HBV-HIV Coinfection Research Network

Since the introduction of highly active antiretroviral therapy (ART) in 1996, there has been
a dramatic reduction in morbidity and mortality among those living with HIV. However, chronic
liver disease due to coinfection with hepatitis B (HBV) or C (HCV) virus has emerged as the
second leading cause of mortality among HIV-infected persons. The natural history of HBV
infection is altered in those with HIV. Current guidelines recommend that most coinfected
patients be treated for both HIV and HBV infection using combinations of ART that include
tenofovir (TDF). Despite widespread adoption in the US, the effect of this regimen on
long-term outcomes of HBV disease such as histologic severity, progression, and risk of
emergence of resistant HBV variants, and the long term risks of TDF therapy remains
unanswered. Further investigation is required to address the following important questions:
(1) what is the proportion of HIV-coinfected patients who have incomplete viral suppression
on TDF?; (2) is incomplete suppression of HBV acceptable in HIV coinfected persons and if so,
what threshold HBV DNA level constitutes an adequate clinical goal?; (3) in view of the lack
of acceptance of liver biopsy among HIV practitioners, can noninvasive markers accurately
assess HBV disease activity and the impact of ART on disease progression?; (4) What are the
long term risks of TDF-based therapy for HBV in HIV coinfection? In short, what are the risks
and benefits of TDF-based therapy for CHB in patients with HIV coinfection? The NIH Hepatitis
B Research Network (HBRN) is the first major effort to elucidate the natural history and
treatment outcomes of persons with chronic HBV the US. The HBRN will not address the critical
issue of HBV liver disease progression in HIV-infected persons because patients with HIV
coinfection will be excluded. The current proposal, an approved ancillary study of the HBRN,
offers a unique opportunity to fill major gaps in HBV-HIV knowledge and to compare HBV-HIV
infected persons to those with HBV monoinfection participating in the HBRN. No other funded
research network in North America has the expertise, patient population, and structure to
carry out the proposed studies. The Specific Aims are: 1. Define the problem. We will
clinically, histologically, serologically, and virologically characterize a well-defined
cohort of HBV-HIV patients in North America in a cross-sectional manner; 2. Define the
benefit of long term therapy. We will longitudinally determine the impact of complete vs.
incomplete viral suppression on clinical and serologic outcomes, and histologic progression
by paired biopsy and 2a. Define a threshold HBV DNA level associated with disease
progression; 2b. Establish the utility of noninvasive assessment of hepatic fibrosis compared
with biopsy; and 2c. Define the frequency of genotypic and phenotypic TDF resistance with
long term therapy; and finally 3. Define the risk of long term therapy. We will assess the
long term renal and bone effects of TDF-based therapy in the HBV-HIV cohort. Collectively,
this study will fulfill many of the key priorities outlined in the NIH Action Plan for Liver
Disease for HBV-HIV coinfection.

Inclusion Criteria: (1) Male and female subjects ≥ 18 years of age; (2) Serologic evidence
of HIV infection by HIV antibody positivity or positive HIV-RNA > 6 months prior to
screening (3) Serologic evidence of chronic hepatitis B infection by HBsAg positivity(4)
Willingness to provide informed consent.

Exclusion Criteria: (1) Estimated life expectancy of less than one year based on clinical
judgment of the investigator; (2) Hepatic decompensation as defined by presence of ascites
or hepatic hydrothorax, variceal or portal hypertensive bleeding, hepatic encephalopathy,
or Child-Turcotte-Pugh (CTP) score of 7 or above; (3) Hepatocellular carcinoma (HCC); (4)
Anti-HCV positive; (5) History of solid organ or bone marrow transplantation; (6) Pregnant
women; (7) Medical or social condition which in the opinion of the study physician would
make the patient unsuitable for the study or will interfere with or prevent follow-up per
protocol; (8) Unable or unwilling to return for follow-up visits; (9) Contraindications to
liver biopsy.