A simple 24-week oral regimen consisting of
sofosbuvir plus full-dose ribavirin cured nearly 70% of previously untreated
people with genotype 1 hepatitis C, many of whom had factors predictive of poor
reported last week
at the 20th Conference
on Retroviruses and Opportunistic Infections (CROI
2013) in Atlanta.
Direct-acting antiviral agents that target
various steps of the hepatitis C virus (HCV) lifecycle have brought about a new
era of treatment for chronic hepatitis C. But many patients and clinicians are
waiting for all-oral regimens that omit interferon, which must be injected
weekly and often causes difficult side-effects including flu-like symptoms and
Anu Osinusi from the
National Institute of Allergy and Infectious Diseases and colleagues tested a
two-drug, interferon-free regimen in a small phase IIa study of
difficult-to-treat patients in inner-city neighbourhoods of Washington, DC, an
area with a high rate of poverty and limited access to health services. Osinusi
noted that the prevalence of hepatitis C in Washington is approximately 1.8%,
representing more than 13,000 cases.
The SPARE Study
evaluated Gilead Sciences' nucleotide analogue HCV polymerase inhibitor sofosbuvir (formerly GS-7977) plus
ribavirin. Sofosbuvir is taken by mouth once daily and studies so far indicate it is well tolerated and appears to
have a high barrier to resistance. As ribavirin can cause anaemia, the
researchers tested whether starting with a lower dose could reduce side-effects
without compromising effectiveness. The study also aimed to learn more about
host and viral factors that predict treatment response.
The study was done in
two parts. In Part 1, ten people with absent-to-moderate liver fibrosis (stage
F0-F2) were treated for 24 weeks with 400mg once-daily sofosbuvir plus
weight-based ribavirin, dosed at 1000mg/day if weight was less than 75kg or
1200mg/day if 75kg or more.
Part 2 included 50
people with all stages of liver disease, including about one-quarter with
advanced fibrosis or compensated cirrhosis (stage F3 or F4). They were randomly
assigned to receive sofosbuvir with either weight-based ribavirin or a lower
fixed dose of 600mg/day regardless of weight.
In Part 2, about 70% of participants were men, the median age was 54 years and about half were
considered obese. About 80% were African American, a group that responds
poorly to interferon largely due to a lower frequency of the favourable IL28B
CC gene pattern, which was seen in only 16%.
Approximately 70% had the more difficult-to-treat HCV sub-type 1a and
about 60% had high baseline viral load.
The Part 1
proof-of-concept analysis showed a 90% sustained virological response rate at
12 weeks post-treatment (SVR12), rising to 100% in a modified analysis of all
participants treated for at least 8 weeks.
Looking at the larger
population in Part 2, HCV RNA declined rapidly across the board, with almost
all participants reaching undetectable viral load by week 4. Response rates remained
high at the end of 24 weeks of treatment, 96% in the weight-based ribavirin
group and 88% in the low-dose arm.
But some participants
began to relapse soon after stopping treatment, especially in the low-dose
ribavirin group. Sustained response rates at week 4 post-treatment (SVR4) were
72 and 56%, respectively. A few later relapses also occurred, resulting in
SVR12 rates – considered a cure – of 68 and 48%. No new drug resistance
mutations were detected amongst relapsers.
difference between the weight-based and fixed-dose ribavirin groups did not
reach statistical significance, Osinusi said, "clearly, low-dose [response] was lower".
Looking only at
people who completed at least 8 weeks of therapy, there were no viral
breakthroughs during treatment. The corresponding SVR12 rates were 71 and 55%,
respectively. In other words, relapse rates were 29% with weight-based
ribavirin and 45% with low-dose ribavirin.
Looking more closely at
HCV RNA decay in a subset of patients, the researchers saw that viral decline
after starting treatment was slower amongst people who eventually relapsed
compared with sustained responders, with clearance occurring in 3.6 vs 5.6 days
In both groups, HCV
clearance was associated with rapid normalization of alanine aminotransferase
(ALT) liver enzyme levels, a biomarker of liver inflammation. All participants
had pre-treatment biopsies and about 70% did so again after finishing
treatment. This is unusual and Osinusi explained that the second biopsy was
optional. Biopsy findings showed a significant improvement in liver
inflammation. There was no improvement in fibrosis in just six months, but
follow-up will continue.
Host and viral
factors associated with relapse included lower baseline viral load (HCV RNA
<800,000 IU/ml), male sex and using low-dose rather than weight-based
ribavirin. Having worse fibrosis or cirrhosis also seemed to predict poorer
response, but only a small number (13 patients) had advanced liver disease and
the difference did not reach statistical significance.
ribavirin was generally safe and well tolerated. There were no serious (grade
4) adverse events, drop-outs due to side-effects or deaths in either dose group.
Side-effects were infrequent overall, with the most common being rash or
itching (one patient in the weight-based ribavirin group and two in the
low-dose group) and nausea (three in the low-dose group).
abnormalities, however, differed according to ribavirin dose. Four people (16%)
in the weight-based group developed anaemia compared with just one (4%) in the
low-dose group. The same difference was seen in frequency of elevated
bilirubin. Elevated phosphate occurred in eight people (32%) in both arms.
inner-city population of HCV genotype 1 subjects with negative treatment
predictors, an interferon-free regimen of sofosbuvir with weight-based
ribavirin was effective in achieving high SVR rates," the researchers
Early results from the ELECTRON trial – which looked at a different patient population so
cannot be directly compared with SPARE – showed that sofosbuvir plus full-dose ribavirin for
12 weeks worked very well for
previously untreated people with easier-to-treat HCV genotypes 2 or 3, yielding
an SVR24 rate of 100%. Sustained response rates were lower for people
with more challenging disease, however, falling to 84% for previously untreated
genotype 1 patients, 68% for treatment-experienced genotype 2/3 patients and a
dismal 10% for genotype 1 prior null responders.
ELECTRON researchers reported last week that adding a third oral drug, Gilead's NS5A inhibitor ledipasvir (formerly
GS-5885), brought cure rates back up to 100% for both genotype 1 treatment
naive and null responders, and that combo is now being tested without
ribavirin. Similarly impressive results were seen with the
two-drug ribavirin-sparing regimen of sofosbuvir plus Bristol-Myers Squibb's NS5A inhibitor daclatasvir (formerly
At a CROI press conference,
Osinusi explained that SPARE started in 2011, when only the genotype 2/3
ELECTRON data had been released. "Going forward, it's clear that combining
some direct-acting agents might be more beneficial than single agents,"
Many controlled clinical trials do not enrol the
most challenging patients in terms of biological, demographic or socioeconomic
factors, so their results may look better than those seen in 'real world'
clinical practice. But the SPARE study shows that even many difficult-to-treat
people can do well on a simple oral regimen, especially if selected based on
factors that predict response.