In Vitro Antihepadnaviral Activities of Combinations of Penciclovir, Lamivudine, and Adefovir

Colledge, Danni; Civitico, Gilda; Locarnini, Stephen; Shaw, Timothy J.

doi:10.1128/aac.44.3.551-560.2000

Cited by 91 publications

(56 citation statements)

References 37 publications

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“…The combination of such compounds was found to be either additive and more rarely synergistic in polymerase assays (reverse transcriptase activity) (Seigneres et al, 2003) as well as in tissue culture experiments (viral DNA synthesis) or in chronically infected woodchucks (Colledge et al, 2000;Colledge et al, 1997;Korba, 1996;Korba et al, 2000;Seigneres et al, 2003).…”

Section: Prevention Of and Combating Drug Resistancementioning

confidence: 99%

Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic Hepatitis B virus infection

Zoulim

2004

Antiviral Research

106

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Section: Prevention Of and Combating Drug Resistancementioning

confidence: 99%

Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic Hepatitis B virus infection

Zoulim

2004

Antiviral Research

106

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“…TableCurve2D was used to determine the best fit values for individual dose-response equations and to estimate the 50% inhibitory concentrations (IC 50 s) for each drug. 23,25,27,28 Relative Replication Yield and Transduction Efficiency. The relative amount of intracellular core-associated single-stranded HBV DNA as quantified by densitometry was used to determine in vitro replication yield phenotypes.…”

Section: Hbv Infectious Clones and Lamivudine-resistant Mutantsmentioning

confidence: 99%

“…HBV DNA was quantified by scanning autoradiograms using a UMAX Astra 2400S scanner fitted with a transparency adaptor and analysing the resulting images with the aid of SigmaGel Gel analysis software (Jandel Scientific, San Rafael, CA). Densitometric data were analyzed using TableCurve2D, (SPSS Software, Chicago, IL) 23,25,27,28 Dose-dependent inhibition of HBV DNA replication, when it occurred, could be described mathematically by a logistic dose response equation of the form: y ϭ a/(1 ϩ (x/b) c ). This equation, in which y is the percentage of virus replication compared with untreated controls (defined as 100%) and x represents the drug concentration, describes a sigmoidal curve.…”

Section: Hbv Infectious Clones and Lamivudine-resistant Mutantsmentioning

confidence: 99%

Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro

et al. 2003

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Hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) is frequently caused by a mutation (G1896A) in the hepatitis B virus (HBV) precore (PC) reading frame that creates a stop codon, causing premature termination of the PC protein. During lamivudine treatment, drug resistance develops at a similar rate in HBeAg positive and HBeAg negative CHB. Lamivudine-resistant HBV mutants have been shown to replicate inefficiently in vitro in the absence of PC mutations, but it is unknown whether the presence of PC mutations affects replication efficiency or antiviral sensitivity. This study utilized the recombinant HBV baculovirus system to address these issues. HBV baculoviruses encoding the G1896A PC stop codon mutation were generated in wild-type (WT) and lamivudine-resistant (rtM204I and rtL180M ؉ rtM204V) backgrounds, resulting in a panel of 6 related recombinant baculoviruses. In vitro assays were performed to compare the sensitivities of the PC mutant viruses with lamivudine and adefovir and to compare relative replication yields. The PC mutation did not significantly affect sensitivities to either adefovir or lamivudine. WT HBV and PC mutant HBV showed similar replication yields, whereas the replication yields of the lamivudine-resistant mutants were greatly reduced in HBeAg positive HBVs, confirming previous observations. However, the presence of the PC mutation was found to compensate for the replication deficiency in each of the lamivudine-resistant mutants, increasing the replication yields of each virus. In conclusion, the PC stop codon mutation appears to increase the replication efficacy of lamivudine-resistant virus but does not affect in vitro drug sensitivity. (HEPATOLOGY 2003;37:27-35.) H epatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB), a phase in the natural history of CHB, is marked by the selection of hepatitis B viruses (HBV) unable to secrete HBeAg and has become the major form of disease presentation in many parts of the world. 1 The most common of several mutations that can cause HBeAg negativity is a guanine to adenine transition at nucleotide position 1,896 (G1896A), which creates a TAG stop codon at codon 28 of the precore (PC) protein. [1][2][3][4][5] Interferon alfa and lamivudine are the only therapeutic agents approved for treatment of CHB. 6 Lamivudine is regarded as safe and as efficacious as interferon alfa, but the percentage of patients with HBeAg positive CHB who undergo HBeAg seroconversion increases with the duration of treatment. 7 Seroconversion rates between 11% and 15% per year have been reported over treatment periods up to 3 years. [7][8][9][10] Unfortunately, the frequency of antiviral drug resistance increases with the duration of therapy, rising to as high as 66% after 3 years. 10,11 The most common mutations conferring lamivudine resistance affect the active site YMDD (tyrosine-methionine-aspartate-aspartate) motif in the C domain of the HBV polymerase protein, causing the methionine (M) residue (amino acid 204) to be replaced with either isole...

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“…Available data suggest that lamivudine, penciclovir, and adefovir use different pathways of cellular entry and activation. 5 The specific viral mutations associated with each drug are also important in designing a combination. In vitro studies indicate that the common YMDD mutant associated with lamivudine resistance confers cross-resistance to famciclovir and emtricitabine.…”

mentioning

confidence: 99%

“…Famciclovir, a deoxyguanosine analogue, has low efficacy as monotherapy but, according to preliminary evidence, may be synergistic in combination with lamivudine. 5,6 Adefovir dipivoxil (bis-POM PMEA) is an acyclic phosphonate of deoxyadenosine monophosphate. Having one phosphate group already, it requires only two cellular phosphorylations to exert its potent anti-HBV activity.…”

mentioning

confidence: 99%

Adding to the Hepatitis B Virus Treatment Arsenal: α–Glucosidase Inhibitor Derivatives

Terrault

2001

Hepatology

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Chronic hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma in the United States and worldwide. Eradication of infection and prevention of complications of chronic infection are the dual goals of treatment. While therapeutic options were limited to interferon until the mid-1990s, anti-HBV drug development has exploded in the last 5 years, largely catalyzed by efforts directed at human immunodeficiency virus (HIV) infection.Interferon alfa and lamivudine are the two approved agents for treatment of chronic HBV infection. Interferon has both immune-modulating and antiviral actions, and its efficacy in the treatment of chronic HBV infection is well established. Compared with untreated controls, interferon, in doses of 5 MU daily or 10 MU 3 times weekly, increases hepatitis B e antigen loss by 20% and hepatitis B surface antigen loss by 6%. 1 Treatment benefits are long term in the majority of cases, and enhanced rates of viral clearance are observed in the years after treatment. Lamivudine is the only oral medication approved for treatment of chronic HBV infection. Lamivudine, the (-)enantiomer of 2Ј-deoxy-3Ј-thiacytidine, undergoes phosphorylation in hepatocytes to form 2Ј-deoxy-3Ј-thiacytidine triphosphate, the active molecule. Lamivudine competes with dCTP for HBV-DNA synthesis, and its incorporation terminates viral DNA synthesis. In placebo-controlled clinical trials, given at 100 mg daily for 12 months, it increased the rate of sustained suppression of HBV DNA by 17% to 33% and hepatitis B e antigen loss by 16% to 19%. 2,3 Relapse or rebound in HBV DNA was common when treatment was discontinued. While long-term lamivudine therapy has resulted in suppression of viral markers of ongoing viral replication and improved liver histology, the rate of treatment breakthrough due to the development of resistant mutants increases with duration of therapy. 4 After the first year of treatment, the incidence of lamivudine-resistant HBV is 14% to 32%. 2,3 Rebound of HBV-DNA replication after discontinuation of lamivudine therapy is likely related, in part, to the persistence of the covalently closed circular DNA (cccDNA) within the cell nucleus (Fig. 1). During infection, attachment and entry of HBV into the cell are followed by viral uncoating and translocation of the viral genome to the nucleus where it is converted to cccDNA with the help of the host DNA polymerase. The host RNA polymerase uses the cccDNA as a template for transcribing viral messenger RNA. Lamivudine and many other antiviral agents have no activity against the cccDNA form of HBV. Another potential reason for virologic relapse after discontinuation of lamivudine therapy is the existence of residual virus in "sanctuaries," such as bile duct epithelial cells or pancreatic islet cells. These privileged sites are presumably less accessible to lamivudine and will release virus that reinitiates the infection, when the antiviral agent is withdrawn. The ideal anti-HBV agent would reduce levels of cccDNA and have activity ...

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In Vitro Antihepadnaviral Activities of Combinations of Penciclovir, Lamivudine, and Adefovir

Cited by 91 publications

References 37 publications

Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic Hepatitis B virus infection

Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic Hepatitis B virus infection

Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro

Adding to the Hepatitis B Virus Treatment Arsenal: α–Glucosidase Inhibitor Derivatives

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