www.hivandhepatitis.com

DDW 2015: Sofosbuvir/ Ledipasvir Cures Most Hepatitis C Patients with Cirrhosis

Sofosbuvir and ledipasvir -- the drugs in Harvoni -- are well-tolerated and highly effective for genotype 1 chronic hepatitis C patients with compensated cirrhosis, producing an overall cure rate of 96%, according to a pooled analysis of more than 500 participants in Phase 2 and 3 studies, according to a presentation at Digestive Disease Week 2015 this month in Washington, DC.

The advent of direct-acting antiviral agents that can be used in interferon-free regimens has brought about a revolution in hepatitis C treatment, curing many patients formerly considered "hard to treat." When interferon-based therapy was the standard of care, people often deferred treatment until they developed progressive liver disease because treatment caused difficult side effects and was often ineffective. But people who progressed to liver cirrhosis do not respond as well to therapy and often cannot tolerate interferon. The new interferon-free regimens offer new options for people with advanced disease.

Rajender Reddy from the University of Pennsylvania and colleagues performed a combined analysis of patients with cirrhosis who took part in several Phase 2 and 3 clinical trials including LONESTAR, ELECTRON, ELECTRON-2, ION-1 and ION-2, and SIRIUS. Since some trials include only a small number of cirrhotic patients, combining them in a pooled analysis can be informative.

This analysis included 513 study participants (two-thirds men) with HCV genotype 1, 60% of whom had harder to treat subtype 1a. Most had unfavorable IL28B gene variants associated with poor interferon response. Nearly 70% were treatment-experienced, and about two-thirds of these had previously received regimens containing an HCV protease inhibitor. 18% were found to have HCV NS5A resistance-associated variants (RAVs) at baseline.

Most patients in the analysis had cirrhosis, but without decompensated liver disease at baseline. More than 90% were diagnosed by liver biopsy (stage F4) or FibroScan (>12.5 kiloPascals); among patients with FibroScan results, nearly half had a liver stiffness measurement >20 kPa. Nearly a quarter started treatment with a baseline platelet count <100,000 and 12% with a baseline albumin level <3.5 g/dL, both indicating impaired liver function.

All participants in this analysis received sofosbuvir/ledipasvir with or without ribavirin for either 12 or 24 weeks:

• Sofosbuvir/ledipasvir without ribavirin for 12 weeks: 118 patients (23%);
• Sofosbuvir/ledipasvir with ribavirin for 24 weeks: 204 patients (40%);
• Sofosbuvir/ledipasvir without ribavirin for 24 weeks: 133 patients (26%);
• Sofosbuvir/ledipasvirwith ribavirin for 12 weeks: 58 patients (11%).

The researchers looked at overall efficacy and safety and evaluated the impact of baseline NS5A RAVs on sustained virological response, or continued undetectable HCV RNA at 12 weeks after completing treatment (SVR12).

Results

• Among previously untreated patients treated for 12 weeks, SVR12 rates were
• 92% without ribavirin and 96% with ribavirin.
• Among treatment-naive patients treated for 24 weeks, SVR12 rates were
• 98% without ribavirin and 100% with ribavirin.
• Among treatment-experienced patients, 90% achieved SVR with 12 weeks of sofosbuvir/ledipasvir without ribavirin.
• Adding ribavirin or extending treatment duration to 24 weeks both increased sustained response rates to at least 96%.
• A small number of treatment-experienced patients with HCV subtype 1a and baseline NS5A RAVs showed a reduced SVR12 rate of 67%.
• Treatment with sofosbuvir/ledipasvir was generally safe and well-tolerated.
• Safety profiles in these patients with cirrhosis were similar to those previously reported for people without cirrhosis.
• Side effects including anemia were more frequent among patients who used ribavirin, but no other trends in adverse events were noted.
• 10% of ribavirin recipients developed anemia with hemoglobin <10 g/dL.

"Based on these results, [sofosbuvir/ledipasvir] is effective, safe, and well-tolerated for the treatment of HCV genotype 1 infection in patients with compensated cirrhosis," the researchers concluded. "High SVR rates were also achieved among treatment-experienced patients with cirrhosis when ribavirin was added to 12 weeks of [sofosbuvir/ledipasvir] or when treatment was extended to 24 weeks."

These findings confirm the growing expert consensus that harder-to-treat patients, like those with cirrhosis, should receive either ribavirin or longer therapy to avoid post-treatment relapse. Adding ribavirin increases the likelihood of side effects -- especially a concern for people with advanced liver disease -- but longer duration doubles the cost of treatment.

6/10/15

Reference

KR Reddy, C Sarrazin, M Sulkowski, et al. An Integrated Safety, Efficacy, and Virology Analysis of >500 Patients with Compensated Cirrhosis Treated with Ledipasvir/Sofosbuvir with or without Ribavirin. Digestive Disease Week 2015. Washington, DC, May 16-19, 2015. Abstract 364.