Traces of hepatitis B virus (HBV) genome can persist for years following recovery from hepatitis B. To determine overall duration, molecular characteristics, and pathological implications of this serologically undetectable form of hepadnaviral carriage, we have analyzed the expression of transcriptionally active virus genomes, their infectivity, and examined liver alterations during the natural lifespan of woodchucks convalescent from acute infection with HBVrelated woodchuck hepatitis virus (WHV). In this study, we document lifelong persistence of scanty amounts of replicating virus both in the liver and lymphatic system after spontaneous resolution of an episode of experimental hepadnaviral hepatitis. Antibodies to virus nucleocapsid (core) were found to be the most reliable immunovirological marker coexisting with occult infection. In the majority of convalescent woodchucks, serial liver biopsies showed protracted minimal to mild necroinflammation with periods of normal morphology; however, hepatocellular carcinoma (HCC) ultimately developed in 2 of 9 animals studied. Inocula derived from lymphoid cells of convalescent animals induced classical acute hepatitis in virus-naive woodchucks that progressed to chronic hepatitis and HCC in 1 of the animals, demonstrating infectivity and pathogenic competence of the carried virus. Our results reveal that low levels of infectious WHV and residual hepatic inflammation usually continue for life after resolution of hepatitis and that this recovery does not avert HCC development. They also demonstrate that, in addition to the liver, the lymphatic system is the site of the occult lifelong maintenance of replicating hepadnavirus. (HEPATOLOGY 1999;29:928-938.)Current evidence indicates that carriage of minute quantities of hepatitis B virus (HBV) genome can continue for years following complete clinical and serological recovery from acute hepatitis B. 1-5 In these convalescent patients, HBV DNA have been detected both in serum and in circulating lymphomononuclear cells, often despite the presence of neutralizing antibodies to virus envelope (hepatitis B surface antigen) 2,3,5 and a vigorous polyclonal HBV-specific cytotoxic T-cell response. 3,4,6 In addition, traces of hepatitis B surface antigen and HBV-DNA-reactive particles with physicochemical properties of intact virions have been detected in the circulation of some of the recovered individuals. 2 These findings imply that HBV eradication does not coincide with the rise of antivirusspecific humoral and cellular immune responses and with clinical resolution of acute hepatitis.It is expected that this serologically undetectable persistence of HBV may have important epidemiological and pathogenic implications, whose range has yet to be established. This assumption is based on a growing number of observations indicating that HBV infection can appear in recipients of organs from HBV serologically negative donors, [7][8][9][10][11][12] and that hepatocellular carcinoma (HCC) with integrated HBV genomic sequences can arise in ...

Background & Aims Chronic hepatitis B virus (HBV) infection is an important cause of cirrhosis and hepatocellular carcinoma worldwide; populations that migrate to the US and Canada might be disproportionately affected. The Hepatitis B Research Network (HBRN) is a cooperative network of investigators from the United States and Canada, created to facilitate clinical, therapeutic, and translational research in adults and children with hepatitis B. We describe the structure of the network and baseline characteristics of adults with hepatitis B enrolled in the network. Methods The HBRN collected data on clinical characteristics of 1625 adults with chronic HBV infection who are not receiving antiviral therapy from 21 clinical centers in North America. Results Half of the subjects in the HBRN are male, and the mean age is 42 years; 72% are Asian, 15% are Black, and 11% are White, with 82% born outside of North America. The most common HBV genotype was B (39%); 745 of subjects were negative for the hepatitis B e antigen. The median serum level of HBV DNA when the study began was 3.6 log10 IU/mL; 68% of male subjects and 67% of female subjects had levels of alanine aminotransferase above the normal range. Conclusions The HBRN cohort will be used to address important clinical and therapeutic questions for North Americans infected with chronic HBV and to guide health policies on HBV prevention and management in North America.

Hepatic steatosis has been reported in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. However, the features of steatohepatitis, including cytologic ballooning and pericellular fibrosis, its risk factors, and the impact on disease severity in such patients are unknown. To assess this, we prospectively reviewed liver histology in consecutive coinfected patients to define the prevalence and severity of the features of steatohepatitis, its risk factors, and its impact on the severity of liver disease. A total of 222 subjects (74% male, mean age 45, 78% African American, 90% genotype 1) were studied. The mean body mass index (BMI) was 26, and 18% had a BMI >30. The prevalence of risk factors for steatosis were: diabetes (31%), hypertension (15%), dyslipidemia (8%), metabolic syndrome (9%), and alcohol abuse (21%). Steatosis was present in 23% and steatohepatitis was present in 17%. The steatosis was mild (5%-33%) in 19%, and moderate to severe (>33%) in 4%. Cytologic ballooning and pericellular fibrosis were present in 30% and 13%, respectively. The mean Ishak score was 6.9, and 33% had bridging fibrosis or cirrhosis. Both steatosis and cytologic ballooning were associated with BMI, metabolic syndrome, and insulin resistance, and presence of either was strongly associated with advanced fibrosis (P < 0.0001). By multiple logistic regressions, the following associations were identified: increased BMI, diabetes, and genotype 3 with steatosis; diabetes with cytologic ballooning; and longer duration of infection with steatohepatitis. Conclusion: Steatosis and steatohepatitis are present in 23% and 30%, respectively, of patients with HIV/HCV coinfection, and both are associated with an increased risk of having advanced fibrosis. Although we did identify genotype 3, increased BMI, and diabetes as risk factors, we found no independent association with antiretroviral therapy.

Background and Aims Fibrosis progression might be accelerated in patients that are co-infected with HIV and hepatitis C virus (HIV/HCV). However, no studies have directly compared fibrosis progression by paired liver biopsy between patients infected with HIV and HCV vs. those infected with only HCV. Methods Liver biopsy samples were collected from patients with HIV/HCV (n=306) and those with HCV; biopsies from 59 without a sustained virologic response (SVR) or cirrhosis were matched with those from patients with only HCV (controls) for initial fibrosis stage, demographics, and HCV treatment. For HIV/HCV patients, categorical variables at baseline and the area under the curve of continuous variables per unit time were analyzed for associations with fibrosis progression. Results Liver biopsies from HIV/HCV patients had more piecemeal necrosis than controls (P=.001) and increased lobular inflammation (P=.002); HIV/HCV patients also had shorter intervals between liver biopsies (4.7 vs. 5.9 yrs, P<.0001). Between the 1st and 2nd biopsies, fibrosis remained unchanged or progressed 1 or 2 units in 55%, 18%, and 18% of HIV/HCV patients, respectively, compared with 45%, 30%, and 9% of controls. The fibrosis progression rate was similar between HIV/HCV and control patients (0.12±0.40 vs. 0.091±0.29 units/yr; P=.72). In paired biopsies from 66 patients, including those with SVR, there were no associations between fibrosis progression and demographics; numbers of CD4+ T cells; levels of aspartate aminotransferase or alanine aminotransferase; use of highly-active anti-retroviral therapy; response to HCV therapy (no treatment, SVR, or non-response); baseline levels of FIB-4; or histological features including inflammation, fibrosis, or steatosis. Conclusions Based on analysis of liver biopsy samples, fibrosis progression was similar between HIV/HCV- and HCV-infected patients; no clinical or laboratory parameters predicted disease progression.