The HBV Drugs Work: Now What?

Abstract

Chemotherapeutic agents for Hepatitis B virus (HBV) suppression work, but only when administered to the patient. They do not appear to promote durable, long-term immunological control. After 3 years of effective anti-HBV therapy, a small percentage of patients maintained good control, manifest by controlled serum liver enzymes, low-level HBV-DNA, and controlled HBsAg concentrations. However, this did not occur in the majority of patients. We need a better understanding of the defects in HBV immunity and how to induce effective reconstitution that will maintain viral suppression, albeit either through innate or adaptive immunity. Am J Gastroenterol 2016; 111:1295-1296 doi: 10.1038/ajg.2016 Chronic Hepatitis B infection continues to be a long-term management conundrum despite a growing armamentarium of eff ective nucleos/tide analogs (NAs). Th e article by Wang et al. ( 1 ) discusses the clinical end points aft er the completion of 3 years of eff ective anti-Hepatitis B virus (HBV) therapy (entecavir). Th ere are two interesting issues surrounding the NA therapy for chronic HBV that are highlighted by this study: one is medical and the other is methodological and social.Th e biology of chronic viral infections continues to unfold. Current reverse-transcriptase inhibitors, although eff ective at suppressing viral replication, are rarely curative, putatively because the covalently closed circular HBV-DNA is thought to be unaff ected by the agents. With cessation of NA therapy, viral replication resumes as the genome persists with no eff ective means to prevent its resumption. Th is study confi rms that for the majority of HBV participants, viral replication will resume with ongoing liver damage aft er completion of 3 years of entecavir therapy.However, the authors identifi ed a few individuals with persistent low level of viral detection (HBV-DNA<2,000 IU/ml and hepatitis B surface antigen (HBsAg)<1,000 IU/ml) aft er 6 months without Entecavir, which appeared likely to maintain a viral hepatitis-"free" course. Th is was a clinical success, and not virological, but nonetheless these patients persisted without clinical hepatitis. In contrast to this, the "old" interferon-based therapy, where, although HBV response occurred at a low frequency, those that did respond had a sustained, durable viral suppression ( 2 ). Why is it that the current NA-based therapies, although inducing a high viral response, fail to produce durable viral control? Chronic HBV is commonly described to be the consequence of "immune exhaustion" ( 3-5 ), a perturbation of innate and adaptive immunity thought to be the consequence of antigenic overstimulation from excess viral products. Why aft er 3 years of viral suppression and substantial reduction in antigen exposure, the immune response has not re-established a state that will prevent the virus from replicating? Th is is a repetitive fi nding with other studies demonstrating that over 80% of the individuals with chronic HBV will relapse aft er stopping eff ective anti-HBV therapy (...