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EASL 2015: Patients Who Fail Short Course of Sofosbuvir/Ledipasvir Can Be Cured with 24 Weeks

More than 70% of genotype 1 chronic hepatitis C patients who did not achieve sustained virological response when treated with sofosbuvir/ledipasvir (Harvoni) for 8 or 12 weeks were cured with a subsequent 24-week course of the same 2 drugs, according to a study presented at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last week in Vienna.

Direct-acting antiviral agents (DAAs) used in interferon-free regimens can now produce sustained response in a large proportion of people with genotype 1 hepatitis C virus (HCV) infection, but the optimal approach for the small percentage of patients who are not cured is not yet established.

Gilead Sciences' nucleotide HCV NS5B polymerase inhibitor sofosbuvir plus NS5A inhibitor ledipasvir -- the drugs in the Harvoni coformulation -- was the first approved interferon-and ribavirin-free combination DAA regimen. In Phase 3 trials this regimen taken for 8 or 12 weeks cured more than 95% of nearly 2000 treated patients, but a small percentage still had detectable HCV viral load at 12 weeks after the end of treatment (that is, they did not achieve SVR12).

Eric Lawitz from the University of Texas Health Science Center evaluated the efficacy of sofosbuvir/ledipasvir without ribavirin taken for 24 weeks as re-treatment for these patients, along with others who experienced treatment failed on similar regimens in Phase 2 trials.

This study included a total of 41 patients from the ION, LONESTAR, and TRIOLOGY 1 trials. Most had previously used sofosbuvir/ledipasvir with or without ribavirin, while 8 had used sofosbuvir/ledipasvir plus the experimental non-nucleoside HCV polymerase inhibitor GS-9669. 

All participants in this open-label study were re-treated with 440 mg sofosbuvir and 90 mg ledipasvir in a once-daily coformulation, without ribavirin, for 24 weeks. The researchers evaluated SVR12, or continued undetectable HCV RNA at 12 week post-treatment, and performed deep sequencing to look for virus with NS5A or NS5B resistance-associated variants (RAVs).

More than 80% of participants were men, a quarter were African-American, and the mean age was 58 years. Not surprisingly, given their prior treatment failure, they were a challenging population: more than 90% had unfavorable IL28B gene variants, 46% had liver cirrhosis (rising to 79% among those with NS5A resistance), and the mean baseline HCV RNA level was 6.2 log₁₀ IU/mL.

About three-quarters of participants had been previously treated for 8 weeks and the rest for 12 weeks. Nearly two-thirds of those previously treated for 8 weeks and everyone treated for 12 weeks had baseline NS5A RAVs that potentially confer resistance to ledipasvir; the 11 people without these RAVs had all been treated for the shorter duration. NS5B RAVs that potentially confer resistance to sofosbuvir were much less common: no participants had these RAVs at baseline.

Results

• HCV viral load declined rapidly after starting treatment and almost all participants had viral load <15 IU/mL by the end of treatment.
• The overall sustained virological response rate at 12 weeks post-treatment was 71%.
• 1 patient experienced viral rebound while on treatment at week 16, and 11 people relapsed, usually between the end of therapy and 4 weeks post-treatment.
• There was not much difference in response rates between people with and without cirrhosis (68% and 74%, respectively).
• However, prior treatment duration and presence of baseline NS5A resistance mutations were associated with greater likelihood of re-treatment failure.
• Patients initially treated for 8 rather than 12 weeks had a substantially higher SVR12 rate: 80% vs 46%, respectively.
• Presence of baseline NS5A RAVs was associated with an even larger difference: 100% of those with and 60% of those without these RAVs achieved SVR12.
• People with a single RAV had a cure rate of 69%, falling to just 50% for those with 2 or more RAVs.
• Looking at specific NS5A RAVs, all patients with Q30R or M28T still achieved SVR12, but the cure rate fell to 80% for those with L31M and to only 33% for those with Y93H/N.
• With regard to NS5B RAVs, no participants had these variants at baseline, but a third did so when tested after virological failure: 2 with S282T, 1 with L159F, and 1 with both mutations.
• As seen in prior studies of this regimen, treatment was generally safe and well-tolerated, with most adverse events being mild to moderate.
• 2 participants had serious adverse events, neither of which were deemed related to the study drugs, and no one stopped treatment for this reason.
• The most common adverse events were headache (15%) and fatigue (10%).

Retreatment with sofosbuvir/ledipasvir for 24 weeks "is feasible in patients who have failed prior [sofosbuvir/ledipasvir]-based regimens," the researchers concluded. "The presence of baseline NS5A RAV(s), which was more likely to develop with longer prior [sofosbuvir/ledipasvir] treatment, was associated with virologic failure."

The key factors that minimize relapse are the depth of viral suppression and a patient's individual immune response, Lawitz explained. Since we can't change the latter, anything that improves the former should help achieve a cure, and we can improve viral suppression with either longer treatment or by adding ribavirin.

4/30/15

Reference

E Lawitz, S Flamm, JC Yang, et at. Retreatment of patients who failed 8 or 12 weeks of ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract O005.