Liver Pathologic Changes After Direct-Acting Antiviral Agent Therapy and Sustained Virologic Response in the Setting of Chronic Hepatitis C Virus Infection

Abstract

Context.— Treatment of chronic viral hepatitis C (HCV) infection with direct-acting antiviral agents (DAAs) results in cure, or sustained viral response (SVR), in more than 90% of patients. However, there are subsets of patients who have persistent liver inflammation and fibrosis and develop hepatocellular carcinoma (HCC) despite achieving SVR. A possible reason for these phenomena may be the presence of virus particles in liver tissue but not blood, otherwise defined as occult infection. Objective.— To describe liver histologic findings following successful DAA therapy, test HCV RNA by (liver) tissue polymerase chain reaction in treated cases, and identify predictive markers for HCC development in treated cases. Design.— A total of 96 identified patients were divided into 4 groups, each differentiated by the presence or absence of SVR and HCC. Groups were compared for several clinicopathologic variables, including degree of inflammation and fibrosis, and the ‘directionality' of fibrosis in cirrhotic livers using the novel progressive-indeterminate-regressive scoring system. Results.— Overall, we found a significant decrease in inflammation in SVR patients. None of the patients showed regression of their cirrhosis following treatment. No evidence of occult HCV infection was seen in 40 livers tested, including 21 with HCC. The number of patients who developed HCC was similar in the SVR and non-SVR groups, and increased inflammation and fibrosis were associated with HCC development. Conclusions.— Following DAA-SVR there appears to be an overall decrease in inflammation, but the fibrosis tends to persist, at least in the short term (median follow-up of 20.2 months).

Comparison of liver biopsies before and after direct-acting antiviral therapy for hepatitis C and correlation with clinical outcome

“…However, in the absence of virus, ongoing inflammation is proposed to be immunologically driven 35 . Some studies have reported that this inflammation has no effect on patient outcomes, while others propose that it causes fibrosis persistence 37 and the development of HCC 38 . Observations that helped distinguish the persistent inflammation in this study from other types of active hepatitis included that the inflammation was isolated to the portal tracts, the biopsies lacked interface and lobular activity, and that all the patients had normal transaminases.…”

“…DAA therapies have only been available since 2011, therefore, long term studies of HCC development in the presence of persistent inflammation and fibrosis are limited when compared to those with IFN-based regimens. Short term studies seem to suggest that the presence of increased inflammation and fibrosis are associated with hepatocarcinogenesis 37 . Discrepancies in the literature may be explained by differences in patient demographics, such as older age, presence of other risk factors such as diabetes mellitus, and those who had impaired liver function with less frequent screening 47 .…”

The utility of P-I-R classification in predicting the on-treatment histological and clinical outcomes of patients with hepatitis B and advanced liver fibrosis

“…[15] Several studies further validated the utility of P-I-R classification in evaluating fibrosis regression in patients with chronic HBV or HCV infection. [16][17][18] However, whether this classification could predict the on-treatment clinical outcomes in patients with chronic hepatitis B (CHB) is still unknown.…”

“…The P-I-R classification had reduced interobserver variation and could identify fibrosis changes not identified by the Ishak score changes 15 . Several studies further validated the utility of P-I-R classification in evaluating fibrosis regression in patients with chronic HBV or HCV infection 16–18 . However, whether this classification could predict the on-treatment clinical outcomes in patients with chronic hepatitis B (CHB) is still unknown.…”

Patients with advanced hepatic fibrosis before or after direct-acting antiviral therapy for chronic hepatitis C are at risk for development of liver cancer

“…However, in the absence of virus, ongoing in ammation is proposed to be immunologically driven [34] . Some studies have reported that this in ammation has no effect on patient outcomes, while others propose that it causes brosis persistence [36] and the development of HCC [37] . Observations that helped distinguish the persistent in ammation in this study from other types of active hepatitis included that the in ammation was isolated to the portal tracts, the biopsies lacked interface and lobular activity, and that all the patients had normal transaminases.…”