Telbivudine: a new option for the treatment of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection affects > 350 million individuals worldwide. Chronic hepatitis B is associated with complications of end-stage liver disease, including cirrhosis and hepatocellular carcinoma. HBV replication is the best predictor of liver disease progression to cancer, and antiviral therapy may diminish or halt this unfavorable outcome. Six drugs have been approved for the treatment of chronic hepatitis B: interferon-alpha(2b), pegylated interferon-alpha(2a), lamivudine, adefovir, entecavir and telbivudine. Most agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efficacy; therefore, new agents and treatment strategies are needed. Telbivudine is the latest approved anti-HBV agent; it is an orally administered nucleoside analog that selectively inhibits HBV replication. It has demonstrated potent activity against HBV in Phase III clinical studies, with good tolerance, lack of mitochondrial toxicity and no dose-limiting side effects.     

Peginterferon-α2b and ribavirin

Hepatitis C virus infection is among the leading causes of chronic liver disease in the USA and has a worldwide prevalence of approximately 300 million people. Chronic hepatitis C virus is the most common indication for liver transplantation in the USA. Due to the chronic nature of hepatitis C virus infection, these numbers are expected to grow fourfold in the next decade. Interferon-α_2b monotherapy followed by combination therapy with ribavirin have been used to treat chronic hepatitis C virus with limited success. The development of pegylated interferon-α_2b, (Peg-intron^®, Schering-Plough) instituted the next chapter in hepatitis C virus therapy. The demonstration of its safety and efficacy led to a major trial studying coadministration with ribavirin for compensated chronic hepatitis C virus infection. Pegylated interferon combination therapy has improved efficacy over standard interferon combination therapy without an increase in adverse effects. This article reviews the data regarding pegylated interferon-α_2b with ribavirin therapy. The pharmacokinetics and pharmacodynamics of combination therapy will be presented along with clinical trial data. The efficacy and ease of usage of Pegintron and ribavirin support its use for chronic hepatitis C virus infection.     

Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B

The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulatory agents, such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir. The NAs work mainly by inhibiting hepatitis B virus (HBV) DNA polymerase activity and thus suppress HBV replication. Oral NAs have become the mainstay of CHB treatment, mainly due to their profound viral suppressive effects and also due in part to the ease of single daily dosing and lack of significant side effects. One major drawback of NA therapy is the development of drug resistance mutations with long-term treatment. Lamivudine, the first oral NA approved for CHB patients, is associated with high rates of drug resistance, with resultant virological relapse and biochemical flare. Fortunately, newer and more potent NAs, such as entecavir and tenofovir, have very low resistance rates, with potent and durable viral suppression. This review is aimed at the current developments in NAs for CHB treatment, detailing the mechanisms of antiviral activity of the different agents, the efficacy of viral suppression, the achievement of treatment endpoints, the development of drug resistance and the optimal strategies for using these drugs.     

Peginterferon-α2a(40 kDa)/ribavirin combination for the treatment of chronic hepatitis C infection

Chronic hepatitis C is the leading cause of liver disease and liver-related mortality in the western world. Treatment of this chronic viral infection has considerably improved with the introduction of ribavirin–interferon combination therapy. Ribavirin (Copegus^®, Rebetol^®) is a synthetic nucleoside analogue with broad antiviral effects. It is absorbed readily upon oral administration with meals. Daily doses of up to 1200 mg are usually well-tolerated, causing dose-dependent haemolysis, reversible with dose reduction in most patients, in particular in those with renal insufficiency. In the circulation it is bound to erythrocytes, and eliminated by phosphorylation and deribolysation. The drug accumulates in blood with renal insufficiency. Impairment of hepatic function does not influence drug levels in the circulation. In animal studies, teratogenic and reproductive toxicity was shown. In chronic hepatitis C virus infection, monotherapy with ribavirin has no effect on concentrations of viral RNA or liver histology. Combination therapy with pegylated interferon-α_2a (40 kDa) (Pegasys^®) produces significantly higher sustained virological response rates in infections with all viral genotypes, even in advanced stages of liver disease compared pegylated interferon-α_2a monotherapy, adverse effects and quality of life are not significantly different.     

Hepatitis B virus replication and liver disease progression: the impact of antiviral therapy

Chronic hepatitis B virus (HBV) infection is a serious health issue worldwide. The presence of HBV replication markers--hepatitis B e antigen (HBeAg) or HBV DNA--is associated with continuing hepatitis activity or intermittent hepatitis flares and subsequent disease progression, including hepatic decompensation and development of liver cirrhosis or hepatocellular carcinoma (HCC). Long-term (>10 years) prospective studies in patients >30 years of age have shown that HBeAg seropositivity is associated with increased risk of disease progression, and the risk of cirrhosis and HCC begins to increase at an HBV DNA level of 10(4) copies/ml. Therefore, elimination of HBV, or at least sustained or maintained suppression of HBV, is the key to reducing hepatitis and thereby halting or preventing disease progression. Therapy with interferon-alpha or a direct antiviral agent has been shown to reduce the risk of cirrhosis and prevent further disease worsening. In both the woodchuck hepatitis model and in HBV patients, maintained suppression of HBV replication by a direct antiviral agent may reduce the progression to HCC. However, the efficacy of current antiviral therapy is still far from satisfactory. The ability to achieve a high rate of sustained or maintained HBV suppression with a low risk of drug resistance would be the ultimate goal in the treatment of chronic HBV infection.     

Peginterferon–α2a (40 kDa) (Pegasys®) for hepatitis B

Chronic hepatitis B virus is a serious and life threatening disease afflicting 350 million people worldwide, despite the availability of effective vaccines. Thus far, current monotherapy with conventional interferon-α, lamivudine and adefovir dipivoxil remains unsatisfactory. In addition, the use of conventional interferon-α needs to be administered subcutaneously three-times weekly and is associated with frequent adverse events. Although nucleoside/nucleotide analogs such as lamivudine and adefovir dipivoxil are well tolerated and can normalize serum alanine aminotransaminase rapidly, 1-year therapy with either lamivudine or adefovir dipivoxil results in low hepatitis B e antigen seroconversion rates. In hepatitis B e antigen-negative patients, most would relapse after lamivudine has been discontinued. Peginterferon-α2a, an immunomodulatory agent, is a new drug that has just completed Phase III clinical trials for the treatment of both hepatitis B e antigen-positive and -negative chronic hepatitis B virus infection. The advantage of peginterferon-α2a in achieving sustained virologic response over nucleoside/nucleotide analogs is particularly obvious in the hepatitis B e antigen-negative group. In both studies, sustained off-treatment response is superior to the use of monotherapy with lamivudine, and concomitant use of lamivudine and pegnterferon-α2a does not have advantages over the use of peginterferon-α2a alone. These recent data put peginterferon-α2a as the antihepatitis B virus therapy of choice, especially in young and motivated patients with chronic hepatitis B virus infection. However, despite the superiority of peginterferon-α2a over currently licensed nucleoside/nucleotide analogs, more research needs to be conducted in order to find the most optimal treatment regimen in our fight against chronic hepatitis B virus infection.     

Update on new antivirals under development for the treatment of double-stranded DNA virus infections

All the currently available antiviral agents used in the treatment of double-stranded (ds) DNA viruses, with the exception of interferon-α, inhibit the same target, the viral DNA polymerase. With increasing reports of the development of resistance of herpes simplex virus (HSV), cytomegalovirus (CMV), and hepatitis B virus (HBV) to some of these drugs, new antiviral agents are needed to treat these infections. Additionally, no drugs have been approved to treat several DNA virus infections, including those caused by adenovirus, smallpox, molluscum contagiosum, and BK virus. We report the status of 10 new antiviral drugs for the treatment of dsDNA viruses. CMX-001 has broad activity against dsDNA viruses; 3 helicase-primase inhibitors, maribavir, and FV-100 have activity against certain herpesviruses; ST-246 inhibits poxviruses; GS-9191 inhibits papillomaviruses; and clevudine and emtricitabine are active against HBV. Most of these drugs have completed at least phase I trials in humans, and many are in additional clinical trials.     

Entecavir for the long-term treatment of chronic hepatitis B

Hepatitis B virus is a major cause of chronic liver disease worldwide and is associated with an increased risk of hepatocellular carcinoma, progressive hepatic fibrosis and end-stage liver disease. Suppression of HBV replication is recognized as the primary on-treatment goal of antiviral therapy, as reduction of serum HBV DNA to low or undetectable levels is highly likely to have a positive impact on long-term clinical outcomes in HBV-associated chronic liver disease. Entecavir is an oral nucleoside analogue that effectively inhibits HBV polymerase, resulting in rapid viral suppression. Long-term data on patients receiving entecavir for chronic hepatitis B have demonstrated high potency, a low incidence of antiviral drug resistance and good tolerability, making entecavir an ideal first-line agent for the treatment of chronic hepatitis B.     

Inhibition of Human Hepatitis B Virus Replication by AT-61, a Phenylpropenamide Derivative,Alone and in Combination with (?)β-l-2′,3′-Dideoxy-3′-Thiacytidine

AT-61, a member of a novel class of phenylpropenamide derivatives, was found to be a highly selective and potent inhibitor of human hepatitis B virus (HBV) replication in four different human hepatoblastoma cell lines which support the replication of HBV (i.e., HepAD38, HepAD79, 2.2.15, and transiently transfected HepG2 cells). This compound was equally effective at inhibiting both the formation of intracellular immature core particles and the release of extracellular virions, with 50% effective concentrations ranging from 0.6 to 5.7 μM. AT-61 (27 μM) was able to reduce the amount of HBV covalently closed circular DNA found in the nuclei of HepAD38 cells by >99%. AT-61 at concentrations of >27 μM had little effect on the amount of viral RNA found within the cytoplasms of induced HepAD38 cells but reduced the number of immature virions which contained pregenomic RNA by >99%. The potency of AT-61 was not affected by one of the mutations responsible for (−)-β-l-2′,3′-dideoxy-3′ thiacytidine (3TC) resistance in HBV, and AT-61 acted synergistic with 3TC to inhibit HBV replication. AT-61 (81 μM) was not cytotoxic or antiproliferative to several cell lines and had no antiviral effect on woodchuck or duck HBV, human immunodeficiency virus type 1, herpes simplex virus type 1, vesicular stomatitis virus, or Newcastle disease virus. Therefore, we concluded that the antiviral activity of AT-61 is specific for HBV replication and most likely occurs at one of the steps between the synthesis of viral RNA and the packaging of pregenomic RNA into immature core particles.Hepatitis B virus (HBV) is estimated to chronically infect approximately 300 million people worldwide. These individuals are at increased risk for the development of liver failure, cirrhosis, and hepatocellular carcinoma (3, 23). In addition, it is estimated that of those chronically infected, approximately 1 million die annually from HBV-induced liver disease (19).At the present, interferon (IFN) is the only available treatment for chronic hepatitis in the United States. However, its efficacy is partial and of limited duration, with less than 30% of the chronic carriers being treated with IFN responding to treatment. In addition, approximately 50% of those who initially respond to IFN therapy experience a recurrence of viremia after the cessation of treatment (6, 29). In clinical trials, two nucleoside analogs, lamivudine [(−)-β-l-2′,3′-dideoxy-3′-thiacytidine; 3TC] and ganciclovir, have proven to be effective in decreasing the levels of HBV DNA in the serum of chronically infected patients (4, 7–9). However, many patients relapsed shortly after the cessation of therapy. In addition, there are now reports of the isolation of 3TC-resistant variants of HBV from the serum of immunosuppressed patients undergoing 3TC therapy (2, 20, 30).Here we report that AT-61, a member of a class of phenylpropenamide derivatives with antiviral activity against HBV replication (22), is a potent inhibitor of the replication of both wild-type and 3TC-resistant HBV in HepAD38, HepAD79, 2.2.15, and transiently transfected HepG2 cell lines. This compound does not inhibit the replication of duck HBV (DHBV), woodchuck HBV (WHBV), human immunodeficiency virus (HIV) type 1 (HIV-1), herpes simplex virus (HSV) type 1, (HSV-1), vesicular stomatitis virus (VSV), or Newcastle disease virus (NDV) and has very low toxicity in a number of cell lines. Moreover, when used in combination with 3TC, AT-61 acted synergistically to inhibit HBV replication in HepAD38 cells. Finally, the data suggest that this compound may exert its antiviral effect by interfering with the packaging of the pregenomic RNA into the immature core particle.     

New developments in the treatment of chronic hepatitis B

Significant progress has been made during the last 2 years in the treatment of chronic hepatitis B (CHB). Treatment decisions differ significantly depending on whether patients are HBeAg⁺ or HBeAg^-, treatment-naive or nucleoside/nucleotide-resistant, and in early or advanced stages of liver disease. Courses of finite duration, aiming to achieve sustained off-therapy responses, are practically restricted to HBeAg⁺ patients with compensated chronic liver disease, whereas long-term therapy aiming to achieve maintained on-therapy remission is mostly applicable to HBeAg^- individuals either with early or advanced liver disease. A course of finite duration with pegylated (PEG)-IFN-α-2a offers the highest probability of sustained off-therapy response in HBeAg⁺ individuals, as well as in some HBeAg^- individuals. Long-term therapy with nucleoside/nucleotide analogues, both in HBeAg⁺ and HBeAg^- CHB, has most favourable effects on patient outcome, provided that virological and biochemical remission is maintained without development of viral resistance. The best results are achievable with potent analogues suppressing serum hepatitis B virus (HBV) DNA to non-detectability by most sensitive techniques. The best 2-year resistance profile has hitherto been reported with entecavir monotherapy, and the best long-term resistance profile was seen with adefovir of 5-year duration. Adefovir is effective in most lamivudine (LAM)-resistant patients, but should be administered as an add-on rather than as a substitute for LAM. Combination therapies have entered the treatment arena of CHB by the side doors of LAM-resistance and of end-stage liver disease, and the most recent results suggest that treatment with combinations of two strong nucleosides/nucleotides with different resistance profiles may turn out to be the optimal first-line/first choice option in CHB.     

Nucleos(t)ide analogues for the treatment of chronic hepatitis B: a systematic review with network meta-analysis

ABSTRACT

Objectives

Chronic hepatitis B (CHB) is a major global health problem caused by hepatitis B virus (HBV) infection, and can put patients at high risk of death from cirrhosis and liver cancer. However, CHB can be treated with nucleos(t)ide analogues. We aimed to evaluate the effectiveness and safety of nucleos(t)ide analogues for the treatment of CHB patients.     

Therapeutic vaccination against chronic hepatitis B virus infection

Chronic liver disease and hepatocellular carcinoma associated with chronic hepatitis B virus (HBV) infection are among the most serious human health problems in highly endemic regions. Despite the existence for many years of effective vaccines against HBV, more than 370 million people remain persistently infected with HBV today. Currently available therapies fail to provide long-term control of viral replication in most patients. Viral persistence has been associated with a defect in the development of HBV-specific cell-mediated immunity. Strategies to boost or to broaden the weak virus-specific T-cell response of patients with chronic hepatitis B have been proposed as a means of terminating this persistent infection. The immunogenicity of HBV envelope- or capsid-based vaccines, new formulations for recombinant vaccines as well as DNA-based vaccines are currently under investigation in clinical trials. Although improvements are still required, vaccination would be the therapeutic procedure with the lowest cost and the potentially greatest benefit.     

Thymosin alpha-1 treatment in chronic hepatitis B

Introduction: Stimulating a successful host immune response may be a promising helpful therapy to achieve elimination of hepatitis B virus (HBV) infection in chronic hepatitis B (CHB). Thymosin α-1 (Tα-1), as an immunomodulatory agent, can enhance T-cell response in CHB patients and has been widely studied either alone or in combination with nucleos(t)ide analogs. This editorial reviews these articles to present the efficacy of Tα-1 in CHB.

Areas covered: English and Chinese articles in MEDLINE, EMBASE, the Cochrane Controlled Trial Registry, Chinese periodical full-text database of science and technology, Chinese periodical full-text database and Wan-fang database by thesis search were collected and reviewed.

Expert opinion: In CHB, Tα-1monotherapy is effective in suppressing viral replication compared with untreated control or conventional interferon. Most of the combination therapy of Tα-1 plus either lamivudine or IFN-α showed better effects on HBV DNA suppression and HBeAg seroconversion. Presently, clinical studies of Tα-1 combined with entecavir on the treatment of HBV-cirrhosis are ongoing.     

Antiviral activities of penciclovir and famciclovir on duck hepatitis B virus in vitro and in vivo

Chronic hepatitis B virus (HBV) infection is a major health problem worldwide. Antiviral strategies available at present, including interferon-alpha, have only limited efficacy, leading us to analyse the antiviral effects of penciclovir and famciclovir in the duck hepatitis B virus (DHBV) model of HBV infection in vitro and in vivo. In DHBV-infected duck hepatocytes, penciclovir effectively inhibited viral replication, with a concentration giving half-maximal inhibition of 0.25 microM. Furthermore, in vivo, penciclovir and its orally administered prodrug famciclovir strongly inhibited DHBV replication. These data demonstrate that penciclovir and famciclovir both have strong antiviral activities, and suggest that these agents might be useful for treating HBV infection in humans.     

Acute liver decompensation on withdrawal of cytotoxic chemotherapy and immunosuppressive therapy in hepatitis B carriers

Five chronic carriers of hepatitis B virus developed a fulminant hepatitis-like picture when immunosuppression or cytotoxic treatment, given for unrelated disorders, was withdrawn. Viral replication at the time of the final illness was confirmed in three of the five cases by measurement of serum HBV DNA or the presence of HBc antigen on liver biopsy. A cytoplasmic and nuclear pattern of HBc was seen in histological material during life, but at post-mortem was limited to a nuclear distribution, suggesting greater destruction of hepatocytes containing cytoplasmic HBc. In two of the cases, chronic liver disease was found at post-mortem, there being no previous clinical or laboratory abnormality, but it is unlikely that this was a factor in the development of the superimposed fulminating hepatitis-like illness. Immunosuppressive and cytotoxic agents must be used with extreme caution in any hepatitis B carrier, as withdrawal can precipitate acute decompensation regardless of whether or not there is underlying chronic liver disease.     

Hypertension in the liver clinic - polyarteritis nodosa in a patient with hepatitis B

Chronic hepatitis caused by hepatitis B virus (HBV) is an endemic disease in India. It is associated with extrahepatic manifestations like polyarteritis nodosa (PAN) which is a vasculitis like disorder, presenting in subacute or chronic phase; involving visceral and systemic vessels. It should always be considered as a possible etiology of hypertension in an underlying setting of hepatitis B. We describe a 56-year-male patient with a history of chronic HBV who presented to the outpatient clinic with history of recent onset hypertension and suspected liver disease. Further work up for the cause of recent hypertension included a contrast computerized tomography of abdomen, which revealed concomitant pathologies of chronic liver disease and multiple aneurysms in bilateral kidneys. This case illustrates the unusual presentation of extrahepatic manifestation of viral hepatitis in the form of PAN of kidneys. PAN as an independent entity may be missed in specialized clinics evaluating liver pathologies, due to its insidious onset, atypical clinical symptoms and multi-systemic manifestations. The knowledge of extrahepatic, renal and vascular manifestations of hepatitis B unrelated to liver disease should be considered by physicians at the time of diagnosis and management of patients with HBV.     

Successful treatment of infantile hepatitis B with lamivudine: A case report

BACKGROUNDHow to treat infantile hepatitis B virus (HBV) infection remains a controversial issue. The nucleoside analogue lamivudine (LAM) has been approved to treat children (2 to 17 years old) with chronic hepatitis B. Here, we aimed to investigate the benefit of LAM treatment in infantile hepatitis B.CASE SUMMARYA 4-mo-old infant born to a hepatitis B surface antigen (HBsAg)-positive woman was found to be infected by HBV during a health checkup. Liver chemistry and HBV seromarker tests showed alanine aminotransferase of 106 U/L, HBsAg of 685.2 cut-off index, hepatitis B “e” antigen of 1454.0 cut-off index, and HBV DNA of > 1.0 × 10⁹ IU/mL. LAM treatment (20 mg/d) was initiated, and after 19 mo, serum HBsAg was entirely cleared and hepatitis B surface antibody was present. The patient received LAM treatment for 2 years in total and has been followed for 3 years. During this period, serum hepatitis B surface antibody has been persistently positive, and serum HBV DNA was undetectable.CONCLUSIONEarly treatment of infantile hepatitis B with LAM could be safe and effective.     

Markers of disease activity in chronic hepatitis B virus infection

BACKGROUND: Assessment of disease activity is important in the management of chronic hepatitis B virus (HBV) infection. Our objective was to study the correlation between serum HBV DNA levels and HBV e antigen (HBeAg) status, alanine aminotransferase (ALT) levels, histologic activity, age and sex in patients who had chronic HBV, with emphasis on those who were HBeAg negative with high replication but had normal or below-normal liver enzyme levels and mild liver disease. METHOD: At our university-affiliated tertiary care medical centre in Turkey, we studied prospectively 179 consecutive patients who were long-term hepatitis B surface antigen carriers. These patients were first separated into 2 groups according to HBeAg positivity and then subdivided into 4 groups according to the presence of HBV DNA, HBeAg status and ALT levels. The clinical, virologic and histologic differences in these patients were evaluated with respect to the HBeAg status. RESULTS: Of the 179 patients, 120 (67%) were HBeAg positive and 59 (33%) were HBeAg negative. The mean (and standard deviation) age in the former group was 24.8 (7.60) and in the latter group was 32.2 (11.2) years (p < 0.001). HBeAg-negative patients had significantly more severe liver disease, more male predominance and lower serum HBV DNA levels than HBeAg-positive patients (p < 0.05). HBeAg status had a close correlation with age. There was a significant correlation between age and serum HBV DNA levels but not between HBV DNA levels and disease activity in study groups. We found that some of anti-HBe-positive patients had below-normal ALT levels with minimal or absent histologic changes despite high viral replication. CONCLUSIONS: Monitoring of ALT is of value in assessing hepatocellular damage in patients with chronic hepatitis B virus infection. HBeAg-negative patients with elevated ALT levels and some with normal ALT levels should be considered highly infectious in the course of chronic HBV infection.