We propose to renew the participation of the Midwest Hepatitis B Consortium as a member of the Hepatitis B Research Network (HBRN). The Midwest Consortium consists of three sites: Saint Louis University adult, Saint Louis University pediatric and Washington University adult. The consortium has functioned well and collaboratively in recruiting and enrolling patients in the HBRN studies and its performance compares favorably to that of other network sites, including some of those in much larger cities with many more individuals at-risk for hepatitis B. In addition to their successes in recruiting an enrolling, investigators at each site within the Midwest Consortium brings a special strength to the Network: Thus, Dr. Di Bisceglie (SLU adult) provides experience and leadership, including his role as co-chair of the Ancillary Studies Committee. Dr Teckman (SLU pediatric) is PI of one of only 7 pediatric sites within the network, and Dr Lisker-Melman (Wash. U adult) is positioned to be a major contributor to the separately- funded ancillary study on HIV-HBV co-infection that is being conducted by the Network. The Midwest Consortium is therefore well positioned to continue enrolling patients in the existing studies and also to contribute to the development of new therapeutic studies for the network. Finally, Dr. Di Bisceglie has been very successful is establishing basic research collaborations to enhance the productivity of the Network. Thus, his long-time collaborator, Dr John Tavis is a recipient of a grant supplement to conduct an approved Virology ancillary study aimed at developing RNaseH inhibitors as a novel method of treatment for hepatitis B. This application also includes a proposal from Dr Adam Gehring, an experienced HBV immunologist at SLU which will make use of biorepository specimens to study antiviral effects of various immunomodulators, including GM-CSF. If these studies confirm preliminary observations, they would form the basis for a novel therapeutic approach to be adopted in the next phase of the HBRN in which patients already on long-term antiviral therapy with complete suppression of HBV could receive immunomodulators in an attempt to enhance the rate of HBsAg clearance and to allow patients to stop their antiviral therapy

Public Health Relevance

The Midwest hepatitis B Consortium has functioned well as a member of the Hepatitis B Research Network and will continue to enroll patients, including special populations of children and those with HIV-HBV co-infection into the Network studies. We have developed RNAse-H inhibition as a completely novel approach to antiviral therapy of hepatitis B and will explore this approach using Network resources. Finally, we propose a new ancillary study to look at the effect of immunomodulatory agents such as GM-CSF to enhance the clearance of hepatitis B, initially in vitro but also possibly later in human subjects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK082871-12
Application #
9743783
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Doo, Edward
Project Start
2008-09-30
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Khalili, Mandana; Shuhart, Margaret C; Lombardero, Manuel et al. (2018) Relationship Between Metabolic Syndrome, Alanine Aminotransferase Levels, and Liver Disease Severity in a Multiethnic North American Cohort With Chronic Hepatitis B. Diabetes Care 41:1251-1259
Rosenthal, Philip; Ling, Simon C; Belle, Steven H et al. (2018) Combination of entecavir/ peginterferon alfa-2a in children with HBeAg-positive immune tolerant chronic hepatitis B virus infection. Hepatology :
Lok, A S; Ganova-Raeva, L; Cloonan, Y et al. (2017) Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment. J Viral Hepat 24:1032-1042
Schwarzenberg, Sarah Jane; Ling, Simon C; Cloonan, Yona Keich et al. (2017) Health-related Quality of Life in Pediatric Patients With Chronic Hepatitis B Living in the United States and Canada. J Pediatr Gastroenterol Nutr 64:760-769
Lomonosova, Elena; Tavis, John E (2017) In Vitro Enzymatic and Cell Culture-Based Assays for Measuring Activity of HBV RNaseH Inhibitors. Methods Mol Biol 1540:179-192
Di Bisceglie, A M; Lombardero, M; Teckman, J et al. (2017) Determination of hepatitis B phenotype using biochemical and serological markers. J Viral Hepat 24:320-329
Lomonosova, Elena; Zlotnick, Adam; Tavis, John E (2017) Synergistic Interactions between Hepatitis B Virus RNase H Antagonists and Other Inhibitors. Antimicrob Agents Chemother 61:
Ren, Yi; Wang, Weihua; Zhang, Xiaoan et al. (2016) Evidence for deleterious hepatitis C virus quasispecies mutation loads that differentiate the response patterns in IFN-based antiviral therapy. J Gen Virol 97:334-43
Villa, Juan Antonio; Pike, Daniel P; Patel, Kunjan B et al. (2016) Purification and enzymatic characterization of the hepatitis B virus ribonuclease H, a new target for antiviral inhibitors. Antiviral Res 132:186-95
Evon, Donna M; Wahed, Abdus S; Johnson, Geoffrey et al. (2016) Fatigue in Patients with Chronic Hepatitis B Living in North America: Results from the Hepatitis B Research Network (HBRN). Dig Dis Sci 61:1186-96

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