For blinding purposes, all patients received placebos for the drug they were not taking.

Doravirine allows for a more flexible dosing schedule than efavirenz. Study participants were instructed to take the doravirine pill or placebo at the same time each day with or without food, while the efavirenz pill or placebo was taken on an empty stomach at bedtime in order to reduce side effects.

Virological response rates were similar at 48 weeks, with 84% of patients in the doravirine arm and 81% in the efavirenz arm having viral load below 50 copies/mL, showing that the new coformulation is non-inferior, Squires reported.

People who started therapy with a higher viral load were more likely to achieve undetectable HIV RNA, but response rates did not differ according to regimen. In a modified analysis, about 90% of those with low baseline viral load and about 80% of those with high baseline viral load reached undetectable levels in both treatment arms.

Patients taking the doravirine combo had more protocol-defined virological failure (6% versus 4%), but they were less likely to stop treatment early for other reasons (10% versus 14%). Among participants with virological failure who underwent successful genotypic testing, 1.6% in the doravirine arm and 3.3% in the efavirenz arm had evidence of NNRTI resistance.

Overall, half as many people in the doravirine arm experienced drug-related adverse events compared with the efavirenz arm (31% versus 63%, respectively). Fewer patients stopped treatment early due to adverse events (3% versus 7%). Serious drug-related adverse events were rare in both arms (1% or less), Squires reported. The most common adverse events in the doravirine arm were headache (13%), diarrhea (11%), and nasopharyngitis (11%), all of which occurred with similar frequency in the efavirenz arm.

The major advantage of doravirine was that it was associated with fewer central nervous system side effects. Several neuropsychiatric symptoms were less common in the doravirine arm compared with the efavirenz arm, including dizziness (9% versus 37%), sleep disorders (12% versus 26%), abnormal dreams (5% versus 12%), altered sensorium (4% versus 8%), and depression or suicidality (4% versus 7%).

Lipid profiles were also showed an advantage for doravirine. Cholesterol and triglyceride levels fell after starting treatment in the doravirine arm, while rising in the efavirenz arm.

"There was a significant difference in favor of doravirine in terms of lipids. Across all parameters we saw an increase with efavirenz and a light decrease with doravirine," Squires said.

A limitation of the DRIVE-AHEAD trial was that it compared doravirine against efavirenz, which is no longer considered a recommended regimen in many guidelines due to its adverse events.

Another limitation is that the doravirine coformulation contains TDF instead of the newer tenofovir alafenamide (TAF) formulation, which causes less kidney and bone toxicity, according to Monica Gandhi, MD, of the University of California San Francisco, who moderated the IAS session. Gandhi said this was done because a generic version of TDF will soon become available, while TAF will remain on patent.

"I think its utility would be better if the drug companies got together and talked, and TAF and [emtricitabine] could be put together with doravirine," Gandhi told MedPage Today. "The TAF data are showing it is safer. If you had a preference when it's time to coformulate, I'd like to coformulate with TAF, but it sounds like they can't."

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