In Vitro Antihepadnaviral Activities of Combinations of Penciclovir, Lamivudine, and Adefovir (original) (raw)
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Hepatitis B virus: old, new and future approaches to antiviral treatment
Journal of Antimicrobial Chemotherapy, 2003
Patients chronically infected with hepatitis B virus (HBV) run the risk of developing cirrhosis and hepatocellular carcinoma in later life. Antiviral treatment offers the only means of preventing such an undesirable outcome. To date, interferon-α (IFN-α), an immunomodulator, and two synthetic nucleoside analogues, lamivudine and adefovir dipivoxil, are the only licensed antiviral agents for the treatment of chronic HBV infection. However, the standard treatment endpoints of loss of HBeAg with or without seroconversion to anti-HBe, normalization of serum transaminase levels, loss of HBV-DNA and improvement in liver histology following monotherapy with either types of agent are only achievable in ∼20-30% of those treated. Long-term treatment with lamivudine is effective in suppressing viral replication, but drug-resistant mutants arise with increased length of treatment. Nevertheless, such mutants appear to be susceptible to adefovir and other nucleoside analogues that are undergoing Phase II/III clinical trials at the moment. Therapeutic vaccination and other molecular approaches such as antisense oligonucleotides, ribozymes, DNA vaccines, dominant-negative proteins and aptamers are possible future antiviral therapies, which will supplement our armamentarium against chronic HBV infection. It seems certain that combination therapies involving two or more nucleoside analogues, immunomodulators or gene therapies will be the future treatment regimens for chronic HBV infection.
Nucleotide analogs as novel anti-hepatitis B virus agents
Current Opinion in Pharmacology, 2005
During the past decade, nucleotide analogs have emerged as novel antiviral agents against hepatitis B virus. Adefovir dipivoxil, a prototype phosphonate analog, has been approved for chronic hepatitis B virus therapy, and additional phosphonate analogs and di-and tri-nucleotides are under development. Several innovative prodrug derivatizations have also been reported to improve the oral bioavailability of nucleotide analogs, which usually carry a negative charge.
Bioorganic & Medicinal Chemistry Letters, 2011
The discovery of a small molecule non-nucleoside inhibitor of Hepatitis B Virus is described. During our work on conocurvone derived naphthoquinone 'trimers' for the treatment of HIV, we discovered a potent inhibitor 9 of Hepatitis B Virus in an antiviral screen. During attempts to resynthesis 9 for proof of concept studies, we altered the synthesis in order to attempt to reduced side reactions and difficult to remove by-products. As a result we discovered a small molecule 19 that also was a potent inhibitor of HBV. Importantly, this small molecule inhibitor of Hepatitis B Virus is also an inhibitor of Hepatitis B Virus resistant to 3TC, a bench mark of nucleoside analogues active in the treatment of Hepatitis B Virus. The development of 19 as an agent to treat HBV infections is discussed.
Antimicrobial agents …, 1994
TIM SHAW,' PENELOPE AMOR,' GILDA CIVITICO,' MALCOLM BOYD,2 AND STEPHEN LOCARNINIl* Macfarlane Burnet Centre for Medical Research and Victorian Infectious Diseases Reference Laboratory, Fairfield Hospital, Victoria 3078, Australia, 1and SmithKline ...
Review Anti-HBV Drugs: Progress, Unmet Needs, and New Hope
2015
Approximately 240 million people worldwide are chronically infected with hepatitis B virus (HBV), which represents a significant challenge to public health. The current goal in treating chronic HBV infection is to block progression of HBV-related liver injury and inflammation to end-stage liver diseases, including cirrhosis and hepatocellular carcinoma, because we are unable to eliminate chronic HBV infection. Available therapies for chronic HBV infection mainly include nucleos/tide analogues (NAs), non-NAs, and immunomodulatory agents. However, none of them is able to clear chronic HBV infection. Thus, a new generation of anti-HBV drugs is urgently needed. Progress has been made in the development and testing of new therapeutics against chronic HBV infection. This review aims to summarize the state of the art in new HBV drug research and development and to forecast research and development trends and directions in the near future.
Anti-HBV Drugs: Progress, Unmet Needs, and New Hope
Viruses, 2015
Approximately 240 million people worldwide are chronically infected with hepatitis B virus (HBV), which represents a significant challenge to public health. The current goal in treating chronic HBV infection is to block progression of HBV-related liver injury and inflammation to end-stage liver diseases, including cirrhosis and hepatocellular carcinoma, because we are unable to eliminate chronic HBV infection. Available therapies for chronic HBV infection mainly include nucleos/tide analogues (NAs), non-NAs, and immunomodulatory agents. However, none of them is able to clear chronic HBV infection. Thus, a new generation of anti-HBV drugs is urgently needed. Progress has been made in the development and testing of new therapeutics against chronic HBV infection. This review aims to summarize the state of the art in new HBV drug research and development and to forecast research and development trends and directions in the near future.
Phosphorothioate Di- and Trinucleotides as a Novel Class of Anti-Hepatitis B Virus Agents
Antimicrobial Agents and Chemotherapy, 2004
Several nucleoside analogs are under clinical development for use against hepatitis B virus (HBV). Lamivudine (3TC), a nucleoside analog, and adefovir dipivoxil (ADV), an acyclonucleotide analog, are clinically approved. However, long-term treatment can induce viral resistance, and following the cessation of therapy, viral rebound is frequently observed. There continues to be a need for new antiviral agents with novel mechanisms of action. A library of more than 600 di- and trinucleotide compounds synthesized by parallel synthesis using a combinatorial strategy was screened for potential inhibitors of HBV replication using the chronically HBV-producing cell line 2.2.15. Through an iterative process of synthesis, lead optimization, and screening, three analogs were identified as potent inhibitors of HBV replication: dinucleotides ORI-7246 (drug concentration at which a 10-fold reduction of HBV DNA was observed [EC90], 1.4 μM) and ORI-9020 (EC90, 1.2 μM) and trinucleotide ORI-7170 (EC...
Antimicrobial agents and chemotherapy, 1996
Penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yI)guanine], an effective antiherpesvirus agent, was found to be a potent and selective antiviral agent against intracellular hepatitis B virus (HBV) replication (drug concentration at which a 10-fold decrease in HBV DNA from the average level in an untreated culture was observed [EC90], 1.6 microM) and extracellular virion release (EC90, 0.7 microM) by cultured human hepatoblastoma (2.2.15) cells. Acyclovir and three other related 9-alkoxypurines with activity against either herpesviruses or human immunodeficiency virus were uniformly inactive against HBV. The activity of penciclovir is discussed in relation to recent findings related to its mode of action against HBV.
Current and future antiviral agents for chronic hepatitis B
Journal of Antimicrobial Chemotherapy, 2003
Effective antiviral therapy for chronic hepatitis B virus (HBV) infection is important since ∼400 million people are affected globally. Loss of hepatitis B e antigen (HBeAg) with or without seroconversion to antibody against HBeAg (anti- HBe), normalization of alanine aminotransferase (ALT) and improvement in liver histology are the usual short-term end- points of therapy.1 To determine whether the ultimate treat- ment target, i.e. prevention of cirrhosis-related complications and hepatocellular carcinoma (HCC), is achieved requires more long-term follow-up of treated patients.1 The two established agents for the treatment of chronic hepatitis B are interferon (IFN)-α and lamivudine. Adefovir dipivoxil has also been licensed recently in the USA and in Europe. Their main modes of action are immunomodulation and direct suppression of viral replication. IFN-α induces HBeAg seroconversion in ∼20-30% of patients. The propor- tion achieving HBeAg seroconversion is lower in Asian patients, who mostly acquire the infection at birth or early in life and consequently have a long period of immunotolerance. More importantly, IFN-α treatment in Asian patients does not prevent the occurrence of cirrhosis-related complications and HCC.2 The substantial side effects during treatment and the possibility of causing hepatic decompensation in patients with pre-existing cirrhosis also limit the use of IFN-α. The rest of the review will concentrate on lamivudine and other more novel nucleoside analogues. The structures of various nucleoside analogues are illustrated in Figure 1. Lamivudine Lamivudine, the (-) enantiomer of the deoxycytidine analogue 2'-deoxy-3'-thiacytidine, exerts its antiviral effect mainly by inhibiting reverse transcription during the replication cycle of HBV. Another postulated site of action is the inhibition of the completion of the double-stranded DNA. The formation of covalently closed circular (ccc) DNA (the template for HBV replication) may therefore be reduced. The efficacy of lamivudine is the same for both Asian and Caucasian patients, since the mode of action is through viral suppression rather than through immunomodulatory effect. Phase 3 randomized placebo-controlled studies in Asian and Caucasian patients show that the rate of HBeAg seroconversion after 1 year of treatment is 16-32%.3,4 Normalization of ALT occurs in 41-72% of patients. More importantly, lamivudine can reduce the severity of necroinflammation and decrease the rate of progression of fibrosis. In one study, lamivudine has been shown to halt or reverse the process of cirrhosis.5 In patients who have been treated with lamivudine for 5 years, the HBeAg seroconversion rate increases to 50% (77% for patients with baseline ALT level greater than twice the upper limit of normal (ULN)). According to a study in Korea,6 relapse after HBeAg seroconversion is common when lamivudine is stopped (37.5% for the first year, 49.2% for the second year). However, the high relapse rate is likely to be related to the early cessation of lamivudine treatment after HBeAg sero- conversion (within 2-4 months). Therefore, it is now recom- mended that lamivudine should be continued for 6-9 months after HBeAg seroconversion. The drug is remarkably free of side effects. In addition, lamivudine treatment is safe even in patients with decompensated cirrhosis. Lamivudine has also been shown to have beneficial effects on two subgroups of patients with chronic hepatitis B. In HBeAg-negative patients, complete biochemical and viro- logical responses can be achieved in two-thirds of the patients after a treatment period of 12-26 months.7,8 There is also improvement in the necroinflammatory activities in the liver in these patients; however, relapse rates are high after ces- sation of lamivudine treatment. The second subgroup of patients are patients with decompensated liver disease. In these patients, lamivudine is effective in inducing HBV DNA suppression, biochemical remission, HBeAg seroconversion and improvement in liver performance status as reflected by the Child-Pugh score.9-11 Importantly, lamivudine therapy is associated with a better survival for decompensated patients.11 The major drawback of lamivudine treatment is the develop- ment of drug-resistant HBV after 6-9 months of therapy. Resistance is due to the mutation of the catalytic domain of the
Antiviral chemotherapy for the treatment of hepatitis b virus infections
Gastroenterology, 2000
Approximately 5% of the world's human population have an increased risk for developing liver cancer and cirrhosis as a direct consequence of chronic infection with the hepatitis B virus (HBV). Antiviral chemotherapy remains the only option for controlling infection in these individuals, for whom the current licensed hepatitis B vaccines provide no benefit. Interferon (IFN)-␣ has proven benefit in a well-defined group of those with hepatitis B but has made little impact on the global burden of chronic liver disease. The development of more effective chemotherapy for treatment of chronic hepatitis B infection has proven to be extremely challenging, the result of both virus-and host-dependent factors, which will be reviewed in this article. Past attempts to treat chronic hepatitis B infection using nucleoside analogues were disappointing, but more recently, several nucleoside (or nucleotide) analogues have been identified that are potent and selective inhibitors of HBV replication. These agents fall into two broad categories: (1) nucleoside/nucleotides that have modified sugar residues in either cyclic or acyclic configurations and (2) stereoisomers of nucleosides in the ''unnatural'' L-configuration. Of the analogues that have been used clinically, representatives of the first category are purine derivatives, e.g., adefovir dipivoxil and famciclovir, whereas representatives of the second category are pyrimidine derivatives, such as lamivudine.