An oral regimen of
sofosbuvir/ledipasvir plus ribavirin taken for 12 weeks cured most hepatitis C
patients with decompensated cirrhosis, the most advanced stage of liver
disease, according to a presentation on Tuesday at the American Association for the Study of Liver
Diseases (AASLD) Liver Meeting in Boston.
Over years or decades,
chronic hepatitis C virus (HCV) infection can lead to serious complications including
cirrhosis and liver cancer. As liver disease progresses, function typically
diminishes gradually at first, as the liver can compensate for some damage.
Eventually, however, scar tissue blocks normal blood flow and the liver cannot
carry out its vital functions such as filtering toxins and producing proteins –
a condition known as decompensated cirrhosis. People at this stage of liver
failure may develop symptoms such as ascites (abdominal fluid build-up),
bleeding veins in the oesophagus and stomach, internal infection and hepatic
encephalopathy (brain impairment).
direct-acting antiviral agents became available, hepatitis C patients with decompensated
cirrhosis were considered too ill to treat with interferon-based therapy. Those
who were treated on an experimental basis did not tolerate drugs well and had a
low likelihood of sustained response. There is currently no approved treatment
for this population.
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.
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
With the advent of new
direct-acting antivirals that are highly effective and well-tolerated, treating
this sickest group of patients has become a priority. Ideally, effective
treatment would eradicate HCV and allow the liver to heal, restoring some
function and perhaps making liver transplants unnecessary.
Steven Flamm from Northwestern University in Chicago
presented findings from SOLAR-1, a study testing an all-oral regimen of direct-acting antivirals that have minimal
side-effects and cure most people with less advanced liver disease.
A total of 108
patients with genotype 1 or 4 chronic hepatitis C and decompensated cirrhosis
were treated with a once-daily co-formulation of Gilead Sciences' HCV
polymerase inhibitor sofosbuvir and NS5A inhibitor ledipasvir (approved and
sold as Harvoni in the US). They were
randomly assigned to receive therapy for 12 or 24 weeks.
Because people with
more advanced liver disease traditionally respond less well to treatment, all
patients also took ribavirin, which helps reduce post-treatment relapse.
Participants started at a low dose of 600mg/day and the amount was escalated
based on tolerability, up to the standard weight-based dose of 1000-1200mg/day.
said that the median dose was just over 600mg/day, with about one-third of
patients tolerating the full dose.
Two-thirds of participants were men, more than 90% were white and the
median age was about 60 years – a bit older than hepatitis C patients with less
advanced disease. Approximately two-thirds had harder-to-treat HCV genotype 1a
and three people had genotype 4; about 80% had unfavourable IL28B genetic
variants. More than
60% had previously undergone unsuccessful hepatitis C treatment.
The patients had decompensated cirrhosis with Child-Pugh-Turcotte (CPT) Class B or C, as determined
based on a set of liver function biomarkers and symptoms. About 15% of patients
with CPT Class B and 40% of patients with CPT Class C had MELD scores (based on
bilirubin, creatinine and blood clotting capacity) of 16-20, about 60% of
people in both classes had scores of 10-15 and about 25% of patients with CPT
Class B had MELD scores <10. About 60% of patients with CPT Class B and
almost all patients with Class C had a history of ascites, and about 60% and
90%, respectively, had hepatic encephalopathy. People with higher MELD scores (indicating
more severe disease and low survival probability), very high bilirubin or low
platelet counts, serious kidney dysfunction or hepatocellular carcinoma were
excluded. This study did not include liver transplant recipients.
Most participants completed treatment. Three people died during the
study, three withdrew due to adverse events and four were able to obtain liver
Overall, 87% of participants treated for 12 weeks and 89% of those treated
for 24 weeks achieved SVR12, or continued undetectable HCV viral load 12 weeks after
completing therapy, which is considered a cure. Rates were similar for patients
with CPT Class B (87% and 89%) and Class C (86% and 90%). Among the few participants
with HCV genotype 4, two achieved SVR12 and two were lost to follow-up.
Four people treated for 12 weeks and two people treated for 24 weeks
relapsed after the end of therapy, but numbers were too small to draw
statistical conclusions about treatment duration. Flamm also noted that the
numbers were too small to discern any obvious predictors of relapse.
Successful treatment not only eradicated HCV, but was associated with
improvement in liver function. Bilirubin levels fell and albumin blood protein
levels rose from baseline to week four post-treatment. Most participants (33)
saw decreases – or improvement – in their CPT scores, with ten having no change
and four having higher scores. Likewise, MELD scores also fell for most
patients in both the Class B and Class C groups.
Sofosbuvir/ledipasvir plus ribavirin was generally safe and
well-tolerated, although almost all participants experienced some adverse
events – not surprising for such a sick population. About one-quarter
experienced serious adverse events, but only four were considered
treatment-related. As noted, three people discontinued therapy due to adverse
Sofosbuvir/ledipasvir plus ribavirin for 12 weeks "resulted in a high SVR12 rate in
HCV patients with genotype 1 and 4 and advanced liver disease," the
rates were similar to relapse rates in patients with compensated
cirrhosis," they continued, and "extending treatment duration to 24
weeks did not increase the response rate."
response was associated with improvements in bilirubin, albumin, MELD and CPT
scores in patients with Class B and Class C, and Flamm stressed that
"sicker patients did equally well."
During the discussion after the presentation, a clinician raised the
issue that by lowering patients' CPT and MELD scores – which are used to
determine transplant priority – patients might be put at a disadvantage.
may get better and not need a transplant, and people can die while waiting,"
Flamm replied. "The onus is on us to help patients,
and I don’t think we're hurting them by curing hepatitis C."