Observational Study of Persons With Hepatitis B Virus Infection in North America

Background:

- Chronic hepatitis B virus infection is a leading cause of morbidity and mortality from end stage liver disease and liver cancer. Although significant progress has been made recently in hepatitis B therapy, current knowledge about how to manage the infection is limited because most treatment trials involve 1 to 2 years of therapy at most, even though most patients require treatment of much longer duration for optimal long-term outcome. To improve current knowledge on the disease and long-term disease progression, the Hepatitis B Research Network is collecting health and disease information from individuals who have been diagnosed with hepatitis B.

Objectives:

- To study individuals with hepatitis B and identify factors that affect the way the disease progresses.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with hepatitis B.

Design:

• Participants will be screened with a physical examination and medical history. Health information will be collected through questionnaires and surveys on health behaviors, and family history of liver disease. Participants will also provide blood samples, and those who have had a liver biopsy within the past 2 years or have one during the course of the study will provide biopsy material for further study.
• Information will be collected during a series of study visits. Each visit will take approximately 1 hour. During the first year, participants will have study visits 12 weeks, 24 weeks, and 48 weeks after entering the study. In subsequent years, participants will have a study visit approximately every 24 weeks (6 months) until the end of the study.
• Additional visits will be required of women who are pregnant when enrolled in the study or become pregnant during the course of the study.
• Participants whose hepatitis B status changes during the course of the study (for example, a flare of disease activity) may be asked to return for more frequent visits.

AIMS

Primary Aim:

- To describe participants with hepatitis B virus (HBV) infection in a prospective cohort in the United States (US) and Canada and identify predictors of disease activation and progression

Secondary Aims:

• To describe clinical, virological, and immunological characteristics of participants with HBV in the US and Canada
• To evaluate changes in HBV infection status and quantitative HBsAg levels and factors associated with those changes
• To verify whether a baseline HBsAg below 1,000 IU/mL and HBV DNA below 1,000 IU/mL is an accurate predictor of people who are, or who will become, inactive carriers, defined as people who are HBsAg positive, HBeAg negative, have normal ALT and HBV DNA under 1,000 IU/mL on at least two occasions over a period of at least 6 months
• To develop a bank of biospecimens (e.g., serum, plasma, DNA, lymphocytes, liver tissue) obtained from participants with HBV infection
• To identify participants with HBV infection who are potential candidates in one of the treatment studies to be conducted by the Hepatitis B Research Network (HBRN)
• To describe the natural history of hepatitis B infection in pregnancy including the frequency of, and clinical and virological characteristics associated with, hepatic flares during pregnancy and post-partum.

Type of Study:

Observational

Cohort Study

Patients with HBV infection will be identified by sites participating in the NIH-funded Hepatitis B Research Network (HBRN). Consenting patients who meet entry criteria will undergo a baseline evaluation. Those who are eligible for one of the treatment studies being conducted by the network will be approached about participating. If they are not eligible, unwilling to participate or have completed their participation in a treatment study, they will be followed longitudinally to observe clinical outcomes and changes in their virologic and immunologic status.

It is estimated that approximately 2,500 participants with HBV infection will be enrolled over a period of approximately 24 months. They will be followed indefinitely until the conclusion of the study, which is estimated presently to be up to 72 months.

Inclusion Criteria

• Written informed consent
• At least 18 years of age
• HBsAg-positive

Exclusion Criteria

• History of hepatic decompensation based on clinical or laboratory criteria
• Hepatocellular carcinoma (HCC)
• History of solid organ transplantation or bone marrow transplantation
• Current hepatitis B antiviral treatment (except pregnant women)
• Chronic immunosuppression therapy
• Known HIV co-infection (patients with HDV or HCV co-infection are not excluded)
• Medical or social condition which, in the opinion of the investigator, would make the patient unsuitable for the study or interfere with or prevent follow up per protocol.
• Unable or unwilling to return for follow-up visits

Briefly, the standard visit schedule for participants will be at baseline, weeks 12, 24 and 48 in their first year of enrollment and every 24 weeks in subsequent years.

Variable follow up visits may be required if certain events are encountered. For example, for participants experiencing an ALT flare, as defined in section 3.2.1 and Appendix A, follow up will occur every 2-4 weeks until resolved and for HBeAg or HBsAg loss, participants will be asked to return in 12 and 24 weeks, and then resume follow-up of every 24 weeks.

The following events will be noted:

• ALT flare
• HBsAg or HBeAg loss
• Cirrhosis
• Hepatic decompensation
• HCC
• Liver transplantation
• Death

For women who are, or become, pregnant while enrolled in the cohort study, one visit will occur early in pregnancy (1st or 2nd trimester) and one later in pregnancy (at or after 28 weeks gestation). Such visits may coincide with a regularly scheduled visit or may be an additional visit. Following delivery, extra data will be collected at 12, 24, and 72 weeks post delivery (see Appendix E), either at a regularly scheduled visit or at a special visit.

• Chronic Hepatitis B e Antigen Positive
• Chronic Hepatitis B e Antigen Negative

• Harrison TJ. Hepatitis B virus: molecular virology and common mutants. Semin Liver Dis. 2006 May;26(2):87-96. Review. Erratum in: Semin Liver Dis. 2006 Aug;26(3):304-5.
• Billerbeck E, Bottler T, Thimme R. Regulatory T cells in viral hepatitis. World J Gastroenterol. 2007 Sep 28;13(36):4858-64. Review.
• Visvanathan K, Lewin SR. Immunopathogenesis: role of innate and adaptive immune responses. Semin Liver Dis. 2006 May;26(2):104-15. Review.

• INCLUSION CRITERIA:
• Written informed consent
• At least 18 years of age
• HBsAg-positive and either
• Pregnant
• Anti-HDV positive
• Diagnosed with acute HBV infection or experiencing a hepatitis flare
• Immune tolerant or immune active phenotype
• Potentially eligible for the Immune Regulation and Costimulation in Natural History of Chronic Hepatitis B ancillary study.

EXCLUSION CRITERIA:

• History of hepatic decompensation
• Hepatocellular carcinoma (HCC)
• History of solid organ transplantation or bone marrow transplantation
• Chronic immunosuppression therapy
• Current hepatitis B antiviral treatment (except pregnant women and patients who are anti-HDV positive)
• Known HIV co-infection (patients with HDV or HCV co-infection are not excluded).
• Medical or social condition which, in the opinion of the investigator, would make the patient unsuitable for the study or interfere with or prevent follow-up per protocol
• Unable or unwilling to return for follow-up visits