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IAS 2017: Doravirine Combo Pill Looks Good for Initial HIV Treatment


A single-tablet regimen containing the next-generation NNRTI doravirine reduced HIV viral load as much as an efavirenz-based coformulation, but it had a more favorable side effect profile, according to results from the DRIVE-AHEAD studypresented at the 9th International AIDS Society Conference on HIV Science (IAS 2017) last month in Paris.

Current first-line antiretroviral therapy regimens are safe and highly effective. Integrase inhibitors have largely replaced non-nucleoside reverse transcriptase inhibitors (NNRTIs) for first-time treatment in recent years, but having multiple potent and well-tolerated drugs from different antiretroviral classes offers more options for individualized therapy.

Kathleen Squires of Thomas Jefferson University in Philadelphiapresented findings from the Phase 3 DRIVE-AHEAD study, which is evaluating a fixed-dose coformulation of 100 mg doravirine, 300 mg lamivudine (3TC), and 300 mg tenofovir disoproxil fumarate (TDF).

Doravirine, an investigational NNRTI being developed by Merck,has a unique resistance profile and is active against HIV with common NNRTI-resistance mutations including K103N. It can be taken with or without food and has low potential for drug-drug interactions.

Previous research showed that doravirine suppressed viral load as much as efavirenz (Sustiva) but with fewer neuropsychiatric side effects in a Phase 2 study. Doravirine plus 2 NRTIs of the investigator's choice -- either TDF/emtricitabine (Truvada) or abacavir/lamivudine (Epzicom) -- worked as well as ritonavir-boosted darunavir (Prezista) but with a better lipid profile in the Phase 3 DRIVE-FORWARD study.

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

Participants in this double-blind studywere randomly assigned to receive the doravirine combination pill or a coformulation of efavirenz, TDF, and emtricitabine (Atripla). Treatment was planned for 96 weeks, with theprimary endpoint being the proportion of people with HIV RNA below 50 copies/mLat week 48.

To "blind" the study, because the drugs' dosing regimens are not the same, participants received placebos for the coformulation they were not taking. Doravirine allows for a more flexible schedule: participants were told to take the doravirine coformulation or placebo any time they chose -- but at the same time each day -- with or without food. They were told to take the efavirenz pill or placebo on an empty stomach at bedtime, as this is thought to lessen neurological side effects.

After 48 weeks on treatment,84% of people in the doravirine arm and 81% in the efavirenz arm had undetectable viral load, showing that the new coformulation was non-inferior. Those who started with a higher viral load had higher response rates overall, but these 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 an undetectable level in both treatment arms.

People taking doravirine were more likely to experience protocol-defined virological failure than those taking efavirenz, but this was infrequent in both arms (6% vs 4%). 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 mutations.

Both treatment regimens were generally safe and well-tolerated, but there were some notable differences in side effects.

Half as many people in the doravirine arm experienced drug-related adverse events overall (31% vs 63%, respectively), but serious events were rare in both arms (1% or less). Less than half as many in the doravirine arm stopped treatment early de to adverse events (3% vs 7%). The most common adverse events in the doravirine arm were headache (13%), diarrhea (11%), and nasopharyngitis (11%), which occurred at similar rates in the efavirenz arm. Skin rash was less common with doravirine (5% vs 12%).

However, doravirine caused significantly fewer central nervous system side effects. For example, 9% of people taking doravirine reported dizziness, compared with 37% of those taking efavirenz. Looking at a set of predefined neuropsychiatric events, half as many doravirine recipients reported sleep disorders or disturbances (12% vs 26%) and altered cognition (4% vs 8%). Depression and suicide or self-injury were also less frequent with doravirine (4% vs 7%).

Lipid profiles, too, favored doravirine. LDL cholesterol, total cholesterol, and triglyceride levels decreased slightly after starting treatment in the doravirine arm, while increasing substantially in the efavirenz arm.

"Doravirine is a novel, once-daily NNRTI for first-line treatment with consistent efficacy regardless of baseline viral load and favorable tolerability and safety profile in 2 Phase 3 clinical trials," the study investigators concluded.

The DRIVE-AHEAD study had some limitations, including the fact that it compared doravirine against efavirenz, which is no longer recommended for first-line therapy in many treatment guidelines due to its side effects. Nevertheless, its low cost and wide availability mean it is still commonly used in resource-limited countries.

In addition, session moderator Monica Gandhi of the University of California at San Francisco School pointed out that the doravirine coformulation contains TDF instead of the newer tenofovir alafenamide (TAF) formulation, which causes less kidney and bone toxicity. This was done because a generic version of TDF is expected to become available soon, while TAF will remain on patent for another five years or so.



K Squires et al.Fixed dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naïve adults with HIV-1 infection: week 48 results of the Phase 3 DRIVE-AHEAD study.9th International AIDS Society Conference on HIV Science.Paris, July 23-26, 2017. Abstract TUAB0104LB.