教育演講6:慢性C型肝炎治療的新進展
Advance in the treatment of chronic hepatitis C

程 序 表

E6-4
Horizon of IFN-free DAAs regimen
Ming-Lung Yu
Professor of Medicine
Hepatitis Center and Department of Internal Medicine
Kaohsiung Medical University Hospital, Kaohsiung Medical University

  For the past decade, the standard-of-care (SOC) for chronic hepatitis C (CHC) has been pegylated interferon (PegIFN) plus ribavirin (RBV). With the approval of two direct acting antiviral agents (DAA), boceprevir and telaprevir—two protease inhibitors, the SOC for HCV genotype-1 (HCV-1) infection, the main genotype worldwide, is now triple therapy with PegIFN, RBV and a protease inhibitor (PI), based on response-guided algorithms. PI-triple therapies have much improved the sustained virological response (SVR) rate in both in treatment-naive and treatment-experienced HCV-1 patients, especially among those regarded as difficult-to-treat, such as individuals with cirrhosis, carriage of IL28 unfavorable genotype and those who do not achieve a rapid virological response (RVR) at treatment week 4 (W4). However, despite enhancing the SVR rates, PIs have increased several issues needed for clinical concern, including interferon/RBV-dependent responses, frequency and intensity of adverse effects, high costs, increased pill burden, drug-drug interactions, and emergence of viral resistance variants. These issues might potentially restrict future treatment options for patients who consequently do not achieve an SVR and for patients who are IFN-ineligible or intolerant.

  Recently, there is much enthusiasm in the field for the development of interferon-free HCV regimens, and numerous candidate regimens are under active investigation in clinical trials worldwide. Although some regimens undoubtedly hold great promise, some of the data generated by these studies indicates that much more work remains to be done. The first reported interferon-free regimen is the combination of daclatasvir (a NS5A inhibitor) and asunaprevir (a 2nd generation PI) for HCV-1 patients. It has been highly effective for HCV subtype-1b patients, whatever treatment-naive or –experienced. Beyond this, encouraging results were reported for combining daclatasvir and sofosbuvir (a nucleotide NS5B polymerase inhibitor), with or without RBV, for the treatment of patients infected with HCV genotypes 1–3. In a phase 2a trial, a 12-week of ABT-450 (a 2nd generation PI)/ritonavir, ABT-333 (a nonnucleoside polymerase inhibitor) and RBV produced SVR12 in 93% to 95% of treatment-naive HCV-1 patients, but only 47% in treatment-experienced HCV-1 patients. In a phase 2b trial (SOUND-C2) of faldaprevir (a 2nd generation PI) and deleobuvir (a nonnucleoside polymerase inhibitor) for treatment-naive HCV-1 patients for 16, 28, or 40 weeks with and without RBV, SVR12 were 52%-69% in those treated with two DAAs + RBV, but only 39% in those treated with two DAAs only. Alisporivir (a host targeting agent) plus RBV achieved high in HCV-2/3 patients if patients had W4 RVR. In phase 3 trials, 12 week of sofosbuvir plus ribavirin could achieve an SVR12 rate of 97% for treatment-naive HCV-2 patients, but only 56% for treatment-naive HCV-3 patients (FISSION); 93% for IFN-ineligible HCV-2 patients, but only 61% for IFN-ineligible HCV-3 patients (POSITRON). For treat-experienced patients, the SVR12 rates of 12-week vs. 16-week regimens were 86% and 94%, respectively, for HCV-2 patients, compared with 30% and 62%, respectively, for HCV-3 patients (FUSSION). The current data suggest that HCV-1a, treatment-experienced HCV-1 and HCV-3 remain unmet issues for current IFN-free regimens.

  The prospects for achieving SVR with future HCV regimens will clearly depend on both the potency and barrier to resistance of the specific combination. In addition, adverse events and tolerability will be key factors when evaluating novel regimens. A key challenge in assessing new combinations will be to identify predictors of response, such as previous treatment experience, use of RBV, and treatment duration. In the near future, there will be many more choices for treatment of chronic HCV infection.