An interferon-free regimen of sofosbuvir plus ledipasvir (Harvoni) taken with ribavirin for 12 or 24 weeks led to sustained virological response in nearly all HCV genotype 1patients with fibrosis or less-advanced liver cirrhosis, researchers reported at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting last month in Boston, United States. Response rates fell for people with more severe cirrhosis and signs of liver decompensation, but still a majority were cured.
Hepatitis C virus (HCV) almost always re-infects the new liver after transplantation, often resulting in rapid disease progression leading to severe fibrosis or cirrhosis and potential graft loss. Liver transplant recipients have historically been difficult to treat because they do not respond as well to interferon-based therapy and often cannot tolerate its side-effects or interactions with immunosuppressant drugs. Now, however, new direct-acting antiviral agents (DAAs) can be combined in interferon-free regimens that produce high cure rates and are very well-tolerated.
K Rajender Reddy from the University of Pennsylvania reported preliminary results from a multicentre trial in which people with recurrent HCV after liver transplantation were treated with Gilead Sciences' recently approved co-formulation containing the nucleotide HCV polymerase inhibitor sofosbuvir (Sovaldi) and the HCV NS5A inhibitor ledipasvir.
This study included 223 liver transplant recipients. Most were white men and the median age was approximately 60 years. More than 80% had previously been treated for hepatitis C. About three-quarters had HCV subtype 1b, one-quarter had subtype 1a and three patients had genotype 4.
Participants were stratified according to liver disease severity:
- 111 had advanced fibrosis or less (Metavir stages F0-F3).
- 51 had Child-Pugh-Turcotte (CPT) class A cirrhosis, the least severe grade.
- 52 had CPT class B cirrhosis.
- 9 had CPT class C cirrhosis, indicating severe disease with a one-year survival probability less than 50%.
The median time from transplantation to treatment was about three years for patients with fibrosis, but closer to seven years for those with cirrhosis. Few people with fibrosis or CPT class A cirrhosis had ascites (abdominal fluid accumulation) or hepatic encephalopathy (brain impairment) – two signs of liver decompensation – but this rose to more than half of those with CPT class B and about 90% of those with CPT class C. MELD scores – a biomarker index with higher scores indicating worse liver function – were <10 for a majority of CPT class A patients, while scores of 10-15 predominated among people with class B or C, and one-third of class C patients had scores of 16-20 or 21-25.
Participants were randomly assigned to receive sofosbuvir/ledipasvir plus ribavirin for either 12 or 24 weeks. People with fibrosis or CPT class A started on weight-based ribavirin, while those with more severe cirrhosis started at 600mg/day and escalated to the standard dose if tolerated.
At 12 weeks post-treatment, SVR12 rates for people with F0-F3 fibrosis were 96% with the 12-week regimen and 98% with the 24-week regimen. Rates were nearly as high for people with CPT A cirrhosis – 96% for both durations.
However, SVR12 rates for patients with CPT class B fell to 85% with 12 weeks and 83% with 24 weeks of therapy, and cure rates were just 60% and 67%, respectively, for those with CPT class C.
Overall, there were six post-treatment relapses.
Along with virological response, participants showed improvements in liver function. Total bilirubin levels fell while albumin levels rose, both indicating improvement. A majority of CPT class A patients and most with CPT class B saw decreases in their MELD scores.
Sofosbuvir/ledipasvir plus ribavirin was generally safe and well-tolerated. Six people stopped treatment early due to adverse events. Serious adverse event rates ranged from 11% among patients with fibrosis treated for 12 weeks to 100% among CPT class C patients treated for 24 weeks. However, most serious adverse events and the seven deaths that occurred were not considered treatment-related. The most common treatment-related serious adverse event was anaemia, seen in six patients.
"In patients with recurrent HCV post transplantation, treatment with [sofosbuvir/ledipasvir + ribavirin] for 12 or 24 weeks resulted in high rates of SVR12, irrespective of disease severity or duration of therapy," the researchers concluded.
Reddy KR et al. Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with post transplant recurrence: preliminary results of a prospective, Multicenter Study. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract 8, 2014.