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HIV Drug Therapy: Doravirine Works as Well as Efavirenz with Fewer CNS Side Effects

Once-daily doravirine (MK-1439), an experimental NNRTI, demonstrated viral suppression similar to that of efavirenz at 48 weeks, and the dose selected for further development was associated with fewer central nervous system (CNS) side effects, researchers reported this week at the International Congress on Drug Therapy in HIV Infection in Glasgow.

Efavirenz (Sustiva, also in the widely used Atripla single-tablet regimen) is generally a safe and effective component of combination antiretroviral treatment, but a substantial number of people who take it experience neuropsychiatric side effects such as insomnia, abnormal dreams, and dizziness.

Josep Gatell from the University of Barcelona and colleagues conducted a Phase 2b clinical trial (P007/NCT01632345) comparing Merck's next-generation non-nucleoside reverse transcriptase inhibitor doravirine versus efavirenz in people with HIV starting antiretroviral therapy (ART) for the first time.

In Part 1 of the study, 208 participants were randomly assigned to receive doravirine at doses of 25 mg, 50 mg, 100 mg, or 200 mg once-daily, or else 600 mg efavirenz once-daily, all in combination with tenofovir/emtricitabine (the drugs in Truvada).

Based on a 24-week analysis (reported at this year's Retrovirus Conference), the 100 mg dose was selected. All doravirine recipients switched to this dose starting at week 36 and will continue on blinded treatment through week 96. Gatell reported findings from a 48-week safety and efficacy analysis in Glasgow.

Part 1 included 208 participants in the U.S., Canada, Europe, Russia, and Australia. More than 90% were men, nearly 80% were white, and the median age was about 35 years. At baseline about 33% had high viral load (HIV RNA >100,000 copies/mL). The median CD4 T-cell count was approximately 390 cells/mm³ and about 12% had an AIDS diagnosis.

Part 2 of the study enrolled an additional 132 participants assigned to receive either the selected 100 mg dose of doravirine or efavirenz. Central nervous system adverse events at week 8 were compared between 108 people who took 100 mg doravirine (in both Parts 1 and 2) and 108 who took efavirenz. Characteristics in this population were generally similar, though the median CD4 count was a bit higher and fewer had AIDS.

Results

• At 48 weeks, 72.5%, 72.1%, 76.2%, and 82.9% of participants taking doravirine at doses of 25 mg, 50 mg, 100 mg, and 200 mg, respectively, had undetectable viral load (<40 copies/mL), compared with 71.4% of those taking efavirenz.
• In an ad hoc analysis, virological response rates were a bit higher for all doses of doravirine (85%-89%) compared with efavirenz (74%) for people with low baseline viral loads.
• Among those with high viral loads, however, the 25 mg and 50 mg doses of doravirine (64%) did not work as well as the higher doses (73%-92%) or efavirenz (83%).
• CD4 cell gains were 190, 134, 155, and 194 cells/mm³, respectively, for doravirine recipients and 179 cells/mm³ for efavirenz recipients.
• Emergence of drug resistance among people with virological failure was rare, observed in only 1 doravirine recipient and no one taking efavirenz.
• Looking at adverse events in Part 1, 4.8% of people taking doravirine (all doses combined) experienced serious adverse events compared with 9.5% of those taking efavirenz.
• 4.2% and 4.8%, respectively, stopped treatment early due to adverse events.
• The most frequently reported side effects were dizziness (3.0% of people taking all doses of doravirine vs 23.8% of those taking efavirenz), abnormal dreams (10.2% vs 9.5%), diarrhea (4.8% vs 9.5%), nausea (7.8% vs 2.4%), and fatigue (7.2% vs 4.8%).
• Grade 2 or higher laboratory abnormalities were uncommon in all treatment arms, though people taking efavirenz were more likely to have elevated LDL and total cholesterol.
• In the 8-week analysis of central nervous system side effects, 22.2% of people taking the 100 mg dose of doravirine reported at least 1 neuropsychiatric symptom, compared with 43.5% of efavirenz recipients -- a significant difference.
• The most common CNS side effects were dizziness (9.3% with doravirine vs 27.8% with efavirenz), abnormal dreams (5.6% vs 16.7%), and nightmares (5.6% vs 8.3%); insomnia was more common in the doravirine arm (6.5% vs 2.8%).
• Depression (0.9% vs 1.9%) and suicidal thoughts (0.0% vs 0.9%) were rare in both arms.

In ART-naive patients, doravirine demonstrated "antiretroviral activity and immunological effect similar to efavirenz" with a "low frequency of resistance development" and a "good safety and tolerability profile," the researchers concluded.

At 8 weeks the 100 mg once-daily dose of doravirine "demonstrates a significantly lower rate of treatment-emergent CNS events than efavirenz," they added.

Merck announced that it plans to start the first Phase 3 clinical trial of doravirine for previously untreated people with HIV by the end of 2014. This study will compare doravirine against ritonavir-boosted darunavir (Prezista). Further information is available at www.clinicaltrials.gov (study NCT02275780).

11/7/14

Reference

JM Gatell, JO Morales-Ramirez, DP Hagins, et al. 48-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients. HIV Drug Therapy 2014. Glasgow, November 2-6, 2-14. Abstract O434.

Other Source

Merck. Merck Announces Data from 48-Week Phase 2b Study of Investigational HIV Therapy Doravirine (MK-1439) in Treatment-Naive Patients. Press release. November 3, 2014.