Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy

Summers, Jesse; Mason, William S.

doi:10.1073/pnas.0307422100

Cited by 88 publications

(67 citation statements)

References 27 publications

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“…The results were similar to those collected at the later time point (Table 2). A similar stability of integrated WHV DNA was also observed when chronically infected woodchucks were treated with clevudine (2Ј-fluoro-5-methyl-␤-L-arabinofuranosyluracil), another inhibitor of hepadnavirus DNA synthesis (22).…”

Section: Downloaded Fromsupporting

confidence: 54%

The Amount of Hepatocyte Turnover That Occurred during Resolution of Transient Hepadnavirus Infections Was Lower When Virus Replication Was Inhibited with Entecavir

Mason

Low

et al. 2009

J Virol

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Transient hepadnavirus infections can involve spread of virus to the entire hepatocyte population. In this situation hepatocytes present following recovery are derived from infected hepatocytes. During virus clearance antiviral cytokines are thought to block virus replication and formation of new covalently closed circular DNA (cccDNA), the viral transcriptional template. It remains unclear if existing cccDNA is eliminated noncytolytically or if hepatocyte death and proliferation, to compensate for killing of some of the infected hepatocytes, are needed to remove cccDNA from surviving infected hepatocytes. Interpreting the relationship between hepatocyte death and cccDNA elimination requires knowing both the amount of hepatocyte turnover and whether cccDNA synthesis is effectively blocked during the period of immune destruction of infected hepatocytes. We have addressed these questions by asking if treatment of woodchucks with the nucleoside analog inhibitor of viral DNA synthesis entecavir (ETV) reduced hepatocyte turnover during clearance of transient woodchuck hepatitis virus (WHV) infections. To estimate hepatocyte turnover, complexity analysis was carried out on virus-cell DNA junctions created by integration of WHV and present following recovery in the livers of WHV-infected control or ETV-treated woodchucks. We estimated that, on average, 2.2 to 4.8 times less hepatocyte turnover occurred during immune clearance in the ETV-treated woodchucks. Computer modeling of the complexity data suggests that mechanisms in addition to hepatocyte death were responsible for elimination of cccDNA during recovery from transient infections.Hepadnavirus infection can spread to the entire hepatocyte population of the liver and result in a period of high-titer virus production of 4 to 6 weeks or more. A vigorous immune response then initiates the immune clearance phase with hepatocyte destruction and suppression of virus replication (11,12,19,23,24). Previous work indicated that uninfected hepatocytes in the recovered liver were derived either directly from or as progeny of hepatocytes that had been infected (12, 21). However, it remains to be determined how uninfected hepatocytes arise from infected hepatocytes, a process that requires elimination of virus replicative intermediate (RI) DNA from the cytoplasm and, more importantly, covalently closed circular DNA (cccDNA) from the nucleus of the infected hepatocytes or from their progeny.Three models have been proposed to explain how transient hepadnavirus infections are cleared from the liver. In all three models hepatocytes present at recovery are derived from previously infected hepatocytes. In model 1, cytokines released during the immune response to the infection inhibit virus replication, prevent synthesis of viral RI DNA and cccDNA, and eliminate both RI DNA and cccDNA from infected hepatocytes. Immunemediated attack on infected hepatocytes may be considered crucial to the process that causes cytokine release, but the resulting hepatocyte death and compensatory prolifer...

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confidence: 54%

The Amount of Hepatocyte Turnover That Occurred during Resolution of Transient Hepadnavirus Infections Was Lower When Virus Replication Was Inhibited with Entecavir

Mason

Low

et al. 2009

J Virol

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“…In woodchuck models of HBV, viral cccDNA declined 20-to 100-fold after 30 weeks treatment with clevudine [18] . Therefore, suppression of cccDNA in addition to inhibition of viral DNA polymerase activity may lead to truly durable responses of clevudine.…”

Section: Discussionmentioning

confidence: 99%

Clevudine Therapy for 24 Weeks Further Reduced Serum Hepatitis B Virus DNA Levels and Increased ALT Normalization Rates without Emergence of Viral Breakthrough than 12 Weeks of Clevudine Therapy

Lee

Byun²,

Chung

et al. 2007

Intervirology

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Objectives: The objectives of the study were to evaluate the safety and antiviral activity of 24-week treatment with clevudine 30 mg in HBeAg(+) chronic hepatitis B patients. Biochemical and serological responses were also assessed. Method: Twenty-one patients received clevudine 30 mg for 24 weeks and were followed up for another 24 weeks off therapy. Results: Median decreases from baseline in HBV DNA were 4.65 and 1.96 log₁₀ copies/ml at week 24 (end of treatment) and week 48 (24 weeks off therapy), respectively. Analysis of individual data showed that HBV DNA levels were below the lower limit of detection (300 copies/ml) by Amplicor PCR assay in 19, 57, 19 and 0% at week 12, 24, 34 and 48, respectively. The proportion of patients with normal ALT were 67, 81 and 75% at week 24 (end of treatment), 34 and 48 (24 weeks off therapy), respectively. The rates of HBeAg loss were 24 and 20% at week 24 and 48, respectively. No viral breakthrough during treatment was observed. Conclusion: Clevudine 30 mg treatment for 24 weeks was well tolerated and exhibited more potent antiviral activity and a higher ALT normalization rate than 12-week treatment with durable efficacy at week 24 off therapy.

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“…No evidence of virusdrug resistance was noted during the treatment period if extended to 24 weeks [219]. The sustained viral suppression achieved by clevudine appeared to be associated with, and may be attributed to, a significant reduction of covalently closed circular DNA (cccDNA) in hepatocytes [220,221].…”

Section: Hepadnaviruses (Hepatitis B Virus (Hbv))mentioning

confidence: 98%

Anti‐DNAVirus Agents

Holý

Clercq

2010

Burger's Medicinal Chemistry and Drug Discovery

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Anti‐DNA virus agents that are inhibitory to the replication of DNA viruses have been reviewed by Tim Middleton and Rockway in Burger's Medicinal Chemistry, 6th ed., volume 5. Here we will address the various agents effective against these different viruses. For each of the (classes of) compound(s), we will, where applicable, specifically focus on (i) the antiviral compounds that are clinically available; (ii) the antiviral compounds that are under (pre)clinical development; (iii) the mechanism of action of the compounds; (iv) their structure–activity relationship (SAR); (v) resistance that may have arisen; (vi) recent clinical data obtained with the compounds while under development. Previous reviews on antiviral agents have been dealing with “looking back in 2009 at the dawning of antiviral therapy now 50 years ago: an historical perspective,” highlighting the discovery of acyclovir [9‐(2‐hydroxyethoxymethyl)guanine] as a specific antiherpetic agent, “the design of drugs for HIV and HCV,” “HIV drug development: the next 25 years,” “interferons at age 50: past, current, and future impact on biomedicine,” “the way forward in HCV treatment‐finding the right path,” “antiviral treatment of chronic hepatitis B virus infections: the past, the present, and the future,” “antiviral agents active against influenza A viruses,” “the war against influenza: discovery and development of sialidase inhibitors,” “antivirals and antiviral strategies,” and “clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections.”

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Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy

Cited by 88 publications

References 27 publications

The Amount of Hepatocyte Turnover That Occurred during Resolution of Transient Hepadnavirus Infections Was Lower When Virus Replication Was Inhibited with Entecavir

The Amount of Hepatocyte Turnover That Occurred during Resolution of Transient Hepadnavirus Infections Was Lower When Virus Replication Was Inhibited with Entecavir

Clevudine Therapy for 24 Weeks Further Reduced Serum Hepatitis B Virus DNA Levels and Increased ALT Normalization Rates without Emergence of Viral Breakthrough than 12 Weeks of Clevudine Therapy

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