Rajender Reddy of the University of Pennsylvania and colleagues analysed
outcomes among people with decompensated cirrhosis in HCV-TARGET, an
observational study by a consortium of 39 academic and 13 community medical
centres in the US, Canada, Germany and Israel. The study enrolled more than 2200
people from December 2013 through October 2014.
The researchers looked at people treated with
all-oral regimens including sofosbuvir with ribavirin alone, and sofosbuvir
plus simeprevir with or without ribavirin. As this was an observational study,
treatment was selected by participating clinicians according to local standards
of care, not randomly assigned.
This analysis included 253 participants with cirrhosis and a MELD score >10
who had not undergone liver transplantation. MELD score is an indicator of
liver disease severity calculated using bilirubin and creatinine levels and
blood clotting capacity (INR). It is used to predict how urgently a patient
needs a liver transplant. Scores of 10-19 predicted three-month mortality of
6%, rising to 20% with a score of 20-29, more than 50% with a score of 30-39
and more than 70% with a score above 40.
Just over two-thirds of study participants were men, most were white and
the mean age was 59 years. Around 75% had HCV genotype 1, with the remainder
about evenly divided between genotypes 2 and 3. Nearly 60% were non-responders
to prior treatment, including 15% who had experienced treatment failure with prior triple therapy with boceprevir
(Victrelis) or telaprevir (Incivo or Incivek).
More than 80% had MELD scores of 10-15, but 11% had scores of 16-21 and
4% had scores >21. The mean albumin level was 3.3 g/dl, mean bilirubin was
2.1 mg/dl, mean creatinine was 0.9 mg/dl, platelet count was 84,000 and INR was
1.4. Three-quarters had a history of decompensation (when the liver can no
longer carry out its vital functions) and 17% had liver cancer.
Patients were treated with either sofosbuvir and
ribavirin (n = 76), sofosbuvir plus simeprevir (n = 108), or sofosbuvir plus
simeprevir with ribavirin (n = 32). As simeprevir is primarily effective against
HCV genotype 1, almost all participants with genotypes 2 or 3 received sofosbuvir
with ribavirin alone. Most were treated for 12 weeks, although a few were treated for 24
The researchers looked at an efficacy cohort of 216 participants who completed therapy and had adequate follow-up to determine
sustained virological response, or undetectable HCV viral load at 12 weeks
Looking first at the genotype 1 group, the overall SVR12 rates were 52%
for sofosbuvir and ribavirin alone, 74% for
sofosbuvir plus simeprevir, and 66% for sofosbuvir plus simeprevir with
ribavirin. Cure rates did not differ much between treatment-naive (43%, 78% and
60%, respectively) and treatment-experienced (57%, 72% and 68%) participants with genotype 1.
Only half of participants with HCV subtypes 1a or 1b were
cured with sofosbuvir and ribavirin alone, but sofosbuvir/simeprevir seemed to
work somewhat better against subtype 1b than 1a (87% vs 66%). Adding ribavirin
to sofosbuvir/simeprevir "did not seem to have major impact" for either subtype, Reddy said.
People with HCV genotype 2 did well using sofosbuvir
with ribavirin alone: 81% achieved SVR12. But people with HCV genotype 3 had
the lowest sustained response rate, with just 39% being cured while 46%
scores did not appear to have a negative effect on response rates – in fact,
all seven people with scores >21 achieved SVR12 using sofosbuvir/simeprevir
with or without ribavirin. Among the genotype 1 group, higher albumin and lower bilirubin levels were the
only independent predictors of sustained response; subtype 1a vs 1b did not quite
reach statistical significance.
A majority of participants experienced an improvement in
liver function status after treatment, especially those with sustained response.
Among 64 people with baseline MELD scores of 10-15 and available
post-treatment data, 55% saw a decrease in their score, 25% had no change and
20% saw an increase.
Treatment was generally safe. Adverse events were common given the
patients' advanced state of disease, but most were classified as mild. There
were 16 cases of liver decompensation, 10 serious infections and three deaths; 12
people received liver transplants during treatment. The most frequently
reported adverse events were fatigue (36%), anaemia (18%), nausea (17%),
infections (14%) and flu-like symptoms (12%). Not surprisingly, anaemia was
more common among people who took ribavirin.
DAA therapy has been readily used to treat HCV cirrhosis with MELD score >10,"
the researchers concluded. "MELD score and serum albumin improved or
remained stable in the majority of patients," they added. "Long-term
follow-up is needed to assess the impact of SVR on the reversibility of the
severity of liver disease."
Commenting on the selection of regimens, Reddy noted
that "these are very
sick patients, and physicians wanted to use what was out there."
plus simeprevir is no longer as widely used for people with genotype 1 since the
debut of Gilead's Harvoni sofosbuvir/ledipasvir
coformulation and AbbVie's paritaprevir/ombitasvir/dasabuvir '3D' regimen (Viekirax/Exviera or Viekira Pak), as the cross-company combination has a much higher
cost. Sofosbuvir plus ribavirin remains an effective standard of care for
genotype 2, but better treatment options are still needed for people with