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Adding Ribavirin to Harvoni for Hepatitis C Increases Side Effects But Not Efficacy

Combining sofosbuvir/ledipasvir (Harvoni) with ribavirin was associated with a greater likelihood of adverse events and laboratory abnormalities, but did not significantly increase the chances of sustained response for genotype 1 chronic hepatitis patients compared to sofosbuvir/ledipasvir alone, according to an analysis of the Phase 3 ION trials described in the July edition of Hepatology.

The advent of oral direct-acting antiviral agents that can be used in interferon-free regimens has brought about a revolution in hepatitis C treatment. But many providers and people with hepatitis C virus (HCV) would also like to get rid of ribavirin, which can cause anemia -- which, if severe, may require additional drugs or blood transfusions -- and should not be used by pregnant women.

Gilead Sciences' 1-pill-once-daily sofosbuvir/ledipasvirregimen has demonstrated very good efficacy in clinical trials, with sustained virological response (SVR) rates approaching 100% in treatment-naive and previously treated genotype 1 patients, including some with compensated liver cirrhosis.

The standard recommended duration of sofosbuvir/ledipasviris 12 weeks. But many experts think the hardest-to-treat patients -- prior non-responders with HCV subtype 1a and advanced liver disease -- should either extend therapy to 24 weeks or include ribavirin. Doubling the duration raises the cost of treatment while adding ribavirin can increase side effects.

Saleh Alqahtani and Mark Sulkowski from Johns Hopkins and colleagues analyzed data from the ION trials to compare the safety and tolerability profiles of sofosbuvir/ledipasvirwith and without ribavirin. They looked at treatment-emergent adverse events and laboratory abnormalities among patients randomly assigned to receive sofosbuvir/ledipasvirfor 8, 12, or 24 weeks, with or without ribavirin:

• ION-1:previously untreated HCV genotype 1 (16% with cirrhosis) -- 12 vs 24 weeks with or without ribavirin (n=865);
• ION-2:prior non-responders HCV genotype 1 (20% with cirrhosis) -- 12 vs 24 weeks with or without ribavirin (n=440);
• ION-3:previously untreated HCV genotype 1 (non-cirrhotic only) -- 12 weeks without ribavirin, or 8 weeks with or without ribavirin (n=647).

The analysis included data from 1080 patients who received sofosbuvir/ledipasviralone and 872 who received sofosbuvir/ledipasvir plus ribavirin. Overall, about 60% were men, 16% were African-American, and 26% were considered obese (body mass index >30). Just under a quarter (23%) were treatment-experienced and 11% had compensated cirrhosis.

Results

• As previously reported, SVR rates at 12 weeks post-treatment were 97%-99% in ION-1, 94%-99% in ION-2, and 93%-95% in ION-3.
• Relapse was more common among people treated for 8 weeks, but SVR rates did not differ significantly between those treated for 12 and 24 weeks.
• The pooled overall SVR rate was the same -- 97% -- for people who did or did not receive ribavirin.
• 45% of patients treated with sofosbuvir/ledipasviralone experienced treatment-related adverse events, compared with 71% of those who took sofosbuvir/ledipasvirplus ribavirin.
• Reported side effects included fatigue, insomnia, irritability, rash, and pruritus (itching).
• Patients receiving sofosbuvir/ledipasvirwith ribavirin were more likely to require dose modification, treatment interruption due to adverse events, or use of concomitant medications.
• Rates of treatment-related serious adverse events and treatment discontinuations due to adverse events were similarly low (<1%) in both groups.

"[Sofosbuvir/ledipasvir] plus ribavirin was associated with a greater incidence of adverse events as well as concomitant medication use than [sofosbuvir/ledipasvir] alone," the study authors concluded. "Use of ribavirin did not impact the efficacy of [sofosbuvir/ledipasvir] regimens in the ION Phase III studies."

While the overall SVR rates with and without ribavirin were the same in these studies -- in which a majority of participants were treatment-naive and did not have cirrhosis -- ribavirin may still have a role to play in treating the most challenging patients.

6/26/15

Reference

SA Alqahtani, N Afdhal, S Zeuzem,  Mark Sulkowski, et al. Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: Analysis of phase III ION trials. Hepatology 62(1):25-30. July 2015.