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.

Efficacy of thymosin α-1 plus peginterferon α-2a combination therapy compared with peginterferon α-2a monotherapy in HBeAg-positive chronic hepatitis B: a prospective, multicenter, randomized, open-label study.

OBJECTIVE: Thymosin α-1 plus interferon α-2a offers superior efficacy over interferon α-2a alone in patients with chronic hepatitis B. The aim was to compare the antiviral efficacy of thymosin α-1 plus peginterferon α-2a and peginterferon α-2a alone in HBeAg-positive chronic hepatitis B patients. MATERIALS AND METHODS: HBeAg-positive CHB patients were enrolled in this prospective, randomized, open-label study. Fifty-one patients were assigned to either combination (26 patients; 180 µg of peginterferon α-2a weekly for 48 weeks and 1.6 mg of thymosin α-1 twice a week for the first 12 weeks) or monotherapy (25 patients; 180 µg of peginterferon α-2a weekly for 48 weeks) groups. RESULTS: The rates of the combined response, defined as HBeAg seroconversion, HBV DNA suppression, and normalization of serum ALT, were 4/26 (15.4%) and 3/25 (12.0%) for the combination group and the monotherapy group at the end of treatment (p = 0.725), and 6/26 (23.1%) and 5/25 (20.0%) at the end of follow-up (p = 0.789), respectively. Based on multiple logistic regression analysis, a >2 log10 IU/mL reduction of HBV DNA at week 12 was identified as an independent predictor for combined response (OR, 9.72; 95% CI, 1.33-71.06; p = 0.025) at the end of follow-up. A lower pretreatment HBV DNA level (≤ 7 log(10) IU/mL) was another predictor for combined response (OR, 9.64; 95% CI, 1.23-75.32; p = 0.031). No significant differences in adverse events were observed. CONCLUSIONS: The short-term addition of thymosin α-1 was not superior to peginterferon α-2a alone in HBeAg-positive CHB patients on the basis of antiviral efficacy.

Serum HBsAg levels during peginterferon α-2a treatment with or without thymosin α-1 in HBeAg-positive chronic hepatitis B patients.

The importance of serum hepatitis B surface antigen (HBsAg) level as a surrogate marker for viral load and a predictor of treatment response remains unclear. The aim of this study was to investigate whether serum HBsAg correlates with serum hepatitis B virus (HBV) DNA during peginterferon (PEG-IFN) α-2a treatment (with or without thymosin α-1) in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients and whether it can predict treatment response. Sera from 37 HBeAg-positive chronic hepatitis B patients receiving 48-weeks PEG-IFN α-2a with (n = 20) or without (n = 17) an initial 12-weeks thymosin α-1 were obtained at baseline and at weeks 12, 24, 36, 48 (end of treatment), 56, 72, 84, and 96 (end of follow-up). Taqman HBV DNA tests (Roche) and Architect HBsAg QT (Abbott) were performed. There was a moderate correlation between the HBsAg and HBV DNA levels (r = 0.452, P < 0.001). Median HBsAg levels at baseline and at week 96 were 6,218 IU/ml and 4,038 IU/ml, respectively. The mean HBV DNA and alanine aminotransferase (ALT) levels were 7.48 log(10) IU/ml and 173 IU/L at baseline and 5.37 log(10) IU/ml and 102 IU/L at week 96, respectively. A decrease to <60% of baseline levels of HBsAg at week 12 was identified as an independent predictive factor for HBeAg seroconversion (OR = 45.7, P < 0.05) at week 96. Serum HBsAg levels may be helpful for predicting the response to PEG-IFN therapy in HBeAg-positive chronic hepatitis B patients.

A phase IIIb study of ledipasvir/sofosbuvir fixed-dose combination tablet in treatment-naïve and treatment-experienced Korean patients chronically infected with genotype 1 hepatitis C virus.

BACKGROUND: The standard-of-care regimen for chronic hepatitis C virus (HCV) infection in Korea, pegylated-interferon-alpha plus ribavirin, is poorly tolerated. Ledipasvir/sofosbuvir is a two-drug, fixed-dose combination tablet approved in the USA, European Union, and Japan for chronic genotype 1 HCV infection. METHODS: This single-arm, phase IIIb study (NCT02021656) investigated the efficacy and safety of ledipasvir/sofosbuvir fixed-dose combination tablet for 12 weeks in treatment-naïve and treatment-experienced Korean patients chronically infected with genotype 1 HCV with or without compensated cirrhosis. RESULTS: The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 99 % (92/93), with rates of 100 % (46/46) and 98 % (46/47) in treatment-naïve and treatment-experienced patients, respectively. There were no on-treatment failures. One patient relapsed after the end of treatment. The most common treatment-emergent adverse events were headache (8 %, 7/93) and fatigue (6 %, 6/93). There were no grade 3 or 4 adverse events, seven grade 3 laboratory abnormalities, and one premature discontinuation of study treatment (due to nonserious mouth ulceration). None of the three reported serious adverse events were related to treatment. CONCLUSIONS: These data suggest that 12 weeks of ledipasvir/sofosbuvir is effective and well tolerated in treatment-naïve and treatment-experienced Korean patients with chronic genotype 1 HCV infection.