Peginterferon Alfa-2a (40KD) Plus Lamivudine or Entecavir in Children With Immune-Tolerant Chronic Hepatitis B.

OBJECTIVE: Treatment guidelines for chronic hepatitis B (CHB) do not recommend antiviral therapy for patients in the immune-tolerant phase of the disease, which generally occurs in children who acquire hepatitis B virus (HBV) vertically and may last for decades. On the basis of promising results of a pilot study, we conducted a randomized, controlled, multicenter study to evaluate the efficacy and safety of antiviral therapy in children and adolescents with immune-tolerant CHB. METHODS: Fifty-nine children aged 3 to <18 years hepatitis B e antigen-positive with an HBV DNA titer >20,000 IU/mL and persistently normal alanine aminotransferase levels were randomized to 56 weeks of antiviral therapy with an oral nucleoside analogue [entecavir or lamivudine], combined with subcutaneous peginterferon alfa-2a from week 8, or 80 weeks of untreated observation. The primary efficacy outcome was hepatitis B surface antigen loss 24 weeks post-treatment in the antiviral therapy group or at the end of observation in the control group. RESULTS: Enrollment was terminated after the results of two similar studies showed that similar antiviral regimens were ineffective in children and adults with immune-tolerant CHB. At 24 weeks post-treatment, 1 of 26 patients in the antiviral treatment group experienced HBsAg loss (vs none of 33 patients in the control group). No serious treatment-related adverse events were reported, and no patients discontinued treatment because of adverse events. CONCLUSIONS: The antiviral regimen evaluated in this trial had an acceptable tolerability profile, but was ineffective in children and adolescents with immune-tolerant CHB.

Ritonavir-boosted danoprevir plus peginterferon alfa-2a and ribavirin in Asian chronic hepatitis C patients with or without cirrhosis.

BACKGROUND AND AIM: Chronic hepatitis C is an important public health problem in Asia. We evaluated the safety, efficacy, and pharmacokinetics of fixed-dose ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in treatment-naive Asian patients with chronic hepatitis C virus (HCV) genotype (G)1 infection. METHODS: Treatment-naive G1 patients in Taiwan, Thailand, and Korea with serum HCV-RNA level ≥ 105 IU/mL received ritonavir-boosted danoprevir 125/100 mg twice daily plus peginterferon alfa-2a/ribavirin for either 12 (noncirrhotic patients: Arm A, n = 34) or 24 weeks (cirrhotic patients: Arm B, n = 27) in this phase II open-label study. Sustained virologic response was defined as HCV-RNA < 25 IU/mL 12 weeks after end of treatment (SVR12). RESULTS: Similar SVR12 rates were achieved in Arms A (88.2%; 95% confidence interval, 73.4-95.3%) and B (88.9%; 71.9-96.2%). Most patients had G1b infection, among whom SVR12 rates in Arms A and B were 96.7% and 91.7%, respectively. The overall SVR12 rate was 94.0% in noncirrhotic Taiwanese patients (100% in the subset of G1b patients). No patients withdrew for safety reasons. Three (11%) cirrhotic patients (Arm B) experienced serious adverse events, none of which was considered to be related to treatment. No Grade 3/4 alanine aminotransferase elevations were reported. The pharmacokinetic properties of danoprevir were broadly overlapping in noncirrhotic and cirrhotic patients both on Days 1 and 14. CONCLUSIONS: Ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin produced sustained virologic response rates > 90% after 12 weeks' treatment in noncirrhotic and 24 weeks' treatment in cirrhotic Asian patients with G1b infection and was well tolerated. These regimens are well suited to countries where G1b predominates.

DAUPHINE: a randomized phase II study of danoprevir/ritonavir plus peginterferon alpha-2a/ribavirin in HCV genotypes 1 or 4.

BACKGROUND & AIMS: Danoprevir is a hepatitis C virus (HCV) protease inhibitor with activity against genotypes (G)1/G4, which is maintained at lower doses by ritonavir-boosting. We report results of a large, randomized, active-controlled phase IIb study of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a/ribavirin (P/R) in treatment-naive patients with HCV G1/4 infection. METHODS: Treatment-naive patients with HCV G1/4 infection were randomized to twice-daily danoprevir/r 200/100 mg (A, n = 92); 100/100 mg (B, n = 93); or 50/100 mg (C, n = 94) plus P/R for 24 weeks; twice-daily danoprevir/r 100/100 mg (D, n = 94) plus P/R for 12 or 24 weeks; or P/R alone (E, n = 44) for 48 weeks. Patients in the response-guided therapy arm (D) with an extended rapid virological response (eRVR2: HCV RNA <15 IU/ml during Weeks 2-10) stopped all therapy at Week 12; non-eRVR2 patients continued all treatment to Week 24. The primary efficacy endpoint was sustained the virological response (SVR24: HCV RNA <15 IU/ml after 24 weeks of untreated follow-up). RESULTS: SVR24 rates in Arms A, B, C, D and E were 89.1%, 78.5%, 66.0%, 69.1% and 36.4%, respectively, in the overall population; 83.6%, 69.6%, 60.3%, 59.2% and 38.5% in G1a-infected patients, 96.6%, 93.1%, 73.1%, 78.4% and 28.6% in G1b-infected patients and 100%, 87.5%, 100%, 100% and 66.7% in G4-infected patients. Danoprevir/r plus P/R was generally well tolerated compared with P/R alone. There was a higher incidence of serious adverse events in danoprevir-treatment arms, but most were associated with P/R. CONCLUSIONS: The combination of danoprevir/r plus P/R is efficacious in treatment-naïve patients with HCV genotype 1 or 4 infection.