Do we need to determine viral genotype in treating chronic hepatitis B?

Many studies have attested that not only does HBV genotype influence the outcome of the disease but it also influences the outcome of therapy with interferons and pegylated interferons, with genotype A doing better than genotype D in Caucasians and genotype B better than genotype C in Asians. However, the guidelines from three regional bodies - AASLD, APASL and EASL - all stop short of recommending genotyping as part of the management of chronic hepatitis B. The recommendations, however, from several national organizations as well as from individual reviewers suggest that genotyping is essential to detect patients in whom the use of pegylated interferon will give a high likelihood of response with a finite course of therapy and avoid the disadvantages of nucleoside analogues with their viral resistance. It is concluded that determination of HBV genotype should form part of the management in treating chronic hepatitis B.

Living with chronic hepatitis C means 'you just haven't got a normal life any more'.

OBJECTIVE: To explore psychosocial factors that impact on quality of life for people living with self-reported chronic hepatitis C. METHODS: A purposeful sample of 70 people who were self-identified as being hepatitis C virus (HCV)-positive was recruited through a variety of institutions and community agencies. Semi-structured interviews were held with 12 groups and 21 individuals. A qualitative grounded-theory methodology was used for data collection and analysis. Experiences of physical and psychological symptoms, stigma and discrimination, and living with an infectious disease, were explored using matrices. RESULTS: Phenomena emerging from the data included previously undocumented illness 'attacks' that were associated with depressive symptoms and a perception of hepatitis C as fatal. Uncertainty related to disease progression and transmission of the virus were common experiences among participants. A universal experience was fear and anxiety about stigma and discrimination. DISCUSSION: The findings of this study indicate that chronic hepatitis C has a pervasive impact on quality of life with a complexity that has not been explored with quantitative research approaches. Primary healthcare professionals need to be alert to the psychological and social impacts of chronic hepatitis C and to avoid behaviours that lead to perceptions of stigma and discrimination. The research indicates a need for further investigation into the relationship between psychosocial factors, disease management and disease progression.

Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B.

Current therapies for chronic hepatitis B (CHB) have a number of limitations, and better treatment options are needed. Peginterferon alpha-2a (40 kDa) is superior to conventional interferon alpha-2a in the treatment of chronic hepatitis C. This is the first report on peginterferon alpha-2a (40 kDa) in the treatment of CHB. In this phase II study, 194 patients with CHB not previously treated with conventional interferon-alpha were randomized to receive weekly subcutaneous doses of peginterferon alpha-2a (40 kDa) 90, 180 or 270 microg, or conventional interferon alpha-2a 4.5 MIU three times weekly. Twenty-four weeks of therapy were followed by 24 weeks of treatment-free follow-up. All subjects were assessed for loss of hepatitis B e antigen (HBeAg), presence of hepatitis B antibody (anti-HBe), suppression of hepatitis B virus (HBV) DNA, and normalization of serum alanine transaminase (ALT) after follow-up. At the end of follow-up, HBeAg was cleared in 37, 35 and 29% of patients receiving peginterferon alpha-2a (40 kDa) 90, 180 and 270 microg, respectively, compared with 25% of patients on conventional interferon alpha-2a. The combined response (HBeAg loss, HBV DNA suppression, and ALT normalization) of all peginterferon alpha-2a (40 kDa) doses combined was twice that achieved with conventional interferon alpha-2a (24%vs 12%; P = 0.036). All treatment groups were similar with respect to frequency and severity of adverse events. These results indicate that peginterferon alpha-2a (40 kDa) is superior in efficacy to conventional interferon alpha-2a in chronic hepatitis B based on clearance of HBeAg, suppression of HBV DNA, and normalization of ALT.

A novel variant genotype C of hepatitis B virus identified in isolates from Australian Aborigines: complete genome sequence and phylogenetic relatedness.

There have been no reports of DNA sequences of hepatitis B virus (HBV) strains from Australian Aborigines, although the hepatitis B surface antigen (HBsAg) was discovered among them. To investigate the characteristics of DNA sequences of HBV strains from Australian Aborigines, the complete nucleotide sequences of HBV strains were determined and subjected to molecular evolutionary analysis. Serum samples positive for HBsAg were collected from five Australian Aborigines. Phylogenetic analysis of the five complete nucleotide sequences compared with DNA sequences of 54 global HBV isolates from international databases revealed that three of the five were classified into genotype D and were most closely related in terms of evolutionary distance to a strain isolated from a healthy blood donor in Papua New Guinea. Two of the five were classified into a novel variant genotype C, which has not been reported previously, and were closely related to a strain isolated from Polynesians, particularly in the X and Core genes. These two strains of variant genotype C differed from known genotype C strains by 5.9-7.4% over the complete nucleotide sequence and 4.0-5.6% in the small-S gene, and had residues Arg(122), Thr(127) and Lys(160), characteristic of serotype ayw3, which have not been reported previously in genotype C. In conclusion, this is the first report of the characteristics of complete nucleotide sequences of HBV from Australian Aborigines. These results contribute to the investigation of the worldwide spread of HBV, the relationship between serotype and genotype and the ancient common origin of Australian Aborigines.

A longitudinal analysis of cytotoxic T lymphocyte precursor frequencies to the hepatitis B virus in chronically infected patients.

Individuals with acute hepatitis B virus (HBV) infection characteristically mount a strong, multispecific cytotoxic T lymphocyte (CTL) response that is effective in eradicating virus. In contrast, this response in chronic carriers is usually weak or undetectable. Since it is generally acknowledged that HBV pathogenesis is immune-mediated, the occurrence of episodes of active liver disease in many carriers suggests that these individuals can mount active CTL responses to HBV. To see whether the detection of circulating CTLs is related to these flare episodes, we have determined the CTL precursor (CTLp) frequencies to HLA-A2-restricted viral peptides in seven patients over a 12-24-month period of their disease. Limiting dilution analyses (LDA) were performed longitudinally to five epitopes comprising the viral capsid (HBc), envelope (HBs) and polymerase (pol) proteins. Assays were performed against a mixture of peptides, or against each individual peptide, to measure overall CTL activity and the multispecificity of the responses, respectively. Since two of the patients were treated with recombinant human interleukin-12 (rHuIL-12) at the time, with one individual achieving complete disease remission a year later after being treated with interferon-alpha, we were also able to examine the effects of these cytokines on HBV cytotoxicity. Our results indicate that weak but detectable CTL responses do occur in chronic carriers which are generally associated with disease flares, although CTLps were also seen occasionally during minimal disease activity. The range of specificities varied between individuals and within each individual during the course of the disease. Finally, we also provide evidence that CTL reactivity is stimulated following treatment with certain cytokines, but is dependent on the time of administration.

Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.

BACKGROUND: Chronic hepatitis C virus (HCV) infection in patients with cirrhosis is difficult to treat. In patients with chronic hepatitis C but without cirrhosis, once-weekly administration of interferon modified by the attachment of a 40-kd branched-chain polyethylene glycol moiety (peginterferon alfa-2a) is more efficacious than a regimen of unmodified interferon. We examined the efficacy and safety of peginterferon alfa-2a in patients with HCV-related cirrhosis or bridging fibrosis. METHODS: We randomly assigned 271 patients with cirrhosis or bridging fibrosis to receive subcutaneous treatment with 3 million units of interferon alfa-2a three times weekly (88 patients), 90 microg of peginterferon alfa-2a once weekly (96), or 180 microg of peginterferon alfa-2a once weekly (87). Treatment lasted 48 weeks and was followed by a 24-week follow-up period. We assessed efficacy by measuring HCV RNA and alanine aminotransferase and by evaluating liver-biopsy specimens. A histologic response was defined as a decrease of at least 2 points on the 22-point Histological Activity Index. RESULTS: In an intention-to-treat analysis, HCV RNA was undetectable at week 72 in 8 percent, 15 percent, and 30 percent of the patients treated with interferon alfa-2a and with 90 microg and 180 microg of peginterferon alfa-2a, respectively (P=0.001 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). At week 72, alanine aminotransferase concentrations had normalized in 15 percent, 20 percent, and 34 percent of patients, respectively (P=0.004 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). In the subgroup of 184 patients with paired liver-biopsy specimens, the rates of histologic response at week 72 were 31 percent, 44 percent, and 54 percent, respectively (P=0.02 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). All three treatments were similarly tolerated. CONCLUSIONS: In patients with chronic hepatitis C and cirrhosis or bridging fibrosis, 180 microg of peginterferon alfa-2a administered once weekly is significantly more effective than 3 million units of standard interferon alfa-2a administered three times weekly.

Sertraline treatment of interferon-alfa-induced depressive disorder.

Interferon alfa therapy for chronic hepatitis C infection is commonly associated with neuropsychiatric symptoms, including depression. These side effects may necessitate reduction or even cessation of interferon alfa, but there is little information regarding the management of this important problem. We report 10 cases of interferon-alfa-induced depressive disorder treated with the selective serotonin reuptake inhibitor sertraline. All patients obtained rapid symptom relief without the need for reduction or cessation of interferon alfa.

Consensus statement on the role of hepatitis A vaccination in patients with chronic liver disease.

Hepatitis A virus (HAV) is a ubiquitous, easily transmitted virus that can cause severe hepatitis, particularly in the adult population. Improvements in sanitation and hygiene in the developing world have led to a decline in immunity against HAV. A growing number of adults are now susceptible to infection, with those who have not been vaccinated against hepatitis B virus (HBV) being at risk of dual infection and potentially more severe illness. The symposium, "The role of hepatitis vaccination in patients with chronic liver disease", provided the opportunity to develop a consensus statement. It was concluded that patients with non-viral chronic liver disease (CLD) and certain groups with HBV infection can develop more severe disease in the event of HAV infection. It was identified that patients with CLD should be targeted for hepatitis A vaccination as soon as CLD is diagnosed.

What did we learn from the Shanghai hepatitis A epidemic?

A major outbreak of hepatitis A (HAV), associated with consumption of raw clams, occurred in Shanghai, China in 1988. Over 300 000 cases were reported, of which 47 (0.015%) were fatal. An elevated mortality rate was observed in hepatitis B surface antigen (HBsAg)-positive patients (0.05%). The majority of these patients were also hepatitis B e antigen (HBeAg)-positive, indicating active liver disease and high viral replication rates. The increased mortality in hepatitis B virus (HBV)/HAV coinfected individuals is hypothesized to be the result of T-cell-mediated destruction of HBV-infected hepatocytes, enhanced by acute HAV infection. Following recovery from HAV there is an increase in HBV expression and activated cytotoxic cells and subsequent cytolysis. Patients with chronic HBV infection are clearly at considerable risk of severe disease and increased mortality in the event of HAV infection. The period of greatest risk is during the immunoeliminative phase of HBV infection, which generally occurs in early adulthood. With the prevalence of HBV approaching 10% in this group, there is a clear opportunity for benefit from vaccination.

A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B.

BACKGROUND/AIMS: Interleukin-12 (IL-12) may be active against hepatitis B virus (HBV). The objective of the study was to assess the tolerability, activity, pharmacokinetics, and pharmacodynamics of three dose levels (0.03 microg/kg b.w., n=15; 0.25 microg/kg b.w., n=15; 0.50 microg/kg b.w., n=16) of recombinant human (rHu) IL-12 given s.c. once a week for 12 consecutive weeks. METHODS: Forty-six patients with chronic hepatitis B, HBV DNA positivity and aminotransferase elevation were included in a multicenter prospective randomized phase I/II study. RESULTS: Compared with the baseline, HBV DNA levels had decreased significantly at the end of rHuIL-12 treatment and after the 12-week follow-up period (p<0.001). The response to rHuIL-12 treatment was dose-dependent: at the end of the study HBV DNA clearance was greater in patients treated with 0.50 microg/kg b.w. (25%) or with 0.25 microg/kg b.w. (13%) compared with those given 0.03 microg/kg b.w. (7%). Moreover, HBeAg became undetectable at the end of follow-up in five of the patients given the 0.25microg/kg (2/15) or the 0.50 microg/kg (3/16) dose. The drug pharmacology showed that IL-12 had an estimated half-life of 30 h with levels remaining detectable for more than 48 h after rHuIL-12 administration. The serum levels of IL-12, interferon-gamma, IL-10, neopterin and beta2-microglobulin as well as the area under the curve (AUC) were rHuIL-12 dose-related. Side effects were observed more frequently with higher doses, including moderate decreases in lymphocyte and neutrophil counts; three patients withdrew prematurely from treatment. The local reaction observed at the injection site was unrelated to the drug dose. Only one patient showed detectable antibody levels to rHuIL-12 without clinical impact. CONCLUSIONS: Treatment with rHuIL-12 at the doses investigated is safe and tolerable, and appears to be active against HBV in patients with chronic hepatitis B.

Exposure to GB virus type C or hepatitis G virus in selected Australian adult and children populations.

BACKGROUND: The epidemiology and disease association for the GB virus type C (GBV-C) or hepatitis G virus (HGV) are poorly understood. STUDY DESIGN AND METHODS: This study describes the exposure rates to GBV-C/HGV in diverse Australian population groups by testing for current infection and evidence of past infection with a reverse transcriptase polymerase chain reaction and an anti-E2 enzyme-linked immunosorbent assay, respectively. Subjects included volunteer blood donors, hepatitis C antibody (anti-HCV)-positive donors, children, hemodialysis patients, pregnant women attending a prenatal clinic, injecting drug users (IVDUs), and adult hemophiliacs. RESULTS: Combined GBV-C RNA and E2 antibody prevalence was 6.5 percent (6/93) in children, 13.3 percent (75/565) in blood donors, 14 percent (14/99) in pregnant women, 22.5 percent (18/80) in hemodialysis patients, 80 percent (56/70) in anti-HCV-positive donors, 88.6 percent (31/35) in IVDUs, and 85.7 percent (54/63) in adult hemophiliacs. Children had the lowest antibody rate, 1.1 percent, whereas the rate was 10.8 percent for blood donors and rose to 45.7 percent for IVDUs, 57.1 percent for anti-HCV-positive donors, and 74.6 percent for hemophiliacs. In contrast, current infection rates were comparable for children, blood donors, and pregnant women (5.4, 2.6, and 6%, respectively), rising to 11.1 percent for hemophiliacs, 24.3 percent for anti-HCV-positive donors, and 48.6 percent for IVDUs. Ten of 12 blood donors had persistent viremia, while 2 had recent infections, 1 with apparent resolution. CONCLUSION: Exposure to GBV-C can commence at an early age, although ongoing exposure may also occur among adults with no apparent risk factors. GBV-C RNA positivity was not associated with abnormal plasma alanine aminotransferase levels among blood donors.

The influence of iron on chronic hepatitis C.

It has recently been suggested that the hepatic iron concentration can be used to predict the response to interferon in patients with chronic hepatitis C. An hepatic iron concentration greater than 1100 microg/g appears to identify a group of patients that are unlikely to respond to alpha-interferon. It is not known whether this relationship can be explained by associated variables such as age, gender or disease severity or whether the hepatic iron concentration itself influences the response to interferon. Furthermore, the hepatic iron concentration is of no value in discriminating responders from non-responders in patients with hepatic iron concentrations less than 1100 microg/g. The possibility of improving response rates to interferon by pretreatment venesection needs to be explored but currently only limited data are available. Venesection results in a significant fall in the serum transaminases but the preliminary results regarding the efficacy of subsequent interferon therapy are unclear. Until the results of prospective controlled trials are available it is concluded that the available evidence does not support venesection before interferon therapy for chronic hepatitis C.

The C282Y mutation in the haemochromatosis gene (HFE) and hepatitis C virus infection are independent cofactors for porphyria cutanea tarda in Australian patients.

BACKGROUND/AIM: Whether mutations in the putative haemochromatosis gene (HFE) and hepatitis C virus act independently to precipitate porphyria cutanea tarda is unknown. The aim of the study was to investigate the relationship between mutations in HFE, hepatitis C and porphyria cutanea tarda. METHODS: The frequencies of the C282Y and H63D mutations in HFE were determined in 27 patients with porphyria cutanea tarda and compared with the reported control frequencies. In addition, the presence of hepatitis C virus infection was identified and related to the patients' HFE status. RESULTS: The C282Y mutation was found in 44.4% of patients compared with the control frequency of 12% (p<0.001). Three patients were homozygous for the C282Y mutation, two of whom did not meet current clinical diagnostic criteria for expressed haemochromatosis. The proportion of patients with the H63D mutation did not differ from the reported control frequency. The mean transferrin saturation and serum ferritin concentration were similar in porphyria cutanea tarda patients who were homozygous normal and heterozygous for the C282Y mutation, but greater in both groups than previously reported in healthy controls. Seven (25.9%) patients were anti-HCV IgG positive. None of these patients carried the C282Y mutation. Porphyria cutanea tarda patients heterozygous for the C282Y mutation and patients with anti-HCV antibodies had elevated transferrin saturations and serum ferritin concentrations. CONCLUSIONS: The raised frequency of the C282Y mutation in porphyria cutanea tarda indicates that this mutation is likely to be a predisposing factor. However, abnormalities of iron indices also exist in porphyria cutanea tarda patients without mutations in HFE. Hepatitis C virus infection is likely to be another common precipitating factor for porphyria cutanea tarda which acts independently of the C282Y mutation.

Efficacy and tolerance of a 6-month treatment course of daily interferon-alpha 2a for chronic hepatitis C with cirrhosis. The Australian Hepatitis C Study Group.

Response to interferon-alpha (IFN-alpha) treatment in hepatitis C is poorer when cirrhosis is present. In the third Australian multicentre hepatitis C trial, Aushep-3, we examined the efficacy and tolerability of an intensive 24-week course of interferon-alpha 2a in Child-Pugh grade A patients with chronic hepatitis C and cirrhosis. This was an open uncontrolled trial of 4.5 million units (MU) of IFN-alpha 2a daily for 24 weeks; follow-up was 48 weeks. Chronic hepatitis C and cirrhosis were confirmed histologically. HCV RNA was determined in serum by reverse transcriptase polymerase chain reaction (PCR), and viral genotyping was by line-probe assay. Treatment response was defined as a reduction of alanine aminotransferase (ALT) to less than 1.5 times the upper limit of normal (and by at least 50% of pretreatment values) at weeks 20 and 24. Sustained response was defined as normal serum ALT after treatment from trial week 28 until week 48. Among the 56 patients, a treatment response occurred in 18 (32% by intention-to-treat; 42% of those who completed treatment) and eight (14%) had a sustained response. At 24 weeks, HCV RNA was not detectable in 12 of 17 treatment responders, and remained negative at 48 weeks in six of eight sustained responders. Treatment response by genotype occurred in 75% of patients with HCV type 2, in 38% with HCV type 3a and in 12% with HCV genotype 1. Sustained response occurred in only one (4%) patient with HCV genotype 1 but in five (20%) with genotypes 2 or 3a. Among 13 patients withdrawn, nine were for adverse effects, most often haematological; 10 others underwent dose reduction for adverse effects. It is concluded that a sustained biochemical and viral response to treatment with IFN-alpha 2a can be obtained in some patients with hepatitis C and cirrhosis, particularly those with genotypes 2 or 3a. Therefore, patients with cirrhosis should be considered for interferon treatment on an individual basis. Genotyping may improve case selection, but vigilance is required for haematological complications.

Interferon treatment of chronic hepatitis C with cirrhosis.

Among patients with hepatitis C who have cirrhosis the rate of sustained response following interferon therapy is only half that of patients without cirrhosis. Although it has been suggested that a higher dose regime in patients with cirrhosis may improve response, this remains largely untested. The results of a recent Australian study of cirrhotic patients who were given an intense interferon programme of 4.5 MIU daily for 24 weeks were compared with previous studies of patients with hepatitis C. Of 11 studies of interferon response in chronic hepatitis C comparison of pretreatment variables showed considerable differences. Identification of predictors of response by univariate and multivariate analysis regularly indicated the importance of age and fibrosis. Analysis of six studies with either a poor (5% or less) or a reasonable (14-19%) sustained response rate to interferon in patients with cirrhosis suggested that a higher dose or longer duration of therapy was associated with better results. The experience of the Australian study, where 14% of patients had a sustained biochemical response to interferon and side-effects were reasonably tolerated with careful monitoring, suggests that future studies in cirrhosis should be carried out exploring higher doses and longer durations of therapy.

Treatment of cirrhotic hepatitis C virus patients with daily doses of interferon-alpha 2a.

In patients with hepatitis C who have cirrhosis the rate of sustained response following interferon therapy is less than half that of patients without cirrhosis. It has been suggested, however, that a higher dose regime in patients with cirrhosis may improve response. The results of a recent Australian study of cirrhotic patients who were given an intense interferon programme of 4.5 MIU daily for 24 weeks were compared with previous studies of patients with hepatitis C. In the Australian study, 14% of patients had a sustained response at 6 months after end of therapy. Of 11 studies of interferon response in chronic hepatitis C comparison of pretreatment variables showed considerable differences. Identification of predictors of response by univariate and multivariate analysis regularly indicated the importance of age and fibrosis. Analysis of six studies with either a poor (5% or less) or a reasonable (14-19%) sustained response rate to interferon in patients with cirrhosis suggested that a higher dose or longer duration of therapy was associated with better results. The experience of the Australian study, where 14% of patients had a sustained biochemical response to interferon and side-effects were reasonably tolerated with careful monitoring, suggests that future studies in cirrhosis should be carried out exploring higher doses and longer durations of therapy.

Genotype of GB virus C/hepatitis G virus by molecular evolutionary analysis.

GB virus C/hepatitis G virus is a newly described virus. Classification of GB virus C/hepatitis G virus into genotypes has not been established. We analyzed nucleotide sequences within the 5' untranslated region of GB virus C/hepatitis G virus isolates and segregated these isolates into genotypes. Twenty serum samples with GB virus C/hepatitis G virus RNA from Australia, Cameroon, the Congo, Japan, Mongolia, and Bangladesh were studied. Reverse transcription and polymerase chain reaction were used to obtain GB virus C/hepatitis G virus RNA. After nucleotide sequences from the 5' untranslated region were determined, 68 nucleotide sequences, including 48 previously reported sequences, were analyzed by molecular evolutionary methods. The phylogenetic tree of the 5' untranslated region showed that all strains could be divided into three major genotypes, GB type (type 1), HG type (type 2), and Asian type (type 3). Bootstrap analysis indicated that the strains could be divided into three major genotypes but could not be further subdivided. Moreover, frequency histograms of pairwise distances between nucleotide sequences demonstrated only one peak. These result indicated that GB virus C/hepatitis G virus can be classified into three major genotypes, GB type (type 1), HG type (type 2), and Asian type (type 3), and should not be divided into minor subtypes.