Doravirine, an investigational next-generation
non-nucleoside reverse transcriptase inhibitor (NNRTI) from Merck, reduced HIV viral
load as well as boosted darunavir in a phase 3 clinical trial of people
starting antiretroviral therapy (ART) for the first time, but it had a better
lipid profile, according to a late-breaking presentation at the Conference on
Retroviruses and Opportunistic Infections (CROI 2017) this week in Seattle.
Current first-line ART
regimens are safe and highly effective, but having multiple potent and well
tolerated drugs available in multiple antiretroviral classes offers more
options for constructing optimised regimens.
Doravirine (formerly MK-1439) is active against HIV
with common NNRTI-resistance mutations including K103N. It can be taken once
daily with or without food and has low potential for drug-drug interactions. As
previously reported, a phase 2 trial showed
that doravirine suppressed viral load as well as efavirenz (Sustiva or Stocrin), but with fewer neuropsychiatric side-effects.
At CROI Kathleen Squires of Thomas
Jefferson University in Philadelphia
presented results from DRIVE-FORWARD, a phase 3 trial comparing doravirine
against ritonavir-boosted darunavir for first-line therapy.
The study analysis included 769 previously untreated
adults with HIV. Most (84%) were men, nearly 80% were white and the average age
was 35 years. At baseline the mean CD4 T-cell count was
approximately 420 cells/mm3 and the mean viral load was 4.4 log10
copies/mL; 20% had high viral load
above 100,000 copies/ml. At baseline they had no genotypic resistance to any
Participants in this double-blind study were randomly
assigned (1:1) to take either 100mg doravirine or 800mg darunavir (Prezista) plus 100mg ritonavir. In
addition they received two nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs), either tenofovir DF/emtricitabine (Truvada; 87%) or abacavir/lamivudine (Kivexa or Epzicom; 13%). In
each arm participants received matching placebos for the drug not assigned, so they
all took four pills a day.
Treatment continued for 96 weeks. The primary endpoint was the proportion of people with HIV RNA below 50
copies/ml at week 48.
At 48 weeks, 84% of participants in the doravirine arm
and 80% of those assigned to boosted darunavir had undetectable HIV RNA below 50 copies/ml. The difference was not
significant and doravirine was shown to be non-inferior to darunavir/ritonavir.
Efficacy was comparable among people who started
with high viral load (81% for doravirine and 76% for darunavir/ritonavir), as
well as among those who started with lower levels (90% vs 89%, respectively).
The response rate was somewhat higher with doravirine among people who started
with a CD4 count below 50 cells/mm3 (83% vs 67%, respectively), but
the number of people in this category was small. There was no difference
based on whether they took tenofovir/emtricitabine or abacavir/lamivudine.
rates were similar in the doravirine and darunavir/ritonavir arms (11% vs 13%,
respectively). Among the 15 non-responders who underwent resistance testing, there
were no genotypic or phenotypic NNRTI, NRTI or protease inhibitor resistance
mutations. Among 40 people who discontinued treatment early with detectable virus, one non-adherent participant
developed doravirine resistance.
CD4 cell gains were "robust" in both arms: 193 cells/mm3 for those on darunavir and 186 cells/mm3 for those on darunavir/ritonavir.
Both regimens were generally safe and well tolerated. The most common
adverse events were diarrhoea, nausea, nasopharyngitis (nose and
throat inflammation) and headache. Rates of serious adverse events were similar
in the doravirine and darunavir/ritonavir arms (5% vs 6%, respectively), as
were events leading to treatment discontinuation (2% vs 3%). Side-effects associated with other NNRTIs,
such as rash and neuropsychiatric symptoms, were similar in both arms. Diarrhoea was the only side-effect with a notable difference, being more
common in the darunavir/ritonavir arm.
In addition to the participants who discontinued treatment
due to adverse events, 3% in the doravirine arm and 4% in the
darunavir/ritonavir arm withdrew consent, and 4% and 5%, respectively, were
lost to follow-up. Squires said that the large number of pills was commonly mentioned
as a reason for quitting early.
The major advantage of doravirine over darunavir/ritonavir was its favourable
effect on lipid levels. Fasting lipid levels decreased slightly in
the doravirine arm while increasing in the
darunavir/ritonavir arm for LDL (-4.51 vs + 9.92 mg/dl), non-HDL (-5.3% vs
+13.75 mg/dl), total cholesterol (-1.37 vs +17.9 mg/dl) and triglycerides
(-3.14 vs +21.97 mg/dl). HDL levels rose by about 4.0 mg/ml in both arms.
"Doravirine is a novel once-daily NNRTI for
first-line treatment with consistent efficacy regardless of baseline viral load
and very good tolerability," the researchers concluded.
In order to be competitive
in today's market, antiretrovirals must be easy to take as well as safe and
effective, as a majority of people starting first-line treatment can now take
one pill once a day.
Merck has developed a
fixed-dose co-formulation of doravirine, tenofovir disoproxil fumarate (DF) and lamivudine, which is being evaluated in ongoing studies. The phase 3 DRIVE-AHEAD trial is comparing doravirine/tenofovir DF/lamivudine
to efavirenz/tenofovir DF/emtricitabine (Atripla)
for initial treatment, while DRIVE-SHIFT is evaluating a switch from another suppressive
regimen to the doravirine co-formulation, according to a Merck