Many nucleoside analogues have been investigated for the treatment of chronic hepatitis B. Some were withdrawn because of significant adverse effects and some are still in the early stage of clinical assessment. Lamivudine has been demonstrated to have consistent efficacy and safety in large-scale, phase III clinical trials. It has achieved a milestone in the treatment of chronic hepatitis B and is now commercially available in many countries. Being a potent inhibitor of hepatitis B viral replication, it achieved around 18% HBeAg seroconversion in HBeAg-positive patients after 1 year of therapy. HBeAg seroconversion is a good endpoint for therapy and has been shown to be 80% durable. The response was better among patients with raised pretreatment alanine aminotransferase levels. Liver necro-inflammation and fibrosis improved significantly after 1 year. Further improvement on extended therapy was observed together with an incremental increase in HBeAg seroconversion. Similar efficacy was demonstrated in HBeAg-negative viraemic patients. The main drawback is the emergence of drug-resistant variants starting from the sixth to ninth month of treatment. This can be associated with varying degrees of relapse of disease activity and may offset the benefit of therapy. With extended therapy, drug-resistant variants continue to emergence at a rate of around 20% per year. Adefovir dipivoxil and entacavir are nucleoside or nucleotide analogues shown to suppress both the wild-type and lamivudine-resistant virus. Combination of these nucleoside/nucleotide analogues with immune modulators may be the answer to eradicate the virus in short-term therapy and avoid the issue of drug resistance.

Adefovir dipivoxil (bis-POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co-infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double-blind, placebo-controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for > or = 6 months, with elevated hepatic transaminases and serum HBV DNA > or = 50 pg ml-1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml-1) but increased by 0.01 log10 pg ml-1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1-6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l-1 were observed in three patients during therapy (leading to protocol-specified treatment discontinuation or dose reduction) and in four patients during follow-up. On-treatment transaminase elevations were associated with HIV status, occurring in three of six HIV-uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non-HIV-infected patients. Treatment for chronic hepatitis B as a once-daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.

Hepatitis B virus (HBV) and HIV infections share risk-factors; therefore coinfection is common. Interactions have been reported but controlled studies have been limited. Our objective was to study the effect of HIV infection on the natural history of chronic HBV infection and the reverse effect of the HBV carrier state on HIV infection.

Prospective observational cohort study.

Open-access outpatient HIV/genitourinary medicine clinic at a Central London hospital.

Total of 152 untreated homosexual male HBV carriers and 212 HBV surface antigen-negative controls (41.4 and 70.3% HIV-seropositive, respectively).

The rate of loss of serum HBV e antigen (HBeAg) and its reappearance in HIV-infected and HIV-uninfected HBV carriers; serum HBV DNA levels measured by dot-blot hybridization assay), HBV DNA polymerase activity and liver transaminase activities, the progression of HIV infection to symptomatic disease or AIDS in HIV-infected compared with HBV-HIV coinfected patients.

In HIV-infected HBV carriers, serum HBV DNA polymerase activity was higher, alanine aminotransferase was lower and loss of serum HBeAg (mean follow-up, 2.8 years) occurred at a lower rate when compared with HIV-uninfected HBV carriers (estimated relative hazard, 0.39; 95% confidence interval, 0.161-0.942) Concomitant chronic HBV infection had no detectable effect on the rate of progression of HIV disease after correction for lead-time bias.

This study strengthens the evidence for a significant effect of HIV infection on the natural history of chronic HBV infection, which by prolonging the period of infectivity could have an important impact on the epidemiology of HBV infection in regions, or patient groups, with high HIV seroprevalence. There was no evidence of an important effect of HBV carriage on HIV disease progression.

Despite hepatitis B immunoprophylaxis hepatitis B virus (HBV) recurrence is a frequent and often fatal complication after orthotopic liver transplantation (OLT). The purine nucleoside analogues penciclovir and its oral form famciclovir (FCV) proved to be well tolerated and effective against herpes simplex and zoster virus infections. In addition, an effective reduction of duck and human HBV replication was observed. Therefore, we conducted an uncontrolled pilot study of famciclovir in patients with HBV recurrence after OLT. Twelve patients have received famciclovir for at least 3 months in an open compassionate-use protocol. FCV was administered orally 500 mg three times a day for all patients (except one patient who was started on 750 mg three times a day for the first 2 weeks). Immediately after starting famciclovir, serum HBV DNA levels declined in 9 of 12 patients (75%) with a mean reduction from baseline levels of 80% after 3 months, 90% after 6 months, and > 95% after 12 months of treatment. With continued treatment, 5 of these 9 patients became negative by conventional hybridization assay, and in one of these HBV DNA became undetectable by polymerase chain reaction (PCR) 28 weeks after the start of treatment. Three patients showed no (sustained) reduction in HBV DNA after at least 3 months of treatment; therefore, FCV was stopped. Latest serum alanine aminotransferase (ALT) levels decreased in 6 of 12 patients (50%) with a median decrease of 80% (range, 40%-95%) in comparison to pretreatment ALT values. ALT levels normalized in 4 patients (33%). One patient died due to sepsis and peritonitis in week 13 of treatment. This event was not related to FCV. No clinically significant side effects were noticed in any patient. The oral nucleoside analog famciclovir reduces HBV replication and transaminase levels in patients with HBV recurrence after liver transplantation. Because long-term FCV treatment is well tolerated, famciclovir appears to be a promising antiviral strategy in the treatment of HBV in immunocompromised patients.

This study compared the response to adenine arabinoside 5'-monophosphate (ARA AMP) in 60 patients with chronic hepatitis B according to the pretreatment serum hepatitis B virus DNA concentration. The level of hepatitis B virus replication was defined as low (30 patients) or high (30 patients) when serum hepatitis B virus DNA concentration was below or above 100 pg/ml, respectively. Patients received a 28 day course of ARA AMP and a second course of ARA AMP was given six months later to patients with persistent hepatitis B virus replication. At the end of the first course of ARA AMP, 11 of the patients (37%) with low replication and one of the patients (3%) with high replication became negative for hepatitis B virus DNA (p = 0.0012); five of the patients (17%) with low replication and none of the patients with high replication had HBe seroconversion (p = 0.06). Two of these five patients lost HBsAg. Kinetics of serum hepatitis B virus DNA during treatment showed a considerable but transient antiviral effect of ARA AMP. Three of 32 retreated patients became negative for hepatitis B virus DNA and one patient had HBe seroconversion. In conclusion, ARA AMP exerts a considerable but transient antiviral effect on hepatitis B virus. Complete and sustained inhibition of hepatitis B virus replication was only obtained in the patients with low hepatitis B virus replication.

The aim of this study was to review all published randomized clinical trials evaluating the efficacy of a combination of prednisone and interferon in treatment of chronic hepatitis B and to subject these studies to metanalysis. Two types of metanalyses were carried out: direct metanalysis, comparing the prednisone-interferon combination with interferon on its own; and indirect metanalysis, comparing the treatment efficacy of prednisone-interferon and of interferon with control results. At the end of follow-up, four assessable end points were analyzed: HBeAg, hepatitis B virus DNA, HBsAg loss and serum ALT normalization rate. The direct metanalysis included seven trials comparing prednisone-interferon with interferon treatment. No significant differences were observed between the two types of therapy, for all the criteria given. However, in patients with low ALT levels, the prednisone-interferon combination gave significantly better results than interferon alone--HBeAg loss was 48% in the former group vs. 18.4% with interferon alone (p < 0.01). Fifteen trials compared interferon with control values; all end points were significantly improved. Seven trials compared prednisone-interferon with control results and showed all end points to be significantly improved by treatment. Indirect metanalysis showed that the differences in odds ratios for prednisone-interferon/control group and interferon/control group studies were negative for all assessable end points. In conclusion, the use of corticosteroids did not produce any significant increase in the efficacy of interferon treatment in adults with chronic hepatitis B and high initial ALT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic infection with the hepatitis B virus (HBV) is a major cause of worldwide morbidity and mortality. A large number of therapeutic approaches has been tried, including interferon (IFN), nucleoside analogues and immunomodulators. To date controlled clinical trials have shown that only IFN is of long-term value but many patients fail to respond to treatment. New approaches to treating patients with IFN-resistant hepatitis B are currently undergoing clinical and experimental evaluation, and it seems likely that new therapeutic agents will be available in the near future.

To determine the efficacy of interferon-alpha 2a in chronic active hepatitis B, 238 patients were randomly divided, into four groups: three groups received either 2.5 MIU m-2, 5.0 MIU m-2 or 10.0 MIU m-2, three times weekly by intramuscular injection for 12-24 weeks; and a control group received no treatment. Patients were followed for up to 12 months after treatment was discontinued. There was a statistically significant difference in response [clearance of hepatitis B e antigen (HBeAg) and hepatitis B viral DNA (HBV-DNA)] between treated and untreated patients (37 vs 13%) but no statistically significant difference was seen between treatment groups (33%, 34% and 43% for the 2.5, 5.0 and 10.0 MIU m-2 groups, respectively). A transient rise in transaminases (seroconversion hepatitis) was seen in responders, but levels returned to within the normal range after response to treatment. In patients responding to interferon therapy there was a significant reduction in the severity of the hepatitis. Interferon-alpha 2a was generally well tolerated with respect to vital signs and laboratory parameters.

At the present time, interferon is considered the only effective therapeutic approach in the treatment of both chronic hepatitis B and chronic hepatitis C. It is clear that the disappointing response rates in both chronic hepatitis B and C place added emphasis on efforts to identify alternative forms of therapy. In addition to the development of other antiviral agents including the nucleoside analogs which might prove more effective and have fewer associated side-effects, other agents currently under investigation include thymic peptides such as thymosin alpha 1. In the future, the therapeutic approach to the treatment of chronic hepatitis B and C may consist of combination therapy using perhaps an immune modulator and an antiviral agent or, several antiviral drugs. Alternatively, there is indication that cellular targeting systems with delivery of the toxic material to the specific cell containing the virus may be more effective, while minimizing side-effects. Finally, there are agents such as ursodeoxycholic acid which perhaps, makes bile less toxic and can be used as adjunctive therapy with improvement in liver chemistry values. The treatment of chronic hepatitis B and chronic hepatitis C has shifted in emphasis form the concept of treating liver disease towards that of treating viral infections which happen to effect primarily the liver.

The aim of the study was to evaluate the safety and effectiveness of interferon alpha-2b with or without concomitant corticosteroid treatment in patients with chronic hepatitis B. Fifty-six patients were randomly allocated to two treatment groups. Group I (n = 25) received interferon alpha-2b (INTRON A, Schering-Plough Corporation) 5 million unit subcutaneously, three times a week for 24 weeks. Group II (n = 31) received interferon according to the same protocol and prednisolone in decreasing doses of 60, 40, 20 mg for 6 weeks. The two groups were well matched for demographic, biochemical, virological and histologic features. Both groups were followed up for 24 weeks after treatment. No statistical difference was observed between the two groups at the end of the follow-up in alanine aminotransferase values, HBV DNA negativation, HBeAg loss, anti-HBe seroconversion and the Knodell score. The greater proportion of HBsAg clearance in the combination group, particularly in patients with low alanine aminotransferase values, was, however, not significant. In patients with low alanine aminotransferase values, only the Knodell score was significantly decreased in patients treated with interferon and prednisolone. The only factor which was found to be a predictor of response was the assumed duration of hepatitis. These findings showed that a concomitant short administration of corticosteroids during the first weeks of interferon therapy did not improve results with interferon alone.

Recent advances have been made in the treatment of chronic viral hepatitis, mainly with recombinant interferon (IFN) alpha. However, the present treatment of chronic viral hepatitis is not entirely satisfactory because the efficacy is inconstant and/or incomplete. In chronic hepatitis B IFN-alpha induces a sustained interruption of hepatitis B virus (HBV) replication, with a HBeAg to anti-HBe seroconversion in about 30% of patients. Patients most likely to respond are those with no immunosuppression, HBV infection acquired during adulthood or active liver disease with low HBV replication. Responders usually show a significant decrease in serum HBV DNA levels during the first 2 months of therapy, followed by a significant increase in the level of aminotransferases. New nucleoside analogues might be useful in combination with IFN-alpha in the treatment of those who do not respond to IFN therapy. In chronic hepatitis B-D, the rate of sustained response to IFN-alpha therapy is low. To be effective, IFN-alpha must be used at a high dosage (9-10 mega units) with a long duration (1 year). In chronic hepatitis C, IFN-alpha at a dosage of 3 mega units over 6 months, induces a sustained response in about 20% of patients. A higher dosage of IFN (5-10 mega units) and a longer duration of treatment increases the rate of sustained response but is associated with poor tolerance. Non-responders to a first course of IFN do not respond to a second course of treatment. In patients who respond but relapse after treatment, the rate of sustained response after a second course of IFN needs to be assessed. Ribavirin, which has a significant antiviral effect on hepatitis C virus, might be useful in combination with IFN-alpha. At the dosage (3-6 mega units) usually used, IFN-alpha is relatively well tolerated. In about 10% of the patients therapy is interrupted, mainly because of severe fatigue, thyroid dysfunction or depression.

Mutations in the precore region of hepatitis B virus (HBV) have been associated with failure of expression of HBV e-antigen (HBeAg), however, the prevalence of these and other mutations in HBV carriers without overt chronic liver disease remains uncertain. Homosexual or bisexual males (n = 65) with chronic HBV infection attending The Middlesex Hospital, London were studied, of whom two had clinical evidence of chronic liver disease. HBV DNA was amplified from 62 of 65 serum samples using nested and double nested polymerase chain reaction (PCR) assays. Direct sequencing of the PCR products was employed to investigate sequence variation. HBV-DNA from all available HBeAg-negative (n = 9) and selected HBeAg-positive (n = 33) sera were sequenced in the entire precore gene, the 3' terminal portion of the X gene (aa128-154), and the 5' terminus of the core gene (aa18-73). Sequences were highly conserved in all regions studied. Samples from two anti-HBe-seropositive patients contained mutations in the precore region. In one, a single mutation in the first amino acid resulted in a change to leucine, which would prevent translation of this region and therefore HBeAg expression. Wild type sequences were also detected in this sample. In the other sample from a patient with overt chronic liver disease, a mutation of precore amino acid 28 changed a tryptophan residue to a stop codon which would also prevent HBeAg expression.(ABSTRACT TRUNCATED AT 250 WORDS)

The anti-hepatitis B (anti-HBV) activities of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (2'-deoxy-3'-thia-5-fluorocytosine [FTC]) were studied by using an HBV-transfected cell line (HepG2 derivative 2.2.15, subclone P5A). The (-) isomer was found to be a potent inhibitor of viral replication, with an apparent 50% inhibitory concentration of 10 nM, while the (+) isomer was found to be considerably less active. Both isomers showed minimal toxicity to HepG2 cells (50% inhibitory concentration, > 200 microM) and showed minimal toxicity in the human bone marrow progenitor cell assay. In accord with the cellular antiviral activity data, the 5'-triphosphate of (-)-FTC inhibited viral DNA synthesis in an endogenous HBV DNA polymerase assay, while the 5'-triphosphate of the (+) isomer was inactive. Unphosphorylated (-)-FTC did not inhibit product formation in the endogenous assay, suggesting that the antiviral activity of the compound is dependent on anabolism to the 5'-triphosphate. Both (-)- and (+)-FTC were anabolized to the corresponding 5'-triphosphates in chronically HBV-infected HepG2 cells. The rate of accumulation and the steady-state concentration of the 5'-triphosphate of (-)-FTC were greater. Also, (-)-FTC was not a substrate for cytidine deaminase and, therefore, is not subject to deamination and conversion to an inactive uridine analog. The (+) isomer is, however, a good substrate for cytidine deaminase.

A conjugate of adenine arabinoside monophosphate with lactosaminated albumin produced vacuoles in hepatic cells of rats and mice when given at doses 5-10 times higher than that (35 mg/kg) capable of inhibiting hepatitis B virus replication in patients with chronic hepatitis B. The vacuoles were due to the swelling of secondary lysosomes probably caused by incapacity of the lysosomal enzymes to rapidly digest large amounts of conjugate into products able to cross the lysosomal membrane. Although vacuoles progressively disappeared when conjugate administration was discontinued, the present observation suggests caution in giving the conjugate to man at daily doses higher than 35 mg/kg.

The woodchuck was selected to study the efficacy of liver-targeted antiviral drugs on hepadnavirus replication. Nineteen woodchucks chronically infected with woodchuck hepatitis virus were treated with adenine arabinoside monophosphate or acyclovir monophosphate, either free or conjugated with the liver-targeting molecule lactosaminated human serum albumin. Circulating woodchuck hepatitis virus DNA levels remained unchanged in untreated animals and in those receiving the carrier lactosaminated human serum albumin alone; in contrast, they were consistently lower after 5 days of treatment with the antiviral drugs. Free and conjugated adenine arabinoside monophosphate were active at doses of 10 and 0.75 mg/kg, respectively, and free and coupled ACVMP were active at doses of 20 and 2.6 mg/kg, respectively. These results indicate that the dosages of adenine arabinoside monophosphate and acyclovir monophosphate required to inhibit hepadnavirus growth can be sharply reduced by coupling the drugs to lactosaminated human serum albumin.

Twenty-nine patients with chronic hepatitis B, presenting both hepatitis B surface antigen and hepatitis B virus deoxyribonucleic acid in serum, were studied in a randomized trial treatment consisting of oral prednisolone for 28 days followed 14 days after steroid withdrawal, by either a 55 s.c. injection course of 5 M unit recombinant human alpha-interferon (group 1, 14 patients) or by adenine-arabinoside (for 21 days) combined from the fourteenth day on with the same 55 s.c. injection schedule of interferon (IFN) (group 2, 15 cases). The two groups were well matched with respect to demographic, biochemical, virological and histologic features. Significant side-effects leading to premature discontinuation of interferon were observed in only four cases in group 2 and were always reversible. Efficacy was judged on a mean follow-up period of 17 months. For the whole population, 17 patients (59%) exhibited a sustained serum hepatitis B virus deoxyribonucleic acid disappearance which corresponded to a marked improvement in liver function as demonstrated by a quasi-normalization of their serum transaminase values (ALT with n less than 22 UI/l: 23 +/- 24 vs. 139 +/- 115 before treatment; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-one adult patients with chronic hepatitis B and active viral replication as indicated by the presence of hepatitis Be antigen (HBeAg), increased DNA polymerase (DNAp) and positive hepatitis B virus DNA (HBV-DNA) for more than 6 months, were entered into a prospective trial of recombinant human interferon therapy. Ten patients had chronic persistent or chronic lobular hepatitis, 8 chronic active hepatitis and 3 postnecrotic cirrhosis. All cases were treated with 5 x 10(6) units of recombinant interferon alfa-2B given subcutaneously every other day for 12 weeks. During treatment, 18 patients (86%) showed a significant reduction of DNAp levels, which reached normal values in 10 patients (48%). Viral replication was controlled over a 10-month follow-up period in 7 out of 21 patients (33%). Of these 7, five patients became HBeAg negative and HBeAb positive. HBsAg disappeared in one patient. The only serious adverse effect was thrombocytopenia in one patient in whom rapid recovery occurred when interferon was withdrawn. Treatment was also terminated in a second patient because of local reactions at the injection sites occurring after 10 weeks of therapy. Our data indicate that relatively small doses of recombinant alfa-2B interferon given during a 12-week period induce a significant reduction in viral replication and might approximately triple the spontaneous seroconversion rate observed in patients with chronic hepatitis B.

Twenty-two heterosexuals and 21 homosexuals with chronic active hepatitis B and who had HBsAg, HBeAg and hepatitis B virus DNA in serum were randomized separately to receive adenine arabinoside monophosphate or placebo. In the 10 heterosexuals and nine homosexuals who received placebo, no change in hepatitis B virus DNA level and HBeAg was observed. Among the patients who received adenine arabinoside monophosphate, seven of the 12 heterosexuals and five of the 12 homosexuals lost hepatitis B virus DNA; five heterosexuals and three homosexuals also lost HBeAg; one homosexual lost HBsAg. There was no significant differences in response between heterosexual and homosexual patients. When results were pooled, there was a significant effect of adenine arabinoside monophosphate on hepatitis B virus replication. None of the 19 patients who received placebo but 50% of the 24 patients who received adenine arabinoside monophosphate were negative for serum hepatitis B virus DNA at 10 months after treatment (p less than 0.001) and none of the 19 patients who received placebo and 33% of the 24 patients who received adenine arabinoside monophosphate were negative for HBeAg in serum (p less than 0.005). Retrospective analysis showed that disappearance of hepatitis B virus DNA after administration of adenine arabinoside monophosphate was more common (i) in patients with a low pretreatment hepatitis B virus DNA level than in patients with a high pretreatment hepatitis B virus DNA level (8/11 vs. 4/13, p less than 0.05); (ii) in patients with a high pretreatment ALT level than in patients with a low pretreatment ALT level (10/14 vs. 2/10, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

In a randomised controlled trial recombinant interferon alpha 2A (Roferon-A, rIFN alfa A) given at a dosage of 10 million units (MU)/m2 thrice weekly for six months was significantly better (p less than 0.02) than no treatment in producing a sustained loss of hepatitis Be antigen (HBeAg) in hepatitis B virus (HBV) chronic carriers. Although lower doses (5 MU/m2 and 2.5 MU/m2) also produced some responses, the seroconversion rate was not significantly greater than that observed in the control group. Sixteen of the 45 patients receiving interferon were human immunodeficiency virus (HIV) antibody positive: none of these responded. Forty one per cent of the anti-HIV negative patients receiving interferon (12/29, p less than 0.005) lost HBeAg and 17% (5/29) lost hepatitis B surface antigen (HBsAg). The response rate among these anti-HIV negative patients receiving at least three months therapy was 46% and 19% respectively. Low pretreatment HBV-DNA and absence of anti-HIV were the only significant independent variables predicting response to therapy (p less than 0.03 and p less than 0.05 respectively). In six patients, neutralising antibodies to alpha interferon were detected during therapy, the majority being non-responders.

Chronic viral hepatitis is a common clinical problem; it must be differentiated from other forms of chronic liver disease by history, laboratory data, and liver biopsy. This article reviews the treatment of chronic hepatitis B, delta hepatitis, and nonA and nonB viral hepatitis and emphasizes the controlled trials when available.

Sequential liver biopsies were taken from 66 patients with chronic hepatitis B virus (HBV) infection being followed in randomised controlled trials of therapy with alpha interferons or adenine arabinoside 5'-monophosphate. In the group of 23 patients responding to treatment with the permanent loss of HBe antigen and HBV-DNA from their serum, there was a significant reduction in hepatic inflammatory activity and none developed cirrhosis. In contrast, inflammatory activity continued in the group of 24 patients that did not respond to therapy, and in the group of 19 patients who received no therapy. Two untreated controls progressed to cirrhosis. Further studies confirmed that in those clearing HBeAg and HBV-DNA from the serum, HBcAg and HBeAg were also lost from the liver. This study demonstrates that, as in natural seroconversion, successful treatment of chronic HBV infection is associated with loss of hepatic as well as serum markers of HBV replication, and is followed by a reduction in hepatic inflammation. Antiviral therapy may prevent progression to cirrhosis in some cases.

Vidarabine (ara A) produces severe dose-dependent side-effects. To examine whether its monophosphate ester (ara-AMP) can be effective in the treatment of chronic hepatitis B when given in reduced dosage as a conjugate with lactosaminated human serum albumin (L-HSA), which selectively enters hepatocytes, five patients with chronic type B hepatitis (HBsAg/HBV-DNA positive for at least 2 years) were treated with the conjugate. The daily dose of conjugate given (35 mg/kg) contains 1.5 mg ara-AMP, whereas the usual daily dose of free ara-AMP is 5-10 mg/kg. In three patients HBV-DNA fell to undetectable levels and remained negative in two; in one of them anti-HBe developed. In the other two patients HBV-DNA decreased but was detectable during treatment--one received three cycles of therapy, and became HBV-DNA negative and anti-HBe positive 45 days after the end of treatment; the other remained HBeAg/HBV-DNA positive. No adverse effects were observed, and biochemical variables (including aminotransferases) remained unchanged or decreased with viraemia. No antibodies (IgM and IgG classes) that bound the conjugate were detected. Thus L-HSA-ara-AMP inhibits HBV replication as well as free ara-AMP but at a third to a sixth of the dose.

Chronic hepatitis B is no longer untreatable. With the advent of powerful antiviral agents such as adenine arabinoside, and, more importantly, with recombinant DNA technology and advanced culture systems able to produce large quantities of interferons, the prospects for treating patients with chronic hepatitis B virus (HBV) infection have changed completely. In the U.K., carriers not infected at birth are currently being treated with an approximately 50% chance of permanently inhibiting viral replication. In some of these, viral markers appear to be completely eliminated.

This study set out to examine the relative effectiveness and tolerability of 12- versus 24-week courses of thrice weekly intramuscular lymphoblastoid interferon in the treatment of hepatitis B 'e' antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection, and to identify pretreatment factors predicting the outcome of therapy. Twenty patients were randomised to each treatment group. Treatment was associated with clearance of HBeAg and HBV-DNA in 59% of the 32 male patients, whereas none of the eight women responded (48% overall response rate). This response rate in males is at least three times the recorded spontaneous seroconversion rates in this population. Most of the women (5/8) were of Oriental origin and had minimal disease, factors that may have influenced response. The longer course was poorly tolerated and was therefore no more effective: eight of 20 patients withdrew because of side-effects. Variables associated with response included high AST (aspartate transaminase), short duration of disease and previous history of acute hepatitis. A response to antiviral therapy was accompanied by clinical and biochemical evidence of improvement in liver disease.

We have characterized the hepatitis B virus state in liver and serum of 38 HBsAg-positive chronic hepatitis patients (chronic active hepatitis (CAH), 19; chronic persistent hepatitis (CPH), 7; cirrhosis, 11; 'normal' carrier, 1) and 21 HBsAg-negative patients. Episomal HBV-DNA in liver, without detectable integrated HBV-DNA sequences, concomitant with HBV-DNA in serum was found in 19 HBeAg-positive patients (CAH, 16; CPH, 1; cirrhosis, 2). Integrated sequences were detected in 13 HBsAg-positive HBeAg-negative patients (CAH, 1; CPH, 5; cirrhosis, 7) and in 1 HBsAg-negative patient. Episomal HBV-DNA and integrated HBV-DNA sequences were observed simultaneously in 1 HBsAg-positive HBeAg-negative CPH patient and in 4 HBsAg-positive cirrhosis patients (2 HBeAg-positive, 2 HBeAg-negative). The presence of HBcAg immunofluorescence corresponded well with that of episomal HBV-DNA. Antiviral therapy is advised for HBsAg-positive chronic hepatitis patients with episomal HBV-DNA, irrespective of the presence of integrated sequences. Since the presence of episomal HBV-DNA in liver is not always accompanied by the presence of serum HBV-DNA, procedures for the selection and evaluation of patients for antiviral therapy should be extended by characterization of the HBV-DNA state in liver biopsies.

Five hundred twelve (373 men, 139 women) patients, aged 1-75 yr, with chronic hepatitis B virus infection seen during a 5-yr period were analyzed. Of these, 43.8% were hepatitis B e antigen (HBeAg)-positive, 49.2% were positive for hepatitis B e antibody, and 7% were negative for both HBeAg and hepatitis B e antibody at presentation. The cumulative probability of clearing HBeAg at the end of the first, second, and third years was 17%, 30%, and 34%, respectively. The probability of clearing HBeAg increased with the age of the patients. Reversion to HBeAg occurred in 7.8% of patients who were HBeAg-negative at presentation and 32.3% of HBeAg-positive patients who cleared HBeAg. In 70.6% of these patients, serum hepatitis B virus-deoxyribonucleic acid was persistently positive or became detectable at the time of HBeAg reversion. Most reversions occurred during the "e-window" phase. The reversions were transient in 31.8% of the cases. Recognition of the dynamics of these serologic changes is important in the evaluation of therapeutic regimens aimed at suppression of HBV replication and call for controlled trials with adequate duration of follow-up. Biochemical exacerbation of liver disease accompanied 38.7% of HBeAg to hepatitis B e antibody seroconversions and 34.8% of reversions. Such exacerbations may be mistaken for acute attacks of hepatitis B in patients not previously recognized to be hepatitis B surface antigen carriers and, in the absence of serial serologic data, are indistinguishable from superimposed non-A, non-B hepatitis.

Eleven HBsAg chronic carriers were treated with recombinant-interferon (rIFN)-alpha-2A with either 20 X 10(6) (n = 6) or 10 X 10(6) IU/m2 body surface (n = 5), i.m. twice weekly for 6 months. HBV-markers were tested monthly for 15 months. Throughout the follow-up, 6 patients (54%) became HBeAg, HBV-DNAp and HBV-DNA negative (responders). In addition, 8 were HBcAg-negative, 10 anti-HBc-IgM-negative and 2 HBsAg/IgM complexes negative. All patients gave polymerized human serum albumin receptors and HBsAg-positive results. The low rIFN dose seems to be more efficient for clearing HBV-markers than the high dose. Responder patients already showed lower (P less than 0.05) HBsAg concentration and HBsAg/IgM complexes levels in their basal samples as compared to non-responders, and exhibited under rIFN treatment significant decreases (P less than 0.05) in all HBV-markers studied. In conclusion, the most reliable HBV-markers to be assayed in the evaluation of antiviral therapy are HBV-DNA, HBV-DNAp or HBcAg. The testing of pHSA-R, HBsAg/IgM complexes and anti-HBc-IgM does not seem to be very useful.

We have reviewed the results of treating over 100 HBV carriers with adenine arabinoside, adenine arabinoside monophosphate and lymphoblastoid interferon. In the homosexual group of carriers, adenine arabinoside and its monophosphate have no value. However in this group, lymphoblastoid interferon will produce a response in over 50% of cases. This lack of effectiveness of adenine arabinoside monophosphate in this group may stem from its immunosuppressant properties. In heterosexual carriers both adenine arabinoside monophosphate and lymphoblastoid interferons are effective in approximately 50% to 60% of cases. However, the response rate is different in the various racial groups. Northern European and Mediterranean people appear to respond whereas those from the Far East do not. This may reflect the fact that there are at least two mechanisms by which the chronic carrier state may arise. In 5% to 10% of adults, a relative deficiency of alpha interferon production exists, and this defect is found in the majority of HBV carriers in Western Europe. In these, interferon acts as a replacement therapy and excellent results may be obtained if the patient is treated early in the course of the disease. It would appear that as the duration of the infection increases, the virus may integrate into interferon-reactive consensus sites and prevent the cell from responding to interferon. In patients infected at birth, transplacental anti-HBc appears to modulate the immune response and, along with immaturity of the immune system at this age, results in failure to lyse infected cells. These patients do not benefit from interferon treatment: some form of immune manipulation is required.(ABSTRACT TRUNCATED AT 250 WORDS)

Developments over the last four years in our understanding of viral hepatitis are analyzed. The molecular structure of hepatitis A has been established, and vaccines for prevention are under development. The recognition of the replicative and integrated stages of hepatitis B infection has allowed more rational approaches to therapy. Vaccines are of proven value. Delta virus infection has assumed an important role world wide as a cause of serious and fulminant liver disease in hepatitis B carriers. The agents for non-A, non-B virus hepatitis have eluded identification. These are important causes of chronic liver disease particularly in recipients of blood transfusion.

We have reviewed the results of treating over 100 HBV carriers with adenine arabinoside, adenine arabinoside monophosphate and lymphoblastoid interferon. In the homosexual group of carriers, adenine arabinoside and its monophosphate have no value. However, in this group, lymphoblastoid interferon will produce a response in over 50% of cases. The lack of effectiveness of adenine arabinoside monophosphate in this group may stem from its immunosuppressant properties. In heterosexual carriers both adenine arabinoside monophosphate and lymphoblastoid interferon are effective in approximately 50-60% of cases. However, the response rate is different in the various racial groups. Northern European and Mediterranean people appear to respond whereas those from the Far East do not. This may reflect the fact that there are at least 2 mechanisms by which the chronic carrier state may arise. In 5-10% of adults, a relative deficiency of alpha-interferon production exists and this defect is found in the majority of HBV carriers in Western Europe. In these, interferon acts as a replacement therapy and excellent results may be obtained if the patient is treated early in the course of the disease. It would appear that as the duration of the infection increases, the virus may integrate into interferon-reactive consensus sites and prevent the cell from responding to interferon. In patients infected at birth, transplacental anti-HBc appears to modulate the immune response and along with immaturity of the immune system at this age, results in failure to lyse infected cells. These patients do not benefit from interferon treatment: some form of immune manipulation is required.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis B virus (HBV) infection is prevalent in Chinese populations. 40.4% of 383 Chinese HBV carriers studied were HBeAg-positive. The annual rate of spontaneous clearance of HBeAg was 11%. Twenty-six patients with HBsAg- and HBeAg- and HBeAg-positive non-malignant chronic liver disease randomised to receive recombinant alpha-2 interferon or no treatment have been followed for 6 months or longer. Seven of the 20 treated patients cleared HBeAg during or shortly after treatment but this was sustained in only 1 patient. One of the 6 controls had transient loss of HBeAg. It is too early to conclude whether interferon has any long-term effect on the suppression of HBV replication in Chinese patients. Sixty-nine patients with histologically proven hepatocellular carcinoma were randomised to receive adriamycin or interferon. Although there was no significant benefit on survival, interferon therapy was associated with greater than 25% regression in tumor size in 12.5% of patients and less toxicity.

The future design of controlled trials of antiviral therapy which might include homosexual hepatitis B virus (HBV) carriers requires base-line data on the spontaneous rate of loss of HBeAg and the prevalence of human T-lymphotropic virus III (HTLV-III/LAV) infection. Fifty-one untreated HBsAg and HBeAg-positive homosexual HBV carriers were followed for a median HBeAg-positive time of 23.5 months (range 6-85.5). Ten lost HBeAg, giving an annual rate of spontaneous loss of HBeAg of 10%. This rate is considerably higher than the apparent rate in a previous report and has considerable implications for the interpretation of previous, and the design of future, controlled trials in this population. A rapid rise in the prevalence of anti-HTLV-III/LAV amongst HBV carriers was demonstrated from 1981 such that by 1984 over 60% of HBV carriers were anti-HTLV-III-positive. HBV-DNA polymerase levels were not significantly different in asymptomatic anti-HTLV-III/LAV-positive compared to anti-HTLV-III/LAV-negative HBV carriers. Nevertheless, since chronic HTLV-III/LAV infection in its later stages may potentiate HBV replication, it is a factor that will need to be considered together with many others in any trial stratification procedure.

Lymphoblastoid interferon (Wellferon), a combination of at least 8 alpha-interferons, has been shown to be effective therapy in male chronic carriers of HBV infection, resulting in the loss of HBeAg and HBV-DNA in 50% of those treated. However, 0/8 women (5 Chinese) treated in this trial responded to treatment. Patients with higher ASTs, CAH on biopsy and a history of acute hepatitis are more likely to respond to treatment. Recombinant alpha-A interferon has not been as successful in our particular group of patients. However, this may be explained by the observation that most of these patients are asymptomatic, homosexuals and have lower transaminases, less histological inflammation and a higher percentage of HTLV-III antibody positivity than the Wellferon group. In the HTLV-III-negative group of HBV carriers, the response to recombinant alpha-A interferon is similar to that achieved with lymphoblastoid interferon.

Acyclovir only demonstrated activity in CAH patients with low HBV replication (DNA-p less than or equal to 80 cpm). In those, oral acyclovir 4 g/day for 4 months was able to permanently inhibit DNA-p in 5/5 cases without significant side-effects.

Twenty-nine HBV carriers were randomised to receive ARA-AMP 10 mg/kg/day given as intramuscular injections 12 h apart for 5 days followed by 5 mg/kg/day for 23 days (15 patients) or no treatment (14 patients). Serum HBV-DNA polymerase and DNA decreased in all patients during therapy and 6 patients lost HBeAg. Five developed anti-HBe and 1 lost HBsAg and developed anti-HBs. No such changes occurred in the untreated control group over the 18-month period of observation. A 1-month course of ARA-AMP inhibits productive HBV replication and in some patients this is associated with a later loss of HBeAg and development of anti-HBe. However, intercurrent infection occurred in 3 of the treated patients with other hepatotrophic viruses known to inhibit HBV replication.

BW A515U (6-Deoxyacyclovir) is a pro-drug of acyclovir and almost 100% is absorbed orally. 250 mg orally 6-hourly for 10 days was given to 4 hepatitis B surface antigen/e antigen-positive carriers. No consistent effect on productive viral replication, as determined by serum DNA polymerase and DNA levels was observed. The changes that occurred in these markers and transaminases in 1 patient were attributed to a spontaneous depression of productive viral replication.

A total of 32 individuals with HBsAg-positive and anti-delta-negative chronic hepatitis were treated with recombinant alpha-A interferon in phase I and phase II studies. In 5/32 patients HBsAg could be eliminated and in 19/32 individuals HBeAg became negative including all those who also eliminated HBsAg. Side-effects were tolerable in most patients and were readily reversible upon discontinuation of interferon therapy. In conclusion, treatment of HBsAg-positive chronic hepatitis with interferon seems to be a promising therapeutic approach. Future studies will have to establish the optimal dose, duration of treatment and factors predicting a favourable outcome of the treatment.

A clearer view of the natural history of chronic hepatitis B virus (HBV) infection has permitted recognition of a phase of viral replication associated with progressive liver damage, and one of absent replication when the disease is inactive and when continued presence of hepatitis B surface antigen (HBs) is due to the integration of viral genes with the host genome. These two phases can be identified by HBe antigenaemia and anti-HBe, respectively. Several active antiviral drugs are available and may significantly benefit certain HBe Ag-positive groups. The antiviral activity of vidarabine and its analogues and of alpha-interferons is established, and insight is being gained into factors that predict response. In general, results depend on duration of infection, and integrity of the patient's immune response. Anti-HBe positive carriers usually need no treatment, but in those with continuing low-level HBV replication or delta superinfection antiviral therapy, although of unproven value, may be tried. In patients without HBV or hepatitis delta virus (HDV) replication who have signs of active disease, immunosuppressants may be tried with benefit.

A previous randomized controlled study has shown a 30% rate of HBe antigen/antibody seroconversion within 1 year of a month course of adenine arabinoside-5'-monophosphate; no seroconversion occurred in the control group. In this study of patients derived from the same population, 45 hepatitis B virus carriers with chronic liver disease were randomized to receive either a short (4-week) course of adenine arabinoside-5'-monophosphate, a long (7 to 8-week) course of adenine arabinoside-5'-monophosphate or a 12-week course of lymphoblastoid interferon. Long-lasting suppression of hepatitis B virus replication with disappearance of serum hepatitis B virus DNA and clearance of HBeAg occurred within 12 months of treatment in four patients who received the short course of adenine arabinoside-5'-monophosphate and in five who received interferon. Of the nine responders, four also lost HBsAg. A response to antiviral therapy was accompanied by clinical and biochemical evidence of improvement in liver disease. None of the patients who received a long course of adenine arabinoside-5'-monophosphate responded. Peripheral neuropathy and myalgia were the most serious adverse effect affecting three recipients of the short course of adenine arabinoside-5'-monophosphate and eight recipients of the long course. Thrice weekly administration of interferon was well-tolerated. Further studies to identify the characteristics of the "responder patients" and large-scale controlled trials of antiviral therapy in these subgroups are indicated.