Chronic hepatitis B (CHB) affects =1.5 million Americans, with Asian-Americans disproportionately affected, and =5000 deaths annually due to cirrhosis and hepatocellular carcinoma. With the availability of effective, well-tolerated HBV treatments, reductions in liver-related deaths are achievable. However, unanswered questions include whether the current target groups for treatment should be expanded, if combinations of drugs are superior to a single drug, whether interferon-containing regimens can modulate a favorable immune response that augments Early (HBe) and Surface (HBs) antigen seroconversion, and what treatment durations and endpoints should optimally be used? The San Francisco HBV Consortium together with other Hepatitis B Research Network (HBRN) investigators has implemented 5 clinical protocols (2 observational studies and 3 clinical trials) and 16 ancillary studies including quality of life, epidemiology, immunology, virology, and genomic. To date 1,875 adults and 375 children are in longitudinal follow-up and the biorepository acquired 191,000 aliquots of serum/plasma, 9,300 aliquots of DNA, 1,800 liver biopsy slides and 120 liver tissue specimens for translational studies. Our study aims for the longitudinal cohort are to identify predictors of disease activation (hepatitis flares, HBV clinica phenotype transitions, HBeAg/HBsAg loss) and progression to cirrhosis, liver failure, and HCC. Special populations under study include pregnant women, those with HDV coinfection, acute hepatitis B and patients with flares. Additionally, we are executing 2 clinical trials, with the primary goal of comparing combination versus monotherapy as first-line therapy The Immune Active (IA) trial is a randomized (1:1) parallel group design trial comparing (i) Tenofovir (TDF) 300 mg daily for 192 weeks (4 years) and (ii) peg-IFN alfa-2a 180g weekly for 24 weeks plus TDF 300 mg daily for 192 weeks in 200 patients with HBeAg positive and negative active CHB. The primary endpoint is HBsAg loss after a finite period of treatment (4 years) and 48 weeks after stopping treatment. The Immune Tolerant (IT) trial is a single arm pilot to evaluate 8 weeks of entecavir (ETV) followed by 40 weeks of both ETV and peg-IFN alfa-2a in 40 adults and 60 children with HBeAg- positive CHB with normal or near normal ALT levels and high serum levels of HBV DNA. The primary endpoint is HBeAg loss and HBV DNA =1,000 IU/mL 48 weeks after stopping therapy. The San Francisco HBV Consortium further proposes to explore the role for vitamin D status in shaping the clinical phenotypes, immunologic transitions and treatment outcomes of adult and pediatric patients with chronic hepatitis B.

Public Health Relevance

We are poised to significantly reduce the morbidity and mortality associated with CHB. With an improved understanding of the natural history, influences and pathogenesis of CHB, and with appropriate application of available therapies, lives will be saved. The most pressing therapeutic issues are whether to use single or combination antiviral therapy and to define who should be treated and for how long. Our study results will shape clinical practice and positively impact the outcomes of CHB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK082944-08
Application #
8975507
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (M2))
Program Officer
Doo, Edward
Project Start
2008-09-30
Project End
2020-05-31
Budget Start
2015-09-01
Budget End
2016-05-31
Support Year
8
Fiscal Year
2015
Total Cost
$884,648
Indirect Cost
$374,437
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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 :
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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
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
Park, Jang-June; Wong, David K; Wahed, Abdus S et al. (2016) Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B. Gastroenterology 150:684-695.e5
Khalili, Mandana; Lombardero, Manuel; Chung, Raymond T et al. (2015) Diabetes and prediabetes in patients with hepatitis B residing in North America. Hepatology 62:1364-74
Schwarz, Kathleen B; Cloonan, Yona Keich; Ling, Simon C et al. (2015) Children with Chronic Hepatitis B in the United States and Canada. J Pediatr 167:1287-1294.e2
Ghany, Marc G; Perrillo, Robert; Li, Ruosha et al. (2015) Characteristics of adults in the hepatitis B research network in North America reflect their country of origin and hepatitis B virus genotype. Clin Gastroenterol Hepatol 13:183-92

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