Thursday, November 13, 2014

Sofosbuvir Plus Ribavirin in Patients With Genotype 2 HCV

Journal of Viral Hepatitis

Sofosbuvir Plus Ribavirin in Japanese Patients With Chronic Genotype 2 HCV Infection

An Open-label, Phase 3 Trial

Discussion Only

Read More @ Medscape

In this phase 3 trial, twelve weeks of treatment with sofosbuvir and RBV resulted in high rates of sustained virologic response (>95%) in treatment-naïve and previously treated Japanese patients with chronic genotype 2 HCV infection. Patients with host and viral characteristics that have historically been predictive of lower rates of SVR – older age, presence of cirrhosis, high viral load, non-CC IL28B alleles – had rates of SVR12 similar to patients without these characteristics. In patients who had been previously treated for HCV infection, the nature of the prior response was not associated with significant differences in rates of SVR following treatment with sofosbuvir and ribavirin; patients who had nonresponse to prior treatment had similar response rates as patients who had previously experienced relapse or viral breakthrough. No clear or consistent baseline predictors of treatment failure were evident among the five patients who relapsed after treatment.

The current standard-of-care treatment for Japanese patients with chronic genotype 2 HCV infection is 24 weeks of Peg-IFNα+RBV. Although patients who received this regimen in clinical trials achieved SVR12 rates ranging from 72% to 86%, these studies were restricted to patients <65 years of age.[12,13] However, the Japanese population chronically infected with genotype 2 HCV includes many patients with characteristics that make the use of interferon-based therapy problematic – older age, progressive liver disease, prior treatment experience and comorbid conditions such as diabetes and cardiovascular disease.[14] Moreover, many patients cannot receive interferon therapy due to relative or absolute contraindications. The interferon-free combination of sofosbuvir and ribavirin may represent a promising treatment option for these patients.

Given the characteristics of the patient population in Japan with HCV infection – generally older, and more likely to have advanced liver disease – safety and tolerability of therapeutic regimens is an important issue. In the present study, 22% of patients were aged 65 or older and 11% had cirrhosis. Analyses of safety data by age (<65 vs ≥65 years) showed increases in reported adverse events and laboratory abnormalities in older patients, but these differences did not present a barrier to treatment as no premature discontinuation of study treatment occurred in any patient. Analysis of safety data according to the presence or absence of cirrhosis did not indicate clinically important differences in safety or tolerability of the 12-week sofosbuvir plus ribavirin regimen.

Consistent with previous reports, the results of this study confirm the high barrier to resistance afforded by the sofosbuvir plus RBV treatment regimen. Rapid viral suppression was observed with all patients achieving HCV RNA undetectable status by week 4, with no virologic breakthrough observed during treatment in any of the 153 patients. The percentage of patients who relapsed after treatment was low (3%), and none of the subjects who relapsed had S282T or other nucleoside inhibitor resistance-associated variants. No change in susceptibility to sofosbuvir or ribavirin compared with the corresponding baseline or wild-type reference was observed at the relapse time point.

The main limitation of this study was the lack of a control arm to allow direct comparison with interferon-based regimens. Several considerations guided our choice of an uncontrolled study design. Adding an interferon-based control arm would have required exclusion of patients who were ineligible to receive or intolerant of interferon – an important and substantial proportion of patients – as well as previously treated patients, for whom further interferon treatment is not an option. Moreover, given that Peg-IFNα is administered by subcutaneous injection, blinding of treatment arms would not have been possible.

In conclusion, treatment with the all-oral, interferon-free combination of sofosbuvir and RBV resulted in high rates of sustained virologic response in both treatment-naïve and previously treated Japanese patients with chronic genotype 2 HCV infection. The degree of antiviral efficacy coupled with a favourable safety and tolerability profile, including patients with cirrhosis and those aged 65 and older, suggest that this combination may fill an important unmet medical need in Japan.

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