Norio Hayashi

Background Vaniprevir is a potent macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. This phase III study evaluated the safety and efficacy of vaniprevir in combination with peginterferon alfa-2b and ribavirin (PR) for 24 weeks compared with PR alone for 48 weeks in treatment-naive Japanese patients with HCV genotype 1 infection. Methods Treatment-naive Japanese patients with HCV genotype 1 infection were randomly assigned to receive vaniprevir (300 mg twice daily) plus PR for 12 weeks then PR alone for 12 weeks, vaniprevir (300 mg twice daily) plus PR for 24 weeks, or PR alone for 48 weeks. The primary end point was sustained virologic response 24 weeks after completion of treatment (SVR₂₄). Results In total, 294 patients were randomly assigned to receive treatment. Most patients had HCV genotype 1b infection (98 %, 288 of 294 patients). SVR₂₄ was achieved in 83.7, 84.5, and 55.1 % of the patients in the vaniprevir 12-week, vaniprevir 24-week, and control arms, respectively. The difference in SVR₂₄ rates between each vaniprevir arm and the control arm was statistically significant (p < 0.001 for both). Relapse was commoner in the control arm (29.5 %) than in the vaniprevir arms (8.6 % and 10.5 % for the 12-week and 24-week arms, respectively). Commonly reported adverse events were generally similar across treatment arms, with the exception of an increase in the incidence of gastrointestinal adverse events such as nausea, diarrhea, and vomiting in patients receiving vaniprevir. These events were considered manageable. Conclusion Vaniprevir is a valuable addition to the therapeutic options available to Japanese patients with HCV genotype 1 infection who are eligible for interferon-based treatment. ClinicalTrials.gov identifier NCT01370642.

Vaniprevir (MK-7009) is a hepatitis C virus (HCV) non-structural 3/4a protease inhibitor which significantly increases virologic response rates in HCV genotype (GT) 1-infected patients when added to peginterferon and ribavirin (PR).

Background Efficacy, safety and pharmacokinetics of simeprevir (TMC435), a once-daily, noncovalent, oral hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in combination with peginterferon α-2a/ribavirin (PegIFNα-2a/RBV) for treatment-naïve, HCV genotype 1-infected patients in Japan. Methods In a multicenter, randomized clinical trial in Japan, ninety-two patients received either simeprevir (50 or 100 mg QD) for 12 or 24 weeks with PegIFNα-2a/RBV for 24 or 48 weeks (according to response-guided therapy [RGT] criteria), or PegIFNα-2a/RBV for 48 weeks (PR48 group). Results Compared with the PR48 group, plasma HCV RNA reductions in the simeprevir groups were rapid and more substantial (Week 4: −5.2, −5.2 and −2.9 log₁₀IU/mL for simeprevir 50 mg combined, 100 mg combined, and PR48 groups, respectively). High rapid virologic response rates (83, 90, and 8 % for simeprevir 50 mg combined, 100 mg combined, and PR48 groups, respectively) led to high sustained virologic response rates (77–92 %, compared with 46 % for PR48). All but one of the simeprevir-treated patients were eligible to complete treatment after 24 weeks (RGT). Relapse rates in simeprevir-treated patients were low (8–17 %, compared with 36 % for the PR48 group). There were no notable differences in the safety profile between the simeprevir and PR48 groups. Conclusions The addition of simeprevir QD to PegIFNα-2a/RBV, as compared with PegIFNα-2a/RBV alone, demonstrated potent antiviral activity and significantly improved the rates of sustained virologic response, with a shortened 24-week treatment duration, in treatment-naive patients infected with HCV genotype 1 in Japan. Simeprevir was generally safe and well tolerated. (ClinicalTrials.gov number, NCT00996476).

B型慢性肝炎に対するペグインターフェロンアルファ-2a（PEG-IFNα-2a）の有効性，安全性を検討した． HBe抗原陽性例はPEG-IFNα-2a 90 μg，180 μg/週の各々24週投与，48週投与又は天然型IFNα6 MIU週3回24週投与（HLBI群）の5群に無作為割付けし，投与終了後24週時のALT正常化，HBeセロコンバージョン及びHBV-DNA量抑制の複合評価で有効性を評価した． PEG-IFNα-2a群では用量，投与期間に応じて高い有効率を示した．PEG-IFNα-2a 48週併合群とHLBI群の有効率の差は11.3％（95％CI：0.0-22.6）とHLBI群に対し非劣性が検証され，安全に使用できた． HBe抗原陰性例に対するHBV-DNA抑制率は，180 μg，90 μg/週48週投与でそれぞれ37.9％，37.5％であった． 以上，B型慢性肝炎に対する有効性，安全性が確認された．

Summary.  The aims of this phase III study were to assess the efficacy and safety of telaprevir in combination with peginterferon alfa‐2b (PEG‐IFN) and ribavirin (RBV) for difficult‐to‐treat patients who had not achieved sustained virological response (SVR) to prior regimens in Japan. The subjects were 109 relapsers (median age of 57.0 years) and 32 nonresponders (median age of 57.5 years) with hepatitis C virus genotype 1. Patients received telaprevir (750 mg every 8 h) for 12 weeks and PEG‐IFN/RBV for 24 weeks. The SVR rates for relapsers and nonresponders were 88.1% (96/109) and 34.4% (11/32), respectively. Specified dose modifications of RBV that differed from that for the standard of care were introduced to alleviate anaemia. RBV dose reductions were used for 139 of the 141 patients. The SVR rates for relapsers did not depend on RBV dose reduction for 20–100% of the planned dose (SVR rates 87.5–100%, P < 0.05). Skin disorders were observed in 82.3% (116/141). Most of the skin disorders were controllable by anti‐histamine and/or steroid ointments. The ratios of discontinuation of telaprevir only or of all the study drugs because of adverse events were 21.3% (30/141) and 16.3% (23/141), respectively. A frequent adverse event leading to discontinuation was anaemia. Telaprevir in combination with PEG‐IFN/RBV led to a high SVR rate for relapsers and may offer a potential new therapy for nonresponders even with a shorter treatment period.