Sofosbuvir in the Treatment of Chronic Hepatitis C
Sofosbuvir in the Treatment of Chronic Hepatitis C
Recurrence of HCV infection in liver transplant recipients in whom HCV RNA is detected at the time of transplantation has been nearly universal, and in a significant proportion of patients, recurrent HCV infection leads to cirrhosis and reduced survival within 5 years of transplantation. In a small phase 2 study of patients who were candidates for transplantation for hepatocellular carcinoma, and in whom cirrhosis was well compensated, the efficacy of pre-transplant treatment with sofosbuvir and ribavirin for as long as 48 weeks in an attempt to prevent recurrence was assessed. A total of 41 patients, with any genotype, were HCV RNA undetectable at the time of transplant and 64% of these achieved SVR12. The longer the period on treatment with HCV RNA undetectability before transplant, the lower the relapse rate observed. The lowest relapse rates were seen in patients who had been HCV RNA negative for more than 30 days prior to transplantation. Treatment was well tolerated in these compensated cirrhosis patients and drug interactions with anti-rejection drugs were not observed.
Among mainly G1 patients with severe HCV recurrence or with fibrosing cholestatic hepatitis following liver transplantation, early initial data from a compassionate use program in which sofosbuvir was combined with ribavirin with or without peginterferon, the latter at the discretion of the treating physician, have been reported for the first 44 patients. Clinical improvement was noted in 64% of patients and liver chemistry abnormalities also improved. Overall SVR12 was 56%; in those receiving sofosbuvir plus ribavirin, it was 60% and in those receiving triple therapy, it was 50%.
In a prospective, multicentre trial of sofosbuvir plus ascending doses of ribavirin (400–1000 mg daily) given for 24 weeks to patients with recurrent HCV infection after liver transplantation, 100% of patients had undetectable HCV RNA levels at week 4 of treatment. HCV RNA undetectability at end-of-treatment was 100% and SVR4 was 77%. SVR12 data were not yet available. No net change in immunosuppression dose requirements was found.
To date, no studies of nonliver organ transplant recipients with chronic hepatitis C have been reported.
Decompensated Cirrhosis and Renal Failure. Data on the efficacy and safety of sofosbuvir-containing regimens in decompensated cirrhosis or renal failure, with or without dialysis, are not available and for the latter, treatment is now considered contraindicated.
The efficacy and safety of sofosbuvir plus ribavirin, in the absence of peginterferon, has been assessed in human immunodeficiency virus (HIV) coinfected patients with HCV G1–3 in a preliminary study. In this nonrandomised open-label trial, in which all patients were HIV stable and nearly all were on antiretroviral therapy (ART) for HIV, 63% of patients were G1. Multiple ART regimens were permitted, but relatively few patients had cirrhosis. Patients with G1 were treated with sofosbuvir plus ribavirin for 24 weeks, whereas those with G2 or G3 received the combination for 12 weeks. Treatment was completed in 90% of patients. At week 4 of treatment, 96–100% of patients had undetectable HCV RNA. SVR12 was 76% in G1, 88% in G2 and 67% in G3. SVR12 rates were higher in patients with G1a at 82% than with G1b at 54%. Response rates were lower in patients with cirrhosis. HCV virological breakthrough was identified in only one patient in whom non-adherence was documented. HIV breakthrough occurred in two patients, one with non-adherence. The other HIV breakthrough occurred in a patient who regained HIV control without a change in therapy. Regardless of genotype, all relapses occurred by week 4 after ending treatment. Sofosbuvir plus ribavirin was well tolerated. Additional studies of sofosbuvir-containing regimens, with peginterferon or direct anti-virals, will be necessary to determine the optimal management strategy for HIV-coinfected patients.
No studies in children have been reported to date.
Specific Populations
Liver Transplant Recipients
Recurrence of HCV infection in liver transplant recipients in whom HCV RNA is detected at the time of transplantation has been nearly universal, and in a significant proportion of patients, recurrent HCV infection leads to cirrhosis and reduced survival within 5 years of transplantation. In a small phase 2 study of patients who were candidates for transplantation for hepatocellular carcinoma, and in whom cirrhosis was well compensated, the efficacy of pre-transplant treatment with sofosbuvir and ribavirin for as long as 48 weeks in an attempt to prevent recurrence was assessed. A total of 41 patients, with any genotype, were HCV RNA undetectable at the time of transplant and 64% of these achieved SVR12. The longer the period on treatment with HCV RNA undetectability before transplant, the lower the relapse rate observed. The lowest relapse rates were seen in patients who had been HCV RNA negative for more than 30 days prior to transplantation. Treatment was well tolerated in these compensated cirrhosis patients and drug interactions with anti-rejection drugs were not observed.
Among mainly G1 patients with severe HCV recurrence or with fibrosing cholestatic hepatitis following liver transplantation, early initial data from a compassionate use program in which sofosbuvir was combined with ribavirin with or without peginterferon, the latter at the discretion of the treating physician, have been reported for the first 44 patients. Clinical improvement was noted in 64% of patients and liver chemistry abnormalities also improved. Overall SVR12 was 56%; in those receiving sofosbuvir plus ribavirin, it was 60% and in those receiving triple therapy, it was 50%.
In a prospective, multicentre trial of sofosbuvir plus ascending doses of ribavirin (400–1000 mg daily) given for 24 weeks to patients with recurrent HCV infection after liver transplantation, 100% of patients had undetectable HCV RNA levels at week 4 of treatment. HCV RNA undetectability at end-of-treatment was 100% and SVR4 was 77%. SVR12 data were not yet available. No net change in immunosuppression dose requirements was found.
To date, no studies of nonliver organ transplant recipients with chronic hepatitis C have been reported.
Decompensated Cirrhosis and Renal Failure. Data on the efficacy and safety of sofosbuvir-containing regimens in decompensated cirrhosis or renal failure, with or without dialysis, are not available and for the latter, treatment is now considered contraindicated.
HIV/HCV Coinfected
The efficacy and safety of sofosbuvir plus ribavirin, in the absence of peginterferon, has been assessed in human immunodeficiency virus (HIV) coinfected patients with HCV G1–3 in a preliminary study. In this nonrandomised open-label trial, in which all patients were HIV stable and nearly all were on antiretroviral therapy (ART) for HIV, 63% of patients were G1. Multiple ART regimens were permitted, but relatively few patients had cirrhosis. Patients with G1 were treated with sofosbuvir plus ribavirin for 24 weeks, whereas those with G2 or G3 received the combination for 12 weeks. Treatment was completed in 90% of patients. At week 4 of treatment, 96–100% of patients had undetectable HCV RNA. SVR12 was 76% in G1, 88% in G2 and 67% in G3. SVR12 rates were higher in patients with G1a at 82% than with G1b at 54%. Response rates were lower in patients with cirrhosis. HCV virological breakthrough was identified in only one patient in whom non-adherence was documented. HIV breakthrough occurred in two patients, one with non-adherence. The other HIV breakthrough occurred in a patient who regained HIV control without a change in therapy. Regardless of genotype, all relapses occurred by week 4 after ending treatment. Sofosbuvir plus ribavirin was well tolerated. Additional studies of sofosbuvir-containing regimens, with peginterferon or direct anti-virals, will be necessary to determine the optimal management strategy for HIV-coinfected patients.
Paediatric
No studies in children have been reported to date.
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