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SAN FRANCISCO -- A once-daily combination pill containing doravirine offers good HIV suppression when used as first-line treatment or as a switch option for people with undetectable viral load, researchers reported here.

Follow-up results from the DRIVE-AHEAD study showed that a recently approved combination pill containing doravirine, tenofovir disoproxil fumarate (TDF), and lamivudine (3TC) maintains viral suppression in newly treated patients through 96 weeks (undetectable viral load in 77.5% versus 73.6% for the comparator arm).

And the first reported data from DRIVE-SHIFT showed that the combo pill keeps HIV suppressed in people with well-controlled virus who switch from a different potent regimen.

Both studies were presented at a late-breaking session at the annual IDWeek meeting, a joint conference of the (IDSA), the (HIVMA), the (SHEA), and the (PIDS).

Merck's next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine has a unique resistance profile and remains active against HIV with resistance to other drugs in its class. In August as a stand-alone tablet (marketed as Pifeltro) and as part of a three-drug coformulation with TDF and lamivudine (marketed as Delstrigo).

Kathleen Squires, MD, of Merck and Thomas Jefferson University in Philadelphia, presented the 96-week findings from the phase III DRIVE-AHEAD trial, which compared the safety and efficacy of the doravirine triple-combination pill and an older coformulation containing efavirenz, TDF, and emtricitabine (Atripla).

All the component medications in both combinations are considered generally safe, but efavirenz is associated with central nervous system side effects, and TDF can cause kidney toxicity and bone loss in susceptible individuals.

DRIVE-AHEAD included 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 once daily. Everyone also received a placebo for the opposite assignment. Doravirine can be taken at any time, but efavirenz is typically taken at bedtime to reduce neuropsychiatric side effects.

Squires previously reported 48-week findings at the 2017 International AIDS Society Conference on HIV Science in Paris. At that point, 84% of patients in the doravirine arm and 81% in the efavirenz arm had HIV RNA below 50 copies/mL.

The doravirine combo remained non-inferior at the longer follow-up time, Squires said. CD4 counts rose by approximately 230 cells/mm³ in both arms.

The doravirine and efavirenz combinations worked about equally well for people who started with either a low or high viral load at baseline. Those who started with very low CD4 cell counts appeared to respond less well to efavirenz (65.0% versus 82.1% with undetectable viral load), but the number of patients in this category was small.

Among participants who underwent genotypic and phenotypic resistance testing due to virological failure, overall resistance rates were low (under 2%) and no additional resistance to doravirine was observed between week 48 and week 96, Squires reported.

"As a clinician, that's usually what I see," Squires said. "If patients are doing well on a regimen and are taking a regimen that's tolerable, I see little resistance after they are settled into taking a drug."

Switching to Doravirine

Switching to once-daily doravirine/TDF/lamivudine "is an effective and generally well-tolerated option for maintaining viral suppression in patients considering a change in therapy," said Princy Kumar, MD, of Georgetown University, who presented the phase III DRIVE-SHIFT findings here.

This study included 670 patients on stable antiretroviral therapy with HIV RNA below 40 copies/mL for at least 6 months. Again, about 85% were men, but the median age was older (approximately 43 years), reflecting a longer history of HIV infection.

About 16% had a history of AIDS and the mean baseline CD4 count was approximately 660 cells/mm³. About 70% were taking regimens containing a boosted protease inhibitors, about a quarter were taking NNRTIs, and just over 5% were taking the integrase inhibitor elvitegravir. They had no history of prior treatment failure or known resistance to the study drugs.

Participants were randomly assigned to either switch to the doravirine coformulation immediately (yielding 48 weeks of follow-up) or after a 24-week delay (yielding 24 weeks of follow-up).

At week 24, 93.7% of people in the doravirine arm had HIV RNA below 50 copies/mL, compared with 94.6% of those who stayed on their existing regimen, showing that the doravirine coformulation was non-inferior to comparator regimens. At week 48, 90.8% in the doravirine arm had undetectable viral load.

Virological failure rates were low in both arms (<2%). No one who received the doravirine regimen developed drug resistance during the study, and all 24 patients with NNRTI resistance at baseline maintained viral suppression, Kumar reported.

Drug Safety

Treatment was generally safe in both studies.

In DRIVE-AHEAD, about half as many people in the doravirine arm compared with the efavirenz arm experienced drug-related adverse events at 96 weeks (32% versus 65%, respectively) or discontinued treatment due to adverse events (3% versus 7%). Serious drug-related adverse events were rare in both arms (1% or less).

The difference in adverse events was largely driven by a lower rate of neuropsychiatric side effects in the doravirine compared with the efavirenz arm, especially dizziness (10% versus 38%), abnormal dreams (14% versus 28%), and altered sensorium (5% versus 9%).

In DRIVE-SHIFT, about 20% of those who switched to doravirine had drug-related adverse events compared with 2% of those who remained on their baseline regimen. However, only 1.6% of doravirine recipients stopped treatment for this reason.

In both studies, lipid profiles favored doravirine. Among newly treated patients in DRIVE-AHEAD, cholesterol and triglyceride levels showed little or no change in the doravirine arm but increased in the efavirenz arm. In DRIVE-SHIFT, lipid levels fell in patients who switched to doravirine while remaining stable in those who stayed on their existing regimen.

A limitation of the doravirine coformulation is that it contains TDF instead of the newer tenofovir alafenamide (TAF), which has been shown to cause less kidney and bone toxicity. In DRIVE-SHIFT, kidney function was monitored, with no notable safety signals; DEXA bone scans were not done.

"We know that there could be more renal side effects, but we have more than two decades of use of TDF," Kumar said. "As clinicians, we have learned to be able to understand and recognize the side effects and avoid TDF in patients who have renal or bone problems or who are at high risk. These years of experiencing knowing how to manage TDF makes me feel very comfortable that this is an option for patients who would like to make a switch."

However, Monica Gandhi, MD, of the University of California at San Francisco suggested the doravirine combo may be used less in countries where TAF is available.

"Overall, I think doravirine is looking like all the other NNRTIs. It's pretty effective but it has resistance associated with it," Gandhi told MedPage Today. "The question about doravirine being paired with TDF/3TC is a valid one. In our setting we're turning to TAF, and I think it's going to have less use in the United States."