Robert S. Kauffman

Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection

BACKGROUND In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)

The σ1 protein determines the extent of spread of reovirus from the gastrointestinal tract of mice

After intragastric inoculation of adult mice, type 1 reovirus was initially concentrated in Peyers patches over the first 4 hr after inoculation, then spread sequentially to the mesenteric lymph nodes and spleen. For type 3 reovirus, however, initial entry into Peyers patches in adult mice was followed by loss of viral infectivity so that by 4 hr after inoculation virtually no infectious virus was detected in the intestine, and spread to extraintestinal tissues did not occur. In 10-day-old mice, type 3 was capable of spread to the mesenteric lymph nodes but not the spleen. Thus, as animals aged there was a greater restriction of the spread of type 3 from the intestine. Studies using a field isolate of type 3 reovirus that is resistant to intestinal proteases, and genetic studies utilizing type 1 x type 3 viral reassortants, revealed that the viral sigma 1 protein determined the capacity of reovirus to spread from the intestine in both adult and 10-day-old mice. Thus, the interaction of reovirus with host defense mechanisms, and the age-dependent restriction of spread of type 3 reovirus from the intestine are mediated by the viral sigma 1 protein.

Modeling, Clinical and Virology Data From Phase 2 and 3 Studies Support 12-Week Telaprevir Duration in Combination With 24- or 48-Week Peginterferon/Ribavirin

assess the association of HBsAg loss with different clinical phases of HBV and coinfection with HCV or HDV. Method: A total of 3335 patients (2064 male, 1271 female; mean age: 39.5±12.8), who have been HBsAg positive for at least 1 year and those who followed up for at least 6 months are included in the study. HbsAg loss rates in different clinical phases and coinfection with HBV or HDV were assesed. Differences were determined by log-rank test. Results: Among this cohort; 1160 (34.7%) were inactive carriers, 1675 (50.2%) were chronic hepatitis B, 298 (8.8%) were HBV cirrhosis, 77 (2.3%) were chronic HDV hepatitis, 43 (1.2%) were compensated HDV cirhosis, 44 (1.31%) were co-infected with hepatitis B and C. HBsAg loss rates among different groups were depicted in Figure 1. During a mean follow-up period of median 198 week (range: 24–1306 week), annual Hbs Ag loss rates were 1.88% in HBV and HCV co-infection, 1.64% in inactive carriers, 1.14% in HBV cirrhosis, 0.52% in chronic hepatitis B, 0.64% in HDV. No difference of HBsAg loss was observed between compensated and decompensated cirrhosis. None of HDV cirrhotics had seroclearance. 58.5% of HBV and HCV coinfected, 59% of HDV infected, 20% of chronic hepatitis B patients who had loss of HBsAg were treated with interferon or pegylated interferon. Conclusion: Although HDV infection supresses HBV replication, it does not increase the HBsAg loss rates. However, co-infection with HCV increases the seroclerance rates. HBsAg loss was markedly higher among inactive carriers comparing to chronic hepatitis.