Robert P. Perrillo M.D.

Alter, H., T. Block, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, F. V. Chisari, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. Greten, H. Guo, J. T. Guo, Y. Hoshida, J. Hu, K. V. Kowdley, W. Li, J. Liang, S. Locarnini, A. S. Lok, W. Mason, B. McMahon, A. Mehta, R. Perrillo, P. Revill, C. M. Rice, J. Rinaudo, R. Schinazi, C. Seeger, K. Shetty, J. Tavis and F. Zoulim (2018). “A research agenda for curing chronic hepatitis B virus infection.” Hepatology 67(3): 1127-1131.

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We encourage the scientific community to focus on research leading to discovery of a cure for chronic HBV infection based on these principles: 1) The surest way to cure HBV is to eliminate or permanently silence its cccDNA. 2) The most important impediment to this achievement is our limited understanding of the fundamental molecular mechanisms that control cccDNA biogenesis, homeostasis, and decay. 3) Understanding these mysteries is now within reach, thanks to recent technological advances that enable definition of these mechanisms. 4) Vulnerabilities in the cccDNA “life cycle” that are discovered in the course of these studies can be exploited to develop small molecule and other molecular strategies to eradicate or permanently silence the cccDNA. 5) Because these studies will explore the unknown, the outcome, like all great adventures, cannot be predicted. Thus, we suggest that in addition to approaches that directly target cccDNA, independent approaches that target other vulnerabilities in the viral life cycle and either indirectly repress HBV cccDNA or safely establish a curative antiviral immune response be pursued in parallel. 6) Such projects could include genetic approaches to cccDNA mutagenesis, epigenetic modification, or other strategies that can suppress cccDNA transcription (e.g., HBV-targeted antisense and small interfering RNA, HBV X protein inhibition, etc.) or to prevent its recycling (e.g., capsid inhibitors). (Excerpt from text, p. 1128; no abstract available.)

Block, T. M., H. Alter, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. F. Greten, J. T. Guo, Y. Hoshida, K. V. Kowdley, W. Li, A. S. Lok, B. McMahon, A. Mehta, R. Perrillo, C. M. Rice, J. Rinaudo, R. F. Schinazi and K. Shetty (2018). “Research priorities for the discovery of a cure for chronic hepatitis B: Report of a workshop.” Antiviral Res 150: 93-100.

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In early 2017, the Hepatitis B Foundation invited 30 experts in the fields of hepatitis B and liver cancer research to identify projects they deemed important to the goal of finding a cure for chronic hepatitis B and D and the diseases with which these viral infections are associated. They were also asked to identify general categories of research and to prioritize sub-project topics within those areas. The experts generally agreed on broadly defined areas of research, but there was usually little difference between the highest and lowest scoring projects; for the most part, all programs described in this document were considered valuable and necessary. An executive summary of this discussion was recently published (Alter et al., Hepatology 2017). The present manuscript reports the areas of research identified by the workshop participants, provides a brief rationale for their selection, and attempts to express differences among the priorities assigned to each area of research, when such distinctions were expressed.

Block, T. M., H. Alter, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. F. Greten, J. T. Guo, Y. Hoshida, K. V. Kowdley, W. Li, A. S. Lok, B. McMahon, A. Mehta, R. Perrillo, C. M. Rice, J. Rinaudo, R. F. Schinazi and K. Shetty (2017). “Research priorities for the discovery of a cure for chronic hepatitis B: Report of a workshop.” Antiviral Res 150: 93-100.

Full text of this article.

In early 2017, the Hepatitis B Foundation invited 30 experts in the fields of hepatitis B and liver cancer research to identify projects they deemed important to the goal of finding a cure for chronic hepatitis B and D and the diseases with which these viral infections are associated. They were also asked to identify general categories of research and to prioritize sub-project topics within those areas. The experts generally agreed on broadly defined areas of research, but there was usually little difference between the highest and lowest scoring projects; for the most part, all programs described in this document were considered valuable and necessary. An executive summary of this discussion was recently published (Alter et al., Hepatology 2017). The present manuscript reports the areas of research identified by the workshop participants, provides a brief rationale for their selection, and attempts to express differences among the priorities assigned to each area of research, when such distinctions were expressed.

Alter, H., T. M. Block, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, F. V. Chisari, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. Greten, H. Guo, J. T. Guo, Y. Hoshida, J. Hu, K. V. Kowdley, W. Li, J. Liang, S. Locarnini, A. S. Lok, W. Mason, B. McMahon, A. Mehta, R. Perrillo, P. Revill, C. M. Rice, J. Rinaudo, R. Schinazi, C. Seeger, K. Shetty, J. Tavis and F. Zoulim (2017 ). “A research agenda for curing chronic hepatitis b virus infection.” Hepatology 2017 Sep [Epub ahead of print].

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There is a growing interest in discovery and development of new therapeutics that will cure chronic hepatitis B virus (HBV) infection, due to the recent establishment of new cell culture-based and small animal-based models. These new systems create unprecedented opportunities to study the entire viral life cycle and to search for vulnerabilities that can be exploited for curative purposes. Here we propose a scientific pathway that we believe will lead to the development of curative therapies for chronic HBV infection and its associated diseases.

Perrillo, R. P. (2017). “HBV Reactivation During DAA Treatment of Chronic Hepatitis C: A Hidden Danger of an Otherwise Major Success Story.” Hepatology: 2017 Mar [Epub ahead of print].

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It has been estimated that 250 million and 170 million people worldwide are infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. Co-infection is relatively common in regions where both viruses are endemic and transmission is facilitated by common routes of exposure. In a recent study of 1287 New York City residents with hepatitis C, most of whom were born in United States, 62% had resolved HBV infection and 6% were HBsAg positive. Dual infection with HBV and HCV leads to accelerated liver disease and a higher risk for cirrhosis and hepatocellular carcinoma. Treatment of coinfected patients is controversial, but it is a common practice to treat the virus that genomic testing reveals to be dominant. The intracellular interactions of the two viruses are unclear. Cross sectional studies have shown that co-infected individuals often have high levels of HCV RNA, low or non-detectable HBV DNA, anti-HBe reactivity, and lower levels of HBsAg when compared to HBV mono infection. Thus, HCV is most often the primary target of antiviral therapy. However, longitudinal studies have demonstrated that the levels of HBV DNA and HCV RNA may fluctuate with time suggesting that competitive interactions between the two viruses is more dynamic than previously thought.