next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI)
doravirine (formerly MK-1439) showed potent antiretroviral activity and good
tolerability in combination with tenofovir/FTC (the drugs in Truvada) in a dose-finding study
presented at the 21st Conference on Retroviruses and
Opportunistic Infections (CROI) last week in Boston.
NNRTIs are generally well tolerated and well suited
for first-line HIV treatment, but as a class they are susceptible to resistance.
Pre-clinical studies showed that Merck's doravirine has a distinct resistance profile and remains
active against HIV with common NNRTI resistance mutations including K103N and
As reported at last year's CROI, doravirine reduced
HIV viral load by about 1.3 log in a seven-day monotherapy study. Doravirine is
processed by the CYP3A4 enzyme, but it is neither a CYP3A4 inducer nor
inhibitor, so it is not expected to have major drug interaction concerns.
Javier Morales-Ramirez from Clinical Research Puerto Rico reported
late-breaking findings from a phase 2b study evaluating the safety and efficacy
of various doses of doravirine versus efavirenz (Sustiva) for initial antiretroviral therapy.
This study included 208 treatment-naive people living with HIV from North
America, Europe and Asia. More than 90% were
men, 74% were white, 20% were black and the median age was 35 years. At
baseline, the median CD4 cell count was approximately 375 cells/mm3
and 13% had received an AIDS diagnosis. Study participants were stratified by
whether their viral load was above (about 30%) or below 100,000 copies/ml;
median HIV RNA was approximately 4.5 log10.
Morales-Ramirez reported 24-week results from part 1 of the study, which
will continue for a total of 96 weeks. In this part, participants were randomly
allocated into five equal-sized arms receiving doravirine at doses of 25, 50, 100 or 200mg once daily, or
else efavirenz once daily, all in combination with tenofovir/FTC.
At 24 weeks, 76.4% of participants taking doravirine
had viral load below 40 copies/ml compared with 64.3% of people taking efavirenz.
Response rates were similar across doravirine doses (25mg: 80.0%; 50mg: 76.2%;
100mg: 71.4%; 200mg: 78.0%). More than 80% of participants in all treatment
arms reached the less stringent virological response threshold of <200
Both doravirine and efavirenz worked better
for people with lower pre-treatment viral load in an ad hoc analysis. For people with <100,000 copies/ml at
baseline, response rates (<40 copies/ml) ranged from 83 to 89% with
doravirine compared with 74% with efavirenz. For those with >100,000
copies/ml, response rates ranged from 50 to 91% with doravirine vs 54% with
Median CD4 cell gains were 137 cells/mm3
for all doravirine arms combined and 121 cells/mm3 for the efavirenz
Doravirine was generally safe and well tolerated.
People taking doravirine were less than half as likely as people taking efavirenz
to experience serious adverse events (3.0% across all doravirine arms vs 7.1%
with efavirenz) or to stop treatment for this reason (2.4 vs 4.8%). Four people
taking doravirine and two people taking efavirenz discontinued due to adverse
events considered to be drug-related.
The most common side-effects were dizziness
(3.6% with doravirine vs 23.8% with efavirenz), abnormal dreams (9.0 vs 7.1%),
diarrhoea (4.8 vs 9.5%), nausea (7.8 vs 2.4%) and fatigue (6.6 vs 4.8%). Other central
nervous system (CNS) adverse events of interest included insomnia (5.4 vs 7.1%),
nightmares (1.2 vs 9.5%) and hallucinations (0.6 vs 2.4%). Overall, 20.5% of people
taking doravirine reported at least one CNS side-effect, compared with 33.3% of
people taking efavirenz.
People taking doravirine
had more favourable lipid profiles and less frequent liver enzyme (ALT and AST)
elevations compared with people taking efavirenz.
researchers concluded that doravirine demonstrated potent antiretroviral
activity in treatment-naive patients, a favourable safety and tolerability
profile, and fewer drug-related adverse events compared with efavirenz.
on these findings, the 100mg once-daily dose was selected for future development
and will be used in part 2 of this study, a dose-confirmation analysis that
will enrol an additional 120 participants.
In the discussion following
the presentation, Daniel Kuritzkes from Harvard Medical School noted that sometimes it takes
longer for viral load to go down in people who start with a high level, so with
further follow-up past 24 weeks doravirine may no longer look less effective in