Baseline Characteristics

A total of 410 patients with HCV genotype 2 or 3 infection for whom interferon treatment was not an option were initially screened for the POSITRON trial. Of these patients, 280 underwent randomization, and 278 began treatment (Fig. S1 in the Supplementary Appendix). A total of 277 patients who had received prior treatment for HCV genotype 2 or 3 infection were initially screened for the FUSION study; 202 underwent randomization, and 201 began treatment (Fig. S2 in the Supplementary Appendix). The demographic and baseline clinical characteristics were balanced between the two groups in each study.

Table 1. Table 1. Baseline Demographic and Clinical Characteristics of the Patients in the Two Studies.

In the POSITRON trial, the distribution of patients on the basis of the classification that interferon therapy was not an option (contraindication, unacceptable side effects, or patient's decision) was similar between the treatment and placebo groups (Table 1). The most common reasons that interferon treatment was not an option were clinically significant psychiatric disorders (in 57% of patients) and autoimmune disorders (in 19%) (Fig. S3 in the Supplementary Appendix).

Approximately 75% of the previously treated patients enrolled in the FUSION trial had either virologic breakthrough during the prior treatment or virologic relapse afterward; the remainder did not have a response. A total of 16% of the patients in the POSITRON study and 34% of those in the FUSION study had cirrhosis. A higher percentage of patients with HCV genotype 3 infection were enrolled in the FUSION study (63% of patients) than in the POSITRON study (49%).

Efficacy

Overall Population

Table 2. Table 2. Response during and after Treatment in the Two Studies.

Treatment with sofosbuvir and ribavirin resulted in a rapid decline in circulating HCV RNA levels, with similar reductions in the two studies and among patients with HCV genotype 2 or 3 infection. By week 2 of treatment, 81 to 91% of patients in the sofosbuvir groups had an HCV RNA level that was less than the lower limit of quantification. By week 4, the rates of virologic suppression were 97 to 99%, and at the end of treatment, no patient who could be evaluated had an HCV RNA level that was higher than the lower limit of quantification (Table 2). Among the 402 patients receiving sofosbuvir in these studies, none had virologic breakthrough during treatment, and thus all treatment failures involved virologic relapse after the cessation of therapy.

POSITRON Trial

In the population of patients for whom interferon treatment was not an option, the rate of sustained virologic response at 12 weeks after treatment was 78% (95% confidence interval [CI], 72 to 83) among patients receiving sofosbuvir and ribavirin, as compared with 0% among those receiving placebo (P<0.001) (Table 2). There was complete concordance (100%) between rates of sustained virologic response at 12 weeks and at 24 weeks among patients who received sofosbuvir and ribavirin, with none of the 153 patients who could be evaluated having virologic relapse after week 12.

Figure 1. Figure 1. Rates of Sustained Virologic Response, According to Demographic and Baseline Clinical Characteristics in Both Studies. The position of each symbol indicates the rate of sustained virologic response 12 weeks after the end of treatment for each prespecified subgroup; the horizontal lines indicate 95% confidence intervals. The vertical dashed lines represent the overall rates of sustained virologic response for the sofosbuvir treatment groups. Arrows indicate confidence intervals that exceed the x-axis scale. Race and ethnic group were self-reported. The body-mass index is the weight in kilograms divided by the square of the height in meters. The P values shown are for the interactions between treatment durations and subgroups in the FUSION study. There were not enough black patients in the study for the calculation of an interaction P value. For confidence intervals of response rates, see Tables S3 and S7 in the Supplementary Appendix. ALT denotes alanine aminotransferase, HCV hepatitis C virus, RBV ribavirin, and SOF sofosbuvir.

Rates of sustained virologic response in patient subgroups are shown in Figure 1 and in Tables S3 and S4 in the Supplementary Appendix. Logistic-regression analysis showed that HCV genotype 3 infection was significantly associated with reduced rates of sustained virologic response, as compared with HCV genotype 2 infection (Table S6 in the Supplementary Appendix).

Among patients who received sofosbuvir and ribavirin, 93% of patients with HCV genotype 2 infection had a sustained virologic response, as compared with 61% of those with HCV genotype 3 infection. Likewise, 81% of patients without cirrhosis (92% of patients with HCV genotype 2 infection and 68% of those with HCV genotype 3 infection) had a sustained virologic response, as compared with 61% of patients with cirrhosis (94% of patients with HCV genotype 2 infection and 21% of those with HCV genotype 3 infection).

FUSION Trial

The rates of sustained virologic response achieved with sofosbuvir and ribavirin in the population of patients with prior treatment were superior to the historical control rate of 25%, with rates of 50% (95% CI, 40 to 60) in the 12-week group and 73% (95% CI, 63 to 81) in the 16-week group (P<0.001 for each comparison). The secondary analysis comparing rates of sustained virologic response between the groups showed that patients receiving 16 weeks of treatment had a significantly higher rate of sustained virologic response than patients receiving 12 weeks of treatment (difference, −23 percentage points; 95% CI, −35 to −11; P<0.001) (Figure 1).

The rates of sustained virologic response in various patient subgroups are shown in Figure 1 and in Tables S7 and S8 in the Supplementary Appendix. Multivariate logistic-regression modeling was performed independently for each treatment group to investigate predefined covariate effects. HCV genotype 3 infection, as compared with genotype 2 infection, was significantly associated with a lower response rate with both 12 and 16 weeks of treatment (Tables S10 and S12 in the Supplementary Appendix). The rates of sustained virologic response among patients with HCV genotype 2 infection who received 12 weeks of treatment and those who received 16 weeks of treatment were 86% and 94%, respectively (difference, −8 percentage points; 95% CI, −24 to 9), as compared with 30% and 62% for 12 and 16 weeks of treatment, respectively, among patients with HCV genotype 3 infection (difference, −32 percentage points; 95% CI, −48 to −15).

Cirrhosis was associated with a decreased rate of sustained virologic response, particularly among patients with HCV genotype 3 infection who received 12 weeks of treatment. Among patients with cirrhosis who received 12 weeks of treatment, the rate of response was 31% (60% with HCV genotype 2 infection and 19% with HCV genotype 3 infection), as compared with 61% among patients without cirrhosis (96% with HCV genotype 2 infection and 37% with HCV genotype 3 infection). Among patients with cirrhosis who received 16 weeks of treatment, the rate of response was 66% (78% with HCV genotype 2 infection and 61% with HCV genotype 3 infection) as compared with 76% among patients without cirrhosis (100% with HCV genotype 2 infection and 63% with HCV genotype 3 infection).

Virologic Resistance Testing

No patient receiving sofosbuvir in either study had virologic breakthrough during treatment or failed to have a response to treatment. Among the 42 patients in the POSITRON study and the 73 patients in the FUSION study who had a relapse after the end of treatment, sequencing analysis of samples collected at time of relapse showed no resistance-associated variants (see the Supplementary Appendix).

Safety

Table 3. Table 3. Treatment Discontinuations, Adverse Events, and Hematologic Abnormalities.

Premature discontinuation of the study drug due to adverse events was uncommon in all groups: in the FUSION study, one patient in the 12-week group discontinued treatment during the 4-week placebo phase of dosing; in the POSITRON study, four patients who received sofosbuvir and ribavirin (2%) discontinued treatment, as compared with three who received placebo (4%). The rates of serious adverse events in the POSITRON trial were 5% in the group that received sofosbuvir and ribavirin and 3% in the placebo group; in the FUSION study, the rates were 5% in the 12-week group and 3% in the 16-week group (Table 3, and Tables S17 and S18 in the Supplementary Appendix).

In the POSITRON study, the differences in adverse events between the placebo and active-treatment groups included higher rates of fatigue and insomnia among patients receiving sofosbuvir and ribavirin (Table 3, and Table S15 in the Supplementary Appendix). As expected, the incidence of anemia was higher among patients receiving sofosbuvir and ribavirin than among patients receiving placebo (Fig. S7 and S9 in the Supplementary Appendix).11 Otherwise, the rates of laboratory abnormalities, including white-cell, neutrophil, and platelet counts, did not differ significantly between the two groups.

The incidences of adverse events and laboratory abnormalities among patients with cirrhosis who received sofosbuvir and ribavirin were similar to those among patients without cirrhosis (Table S19 in the Supplementary Appendix). In addition, the overall safety profile in patients receiving 16 weeks of therapy was similar to that observed in patients receiving 12 weeks of therapy (Table 3).