Clevudine for the treatment of chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is a major health problem that is responsible for ≤ 1 million deaths and 500,000 cases of hepatocellular carcinoma worldwide each year. Drugs that are currently approved by the FDA for the treatment of chronic HBV consist of two groups: the immunomodulators, such as conventional IFN-α and pegylated IFN-α2a; and nucleoside/nucleotide analogues, such as lamivudine, adefovir dipivoxil and entecavir. However, due to the limitations of these agents, newer agents with improved efficacy are currently being developed. One nucleoside/nucleotide analogue that is drawing a wide range of interest is clevudine, which is an analogue of the unnatural β-L configuration. In the woodchuck hepatitis virus (WHV), clevudine 10 mg/kg has proven to be effective in suppressing viral replication with ≤ 9 log₁₀ decreases in WHV. At this dose, a significant reduction of intrahepatic WHV RNA and covalently closed circular WHV DNA levels can also be observed. Treatment with clevudine 10 mg/kg can confer additional antiviral benefit in the form of a more sustained reduction in WHV replication, serum woodchuck hepatitis surface antigen and intrahepatic woodchuck hepatitis core antigen expression following the withdrawal of clevudine. In humans, clevudine 10, 50, 100 or 200 mg/day for 28 days can reduce the median HBV DNA by -2.5, -2.7, -3 and -2.6 log₁₀, respectively. More importantly, this suppression of antiviral activity is maintained at 12 and 24 weeks post treatment. Based on the early results of clevudine, more large-scale human studies with clevudine monotherapy or combination therapy is eagerly awaited.     

Clevudine: a promising therapy for the treatment of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection, affecting ～ 350 million people worldwide, is associated with significant morbidity and mortality. In the past 10 years, hepatitis B therapy research has led to a multitude of available antiviral therapies: IFN-α, pegylated IFN-α_2a, lamivudine, adefovir, entecavir, telbivudine and tenofovir. To further improve reductions in viral load and resistance profiles, development of new HBV therapeutic strategies has been an important focus. One such therapy is clevudine, an analogue of the β-L configuration. Clevudine is already licensed in Korea for anti-HBV therapy (Bukwang Pharmaceuticals, Seoul, Korea). Unique to clevudine is its ability to maintain antiviral activity following discontinuation of therapy. Typically, hepatitis B treatment requires continuous therapy to prevent reactivation. Sustained response is uncommon except in hepatitis B antigen (HBeAg)-positive patients who developed HBeAg seroconversion. This article reviews chronic HBV and its therapy options. Specifically, it describes clevudine's potent and sustained antiviral activity as observed in vitro and in vivo.     

Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection

Introduction: In April 2017 tenofovir alafenamide (TAF) was added to the list of first-line therapies recommended for chronic hepatitis B (CHB). TAF has pharmacology similar to tenofovir disoproxil fumarate (TDF) with higher cell delivery to the hepatocytes but less systemic exposure.

Areas covered: We review here studies leading to TAF’s approval and comparing it to TDF. In two major clinical trials, TAF was non-inferior to TDF in achieving HBV DNA levels below 29 IU/ml. TAF-treated patients had significantly smaller decreases in bone mineral density (BMD) at the hip and spine in both HBeAg-positive and HBeAg-negative patients, and smaller mean increases in serum creatinine, although the difference was only statistically significant in HBeAg-positive patients. Patients treated with TDF for 96 weeks and then switched to TAF had improvements in renal and BMD measures only 24 weeks after switching.

Expert commentary: With clear evidence from major studies showing that TAF is safe, tolerable, and non-inferior to TDF, its recommendation as a first-line therapy is appropriate. Longer term follow up will be required to determine if the differences in adverse bone and kidney effects seen with TAF in comparison to TDF will be clinically relevant.     

Evolving therapies for the treatment of chronic hepatitis B virus infection

Despite the availability of prophylactic vaccines lamivudine and IFN-alpha, chronic hepatitis B remains an enormous global health problem. Several promising nucleosides/nucleotides are undergoing clinical trials, including adefovir dipivoxil, the latter of which is active against lamivudine-resistant hepatitis B virus (HBV). In addition to nucleosides/nucleotides, it will be important to develop new agents with different modes of action. Novel small molecule inhibitors, as well as gene therapy approaches, have produced encouraging results in vitro and in animal models. Additional immunomodulatory therapies, including thymosin-alpha 1, IL-12 and several therapeutic vaccines, are also being explored. Combination therapy with multiple nucleosides/nucleotides and other agents will play an important role in the treatment of hepatitis and may help achieve complete viral suppression, host-mediated elimination of infected cells and lasting immunity.     

Recent developments in the treatment of chronic hepatitis B virus infection

Infectious diseases are the major cause of death worldwide; in developing countries such diseases are responsible for nearly half the burden of premature death and disability. Therefore, the need for the development of new vaccine strategies aimed at preventing or limiting disease is extremely urgent. Important successes have been achieved against some infectious diseases that were once endemic or, even, epidemic (e.g., polio, smallpox, diptheria). Advances in our knowledge of the pathogenesis and immune correlates of protections are needed to develop novel vaccinal approaches to diseases such as hepatitis C, AIDS and malaria. In this review we will analyse the biological problems associated with the prevention of development and/or improvement of vaccine strategies for infectious diseases, focusing on the difficulties facing the creation of new effective vaccines for HIV infection and malaria.     

Novel treatment options for hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection affects between 350 and 400 million people globally. Interferon-alpha, lamivudine and adefovir (Hepsera) are approved for the treatment of chronic hepatitis B; however, the use of interferon-alpha is limited. Lamivudine and adefovir have excellent antiviral activity and oral bioavailability, although viral rebound after cessation of therapy and development of resistance after long-term therapy with lamivudine are major clinical limitations. Adefovir has proven to be effective against lamivudine-resistant strains in vitro and in vivo. The various steps of HBV replication provide opportunities for new antiviral drugs to interact with the virus. Recent developments, including new antivirals that interfere with viral DNA replication, hold promise for the future. Sustained reduction in viral load and improved treatment of chronic HBV infection could, in future, be achieved by the development of new drugs with different mechanisms of action and resistance profiles, and with combination therapy involving two or more nucleosides with or without immunomodulators.     

Current status of treatment for chronic hepatitis C virus infection

Chronic hepatitis C virus (HCV) infection is responsible for substantial mortality and morbidity worldwide. Until recently, the standard of care for the treatment of chronic HCV infection had been a combination of pegylated interferon (peg-IFN) and ribavirin (RBV). The recent availability of two directly acting agents, telaprevir and boceprevir, has led to significantly improved outcomes for those patients with HCV genotype 1. Unfortunately, each of these agents must be combined with peg-IFN and RBV for optimal efficacy, and substantial treatment-related toxicity continues to challenge clinicians. However, the drug development pipeline for chronic HCV infection is very robust and the emergence of new therapies and therapeutic strategies in the near future for managing chronic HCV infection is eagerly anticipated.     

Systematic review: treatment of chronic hepatitis B virus infection by pegylated interferon

BACKGROUND: Pegylated interferon-alpha has been shown to be more efficacious than conventional interferon in treating chronic hepatitis C. The use of peginterferon in chronic hepatitis B virus infection with positive hepatitis B e antigen has also been tested in a number of trials since 2003. AIM: To systematically summarize and compare the results of these studies. METHODS: Four studies were identified from PubMed, Medline and reference lists. Data from the trials were extracted and analysed. Where appropriate, combined odds ratio of different trials was calculated. Safety data including serious adverse events and emergence of drug-resistant mutants were recorded. RESULTS: Three of the four trials contained predominantly Asian patients. Peginterferon is found to be superior to lamivudine monotherapy and induced sustained biochemical and virological responses in about one-thirds of patients after 12 months of therapy. Coadministration of lamivudine did not result in improvement in viral suppression. Peginterferon appears to reduce the emergence of YMDD mutation in the combination treatment groups. It was well tolerated with serious adverse events reported in <10% of patients in most trials. CONCLUSIONS: Peginterferon-alpha treatment of at least 6 months should be considered as one of the first-line therapeutic options for hepatitis B virus infection.     

Therapeutic strategies for a functional cure of chronic hepatitis B virus infection

Treatment of chronic hepatitis B virus (HBV) infection with the viral DNA polymerase inhibitors or pegylated alpha-interferon has led to a significant retardation in HBV-related disease progression and reduction in mortality related to chronic hepatitis B associated liver decompensation and hepatocellular carcinoma. However, chronic HBV infection remains not cured. The reasons for the failure to eradicate HBV infection by long-term antiviral therapy are not completely understood. However, clinical studies suggest that the intrinsic stability of the nuclear form of viral genome, the covalently closed circular (ccc) DNA, sustained low level viral replication under antiviral therapy and homeostatic proliferation of hepatocytes are the critical virological and pathophysiological factors that affect the persistence and therapeutic outcomes of HBV infection. More importantly, despite potent suppression of HBV replication in livers of the treated patients, the dysfunction of HBV-specific antiviral immunity persists. The inability of the immune system to recognize cells harboring HBV infection and to cure or eliminate cells actively producing virus is the biggest challenge to finding a cure. Unraveling the complex virus–host interactions that lead to persistent infection should facilitate the rational design of antivirals and immunotherapeutics to cure chronic HBV infection.KEY WORDS: Hepatitis B virus, cccDNA, Antiviral agents     

The efficacy of thymosin in the treatment of chronic hepatitis B virus infection: a meta-analysis

BACKGROUND: Trials of thymosin treatment in chronic hepatitis B virus infection have been small and the results have been inconsistent. AIM: To conduct a meta-analysis to evaluate the efficacy of thymosin treatment in chronic hepatitis B virus infection. METHODS: Randomized controlled trials comparing thymosin for over 24 weeks vs. placebo (or usual care) in the treatment of chronic hepatitis B virus infection were identified through MEDLINE, EMBASE and the Cochrane Register of Clinical Trials. Biochemical (normalization of transaminases) and virological (loss of hepatitis B virus DNA and hepatitis B e antigen) responses were analysed using the intention-to-treat method. The odds ratio was used to measure the magnitude of the efficacy. RESULTS: Five trials (353 patients) were identified. The odds ratio (95% confidence interval) of the virological response of thymosin over placebo at the end of treatment, 6 months post-treatment and 12 months post-treatment were 0.56 (0.2-1.52), 1.67 (0.83-3.37) and 2.67 (1.25-5.68), respectively. There was an increasing trend of the virological response with time since the cessation of thymosin treatment (P=0.02). There was no difference in the biochemical response between the thymosin and placebo groups at the end of treatment, 6 months post-treatment and 12 months post-treatment. CONCLUSIONS: Thymosin is effective in suppressing viral replication in chronic hepatitis B virus infection, but the effect is delayed until 12 months after the cessation of treatment.     

New therapeutic strategies in the treatment of hepatitis B virus infection

Principally, because of the association of the chronic carrier state with the development of cirrhotic liver disease and hepatocellular carcinoma, chronic hepatitis B infection is a public health problem of global significance. In the main, therapy for chronic hepatitis B is limited to the use of alpha interferon for a limited number of chronic hepatitis B virus (HBV) carriers who have chronic hepatitis with active viral replication. The development of antiviral nucleoside analogues for the herpes viruses and human immunodeficiency virus (HIV) has resulted in the identification of several compounds which also have activity against HBV. Unfortunately, these agents have not been associated with the clearance of hepatitis B infection, but rather only the suppression of active infection while the patient is receiving medication. In addition, the development of drug-resistance to these agents by the virus will most likely limit their long-term efficacy. Gene therapy has recently been applied to HBV both in vitro and in vivo. This has included the use of antisense oligodeoxynucleotides and RNA, ribozymes, dominant negative mutants and therapeutic HBV vaccines. These newer therapeutic modalities may hold promise as effective treatments for chronic hepatitis B, but to date, have been limited by the problem of delivery to the target cell population or infected organ in vivo. Combination nucleoside analogue therapy may also provide an important treatment modality for chronic hepatitis B, although this will require further investigation.     

Multifaceted functions of B cells in chronic hepatitis C virus infection

Hepatitis C virus (HCV) elicits T- and B-cell responses which are believed to play an important role in infection control. B cells have generally been neglected because they do not seem to significantly influence the course of HCV infection. In this review, B lymphocytes are viewed both as classical antibody producing cells, with the hypervariable region 1 being a biologically relevant target protein and as a model of virus-host interaction in lymphoproliferative disorders characteristic of persistent microbial infections.     

Subcutaneously administered recombinant human β-interferon in the treatment of chronic hepatitis B virus infection

Background: Treatment of chronic replicative hepatitis B virus (HBV) infection is aimed at stopping viral replication and preventing the development of chronic liver disease. β-Interferon treatment has been less well studied than α-interferon. Methods: The efficacy and tolerability of a 6-month course of subcutaneously administered human recombinant β-interferon (rINF-β_ser) was studied and the results of a low-dose regime compared with a high-dose regime. Twenty patients (17 men and three women), aged 24–54 years, with chronic hepatitis B virus infection (all hepatitis B surface antigen-positive with detectable HBV-DNA in their sera for at least 3 months prior to therapy) were randomized into two treatment groups of 10 patients each. The low-dose group received 6×10⁶ U/dose and the high-dose group received 30×10⁶ U/dose, both groups receiving their respective doses three times a week initially for 1 month and continuing for a total of 6 months. Results: The treatment was well tolerated in both groups. None of the patients required dosage reduction or cessation of treatment because of side-effects. HBV-DNA decreased in all patients during treatment, demonstrating the anti-viral efficacy of rINF-β_ser, and was undetectable in 20 and 40% of patients receiving low-dose and high-dose regimes, respectively, at the end of 6 months treatment (P=N.S.). One year after completion of treatment, HBV-DNA was undetectable in 50 and 30% of patients in the low-dose and high-dose groups, respectively (P=N.S.). However, only one patient achieved seroconversion with loss of the hepatitis B surface antigen and appearance of an anti-hepatitis B ‘e’ antigen at the end of 18 months. Conclusion: This study shows that subcutaneously administered rINF-β_ser is well tolerated, but the optimal dose and duration of treatment still needs to be defined by further studies.     

Immunomodulation as an option for the treatment of chronic hepatitis B virus infection: preclinical studies in the woodchuck model

New therapeutic approaches for chronic hepatitis B virus infection based on immunomodulation are now under investigation. The woodchuck model for hepatitis B virus infection has emerged as a useful animal model for the evaluation of such approaches, after developing necessary assays and reagents for immunologic studies in this model. Conventional and novel vaccines such as DNA vaccines were tested in woodchucks for their ability to induce protective immune responses against challenge infection with the woodchuck hepatitis virus (WHV). Furthermore, immunotherapeutic approaches for the control of chronic hepadnaviral infection were evaluated in woodchucks. Immunizations with WHV proteins and DNA vaccines led to the development of antibodies to the WHV surface antigen and to a significant decrease of viral load in chronically WHV-infected woodchucks. Viral vector-mediated gene transfer was explored for the delivery of antiviral cytokines IFN-alpha in woodchucks and resulted in the decrease of viral replication. It is now generally accepted that a combination of antiviral treatment and immunization will be necessary to achieve successful immunomodulation with a long-term control of chronic hepatitis B virus infection.     

Telbivudine for the treatment of chronic hepatitis B

The hepatitis B virus (HBV) has a complex natural history and causes a wide spectrum of disease. Choices of therapy depend on a number of factors predictive of treatment response, clinical circumstances and stage of disease, and the likelihood and consequences of resistance to treatment. Telbivudine (beta-L-2'deoxythymidine) is a thymidine analogue that belongs to a new class of beta-L-configuration nucleoside analogues with specific activity against hepadnavirus. Phase III studies of telbivudine versus lamivudine in hepatitis B e antigen (HBeAg) and anti-HBe have been completed. In HBeAg-positive patients, HBV DNA was not detectable by polymerase chain reaction (PCR) assay in 56% of the HBeAg-positive patients receiving telbivudine after two years of treatment. In HBeAg-negative patients, at two years, HBV DNA was undetectable by PCR in 82% of HBeAg-negative patients (versus 52% of lamivudine recipients). Patients who were PCR-negative after 24 weeks were less likely to develop resistance. HBeAg seroconversion rates were also greatest in patients whose HBV DNA was undetectable at 24 weeks. These results are promising and could be used to devise a strategy to utilize combination therapy or to adjust therapy if an inadequate early viral response is observed. However, resistance is a potential shortcoming of the use of single agents for the treatment of HBV.     

Lamivudine for the treatment of chronic hepatitis B

Lamivudine (Zeffix, Epivir, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-alpha. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.     

Lamivudine for the treatment of chronic hepatitis B

Lamivudine (Zeffix^®, Epivir^®, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-α. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.