Sofosbuvir/velpatasvir, a forthcoming combination that
effectively treats all hepatitis C virus (HCV) genotypes, can be safely used
with most boosted antiretrovirals for people with HIV and HCV co-infection,
according to a study presented at the Conference on Retroviruses and
Opportunistic Infections (CROI 2016) last month in Boston.
About one-third of people living with HIV also have HCV. New
direct-acting antivirals (DAAs) used in interferon-free regimens can
successfully treat hepatitis C in people with HIV and most experts no longer consider
people with co-infection to be a ‘difficult-to-treat’ population. But it is
important to avoid combining DAAs and antiretroviral agents that interact with
each other, which could lead to either high drug levels that worsen side-effects
or low levels that are not as effective.
A coformulation containing sofosbuvir (a
nucleotide HCV NS5B polymerase inhibitor) and velpatasvir (a pan-genotypic HCV NS5A inhibitor) was shown to be highly effective
against HCV genotypes 1 through 6 in the phase 3
ASTRAL trials. It is currently undergoing evaluation by the European Medicines Agency and priority
review by the US Food and Drug Administration, with a decision expected in late
Erik Mogalian from Gilead Sciences and colleagues analysed
drug-drug interactions between sofosbuvir/velpatasvir and HIV regimens
containing antiretrovirals boosted with either ritonavir or cobicistat. These
boosters interfere with liver enzymes that process drugs, so they are most
prone to interactions.
Sofosbuvir is a substrate or target of
P-glycoprotein (P-gp) and the BCRP transporter protein, which pump many drugs
out of cells, while velpatasvir is both a substrate and inhibitor of P-gp and
BCRP, as well as a substrate for the OATP protein and the cytochrome P450
CYP2C8 and CYP3A4, which process drugs in the liver, Mogalian noted as
background. Ritonavir and cobicistat primarily work by inhibiting CYP3A4, which
raises levels of CYP3A4-metabolised drugs including some HIV protease
inhibitors and integrase inhibitors.
team conducted a series of phase 1 multiple-dose randomised cross-over drug-drug
interaction studies in healthy volunteers without HIV or hepatitis C. About 60%
were men, most were white and the mean age was approximately 34 years.
Five cohorts, each with 24 to 30 participants, were allocated to receive
the following regimens, all in combination with 400/100mg
alafenamide or TAF (Genvoya)
disoproxil fumarate or TDF (Stribild)
- Atazanavir (Reyataz)
300mg + ritonavir 100mg + emtricitabine/TDF (Truvada)
- Darunavir (Prezista)
800mg + ritonavir 100mg + emtricitabine/TDF
- Lopinavir/ritonavir (Kaletra) + emtricitabine/TDF
The researchers measured peak, trough, steady state and total (area
under the curve) plasma concentrations of sofosbuvir, its main metabolite GS-331007, velpatasvir and the
antiretrovirals over time, monitored participants for adverse events and laboratory
abnormalities, and performed physical exams and ECG heart rhythm evaluations.
Sofosbuvir levels rose a bit in
the Genvoya arm and fell by about 30%
in the darunavir and lopinavir/ritonavir arms, but these pharmacokinetic changes
were not considered
clinically significant based on prior phase 3 safety and efficacy studies.
levels rose slightly in the Genvoya arm and more than doubled in the atazanavir
arm, but again these pharmacokinetic
changes were deemed to not warrant dose adjustments.
Sofosbuvir/velpatasvir co-administration had no significant effect on plasma
levels of elvitegravir, atazanavir, darunavir, lopinavir or ritonavir. Cobicistat
concentrations were elevated at the end of the dosing interval, but the
researchers said this was “not expected to introduce further drug interaction potential.”
Sofosbuvir/velpatasvir had no significant effect on tenofovir levels
when the TAF formulation was used, but there was a modest (20 to 40%) increase
when using the TDF formulation. Again, this was not considered to warrant dose
adjustments. Sofosbuvir/velpatasvir had no impact on emtricitabine levels.
Treatment was generally safe and well-tolerated. Five participants
withdrew consent before the end of the study and one stopped after becoming
pregnant. About a third of participants (29 to 45%) in the various study arms
reported adverse events, but none of these were serious and no one discontinued
for this reason. The most common side-effects were headache and elevated
bilirubin, both in the atazanavir-containing arm.
At the AASLD Liver Meeting this past November,
Mogalian’s team reported results from studies of sofosbuvir/velpatasvir
interactions with unboosted antiretroviral regimens containing efavirenz (Sustiva), rilpivirine (Edurant), raltegravir (Isentress) or dolutegravir (Tivicay). They found that
sofosbuvir/velpatasvir can be safely co-administered with all but efavirenz,
which lowered velpatasvir levels by about 50%.
Based on the new and previous findings, the researchers concluded that
pharmacokinetic data support co-administration of sofosbuvir/velpatasvir with
widely used antiretrovirals from the nucleoside/nucleotide reverse
transcriptase inhibitor, NNRTI, protease inhibitor and integrase inhibitor
classes, and with both available boosting agents. The exception is efavirenz,
which awaits further data from phase 3 studies.
said that the safety and efficacy of sofosbuvir/velpatasvir with boosted and unboosted antiretroviral
regimens is currently being evaluated for people with HIV and HCV co-infection
in the phase 3 ASTRAL-5 trial.