An oral regimen of sofosbuvir/ledipasvir (Harvoni) and ribavirin taken for 12 or 24 weeks produced sustained
virological response rates of 85-88% for people with genotype 1 or 4 hepatitis C virus (HCV) who had decompensated cirrhosis and 95-98% for liver transplant recipients with
less advanced liver damage, according to results from the SOLAR-2 study
presented yesterday at the European Association for the Study of the Liver (EASL)
50th International Liver Congress in Vienna, Austria.
Direct-acting antiviral agents in interferon-free regimens have
revolutionised hepatitis C treatment, curing most people including those traditionally
considered difficult to treat. But challenges remain for people with advanced
liver disease, including those with decompensated cirrhosis (when the liver can
no longer carry out its vital functions) and people who are awaiting or have
received liver transplants.
Michael Manns of Hannover Medical
School in Germany and fellow investigators with the SOLAR-2 trial evaluated the safety and efficacy of the
nucleotide HCV polymerase inhibitor sofosbuvir and NS5A inhibitor ledipasvir,
taken as a once-daily fixed-dose coformulation, plus daily ribavirin for people
with advanced liver disease.
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
An accumulation of fluid in the abdomen; may be caused by liver damage, especially cirrhosis.
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
A disease or infection affecting the brain.
This phase 2 study enrolled
more than 300 people with chronic hepatitis C in Europe, Canada, Australia and New
Zealand. Three-quarters were men, more than 90% were white and the median age
was nearly 60 years. Most had HCV genotype 1 (about half with 1a and 40% with
1b) while about 10% had genotype 4. About 80% had received prior treatment
without being cured.
SOLAR-2 included 160
people with decompensated cirrhosis who were either awaiting or had received
liver transplants. They were classified as Child-Pugh-Turcotte (CPT) class B or
C, an index of liver disease severity based on bilirubin and albumin levels,
blood clotting capacity and presence of ascites or hepatic encephalopathy. About
one-quarter of the CPT B/C patients had a MELD score greater than 15 (another
measure of liver disease severity). The study also included 168 liver
transplant recipients with recurrent HCV who had less severe liver disease –
CPT Class A and absent to advanced liver fibrosis (stage F0-F3).
randomly assigned to receive sofosbuvir/ledipasvir plus ribavirin for either 12
or 24 weeks. Manns explained that when the study was designed it was not yet
known how well sofosbuvir/ledipasvir without ribavirin would work for people
with advanced disease, so there was no ribavirin-free arm.
showed that after 12 weeks of post-treatment follow-up, the CPT B/C patients
had sustained virological response (SVR12) rates of 85% with 12 weeks of
treatment and 88% with 24 weeks. In the CPT A group, SVR12 rates were 95% and
98%, respectively. A single genotype 1 CPT A patient, six genotype 1 CPT B/C
patients and three genotype 4 CPT B/C patients relapsed after finishing
Overall cure rates
were similar for 12 and 24 weeks of therapy. Participants with CPT B responded somewhat
better than those with CPT C, and within the CPT C group pre-transplant
patients did better than post-transplant patients.
Looking only at the genotype
1 patients, the SVR12 rates were similar to the overall rates. Among genotype 4
CPT B/C patients, however, only 57% were cured with 12 weeks of therapy, rising
to 86% with 24 weeks; the corresponding rates were 91% and 100% for genotype 4 CPT
A patients. Mann cautioned that the genotype 4 numbers were too small to make
meaningful comparisons, though he suggested that 24 weeks is probably preferable
for genotype 4.
suppression was associated with improved liver function. Almost all CPT class A
participants remained the same, 35% of those initially classified as class B
reverted to class A, while 48% of those classified as class C reverted to class
B and 5% to class A. CPT and MELD scores fell largely due to decreased
bilirubin and improved ability to synthesize proteins such as albumin.
Given that this was a
population with advanced disease, almost all participants experienced some adverse
events. About 15% of CPT A patients and 28% of CPT B/C patients had serious
adverse events, but only a few cases were deemed related to the study drugs. Twelve
participants died during the study – mostly due to liver-related complications –
but no deaths were considered treatment-related. Six people
discontinued treatment due to adverse events, all but one of whom had
decompensated cirrhosis. The most common adverse events were fatigue, anaemia,
nausea and headache.
plus ribavirin "resulted in high SVR12 rates in HCV patients with advanced
liver disease, irrespective of transplantation status," the researchers
concluded. They added that this regimen "was generally safe and
well-tolerated in patients with advanced liver disease, pre- and post-liver
Looking at another group of patients with
advanced liver disease, a late-breaking poster presentation by Xavier Forns and
colleagues described 11 participants in SOLAR-1 and SOLAR-2 who developed fibrosing cholestatic hepatitis, a rare severe form of recurrent hepatitis that can occur after liver
transplantation. All of these patients achieved SVR12 after 12 or
24 weeks of treatment with sofosbuvir/ledipasvir plus ribavirin, according to a press
release issued by manufacturer Gilead Sciences.
"The patients included in these analyses
are among the most difficult to both treat and cure and, until now, have had
limited or no treatment options," Mann stated in the release, commenting
on both studies. "These data demonstrate that, even among these
difficult-to-treat patient groups, sofosbuvir-based oral therapy offers the
potential of high cure rates, improves outcomes and is generally well tolerated
with a favourable safety profile."