Hepatitis D viremia following orthotopic liver transplantation involves a typical HDV virion with a hepatitis B surface antigen envelope

Smedile, Antonina; Casey, John L.; Côté, Paul J.; Durazzo, Marilena; Lavezzo, Bruna; Purcell, Robert H.; Rizzetto, Mario; Gerin, John L.

doi:10.1002/hep.510270636

Cited by 71 publications

(51 citation statements)

References 27 publications

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“…IgM anti-HD was measured using a previously described capture immunoassay. 16 Serum samples were tested for HDV RNA as previously reported 17 by semiquantitative single and nested polymerase chain reaction (PCR) assays, with a sensitivity of approximately 1,000 and 1-10 genomes/mL respectively. Serum HBV DNA levels were determined with a commercial quantitative PCR assay (Amplicor HBV Monitor Test, Roche Diagnostics, GmbH Mannheim, Germany) with a sensitivity threshold of about 400 copies/mL.…”

Section: Methodsmentioning

confidence: 99%

Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta

et al. 2006

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Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy. This study was designed to examine the efficacy and safety of peginterferon with or without ribavirin. Thirty-eight serum hepatitis B surface antigen-and HDV RNA-positive patients with alanine aminotransferase (ALT) more than 1.5 times the upper normal limit received peginterferon alpha-2b (1.5 g/kg) alone as monotherapy (n ‫؍‬ 16) or in combination with ribavirin (n ‫؍‬ 22), for 48 weeks. Thereafter, all the patients were maintained on peginterferon for 24 weeks and followed for 24 weeks off therapy. The primary end point studied was the virological and biochemical response at the end of follow-up. HDV RNA was determined by single or nested polymerase chain reaction assays. Twenty-seven patients (71%), 11 receiving monotherapy and 16 receiving the combination treatment, completed the follow-up. At the end of treatment, a virological response was observed in 3 of the patients treated with peginterferon (19%) and in 2 of the patients treated with combination therapy (9%), and a biochemical response was observed in 6 (37.5%) and 9 patients (41%), respectively. In nonresponders, ALT diminished from a mean of 174 ؎ 53 to 86 ؎ 41 IU/L. At the end of follow-up, serum HDV RNA was negative in 8 patients (21%), and a biochemical response was detected in 10 patients (26%). Treatment was discontinued in 25% of the patients, and dosing was modified in 58%. In conclusion, a prolonged course of peginterferon alpha-2b resulted in clearance of serum HDV RNA and ALT normalization in a fifth of patients with chronic hepatitis D, while ribavirin had no effect on the viral clearance rate. Overall tolerance of therapy was poor. (HEPATOLOGY 2006;44:713-720.)

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Section: Methodsmentioning

confidence: 99%

Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta

et al. 2006

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“…Chronic WHV carrier woodchucks were infected at 18 months of age with woodchuck-derived HDV by intravenous administration of a 0.5-ml volume of a 1:5 dilution of the WHDV-1 pool. Serum samples were obtained weekly and analyzed for HDV RNA by reverse transcription and semiquantitative PCR (22,31).…”

Section: Methodsmentioning

confidence: 99%

“…Woodchuck 4928, a chronic WHV carrier, was transfected with 50 g of the HDV construct pGDLx1.2 in a total volume of 0.5 ml of phosphate-buffered saline by direct injection at several separate sites in the surgically exposed liver. Sera were obtained weekly and analyzed by reverse transcription (RT) and semiquantitative PCR for HDV RNA, as described previously (22,31). Highly positive sera from weeks 7 to 15 were combined to create the woodchuck hepatitis delta virus type 1 (WHDV-1) pool.…”

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Genetic Changes in Hepatitis Delta Virus from Acutely and Chronically Infected Woodchucks

Casey

Tennant

Gerin

2006

J Virol

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A woodchuck-derived hepatitis delta virus (HDV) inoculum was created by transfection of a genotype I HDV cDNA clone directly into the liver of a woodchuck that was chronically infected with woodchuck hepatitis virus. All woodchucks receiving this inoculum became positive for HDV RNA in serum, and 67% became chronically infected, similar to the rate of chronic HDV infection in humans. Analysis of HDV sequences obtained at 73 weeks postinfection indicated that changes had occurred at a rate of 0.5% per year; many of these modifications were consistent with editing by host RNA adenosine deaminase. The appearance of sequence changes, which were not evenly distributed on the genome, was correlated with the course of HDV infection. A limited number of modifications occurred in the consensus sequence of the viral genome that altered the sequence of the hepatitis delta antigen (HDAg). All chronically infected animals examined exhibited these changes 73 weeks following infection, but at earlier times, only one of the HDV carriers exhibited consensus sequence substitutions. On the other hand, sequence modifications in animals that eventually recovered from HDV infection were apparent after 27 weeks. The data are consistent with a model in which HDV sequence changes are selected by host immune responses. Chronic HDV infection in woodchucks may result from a delayed and weak immune response that is limited to a small number of epitopes on HDAg.Hepatitis delta virus (HDV) is an obligate subviral satellite of hepatitis B virus (HBV) that causes both acute and chronic liver disease in humans (13). The HDV virion is composed of a ribonucleoprotein core and an envelope formed by the surface antigen protein (HBsAg) of HBV (3-5). The envelope is the sole helper function provided by HBV. HDV is able to replicate within cells in the absence of HBV (17) but requires HBsAg for the packaging and release of HDV virions (29, 33) as well as for infectivity (32). In addition to the envelope of its natural helper HBV, HDV can be packaged by the surface antigen of related hepadnaviruses, including woodchuck hepatitis virus (WHV) (27, 29) and woolly monkey hepatitis B virus (18), and can produce both acute and chronic infection in woodchucks that are chronically infected with WHV (20,27,30).There are two modes of HDV infection: superinfection of an individual with chronic HBV infection and coinfection with both viruses of an individual who has not been exposed previously to HBV. While the latter type of exposure typically leads to recovery from both viral infections, the former results in chronic HDV infection with a frequency of 70% to 80% (13). The determinants of the outcome of HDV superinfection are not known. Previous studies of viral genetic changes during infection have analyzed HDV RNA obtained either from the sera of chronically infected patients during the course of HDV infection (7,14,19) or from the liver of a woodchuck infected with virus that had been passaged several times (21). These studies did not address whether genetic cha...

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“…Twenty-six WHV carriers were inoculated with a dilution of the pooled HDV-positive sera from woodchuck no. 4928 containing 10 8 genomes and were monitored for HDV viremia by reverse transcription-PCR (22,29). HDV RNA was quantified by radiolabeling PCR products, which were separated by acrylamide gel electrophoresis and analyzed by phosphoimager; serial dilutions of HDV RNA standards were used to generate standard curves for quantification.…”

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confidence: 99%

“…There is no long-standing cellular repository for HDV as there is for HBV (29), and the half-life of HDV-infected cells may be brief; in mice, infected cells survive for as little as 2 weeks (19). While in this study it was not possible to determine the long-term outcome of clevudine therapy on the course of chronic HDV infection or disease, the sustained reduction of HDV to undetectable levels by therapy with this potent nucleoside analog suggests that HDV disease in clinical patients would be reduced and that treatment has the potential to eliminate HDV infection in chronically infected individuals.…”

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Clevudine Inhibits Hepatitis Delta Virus Viremia: a Pilot Study of Chronically Infected Woodchucks

Casey

Côté

Toshkov

et al. 2005

Antimicrob Agents Chemother

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In a small controlled study, clevudine, a potent inhibitor of hepadnaviruses, including hepatitis B virus and woodchuck hepatitis virus, suppressed hepatitis delta virus (HDV) viremia in chronically infected woodchucks. Suppression was correlated with the marked reduction of woodchuck hepatitis virus surface antigen in individual animals, consistent with the concept that repression of surface antigen expression may be a useful antiviral strategy for HDV.Type D hepatitis is caused by infection with hepatitis D (delta) virus (HDV), an obligate subviral satellite of hepatitis B virus (HBV) (9). The HDV virion is composed of a ribonucleoprotein core and an envelope formed by the surface antigen protein (HBsAg) of HBV (1-3). The envelope is the sole helper function provided by HBV, in that HDV is able to replicate within cells in the absence of HBV (13) but requires HBsAg for packaging and release of HDV virions (28, 37) as well as for infectivity (31).Chronic type D hepatitis, similar to chronic HBV infection, is typically characterized by necroinflammatory lesions, but it is more severe and frequently progresses rapidly to cirrhosis and liver failure, accounting for a disproportionate association of chronic HDV infection with terminal liver disease and an indication for liver transplantation (26, 30). There is currently no generally accepted effective therapy for type D hepatitis (see reference 21 for a review), and liver transplantation is the only option for the associated end-stage liver disease (36). Exceptionally high doses of alpha interferon have been, at best, moderately successful in treating some cases of type D hepatitis (6,10,27,34). Acyclovir enhances HDV replication in vitro. Ribavirin does not significantly affect virologic or biochemical parameters, and there were severe side effects in clinical trials. Synthetic analogs of thymosin have been ineffective in the treatment of HDV infection (21).The dependence of HDV on HBV could suggest that successful treatment of HDV infection would follow successful treatment of the supporting HBV infection. Unfortunately, this does not always appear to be the case. Although treatment of chronic HBV carriers with lamivudine (␤-L-2Ј,3Ј-dideoxy-3Ј-thiacytidine) leads to decreased levels of HBV in serum and improved liver histology (5,14,20), in patients with chronic delta hepatitis prolonged lamivudine therapy neither lowers HDV RNA levels nor ameliorates disease activity, even though HBV viremia is reduced (15,35). Similarly, treatment with famciclovir was not effective against HDV infection (38). The most likely explanation for the failure of these treatments to affect HDV is that HDV requires the HBsAg function of HBV, and lamivudine treatment does not typically reduce HBsAg levels. We therefore sought to determine whether HDV could be inhibited by an anti-HBV therapeutic agent that dramatically reduces HBsAg levels.Woodchuck hepatitis virus (WHV) and its natural host, the Eastern woodchuck, represent a useful model of HBV-induced disease that is predictive of nuc...

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Hepatitis D viremia following orthotopic liver transplantation involves a typical HDV virion with a hepatitis B surface antigen envelope

Cited by 71 publications

References 27 publications

Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta

Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta

Genetic Changes in Hepatitis Delta Virus from Acutely and Chronically Infected Woodchucks

Clevudine Inhibits Hepatitis Delta Virus Viremia: a Pilot Study of Chronically Infected Woodchucks

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