Nezam Afdhal from Beth Israel Deaconess Medical
Center in Boston presented findings from a study of
sofosbuvir plus ribavirin for people with cirrhosis who have portal
hypertension. When the liver is heavily scarred, blood flow can back up in the
portal vein system, leading to decompensation symptoms such as ascites
(abdominal fluid build-up) and bleeding varices (varicose veins) in the stomach
or oesophagus.
This analysis
included 50 people with chronic hepatitis C and advanced
cirrhosis. About three-quarters were men, most were white and the median age
was approximately 55 years. About 40% had HCV genotype 1a and 30% 1b, with
smaller numbers having genotypes 2, 3 or 4. About 80% had been previously
treated for hepatitis C and a similar proportion had unfavourable IL28B non-CC
gene variants.
About 60% of participants were classified
as Child-Pugh class B and the rest as class A, except for one individual with class
C. Child-Pugh scores are calculated based on bilirubin and serum albumin
levels, blood clotting capacity, and presence of ascites and hepatic
encephalopathy (brain impairment). Class A (5-6 points) indicates compensated
cirrhosis and has the best prognosis; class B (7-9 points) and C (10-15 points)
indicate decompensated cirrhosis.
Participants had portal hypertension
indicated by a hepatic venous pressure gradient (HVPG) of >6mm Hg (mean 16mm
Hg at baseline). They had stomach or oesophageal varices, but without bleeding
for at least six months. Fifteen participants had ascites and seven had
encephalopathy. People with severe anaemia, high bilirubin, low creatinine
clearance, low platelets or liver cancer were excluded, as were liver transplant
recipients.
Half of the participants were randomly
assigned to receive sofosbuvir (400mg once daily) plus ribavirin
(1000-1200mg/day) for 48 weeks, while the remainder were observed without
treatment (considered acceptable since there is no standard therapy for people
with decompensated liver disease). After six months, those in the observation
group crossed over to receive the same treatment. Afdhal presented 24-week data
at the end of the observation period.
Participants responded rapidly to treatment,
with most having undetectable HCV RNA by week 4. However, people with
compensated cirrhosis responded faster than those with decompensated disease,
with rapid virological response rates of 100% and 75%, respectively. No viral
breakthroughs were seen during treatment.
Among those who completed 24 weeks of treatment,
response rates were 100% for people classified as class A and 93% for people
classified as class B (one non-responder at week 8). Twenty-four weeks is the
typical maximum duration of therapy indicated in the sofosbuvir package label,
however, it is too soon to declare a cure as relapse can occur after finishing
treatment.
Sofosbuvir and ribavirin were generally
safe and well-tolerated. Adverse events were common overall, but serious
adverse events were infrequent (seven total, distributed equally between the
treatment and observation arms). One person taking sofosbuvir/ribavirin stopped
treatment due to an adverse event (rash and swelling around the eyes). The most
common side-effects reported by more than 10% of participants in the treatment
arm were nausea (32%), weakness (24%), itching (24%), rash (16%), dizziness
(16%), insomnia (16%) and fatigue (12%).
Platelet counts and albumin levels improved
in the sofosbuvir arm, while declining slightly in the untreated observation
arm. Alanine aminotransferase (ALT) levels – an indicator of liver inflammation
– fell by more than 70 U/L on average among treated patients but remained
stable in the observation arm. However, bilirubin levels rose and haemoglobin
fell in the treatment arm, both attributable to ribavirin. A majority of
treated people classified as class B saw declines in their MELD scores, a measure
used to prioritise people awaiting liver transplants.
Looking at clinical decompensation events,
six people taking sofosbuvir/ribavirin had ascites at study entry, falling to
none after 24 weeks of treatment (vs falling from nine to seven in the
observation group). The number with hepatic encephalopathy fell from five to
none (vs rising from two to four in the observation group). One person taking sofosbuvir/ribavirin
had an episode of bleeding varices, but no one developed new onset liver
decompensation.
"In HCV-infected patients with portal
hypertension with and without hepatic decompensation, treatment with sofosbuvir
+ ribavirin for up to 24 weeks resulted in high rates of virologic suppression
irrespective of severity of liver disease and decreased necroinflammation with
ALT normalisation," the researchers concluded.
Afdhal explained that while this study is still
awaiting post-treatment sustained virological response data, it is important to
present safety findings now because sofosbuvir is coming into clinical use and
these patients currently have no other acceptable treatment options.
However, he said that he has "no intention"
to treat advanced liver disease patients with sofosbuvir plus ribavirin today –
given ribavirin's toxicity – but would instead use sofosbuvir with ledipasvir
or other well-tolerated direct-acting antivirals.