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 co-infection with hepatitis B virus (HBV) or C (HCV) 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 co-infected patients be treated for both HIV and HBV infection using combinations of ART that include tenofovir (TDF). Despite widespread adoption in the U.S., the effect of this regimen on long-term outcomes of HBV disease such as histologic severity, progression, risk of emergence of resistant HBV variants, and the long-term risks of TDF therapy remains unanswered.

The Hepatitis B Research Network (HBRN) was the first major effort to elucidate the natural history and treatment outcomes of persons with chronic HBV in the U.S. This HBRN ancillary study provided 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.

The specific aims of the HBRN ancillary study were to:

• Clinically, histologically, serologically, and virologically characterize a well-defined cohort of HBV-HIV patients in North America in a cross-sectional manner
• Define the benefit of long-term therapy and longitudinally determine the impact of complete versus incomplete viral suppression on clinical and serologic outcomes, and histologic progression by paired biopsy
• Determine a threshold HBV DNA level associated with disease progression
• Establish the utility of noninvasive assessment of hepatic fibrosis compared with biopsy
• Define the frequency of genotypic and phenotypic TDF resistance with long-term therapy
• Characterize the risk of long-term therapy by assessing the long-term renal and bone effects of TDF-based therapy in the HBV-HIV cohort

The primary outcome measure was liver disease severity over time. The secondary outcome measure was the longitudinal outcome of viral suppression.

Inclusion criteria:

• Male and female participants ≥ 18 years of age
• Serologic evidence of HIV infection by HIV antibody positivity or positive HIV-RNA > 6 months prior to screening
• Serologic evidence of chronic HBV infection by HBsAg positivity
• Willingness to provide informed consent

Exclusion criteria:

• Estimated life expectancy of less than one year based on clinical judgment of the investigator
• 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
• Hepatocellular carcinoma (HCC)
• Anti-HCV positive
• History of solid organ or bone marrow transplantation
• Pregnant women
• Medical or social condition based on study physician opinion that would make the participant unsuitable for the study or interfere with follow-up
• Unable or unwilling to return for follow-up visits
• Contraindications to liver biopsy

At entry into the study, 95% of participants were on anti-HBV combination antiretroviral therapy (cART). Clinical events were uncommon during follow-up and no participants had HBsAg loss. Paired biopsy showed minimal improvement in the Histologic Activity Index without significant change in the fibrosis score. Among the cohort, clinical outcomes and worsening histological diseases were uncommon.