Antiviral activity of clevudine [?-FMAU, (1-(2-fluoro-5-methyl-β, ?-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax)

Peek, Simon F.; Côté, Paul J.; Jacob, James R.; Toshkov, Ilia; Hornbuckle, William E.; Baldwin, Betty H.; Wells, Frances V.; Chu, Chen; Gerin, John L.; Tennant, Bud C.; Korba, Brent E.

doi:10.1053/jhep.2001.20899

Cited by 125 publications

(134 citation statements)

References 36 publications

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“…11 In the ongoing trials, we can now use the more recently developed real-time PCR assays (HBV Beacom assay and COBAS TaqMan HBV), which have a dynamic range of 1.0ϫ10 2 to 1.0ϫ10 9 /mL. 12,13 As shown previously in animal models 8 and by a phase I/II short-term clinical trial, 9 clevudine has the unique property of delayed time to viral rebound after treatment. The mechanisms of delayed viral recrudescence observed for 24 weeks after dosing remain to be elucidated.…”

Section: Discussionmentioning

confidence: 91%

“…6,7 In woodchucks infected with woodchuck hepatitis virus (WHV), clevudine led to a decrease in the plasma WHV DNA of up to a thousand-fold. 8 In addition, in a phase I/II clinical study, clevudine at once daily doses between 10 and 200 mg for 28 days was well tolerated and produced significant antiviral activity. Moreover, one particularly beneficial effect of clevudine was that viral suppression was maintained for as long as 24 weeks after discontinuation of treatment.…”

Section: Nfection With Hepatitis B Virus (Hbv) Is Commonmentioning

confidence: 99%

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A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B

et al. 2006

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Clevudine is a nucleoside analog with an unnatural ␤-L configuration. In a phase I/II clinical trial, once daily doses ranging from 10 to 200 mg for 28 days were well tolerated, and produced significant antiviral activity. The present study was conducted to assess the degree and durability of the antiviral response to 12 weeks of clevudine treatment, and to investigate its safety and tolerability. A total of 98 patients with HBeAg-positive chronic hepatitis B were randomized to placebo (n ‫؍‬ 32), 30-mg clevudine (n ‫؍‬ 32), and 50-mg clevudine (n ‫؍‬ 34) groups. Patients were followed up after 12 weeks of treatment for a further 24 weeks off-therapy. Median serum hepatitis B virus DNA reductions from baseline at week 12 were 0.20, 4.49, and 4.45 log 10 copies/mL in the placebo, 30-mg clevudine, and 50-mg clevudine groups, respectively (P < .0001). Posttreatment antiviral activities were sustained, with 3.32 and 2.99 log 10 reductions at week 12 off-therapy and 2.28 and 1.40 log 10 reductions at week 24 off-therapies in the 30-and 50-mg clevudine groups, respectively. Median serum alanine aminotransferase (ALT) levels decreased markedly from baseline during clevudine treatment and were maintained below the upper limit of normal throughout the 24 weeks off-therapy in the two clevudine-treated groups. The incidences of adverse events and treatment-emergent grade 3 or 4 laboratory abnormalities were similar for the three groups. In conclusion, clevudine showed potent antiviral activity during therapy and induced a sustained posttreatment antiviral effect for 6 months after a 12-week treatment period, and this was associated with a sustained normalization of ALT levels. (HEPATOLOGY 2006;43:982-988.)

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Section: Discussionmentioning

confidence: 91%

Section: Nfection With Hepatitis B Virus (Hbv) Is Commonmentioning

confidence: 99%

A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B

et al. 2006

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“…In chronically infected ducks treated with hepatocytotoxic reverse transcriptase inhibitors (24), in WHV-infected woodchucks treated with inhibitors of viral DNA replication (3,25), and in acutely WHV-infected woodchucks undergoing viral clearance (4, 7), there is strong evidence that cccDNA elimination depends on the death and turnover of infected hepatocytes. In other studies performed in HBV transgenic mice (9,15,26) and HBV-infected chimpanzees (10,11), it has been shown that viral replication is strongly and rapidly inhibited noncytopathically by the antiviral effects of IFN-␣͞␤ and IFN-␥, which eliminate the replicative DNA precursors of cccDNA from the cell (13).…”

Section: Discussionmentioning

confidence: 99%

Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees

Wieland

Spangenberg²,

Thimme³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

206

209

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We have previously shown that hepatitis B virus (HBV) replication is controlled by noncytolytic mechanisms that depend primarily on the effector functions of the CD8 ؉ T cell response, especially the production of IFN-␥ in the liver. The mechanisms that control the nuclear pool of viral covalently closed circular DNA (cccDNA) transcriptional template of HBV, which must be eliminated to eradicate infection, have been difficult to resolve. To examine those mechanisms, we quantitated intrahepatic HBV cccDNA levels in acutely infected chimpanzees whose virological, immunological, and pathological features were previously described. Our results demonstrate that the elimination kinetics of the cccDNA are more rapid than the elimination of HBV antigen-positive hepatocytes during the early phase of viral clearance, and they coincide with the influx of small numbers of IFN-␥ producing CD8 ؉ T cells into the liver. In contrast, terminal clearance of the cccDNA is associated with the peak of liver disease and hepatocellular turnover and with a surge of IFN-␥ producing CD8 ؉ T cells in the liver. Collectively, these results suggest that cccDNA clearance is a two-step process mediated by the cellular immune response. The first step reduces the pool of cccDNA molecules noncytolytically, probably by eliminating their relaxed circular DNA precursors and perhaps by destabilizing them. The second step enhances this process by destroying infected hepatocytes and triggering their turnover. Surprisingly, despite this multipronged response, traces of cccDNA persist indefinitely in the liver, likely providing a continuous antigenic stimulus that confers lifelong immunity.H epadnaviruses are small enveloped hepatotropic DNA viruses containing a relaxed circular DNA genome, which is converted into a covalently closed circular DNA (cccDNA) episome in the nucleus of infected cells (1). The cccDNA molecule serves as the transcriptional template for production of viral RNAs that are exported to the cytoplasm and encode the viral structural and nonstructural proteins, including the reverse transcriptase͞DNA polymerase. Reverse transcription of the viral pregenomic (pg)RNA and second-strand DNA synthesis occurs in the cytoplasm within viral capsids formed by the HBV core protein (HBcAg). Capsids containing the mature relaxed circular DNA genome are either enveloped and exported as virions, or they deliver their DNA content to the nucleus, thereby amplifying the pool of cccDNA molecules to 10-50 copies per cell (2-5). The factors that regulate the cccDNA content of infected cells are not very well understood. In the duck hepatitis B virus (DHBV) model, the cccDNA level is regulated by the viral envelope proteins (6). Evidence from the woodchuck hepatitis virus (WHV) system suggests that cccDNA clearance is tightly associated with the destruction and turnover of infected hepatocytes (7,8). The possibility that cccDNA may also be susceptible to control by immune-mediated noncytolytic mechanisms is an open question at this time, at least partiall...

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“…focused primarily on a strategy of inhibiting viral DNA synthesis through the use of nucleoside analogs that are highly specific for the viral DNA polymerase (1)(2)(3)(4)(5)(6)(7)(8)(9). Treatment of patients with such inhibitors can be remarkably effective in reducing viremias to very low levels (2,3).…”

Section: Hemotherapy Of Hepatitis B Virus (Hbv) Infections Hasmentioning

confidence: 99%

Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy

Summers

Mason

2003

Proc. Natl. Acad. Sci. U.S.A.

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We determined the frequency of integrated viral DNA in the livers of three woodchucks chronically infected with the woodchuck hepatitis virus before and during 30 weeks of therapy with the nucleoside analog L-FMAU [1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl)uracil, clevudine]. We found that although viral covalently closed circular DNA declined 20-to 100-fold, integrated viral DNA showed no discernable decrease over the course of treatment. Thus, chemotherapeutic clearance of covalently closed circular DNA did not involve the replacement of the infected hepatocyte population with uninfected progenitors, but rather, uninfected hepatocytes in the treated liver were derived from the infected hepatocyte population. The frequency of integrated DNA in chronically infected woodchucks was found to be 1 or 2 orders of magnitude higher than that in transiently infected woodchucks, implying that integration and other genomic damage accumulate over the duration of infection. Our results indicate that genetic changes from this damage remain in the liver even while virus infection is cleared and argue for early antiviral intervention in chronic hepatitis. C hemotherapy of hepatitis B virus (HBV) infections hasfocused primarily on a strategy of inhibiting viral DNA synthesis through the use of nucleoside analogs that are highly specific for the viral DNA polymerase (1-9). Treatment of patients with such inhibitors can be remarkably effective in reducing viremias to very low levels (2, 3). The reduction of viremia has been shown to occur with biphasic kinetics, with the first phase of rapid reduction attributed to the inhibition of virus production by infected cells, combined with viral clearance from the blood by mechanisms probably unrelated to the action of the drug. The slower second phase has been attributed to the elimination of infected cells from the liver, by either normal or immune-enhanced mechanisms, and the accumulation of uninfected cells (10, 11). The gradual replacement of infected by uninfected hepatocytes has been observed during antiviral therapy of woodchucks chronically infected with the woodchuck hepatitis virus (WHV), an animal model for HBV (7). In 1-(2-f luoro-5-methyl-beta, L-arabinofuranosyl)uracil (L-FMAU)-treated woodchucks, the onset of the reduction in infected cells lags behind the decline of the covalently closed circular DNA (cccDNA), the viral transcriptional template in the nucleus. It has been proposed that the removal of cccDNA occurs by hepatocyte turnover, and that dilution of cccDNA copy numbers in dividing hepatocytes results in eventual segregation of uninfected progeny cells (12). Alternatively, uninfected hepatocytes may arise by differentiation of uninfected progenitors (13) or be generated through a slow loss of cccDNA from infected hepatocytes (14,15).During hepadnavirus infection, a small fraction of hepatocytes undergo recombination with viral DNA molecules in the nucleus and acquire an integrated viral DNA that may be stably retained in that hepatocyte lineage (16)(17)(18)(1...

show abstract

Antiviral activity of clevudine [?-FMAU, (1-(2-fluoro-5-methyl-β, ?-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax)

Cited by 125 publications

References 36 publications

A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B

A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B

Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees

Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy

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