Continued Progress Against Hepatitis C Infection
Authors: Hari Conjeevaram
Journal: JAMA (2015)

The worldwide epidemic of hepatitis C virus (HCV) infection affects more than 130 million people,1 includes healthrelatedoutcomes suchas cirrhosis, reducesquality of life, and poses economic burden on societies. Yet, there has been progress in achieving HCV eradication, reaching sustained virological response (SVR) rates of 90% to 100%, even amongpatientswith characteristics associatedwith lower response rates (ie, black/African American race, high viral load, HCV 1a subgenotype, presence of cirrhosis, and prior null response to then-available standard therapies).Additional progress has beenmade in reducing the effect of the epidemic because the majority of the new drug regimens are orally administered and interferon free, and some are ribavirin free as well. The availability of these regimens has resulted in improved tolerability of antiviral therapy, while broadening the potential use of these agents in several settings in which interferon, ribavirin, or both are contraindicated or difficult to administer. In this issue of JAMA, Poordad and colleagues2 and Muir and colleagues3 report the results of 2 multinational studies evaluating viral eradication rates with an all-oral interferon (IFN)-free drug combination using daclatasvir (an NS5A inhibitor), asunaprevir (anNS3protease inhibitor), andbeclabuvir (a nonnucleoside NS5B inhibitor) in 415 patients infected with HCV genotype 1 who did not have cirrhosis,2 and in 202 patients who had compensated cirrhosis.3 In both studies, treatmentdurationwas for 12weeksand includedpatientswho were treatment naive (312 patients without cirrhosis2 and 112 patients with cirrhosis3) and patients who failed prior treatment regimenswith IFN-basedcombination therapies.Theadditional role of ribavirinwas also studied amongpatientswith cirrhosis. As observed in several recently published studies using all-oral regimens with or without ribavirin, Poordad et al2 report that rates of SVR in patients who were noncirrhotic and using the triple drug oral regimen without ribavirin were high, with an overall SVR12 rate of 91% (92% in patients in the treatment-naive group and 89% in patients in the treatment-experienced group).2 Nearly three-quarters of patients had genotype 1a and the SVR12 rate was lower compared with genotype 1b patients (overall, 89% vs 98%) and especially in patients who were treatment experienced (85% vs 100%). Similar rates of SVR12 were also reported by Muir et al3 among patients with compensated cirrhosis. The addition of ribavirin appeared to benefit only those patients who were in the treatment-experienced group. The overall SVR12 rates among patients whose regimens included ribavirin were 98% in the treatment-naive group and 93% for those in the treatment-experienced group; and for those without ribavirin, overall SVR12 rates were 93% in the treatmentnaive group and 87% in the treatment-experienced group. Even prior null responders (patients who did not obtain viral suppression) responded very well to the treatment combination with and without ribavirin, although overall numbers of patients were small. Similar to thepatientswhowerenoncirrhotic, SVR12 rates were loweramongpatientswithgenotype1a, especiallyamong those who were treatment experienced and who did not receive additional ribavirin (86%) vs those who did (91%). The majority of treatment failures were related to relapse followedbybreakthrough response. Thepresence of resistanceassociated variants to at least 2 drugs predicted relapse, whereas resistance-associated variants to all 3 drugs predicted a breakthrough response. As with other all-oral IFNfree regimens, treatmentwith the tripledrugcombinationwas well tolerated, with few serious adverse events attributed to theantiviral regimensand fewadverse events leading to treatment discontinuation (0.7%-1.9%). These 2 studies2,3 add to the armamentarium of all-oral IFN-free regimens that have revolutionized management of hepatitis C, not only for patients who are treatment naive with no significant liver disease but also for those who are treatment experienced and those with cirrhosis. Several recent studies have shown high rates of SVR with these regimens in all genotypes and with treatment as short as 8 weeks in some patients with treatment naive HCV genotype 1 infection. Among patients without cirrhosis, rates of SVR have exceeded 90% among patients who are treatment naive as well as treatment experienced, even without ribavirin. Although similar SVR rates have been reported among patients who are treatment naive with cirrhosis with 12 weeks’ therapy, the addition of ribavirin or extension of treatment to 24 weeks appears to be warranted with some regimens. The high response rates, especially among patients with cirrhosis, is substantial and important clinically, given that viral eradication has been shown to delay or decrease chance of decompensation of liver disease and also hepatocellular carcinoma. Despite the progress and the success of viral eradication, numerous questions remain unanswered such as response based on race, still difficult-to-treat situations such as patients with end-stage liver disease or undergoing hemodialysis, access to and affordability of these therapies, improvement inqualityof life,andcost-effectiveness. It is timetoreflect on these challenges and find solutions because the influence of HCV infection on global society is an ongoing challenge. Related articles pages 1728 and 1736 Opinion