For the first time in several years, we did not see the presentation of dramatic data from phase III trials of emerging investigational HCV therapies at the American Association for the Study of Liver Diseases (AASLD) meeting. What we learned is that we likely now have the full complement of direct-acting antivirals (DAAs) and - unfortunately - that some relatively promising regimens that were in clinical development are unlikely to come to clinical use.

What did emerge at the meeting were several studies that provided critical evidence that treatment with DAAs leads to important clinical benefits for patients with HCV infection. Although these types of studies can feel like something of a foregone conclusion, they are actually critical for payers, policymakers, and clinicians to be confident that contemporary HCV therapies are associated with the intended benefits.

DAA Therapy and the Risk of Mortality and HCC 
When we treat patients, our goal is always to improve and prolong life; however, most HCV treatment studies are not powered to look at survival. As such, we rely on real-world cohorts to demonstrate this benefit. It took many years to demonstrate the benefits of interferon-based therapy, but landmark studies did show a benefit in liver-related and all-cause mortality in those who received therapy and achieved sustained virologic response (SVR).

Despite the strength of the association between SVR and outcome, some questioned whether it was possible that SVR was simply a marker of good liver disease prognosis. It was, therefore, important to demonstrate the association between SVR and outcomes when HCV treatment moved into the DAA era.

Several studies presented at the AASLD meeting assessed the clinical benefits of SVR following DAA therapy. An observational cohort study from the ANRS in France assessed the short-term effects of DAAs on mortality risk, comparing 6460 patients with HCV who received DAA treatment with 2835 patients with HCV who did not receive DAA treatment. The median follow-up was 24 months. Critical to this study was the use of inverse probability of treatment weighting (IPTW) to ensure that the patients in each study group were similar.

Compared with patients who did not receive DAA treatment, patients who received DAA therapy had lower all-cause death, with an adjusted HR of 0.65 (a 35% reduction in risk). Of importance, this reduction in risk was seen at just 2 years after treatment.

Similar data emerged in a large retrospective cohort study of the VA healthcare system, which assessed the relationship between SVR and hepatocellular carcinoma (HCC) risk in 62,354 patients with HCV receiving antiviral therapy between 1999 and 2015. In patients who received either DAA therapy or interferon therapy, SVR was associated with a marked reduction in the risk of HCC compared with no SVR (SVR with a DAA regimen was associated with 71% decrease in HCC risk). This reduction in risk was observed regardless of cirrhosis status. Of interest, the adjusted HR for HCC was similar if the patients achieved SVR with interferon (0.32) or DAAs (0.29).

Another study from the VA assessed mortality risk in patients with HCV who had advanced chronic liver disease (N = 15,059). Of importance, patients who achieved SVR had a 79% reduced risk of mortality and 85% reduced risk of HCC.

Take-home Points 
These data collectively give us more confidence that DAAs are delivering on their promise - that treating patients with HCV does, in fact, reduce their risk of death and liver cancer, even among cirrhotics. This is particularly important given the controversy that was raised about a possible association of cancer with DAAs. As we continue to accumulate data, we hope to expand treatment to move toward the World Health Organization elimination goal of reducing mortality from viral hepatitis by 65% by the year 2030. These data suggest that we are on the right track.