The US Food and Drug
Administration (FDA) has
approved two new products containing the next-generation non-nucleoside reverse
transcriptase inhibitor doravirine. These products are also under review by the
European Medicines Agency.

Produced by Merck/MSD, Pifeltro
is a stand-alone doravirine tablet that must be taken with other
antiretrovirals. Delstrigo is a
fixed-dose pill (single-tablet regimen) containing doravirine plus the
nucleoside/nucleotide reverse
transcriptase inhibitors tenofovir disiproxil fumarate (sold separately as Viread) and lamivudine (also known as Epivir or 3TC).

Both Pifeltro and Delstrigo were approved for adults with
HIV who are starting antiretroviral treatment for the first time. Both are taken
once daily with or without food. Doravirine (formerly known as MK-1439)
has a unique resistance profile and is active against HIV with common
NNRTI-resistance mutations including K103N.

Approval of the new medications was based on findings from the phase 3 DRIVE-FORWARD
and DRIVE-AHEAD clinical trials.

DRIVE-FORWARD included 766 HIV-positive participants with no prior
treatment experience. They were randomly assigned to receive once-daily
doravirine or boosted darunavir (Prezista),
each in combination with tenofovir DF/emtricitabine (the drugs in Truvada) or abacavir/lamivudine (the
drugs in Kivexa or Epzicom).

Kathleen Squires of Thomas Jefferson University presented the results
at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI). After 48 weeks
on treatment, 84% of people taking doravirine and 80% of those taking boosted
darunavir had undetectable viral load (50 copies/ml), showing that
doravirine was non-inferior.

DRIVE-AHEAD included 728 previously untreated
participants. They were randomised to receive a fixed-dose coformulation of
doravirine, tenofovir DF and lamivudine
— the same as the approved Delstrigo
pill — or a single-tablet regimen containing efavirenz, tenofovir DF and
emtricitabine (the drugs in Atripla).

As Squires reported last summer
at the 2017 International AIDS Society Conference on HIV
Science, 84% of people on the Delstrigo combo and 81% of those on the Atripla combo had undetectable viral
load at 48 weeks, again showing that doravirine was non-inferior.  Viral suppression rates were similar in the two
treatment arms for patients who started with either low or high (100,000
copies/ml) viral load at baseline.

Treatment with doravirine was safe and well tolerated. In DRIVE-FORWARD,
2% of doravirine recipients stopped treatment early due to adverse events
compared with 3% of those taking boosted darunavir. In DRIVE-AHEAD, Delstrigo recipients were about half as likely as Atripla
recipients to discontinue treatment because of adverse events (3% vs 7%).

The most common doravirine side effects in both studies were headache, nausea,
diarrhoea and nasopharyngitis
(nose and throat inflammation). In DRIVE-FORWARD, side effects associated with other NNRTIs, such as rash and
neuropsychiatric symptoms, were similar in both treatment arms. In
DRIVE-AHEAD, Delstrigo was associated
with significantly fewer neuropsychiatric side effects — such as
dizziness, sleep problems, abnormal dreams and altered cognition — than Atripla.

In both studies, participants taking doravirine saw small declines in
LDL and non-HDL cholesterol, while those taking boosted darunavir or the Atripla combination experienced small increases.
Although the differences were statistically significant, the clinical significance
of these small changes is unclear.

The tenofovir DF component in Delstrigo has been associated with kidney problems and bone loss in
susceptible individuals. For this reason, kidney function should be checked
before starting this combination and monitored regularly thereafter. Of note,
Gilead Sciences’ newer tenofovir alafenamide
(TAF) formulation, which causes less kidney and bone toxicity, remains under
patent while a generic version of tenofovir DF is available for Merck to use in
its coformulation.

Because tenofovir is also active against hepatitis B virus (HBV), the Delstrigo label includes a warning about
the possibility of worsening of HBV-related liver inflammation if the
medication is stopped.

Pifeltro and Delstrigo should not be taken with drugs
that are strong inducers of cytochrome P450 enzymes, as this can lead to lower
doravirine levels in the blood that could reduce treatment effectiveness.

The on-going
DRIVE-SHIFT study is evaluating doravirine as a switch option for people with
viral suppression on their current antiretroviral regimen. Doravirine and the Delstrigo combo are currently being
tested in children and adolescents. At this year’s CROI Randolph Matthews of Merck
said that doravirine is also being tested in combination with the company’s
experimental nucleoside reverse transcriptase
translocation inhibitor known as MK-8591 in a phase 2b called DRIVE2SIMPLIFY.