A dual regimen of sofosbuvir plus velpatasvir
was well tolerated and highly effective against hepatitis C virus (HCV)
genotypes 1 through 4 in HIV-positive people with chronic hepatitis C
co-infection, according to results from the phase 3 ASTRAL-5 trial presented at
the 2016 International Liver Congress last week in
The advent of direct-acting antiviral agents (DAAs) has enabled shorter,
better tolerated and much more effective hepatitis C treatment compared to interferon-based
therapy. Studies have shown that HIV-positive people with HCV genotype 1 have a
high likelihood of being cured of HCV with interferon-free DAA therapy, which
is particularly beneficial because they experience more rapid liver disease
Yet there is still room to optimise therapy for people with HCV
genotypes other than 1. Genotype 3 is now considered the most difficult to
treat, while there are fewer data for genotypes 4, 5 and 6. Ideally,
combination DAA regimens will be pangenotypic – active against all genotypes – meaning
they could be prescribed without the need for genotype testing.
David Wyles of the University of California at San Diego presented
findings from the ASTRAL-5 trial, evaluating a pangenotypic combination
consisting of Gilead Sciences’ HCV NS5B polymerase inhibitor sofosbuvir
(marketed as Sovaldi) and the second-generation
NS5A inhibitor velpatasvir (formerly GS-5816) for people with HIV and HCV co-infection.
The sofosbuvir/velpatasvir co-formulation is currently
under review by the US Food and Drug Administration and European regulatory
authorities. As reported at last year’s American Association for
the Study of Liver Diseases Liver Meeting, the combination demonstrated high
sustained response rates in the prior phase 3 ASTRAL trials: ASTRAL for
genotypes 1, 2, 4, 5 and 6; ASTRAL-2 for genotype 2; ASTRAL-3 for genotype 3;
andASTRAL-4 for people with all
genotypes had who decompensated liver disease.
The multicentre ASTRAL-5 trial enrolled
106 HIV-positive people with chronic hepatitis C, in the US, with any HCV
genotype. Most (86%) were men, 45% were black and the mean age was 54 years. A
majority (62%) had HCV genotype 1a, followed by 1b (11%), 2 (10%), 3 (11%) and
4 (5%); no one had genotypes 5 or 6, which are uncommon in the US. About a
third had previously been treated for hepatitis C, the mean HCV RNA level was
6.3 log10 and 18% had compensated cirrhosis.
With regard to HIV status, participants
were on stable antiretroviral therapy (ART) with undetectable HIV viral load
and a mean CD4 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% were
taking a protease inhibitor; the integrase inhibitors raltegravir (Isentress) or elvitegravir (Vitekta) – 34% taking this class); or
the NNRTI rilpivirine (Edurant; 12%).
NRTI backbones included tenofovir (Viread, or with emtricitabine in Truvada) in a boosted regimen (53%),
tenofovir in an unboosted regimen (33%) or abacavir/lamivudine (Epzicom; 14%). This breakdown enabled researchers to see whether boosted
tenofovir was associated with kidney toxicity when combined with the hepatitis
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
The overall SVR12 rate was 95%, or 99 out
of 104 participants (with two still undergoing post-treatment follow-up) –
similar to rates seen in studies of HIV-negative people with hepatitis C. Non-responders
included two relapsers, one loss to follow-up and one withdrawal of consent.
Response rates ranged from 92% for
genotypes 1b and 3 (reflecting a single drop-out in each arm), to 95% for
genotype 1a (reflecting the two relapses and one drop-out), to 100% for
genotypes 2 and 4.
SVR12 rates were similar regardless of the
presence or absence of cirrhosis (100% and 94%, respectively). Cure rates were
also similar for hepatitis C treatment-naive and treatment-experienced patients
(93 and 97%, respectively). The 12% of participants with NS5A
resistance-associated variants at baseline all achieved SVR12.
Sofosbuvir/velpatasvir was generally safe
and well tolerated. There were two serious
adverse events and two treatment discontinuations due to adverse events (one of
whom nevertheless achieved SVR12).
The most frequently reported
side-effects were fatigue (25%) and headache (13%), while the most common laboratory abnormality was elevated bilirubin in
people taking boosted atazanavir. No one experienced HIV viral rebound while on
hepatitis C treatment.
Creatinine clearance – a marker of kidney
function – was lower among people taking boosted versus unboosted tenofovir,
and lowest among people not taking tenofovir (who may have had existing kidney
problems), but it remained relatively stable over time in all groups.
"Sofosbuvir/velpatasvir for 12 weeks
provides a simple, safe, and highly effective treatment for patients coinfected
with HIV-1 and HCV," the researchers concluded.
in this study stopped or changed their antiretrovirals due to kidney concerns,