A dual oral regimen of sofosbuvir
plus ribavirin led to sustained response for 93% of people with genotype 2 hepatitis C
treated for 12 weeks and 85% of people with genotype 3 treated for 24
weeks, researchers reported at The Liver Meeting 2013, the 64th annual meeting of the
American Association for the Study of Liver Diseases (AASLD) held last week in
Washington, DC. A related study found that adding ribavirin to this combination
may be an option for harder-to-treat individuals.
Direct-acting antiviral agents
have brought about a revolution in the treatment of chronic hepatitis C virus
(HCV) infection. While these agents have been initially tested as add-ons to
interferon-based therapy, many people with HCV and their health care providers are awaiting
all-oral regimens without the difficult-to-tolerate pegylated interferon.
Gilead Science's phase 2 ELECTRON
trial showed that the nucleotide HCV polymerase inhibitor sofosbuvir (formerly
GS-7977) plus ribavirin taken for 12 weeks cured most people with HCV genotypes
2 or 3. An advisory committee of the US Food and Drug Administration last month recommended approval for this
indication, which is
expected in early December.
HCV genotypes 2 and 3 have
traditionally been categorised together as 'easier-to-treat', relative to
genotypes 1 and 4. In the past couple years, however, it has become apparent
that genotypes 2 and 3 respond quite differently to some direct-acting
antivirals, with 3 having lower response rates.
presentation by Stefan Zeuzem of Goethe University and colleagues from
several countries in Europe described results from the phase 3 VALENCE
trial (NCT01682720), which tested sofosbuvir/ribavirin
for people with genotype 2 and 3 who had either not taken treatment
before (treatment-naive) or who had previously taken treatment
The initial study design called for more than 300 participants with
genotype 2 or 3 to take 400mg once-daily sofosbuvir plus
1000-1200mg/day weight-based ribavirin for 12 weeks, while a smaller
received only placebo. After other studies indicated that people with
3 did better with longer therapy, the design was amended to treat people
with genotype 2 for 12 weeks and people with genotype 3 for 24 weeks,
The analysis included a total of 419 participants: 73 genotype 2
patients, 261 genotype 3 patients (including 11 treated for 12 weeks before the
protocol change) and 85 genotype 2 or 3 placebo recipients. About 60% were men,
most were white and the median age was approximately 60 years. About one-third
had the favourable IL28B CC gene variant and about 20% had liver cirrhosis.
About 60% were treatment-experienced, with two-thirds of these being prior
relapsers and most of the rest being non-responders.
Looking at the genotype groups as
a whole, 93% of genotype 2 patients and 85% of genotype 3 patients achieved
sustained virological response, or continued undetectable HCV RNA at 12 weeks
People with genotype 2 had high
response rates across the board with 12 weeks of sofosbuvir/ribavirin:
treatment-naive people without cirrhosis, 100% for treatment-naive
people with cirrhosis, 91% for treatment-experienced people without
cirrhosis and 88% for
treatment-experienced people with cirrhosis.
People with genotype 3 did not fare
as well despite doubling the duration of therapy. Treatment-naive people had
high cure rates – 94% for people without cirrhosis and 92% for people with cirrhosis – but these
fell to 87% for treatment-experienced people without cirrhosis and 60% for treatment-experienced people with cirrhosis. Among
the eleven people with genotype 3 treated for just 12 weeks before the protocol
change, only three (27%) were cured.
Univariate and multivariate
analyses did not reveal any factors, including IL28B status, which could
predict which treatment-experienced people with cirrhosis would achieve
sustained response. Resistance was not detected in any patients who relapsed.
Sofosbuvir/ribavirin was generally
safe and well-tolerated. Unlike most late-stage trials of direct-acting agents,
VALENCE initially had a placebo comparison group. Interestingly, a substantial
majority of people in the placebo, 12-week and 24-week treatment arms
experienced adverse events. Grade 3 or worse adverse events (5, 4 and 7%),
serious adverse events (2, 0 and 4%) and events leading to discontinuation
(1, 1 and <1%) occurred with similar frequency across arms.
The two most common side-effects,
headache and fatigue, occurred at similar rates in all treatment arms. Itching,
muscle weakness, nausea and insomnia were reported more often in the
sofosbuvir/ribavirin arms, but with comparable frequency in the 12- and 24-week
arms. Anaemia, however, occurred more often with the longer ribavirin duration
(8 vs 11%).
+ ribavirin for 24 weeks demonstrated SVR rates >90% in treatment-naive HCV
genotype 3 patients," the researchers summarised. "In
treatment-experienced HCV genotype 3 patients, SVR rates were 60% and 87% in
those with and without cirrhosis, respectively."