Chronic infection with hepatitis B virus (HBV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC) worldwide. Globally there are an estimated 400 million persons infected with HBV. In the United States, there are 1.25 million affected individuals and the epidemiology of the infection is changing due to immigration of persons from endemic regions. The natural history of chronic hepatitis B (CHB) also appears to be changing with an increasing prevalence of HBeAg negative chronic hepatitis B. Knowledge of the rate of progression between individuals with HBeAg positive and negative CHB is unknown. An equally important and related issue is the clinical assessment of disease severity in patients with CHB. Unfortunately, there are no good laboratory markers of disease severity. Liver biopsy is the accepted gold standard for assessing disease severity and cirrhosis but is costly, invasive, and associated with complications, which often limits patient acceptability as well as being subject to sampling error ranging from 15% to 25%. Non-invasive methods to assess disease severity are highly desirable for physicians caring for patients with CHB. Despite the recent licensing of several new agents for treatment of CHB, therapy remains problematic due to the need for prolonged therapy with nucleoside analogues and relatively poor response to interferon. Identifying the optimal regimen, defining when to treat, for how long and when to stop therapy are major unresolved issues. In addition, defining the best parameters to monitor patients both on and off therapy are not clear. Hypotheses/problems addressed: 1) Define the host, viral and environmental factors that determine the natural history and outcome of HBV infection. To study this problem, we have created a large database of untreated and treated patients with CHB (n800), which is being analyzed to identify factors that affect the natural history of chronic hepatitis B e antigen positive (HBeAg) positive and negative infections, including factors that predict the course in HBeAg negative CHB and the outcome of patients with normal ALT. The database is being used to develop a non-invasive model to predict fibrosis progression in patients with CHB. We also plan to evaluate the role of transient ultrasound elastography (Fibroscan) to assess fibrosis stage in persons with CHB. These results will be compared to liver biopsy, MRI elastography and plasma will be stored for future proteomic analysis. The goal is to develop a series of blood and imaging tests that will obviate the need for liver biopsy in most patients with CHB. The long-term durability of antibody following vaccination against hepatitis B virus in adults from a non-endemic population is unknown. We have completed a study to assess the long-term durability of HBV vaccination in healthy persons vaccinated as adults. Persons who recovered from hepatitis B served as controls. Results indicate that 25% of patents who received 3 doses of hepatitis B vaccine between 10 and 30 years ago no longer have detectable antibody against hepatitis B surface antigen (anti-HBs). Older age at vaccination was associated with negative anti-HBs titer. A booster vaccination was highly effective (94%) in healthcare workers with negative anti-HBs titers. Our results suggest that a immunological memory persists for up to 30 years and a booster dose is not necessary for most persons vaccinated as adults. The Liver Diseases Branch will participate in a large multicenter study, the Hepatitis B Research Network, to define the natural history of HBeAg positive and negative chronic hepatitis B. This study will enroll 2500 patients at 13 North American sites. Primary questions that will be spearheaded by our group will be to identify the predictors of spontaneous HBeAg loss in immunetolerant patients and to evaluate the natural history of patients with elevated HBV DNA levels but normal ALT who are also HBeAg negative-so called indeterminate phenotype. 2) Develop and evaluate novel, safer and more effective therapies for chronic viral hepatitis. Current therapy of CHB remains less than optimal. Relapse is common if treatment is discontinued after one year in the absence of HBsAg loss. Consequently, nucleos(t)ides must often be administered long-term or indefinitely. However, long-term use is associated with the development of antiviral resistance with resulting loss of clinical benefit. Therefore an important challenge in HBV management is how to use these agents most effectively to achieve a long-term response while avoiding the issue of antiviral resistance. We are taking multiple approaches to this problem. The first is to compare the combination of tenofovir and emtricitabine compared to tenofovir for patients with CHB. Tenofovir is a nucleotide analogue that is more effective than adefovir at suppressing HBV DNA and has an excellent resistance profile. This study will examine the long-term efficacy and safety of tenofovir and emtricitabine versus tenofovir alone in patients with HBeAg positive and negative CHB with the goals of maintaining long-term viral suppression ands preventing the emergence of viral resistance. To date 28 patients have been enrolled and started on therapy. Long-term results are pending. The second approach is to combine peginterferon alfa with tenofovir compared to tenofovir alone. This is being conducted under the auspices of the hepatitis B research network and is a multicenter trial that will enroll 375 subjects. The third approach is to discontinue therapy in patients receiving long-term nucleos(t)ide analogues. To address this question we have initiated a prospective trial to withdraw patients from medication and observe for benefits (HBsAg loss) or adverse events (ALT flares, HBeAg seroreversion and fulminant hepatitis). To date 13 patients have been withdrawn from therapy. 3) Elucidate the viral pathogenesis of HBV infection and mechanisms of anti-viral resistance The course of CHB following the development of anti-viral resistance is highly variable with some patients showing continued viral suppression, some with an accelerated course and others who lie in-between. We hypothesized that following initial viral breakthrough, compensatory mutations that affect viral replication may account for the different clinical presentations observed. We also asked the question whether the outcome of resistance was different in HBeAg positive and negative CHB due to the presence of naturally occurring mutations- the pre-core and the double core promoter mutations, in HBeAg negative patients. Preliminary results suggest a mild (<2-fold) increase in viral replication of the adefovir resistant virus in the presence of the pre-core mutation. We are currently investigating the potential mechanism of this effect, since the pre-core mutation is not in the polymerase gene. An effect of the pre-core gene on the overlapping X-gene is being explored. These results might have clinical implications on how to manage resistance in HBeAg (+) and (-) patients. We are also investigating the role or pre-core and basic core promoter mutations on the natural fluctuations in HBV DNA levels observed during the natural course of HBeAg negative chronic hepatitis B.
|Ghany, Marc G; Doo, Edward C (2009) Antiviral resistance and hepatitis B therapy. Hepatology 49:S174-84|