Low‐level viremia in hepatitis b patients on antiviral treatment: Can we ignore it?

In the landmark REVEAL study on the natural history of patients infected with hepatitis B virus (HBV), an association between baseline HBV DNA levels and the risk of cirrhosis and hepatocellular carcinoma (HCC) was established. With the goal of antiviral treatment being to decrease the morbidity and mortality associated with chronic hepatitis B (CHB), the first-line antiviral agents recommended for treating CHB patients by the American Association for the Study of Liver Diseases (AASLD) include pegylated interferon, entecavir, and tenofovir. With their easy tolerability and efficacy in suppressing viral replication associated with high genetic barrier to resistance, many patients with HBV worldwide were treated with either oral agent, often achieving reversal of cirrhosis and reduced incidence of HCC. One question posed in the recently updated AASLD guidelines for management of CHB was whether there would be a role for adding a second antiviral agent with persistent low-level viremia (LLV; <2000 IU/mL) while on entecavir or tenofovir. The guidelines suggest that such CHB patients with LLV continue monotherapy. This approach was demonstrated in a European cohort study in which long-term entecavir monotherapy led to a virologic response in the vast majority of treatment-na€ıve patients, including those with a partial virologic response after 48 weeks of treatment. In this issue of HEPATOLOGY, a large retrospective study by Kim and Sinn et al. indicates that among patients on antiviral therapy, LLV, defined as persistent or intermittent episodes of HBV DNA greater than the lower detection limit of 12 IU/mL but <2000 IU/mL, was associated with a higher risk of developing HCC when compared with those who maintained virologic response (MVR) with persistently undetectable HBV DNA levels. Previously treatment-na€ıve 875 patients were treated with entecavir for at least 1 year. During a median follow-up of 4.5 years, 85 patients (9.7%) developed HCC. Overall, the development of HCC was more frequent in patients with LLV than MVR (14.3% versus 7.5% at 5 years, P 5 0.016). On multivariate analysis, LLV was an independent risk factor associated with HCC development (HR 5 1.98, P 5 0.002). However, although patients who have cirrhosis with LLV had a higher risk of developing HCC than those with cirrhosis and MVR, among patients without cirrhosis there was no statistically significant difference in the risk of HCC occurrence between patients with LLV and those with MVR, possibly due to a lower risk of HCC in that population than in patients with cirrhosis. Achieving MVR even in noncirrhotic patients may still be important, but we would need a study with a much larger sample size and/or a longer follow-up to show such impact, including stratified analysis by age and sex that may be helpful in accounting for the effect of those strong covariates. Thus, at least for CHB patients with cirrhosis, presence of LLV while on entecavir or tenofovir may not be ignored with a higher risk of developing HCC than those with MVR. Abbreviations: AASLD, American Association for the Study of Liver Diseases; CHB, chronic hepatitis B; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LLV, low-level viremia; MVR, maintained virologic response.