Chronic hepatitis B virus infection : prevention and treatment

Hepatitis B virus (HBV) infection is an increasing public health problem in Australia particularly in certain 'high-risk' subgroups of the population. In order to establish cost-effective screening and vaccination programs directed towards the control and possible eradication of HBV infection, accurate information is needed about the modes of spread and the numbers of "at risk" individuals in particular community subgroups. In addition, treatment strategies must be developed for established HBV carriers since at least 35% of such individuals will die directly related to complications of the disease. This Thesis is the compilation of a series of investigations into familial transmission of chronic HBV infection, the efficacy of alpha interferon treatment of chronic active hepatitis (CAH) B and the effects of such treatment on hepatic drug metabolism. The results have important implications for prevention of HBV infection by screening and vaccination programs, for the selection of patients for inclusion in treatment trials and for the methods by which such treatments can be monitored for responses, and they provide new information about clinically-relevant effects of interferon treatment on the metabolism of other drugs. An overview of the virology of hepatitis B virus (HBV), the biology of HBV infection and the resultant disease states is presented in Chapter 1. In Chapter 2, a prospective study examining the incidence of and factors determining intrafamily HBV transmission in a mixed Caucasian and Asian population is presented. Household contacts of both Asian and Caucasian HBV carriers were clearly demonstrated as being at high-risk for HBV infection. Several factors were identified to be associated with a higher rate of transmission of HBV infection within families; namely, if the index case was Asian rather than Caucasian, had an HBsAg-positive mother rather than an HBsAg-positive father, was HBeAg-positive rather than HBeAg-negative , and had chronic rather than acute HBV infection. In Chapter 3, the first Australian study of alpha interferon (rIFN-aA) in the treatment of CAH-B is reported. While rlFN-aA was demonstrated to have inhibitory effects on HBV replication, the overall response rate was disappointing and not significantly different from the spontaneous seroconversion rate observed in the control group. A major goal of the present study was to establish whether serological changes of HBV infection, that could be induced by interferon, were associated with changes in hepatic function or affected the natural history of this otherwise progressive chronic liver disease. The results provide an important contribution to new knowledge in that although sustained HBV serological improvement was obtained in only 35% of treated patients, this change in the biological state of the virus-host interaction provided a beneficial change in the natural history of chronic liver disease as assessed clinically, biochemically and by direct morphologic examination. In addition, the results presented in Chapter 4 have a novel bearing on whether changes in chronic hepatitis B disease activity improve hepatic metabolic function. Sequential determinations of a simplified 2 point antipyrine clearance (CLAP) test indicated that HBeAg seroconversion was associated consistently with a quantitatively important increase in CLAp while reactivation led to a deterioration in hepatic metabolic function as indicated by the CLAp test. In addition, the CLAp test was a more sensitive and specific indicator of hepatic metabolic function compared to more conventional tests of liver function (serum albumin and bilirubin concentrations, and prothrombin time). Part C describes studies in which the effects of interferon on hepatic drug metabolism have been examined. In human studies in vivo, antipyrine and theophylline were employed as substrates for the cytochrome P-450dependent mixed function oxidase system. The study described in Chapter 6 provides the first direct evidence that interferon inhibits hepatic drug metabolism in humans; a significant reduction in antipyrine clearance was demonstrated following a single intramuscular injection of interferon. In Chapter 7 the clinical relevance of the observed effect of interferon on antipyrine metabolism was confirmed by the demonstration that interferon also impairs theophylline elimination. This demonstrated one of the most profound therapy-induced inhibitions of drug metabolism yet observed in man. In addition, the effect of interferon on hepatic drug metabolism appears to be relatively selective for some cytochrome P-450 isozymes, specifically that concerned with N-demethylation of theophylline. The mechanism for the interferon-mediated impairment of hepatic oxidative drug metabolism observed in the human in vivo studies was then explored by experiments in animals. The isolated perfused rat liver model was utilized to study effects on the intact liver, while hepatic microsomal androstenedione hydroxylation pathways were measured as a probe to assess interferon effects on individual cytochrome P-450 isozymes. The results demonstrated that the effect of IFN on drug metabolism is, at least in rats, species specific. Moreover, the reduction in total hepatic P-450 content produced by lFN appeared to result from a generalized lowering of P-450 isozymes rather than being specific for individual forms. The apparent discrepancy between these findings and the observation in humans that human rlFN-ocA depressed the P-450 isozyme(s) responsible for the Ndemethylation pathway of theophylline metabolism to a greater degree than the 8-hydroxylation pathway may be due to species differences or to the specific types of interferon studied. In any event it is likely that the clearance of many other xenobiotics as well as endogenous substances metabolized by P-450 may be impaired by interferon and future studies should be directed towards examining the effects of interferons on other such clinically-relevant compounds. Moreover, the results of the present study indicate that lFN-treated rats should be a good model with which to obtain clearance data for such compounds