Extending our confidence in sustained virological response

During the recent years, evidence suggestive of a clinical benefit of clearing the hepatitis C virus (HCV) among those chronically infected has been accumulating at almost the same pace by which antiviral therapy was improved. Numerous studies showed that achievement of sustained virological response (SVR) is associated with a reduced occurrence of liver-related morbidity and mortality, with strong, independent and statistically significant hazard ratios (HR) (1). This may not come as a surprise given the natural history of chronic HCV-related liver disease. Patients are indeed at risk of developing cirrhosis and, consequently, liver failure and hepatocellular carcinoma (HCC). Both these cirrhosis-related complications come with a substantial mortality risk. It is certainly plausible that elimination of the underlying cause of liver disease positively impacts the patient’s prognosis. In the current issue of Liver International, Dr Tada and colleagues extend the currently published important observations and thereby contribute to the growing body of evidence in favour of SVR. In their report, the authors assessed the clinical outcome of 1062 Japanese patients with chronic HCV infection who were treated with interferon-based antiviral regimens (587 with SVR and 475 without SVR) and 1681 patients who were not treated. All patients were followed up for at least 3 years in a HCC surveillance program, meaning that routine ultrasonography and blood tests (including the a-foetoprotein level) were performed every 3–6 months. This latter can be considered a methodological strength as it limits the possibility that relevant outcome events were missed. During the long median follow-up of 11.8 years, 574 patients developed HCC and 633 patients died. Consistent with previous cohort studies, patients who were successfully treated had a beneficial clinical outcome. The cumulative HCC incidence after 10 years of follow-up was 4.4, 14.7 and 21.3% among patient with interferon-induced SVR, patients without SVR after interferon-based therapy and patients who remained untreated respectively (P ≤ 0.015). The cumulative 10-year overall survival, an even more relevant clinical endpoint, was 97.7% among patients with interferon-induced SVR, 93.3% among treated patients without SVR and 79.2% among those who were not treated (P < 0.001). As is generally accepted, this suggested overall survival benefit of HCV eradication could be explained by a reduction in liver-related deaths. Liver-related mortality occurred among 0.8% of patients with SVR after 10 years, while this was as much as 4.3% among patient without SVR and 10.1% among untreated patients (P ≤ 0.002). Chronic HCV infection, however, is accompanied by extrahepatic symptoms as well. Although these manifestations were recognized early to negatively influence the patients’ health-related quality of life, their importance in terms of life expectancy was only recently highlighted. In a unique and large natural history study, Lee et al. showed that patients with chronic HCV infection had a cumulative non-liver-related mortality rate of 19.8% after 18 years of follow-up, which was considerably higher as compared to those patients who cleared their HCV infection (11.0%) and those who never encountered HCV (12.2%) (2). Although not as extensively as for the cirrhosis-related complications, data are slowly emerging that achievement of SVR is also associated with a reduced occurrence of solid extra-hepatic clinical endpoints such as renal failure and cardiovascular events (3, 4). These potential clinical benefits may explain the reduced occurrence of death due to extrahepatic causes in case of SVR, which Tada et al. describe here. The authors report a cumulative 10-year non-liver-related mortality of 1.5, 2.4 and 10.7% among patients with SVR, patients without SVR and untreated patients respectively (P ≤ 0.016). These results closely follow the previous findings within another large Asian cohort by Hsu et al., who included 12 384 patients with chronic HCV infection treated with interferon-based regimens and 24 768 patients who were not treated from Taiwan (3). In this study, the 8-year cumulative incidences of end-stage renal disease, acute coronary syndrome and ischaemic stroke between treated and untreated patients were 0.15% vs 1.32% (P < 0.001), 2.21% vs 2.96% (P = 0.027) and 1.31% vs 1.76% (P = 0.001) respectively. As SVR data were lacking in this cohort, detailed analyses with respect to the possible influence of the virological response to antiviral therapy were not possible. Consistent with the findings