Inherent Limitations in Evaluating Long-Term Benefit of DAA-Induced SVR

The long-term clinical benefits of sustained virologic response (SVR) induced by direct-acting antiviral (DAA) treatment among patients with hepatitis C virus (HCV) are yet to be fully elucidated, as follow-up studies of patients are too short to make strong conclusions on hard end points such as liver transplantation and mortality, according to a study recently published in Gastroenterology.

Inherent challenges in designing adequately powered studies to determine hepatic and extrahepatic benefits of DAA-induced SVR may restrict a true estimation of long-term outcomes in HCV therapy. Study researchers reviewed observational studies that assessed clinically relevant outcomes in patients treated with DAA grouped them into 3 categories: patients who achieved DAA-induced SVR compared with patients who did not achieve DAA-induced SVR, patients treated with DAAs compared with patients treated with interferon (IFN)-based regimens, and patients who received DAAs as part of routine clinical care compared with patients left untreated.

The mean combined intervention and follow-up period in 138 short-term trials to evaluate outcomes of patients randomly assigned to receive DAAs or placebo was only 34 weeks, not sufficient time to make conclusions about long-term outcomes. The extent to which IFN-based regimens and DAA-induced SVR were achieved may be confounded by clinical factors could lead to spurious conclusions and require accurate adjustment. Comparisons of the effects of IFN-based regimens vs DAA-induced SVR might be more useful if properly controlled. In addition to confounding factors, considerable selection bias can occur when attempting to compare outcomes of patients who received DAAs in the clinic with those left untreated due to presence of liver disease or non-hepatic comorbidities.

SVRs have been associated with reduction in risk for hepatocellular carcinoma (HCC) regardless of whether it’s achieved with DAAs or IFN, but this data may also be skewed, as greater absolute numbers of HCCs may be observed in older populations with more advanced liver disease. As introduction of DAAs accrues, studies of HCC incidence should be repeated.

Despite these limitations found in the observational study designs, SVR is a widely accepted, clinically relevant end point. Further studies should focus on evaluating hepatic and non-hepatic clinical outcomes in diverse populations infected with HCV.

Disclosure: Jordan J. Feld reports receiving grant and/or consulting support from Abbvie, Gilead, Janssen, and Merck.

Reference

Ioannou GN, Feld JJ. What are the benefits of a sustained virologic response to direct-acting antiviral therapy for HCV infection? [published online October 24, 2018]. Gastroenterology. doi: 10.1053/j.gastro.2018.10.033