The once-daily co-formulation of sofosbuvir and
velpatasvir was highly effective against all hepatitis C virus (HCV) genotypes
in people with HIV/HCV co-infection and was safe and well tolerated in the ASTRAL-5
trial, according to results presented yesterday at the 21st
International AIDS Conference (AIDS 2016) in Durban, South Africa. A related analysis showed that
sofosbuvir/velpatasvir can be safely combined with most widely used
antiretrovirals, with the exception of efavirenz.
People with HIV/HCV co-infection experience more rapid liver
disease progression than those with hepatitis C alone, and liver disease
remains a major cause of morbidity and mortality among people living with HIV.
The advent of direct-acting antiviral agents for hepatitis C has enabled
shorter, better tolerated and much more effective treatment. The latest
interferon-free regimens demonstrate cure rates approaching 100%, and unlike
the older interferon-based therapy, they work as well for people with and
without HIV co-infection.
But most of the new drugs work best against HCV genotype 1, which is the
most prevalent type in Europe and the US. Genotype 3 is now considered the most
difficult to treat, while genotypes 4, 5 and 6 do not have as much data. A
pangenotypic regimen – one that is active against all genotypes – would
simplify treatment because it could be prescribed without the need for genotype
Norbert Bräu of the Icahn School of Medicine at Mt Sinai in New
York City presented findings from ASTRAL-5, a phase 3 trial of people with HIV/HCV
co-infection evaluating Gilead Sciences' pangenotypic co-formulation
combining the HCV NS5B polymerase inhibitor sofosbuvir (marketed alone as Sovaldi) and the second-generation NS5A
inhibitor velpatasvir (formerly GS-5816). European and US regulators recently
approved the co-formulation, marketed as Epclusa.
As reported at last year's AASLD Liver Meeting, the sofosbuvir/velpatasvir combination
demonstrated high sustained response rates for HIV-negative people with hepatitis C
mono-infection in the ASTRAL-1 (genotypes 1, 2, 4, 5 and 6), ASTRAL-2 (genotype
2 only), ASTRAL-3 (genotype 3) andASTRAL-4
liver disease) trials.
ASTRAL-5 enrolled 106 people with HIV and chronic hepatitis C in the US with any HCV genotype. A majority (62%) had HCV genotype 1a,
followed by 1b (11%), 2 (10%), 3 (11%) and 4 (5%); none had genotypes 5 or 6.
Most participants (86%) were men, 45% were black and
the mean age was 54 years. Just under a third were previously treated for
hepatitis C and 18% had compensated liver cirrhosis. At baseline the mean HCV
RNA level was 6.3 log10.
Looking at HIV status, participants were on stable antiretroviral
therapy (ART) for at least 8 weeks with undetectable HIV viral load and a mean
CD4 T-cell count of approximately 600 cells/mm3. They were taking a
variety of ART regimens, most often including the HIV protease inhibitors
atazanavir (Reyataz), darunavir (Prezista) or lopinavir/ritonavir (Kaletra) (47% on a PI); the integrase
inhibitors raltegravir (Isentress) or
elvitegravir (Vitekta) (34% taking
this class); or the NNRTI rilpivirine (Edurant;
12%). Most used NRTI backbones containing tenofovir in a boosted (53%) or
unboosted (33%) regimen.
All participants in this open-label study received
400mg sofosbuvir plus 100mg velpatasvir taken as a once-daily co-formulation
for 12 weeks. They were followed for 12 weeks after completing treatment to
assess sustained virological response (SVR12), or continued undetectable HCV viral
At the end of post-treatment follow-up the overall
SVR12 rate was 95% (101 out of 106 treated people) – similar to cure rates
seen in studies of HIV-negative people with hepatitis C. Response rates ranged
from 92% for genotypes 1b and 3 (reflecting a single drop-out in each arm), to
95% for genotype 1a (two relapses and one drop-out), to 100% for genotypes 2
Cure rates were similar regardless of the presence or
absence of cirrhosis (100% and 94%, respectively) and for hepatitis C
treatment-naive and treatment-experienced patients (93% and 97%, respectively).
HCV drug resistance also did not have a notable effect, as the 12 participants
with NS5A resistance-associated variants at baseline all achieved SVR12.
The sofosbuvir/velpatasvir combination was generally
safe and well tolerated. There were two
serious adverse events not attributed to the study drugs and two treatment
discontinuations due to adverse events; 18% experienced grade 3 or 4 laboratory
abnormalities (mostly elevated bilirubin in people taking boosted atazanavir). The
most common side-effects were fatigue (25%) and headache (13%). No one
experienced HIV viral rebound while on hepatitis C treatment.
The researchers took a closer look at kidney function,
to see whether
boosted tenofovir was associated with kidney toxicity when combined with the
hepatitis C drugs. Creatinine clearance remained stable over time in all ART
regimen arms. It was lower (indicating more impairment) among people taking
boosted versus unboosted tenofovir, but lowest among people not taking
"Sofosbuvir/velpatasvir for 12 weeks provides a
simple, safe and highly effective treatment for patients coinfected with HIV-1
and HCV," the researchers concluded.