glecaprevir/pibrentasvir treatment for hepatitis C is not expected to interact
with or require dose adjustment when taken with commonly used antiretroviral
regimens, offering a new option for people with HIV/hepatitis C virus (HCV) co-infection, according to a study
presented at the Conference on Retroviruses and Opportunistic Infections (CROI
2017) last month in Seattle.
An estimated 25 to 30% of people living
with HIV have HCV co-infection. The advent of direct-acting
antivirals (DAAs) used in interferon-free regimens has made hepatitis C treatment
simpler, shorter and much more effective. Although considered a 'hard-to-treat'
population in the interferon era, people with HIV/HCV co-infection respond to DAAs as
well as people with HCV alone. Current hepatitis C
guidelines recommend that people with HCV/HIV co-infection should be treated the
same as people with HCV mono-infection, taking into account
potential interactions with antiretroviral drugs.
Matthew Kosloski and colleagues of AbbVie
presented findings from a phase 1 drug-drug interaction study assessing the
pharmacokinetics, tolerability and safety of co-administering glecaprevir and
pibrentasvir with the widely used antiretroviral regimens
elvitegravir/cobicistat/tenofovir alafenamide [TAF]/emtricitabine (Genvoya) and
both of which are recommended first-line regimens in European and US HIV
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
The HCV protease inhibitor glecaprevir (formerly
ABT-493) and NS5A inhibitor pibrentasvir (formerly ABT-530) were shown to be a
safe and highly effective treatment for all HCV genotypes. As reported at the 2016 AASLD Liver Meeting, glecaprevir/pibrentasvir cured 98 to 99% of
treatment-naive and treatment-experienced people without liver cirrhosis –
including people with co-infection – in the phase 3 ENDURANCE trials. AbbVie
requested US Food and Drug Administration approval of glecaprevir/pibrentasvir in December, with a decision expected in June,
and it is under accelerated assessment by the
European Medicines Agency.
Glecaprevir and pibrentasvir are
minimally metabolised or eliminated by the kidneys and were shown in earlier
studies to not have clinically significant drug-drug interactions with the
non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (Edurant) or the
integrase inhibitor raltegravir (Isentress),
the researchers noted as background.
This multiple-dose study enrolled 48 healthy
adult volunteers with neither HIV nor HCV. About 95% were men (women of childbearing potential
were excluded), around half
were black and half white, and the average are was approximately 35 years.
Participants received 300mg glecaprevir plus 120mg pibrentasvir
once-daily with elvitegravir/cobicistat/TAF/emtricitabine (150/150/10/200 mg)
or dolutegravir/abacavir/lamivudine (50/600/300 mg), either alone or in
The researchers performed pharmacokinetic
assessments for all drugs on multiple days, and looked at the effects of
glecaprevir and pibrentasvir on the pharmacokinetics of the antiretroviral
drugs, and vice versa. Safety was evaluated based on adverse events, vital signs,
physical exams, electrocardiograms, and laboratory tests.
Glecaprevir and pibrentasvir increased
elvitegravir and cobicistat peak (Cmax), total (AUC24),
and 24-hour post-dose (C24) concentrations by 29% to 72%, but did
not affect tenofovir or emtricitabine levels.
When taken with
elvitegravir/cobicistat/TAF/emtricitabine, glecaprevir peak, total and 24-hour
concentrations increased by 2.5-, 3.1- and 4.6-fold, while pibrentasvir total
and 24-hour concentrations rose by 57% and 89%.
Glecaprevir and pibrentasvir increased the
abacavir 24-hour concentration by 31%, but otherwise had no notable effect on
dolutegravir, abacavir, or lamivudine exposures. When taken with
dolutegravir/abacavir/lamivudine, glecaprevir and pibrentasvir peak and total
concentrations were 25 to 28% lower.
taking glecaprevir and pibrentasvir with
elvitegravir/cobicistat/TAF/emtricitabine stopped the study early due to an adverse event (decreased
neutrophil count). No other clinically significant adverse events and no
clinically significant changes in vital signs or laboratory measurements were
label recommendations for interactions with other well-characterised drugs, the
changes in elvitegravir, cobicistat, emtricitabine and tenofovir levels when
administered with glecaprevir and pibrentasvir were not considered clinically significant.
analysis of phase 3 data, the higher glecaprevir levels when administered with elvitegravir/cobicistat/TAF/emtricitabine were not
expected to significantly affect the safety profile of the glecaprevir/pibrentasvir combination.
Conversely, lower levels of glecaprevir and pibrentasvir when administered with dolutegravir/abacavir/lamivudine were not expected to significantly reduce its
"No dose adjustment is required when the glecaprevir/pibrentasvir combination
is co-administered with elvitegravir, cobicistat, emtricitabine, tenofovir
alafenamide, abacavir, dolutegravir, or lamivudine," the researchers concluded.
In clinical trials to
date, the small number of people with HIV/HCV co-infection treated with glecaprevir/pibrentasvir had a cure rate similar to that of people with HCV alone,
with no notable safety issues. An ongoing study is evaluating glecaprevir/pibrentasvir in a larger co-infection population, including people with