Current and future directions for treating hepatitis B virus infection

Abstract

Hepatitis B virus (HBV) persistently infects approximately 350 million people, and approximately 600000 liverrelated deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma (HCC). The persistence of serum hepatitis B e antigen (HBeAg) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues (NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBeAg to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate.

Immunotherapy for hepatitis B in the direct acting antiviral era: Reevaluating the thymosin α1 efficacy trials in the light of a combination therapy approach

“…The alternative therapy is based on the use of antivirals (NUCs) that typically suppress virus replication but unlike interferon, do not eliminate the virus‐infected cells via generation of an immune response. Although treatment with the first generation of NUCs often resulted in the development of resistance, the second generation of NUCs has emerged as the treatment of choice as they are more potent and less likely to result in the development of resistant mutations . They are administered orally and have few side effects.…”

“…NUCs cause a decline in HBV DNA and normalization of ALT after 1‐2 years of treatment with responses ranging from 48% to 90% depending on the NUC and the population being treated. However, loss of HBeAg and development of anti‐HBe (seroconversion 12%‐21%) is infrequent and loss of HBsAg (0.5%‐8%) even more so . Unfortunately, even after many years of treatment, stopping therapy is rarely an option.…”

“…Unfortunately, even after many years of treatment, stopping therapy is rarely an option. With respect to clinical outcomes, NUCs promote long‐term suppression of viral replication and inflammation often resulting in a reversal of fibrosis and a decrease in the potential development of HCC . The long‐term commitment to therapy is the primary reason that treatment is reserved for patients who have active infection with accompanying liver injury.…”

“…Hepatitis B virus (HBV) is a hepatotropic virus that causes both acute and chronic hepatitis and infects large numbers of individuals worldwide . Prediction of typical clinical outcome is problematic, and there is considerable variability in the frequency, duration and severity of disease progression.…”

The role of peginterferon in nucleos(t)ide‐analogue‐treated chronic hepatitis B patients: A review of published literature

“…New treatment strategies for optimizing HBsAg loss are required for patients currently on NA therapy, the majority of whom are unable to achieve the ideal treatment endpoint and will likely require lifelong therapy. Switching to another NA may have limited benefits owing to the potential for development of drug resistance and cross‐resistance associated with the different NAs, resulting in virological breakthrough . On the other hand, combining NAs may not have the desired additive therapeutic effect and is only recommended as rescue therapy in rare cases where multiresistant virus strains have been analysed and treated unsuccessfully with other monotherapies, including PegIFN …”