Hepatitis B immunisation in persons not previously exposed to hepatitis B or with unknown exposure status.

BACKGROUND: The benefits and harms of hepatitis B vaccination in persons not previously exposed to hepatitis B infection or with unknown exposure status have not been established. OBJECTIVES: To assess the benefits and harms of hepatitis B vaccination in people not previously exposed to hepatitis B infection or with unknown exposure status. SEARCH STRATEGY: Trials were identified from The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS,Science Citation Index Expanded (last search, March 2007). Additionally, we contacted experts and vaccine manufacturers, and read through reference lists for eligible trials. SELECTION CRITERIA: Randomised clinical trials comparing hepatitis B vaccine versus placebo, no intervention, or another vaccine in persons not previously exposed to hepatitis B (HBsAg negative) or with unknown exposure status. DATA COLLECTION AND ANALYSIS: The primary outcome was hepatitis B infection (detecting HBsAg, HBeAg, HBV DNA, or anti-HBc). Secondary outcomes were lack of sero-protection, antibody titre, clinical complications, adverse events, lack of compliance, and cost-effectiveness. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence interval (CI), using intention-to-treat analysis assuming an unfavourable event for missing data. Sensitivity analyses based on methodological quality (risk of bias), available data analysis, intention-to-treat analysis assuming a favourable event for missing data, best-case scenario, and worst-case scenario were conducted. MAIN RESULTS: Twelve trials were eligible. All had high risk of bias and reporting was inconsistent. Hepatitis B vaccine did not show a clear effect on the risk of developing HBsAg (RR 0.96, 95% CI 0.89 to 1.03, 4 trials, 1230 participants) and anti-HBc (RR 0.81, 95% CI 0.61 to 1.07; 4 trials, 1230 participants, random-effects) when data were analysed using intention-to-treat analysis assuming an unfavourable event for missing data. Analysis based on data of available participants showed reduced risk of developing HBsAg (RR 0.12, 95% CI 0.03 to 0.44, 4 trials, 576 participants) and anti-HBc (RR 0.36, 95% CI 0.17 to 0.76, 4 trials, 576 participants, random-effects). Intention-to-treat analysis assuming favourable outcome for missing data showed similar reduction in risk. Hepatitis B vaccination had an unclear effect on the risk of lacking protective antibody levels (RR 0.57, 95% CI 0.26 to 1.27, 3 trials, 1210 participants, random-effects). Development of adverse events was sparsely reported. AUTHORS' CONCLUSIONS: In people not previously exposed to hepatitis B, vaccination has unclear effect on the risk of developing infection, as compared to no vaccination. The risk of lacking protective antibody levels as well as serious and non-serious adverse events appear comparable among recipients and non-recipients of hepatitis B vaccine.

Treatment of children persistently infected with hepatitis B virus: seroconversion or suppression.

We have reviewed the current strategies regarding the treatment of persistent hepatitis B virus (HBV) in children and compared these with adult strategies. The options for achieving suppression of viral DNA replication versus hepatitis B e antigen to antibody seroconversion have been evaluated. The results of studies in different geographical locations have been confounded by HBV genotypes, as it is now clear that some genotypes respond better to treatment than others. Consideration needs to be given as to whether optimal treatment strategies developed for adults are directly applicable to children. In children, early seroconversion to allow improved long-term outcomes should be considered rather than embarking on the long-term complexities of managing patients on a combination of antiviral drugs to achieve viral suppression.

Long-term follow-up of hepatitis B carrier children treated with interferon and prednisolone.

The long-term outcome of treatment with Interferon Alpha 2B with and without Prednisolone priming in children infected perinatally with hepatitis B was reviewed. The group studied included 48 children (aged 2-16 years), who were HBe antigen and hepatitis B DNA positive between 1991 and 1993. Twenty children were randomized to a therapeutic trial at that time, and received Prednisolone in reducing doses for 6 weeks and Interferon for 16 weeks while 22 children were monitored without treatment for 12 months. Fourteen of the untreated group and 6 additional children later received treatment with Interferon alone (n = 20). Eight children for whom treatment was declined were followed long term. Median follow-up was 7.5 years (range 1.5-10.6). There was no significant effect of Interferon therapy on seroconversion with or without Prednisolone at 12 months post-treatment compared to untreated children. On longer term follow-up, the 5-year HBeAg to anti-HBe seroconversion percentages, estimated from Kaplan-Meier curves, were 54% for Prednisolone plus Interferon, 22% for Interferon alone, and 12% for untreated children. The median time to seroconversion was 3.9 years (range 0.4-8.2) and was shortest in those treated with Prednisolone plus Interferon. Children who had elevated hepatic transaminase enzymes prior to treatment or during Prednisolone priming had a better response. In contrast to many European studies, no child cleared HBsAg and produced anti-HBs. Treatment with Prednisolone priming and Interferon, improved both the time and rate of seroconversion compared to no treatment or Interferon alone, suggesting that this combination of drugs might have an immunomodulatory effect.

Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis.

OBJECTIVE: To evaluate the effects of hepatitis B vaccine and immunoglobulin in newborn infants of mothers positive for hepatitis B surface antigen. DESIGN: Systematic review and meta-analysis of randomised clinical trials. DATA SOURCES: Electronic databases and hand searches. REVIEW METHODS: Randomised clinical trials were assessed for methodological quality. Meta-analysis was undertaken on three outcomes: the relative risks of hepatitis B occurrence, antibody levels to hepatitis B surface antigen, and adverse events. RESULTS: 29 randomised clinical trials were identified, five of which were considered high quality. Only three trials reported inclusion of mothers negative for hepatitis B e antigen. Compared with placebo or no intervention, vaccination reduced the occurrence of hepatitis B (relative risk 0.28, 95% confidence interval 0.20 to 0.40; four trials). No significant difference in hepatitis B occurrence was found between recombinant vaccine and plasma derived vaccine (1.00, 0.71 to 1.42; four trials) and between high dose versus low dose vaccine (plasma derived vaccine 0.97, 0.55 to 1.68, three trials; recombinant vaccine 0.78, 0.31 to 1.94, one trial). Compared with placebo or no intervention, hepatitis B immunoglobulin or the combination of plasma derived vaccine and hepatitis B immunoglobulin reduced hepatitis B occurrence (immunoglobulin 0.50, 0.41 to 0.60, one trial; vaccine and immunoglobulin 0.08, 0.03 to 0.17, three trials). Compared with vaccine alone, vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (0.54, 0.41 to 0.73; 10 trials). Hepatitis B vaccine and hepatitis B immunoglobulin seem safe, but few trials reported adverse events. CONCLUSION: Hepatitis B vaccine, hepatitis B immunoglobulin, and vaccine plus immunoglobulin prevent hepatitis B occurrence in newborn infants of mothers positive for hepatitis B surface antigen.

Widespread dissemination in England of a stable and persistent hepatitis B virus variant.

BACKGROUND: Outbreaks of acute hepatitis B among inmates of 6 prisons in 3 regions of northern England occurring from 1992 through 1994 were found to be associated with a single hepatitis B virus (HBV) variant, which was carried by 20 of the 24 case patients. We instigated a study of cases of acute hepatitis B to trace the spread and prevalence of this variant. METHODS: A denaturing gradient gel electrophoresis assay was optimized to detect the HBV variant, and cases of acute HBV infection in 3 regions in England occurring from 1990 through 1996 were screened for its presence. Samples from HBV-transmission incidents that were received for molecular investigation were also tested. RESULTS: The variant was identified in 117 (41%) of the 266 cases of acute hepatitis examined in representative regions in England. In North Humberside, but not in southeast England or the West Midlands, a trend toward an increase in the prevalence of the variant was observed. Furthermore, the same variant was identified in the case patients or the individuals implicated in transmission in 11 (22%) of 51 transmission incidents occurring in England from 1997 through 2002. The spread of the variant was primarily associated with injection drug use. CONCLUSIONS: The finding of a single, genetically identical variant (over the 600 bp sequenced) occupying a large niche among the circulating viruses was unexpected. This finding has major implications for the use of DNA sequencing analysis in the investigation of chains of transmission. The study also highlights the need for better protection of at-risk groups through vaccination against HBV, a strategy that currently achieves poor coverage.

Long-term persistence of immunity to hepatitis B after vaccination during infancy in a country where endemicity is low.

BACKGROUND: The long-term response to hepatitis B vaccination during infancy has not been fully evaluated in countries where endemicity is low. METHODS: The present study was a serological investigation of immunity to hepatitis B during adolescence. In a cohort of children who were born to hepatitis B virus carrier mothers and who were vaccinated during infancy, evidence of past or current infection and the response to a single booster dose of vaccine were analyzed. Sixty-four children whose antibody levels were measured after immunization (group 1) and 52 younger siblings who did not undergo postvaccination antibody tests (group 2) were studied. RESULTS: One child in each group showed evidence of natural infection. In group 1, 32 children (50%) had undetectable antibody to hepatitis B surface antigen (anti-HBs), and only 8 (13%) had levels >100 mIU/mL. After a booster dose of vaccine, only 7 (11%) still had undetectable anti-HBs, 3 (5%) showed a primary response, and 50 (78%) had levels >100 mIU/mL. Five of the 7 vaccine nonresponders and all of the primary responders had also received hepatitis B-specific immunoglobulin (HBIG) at birth. The children in group 2 showed a similar response to the vaccine, but with slightly higher levels of anti-HBs. CONCLUSIONS: Most children vaccinated at birth retain immunological memory to hepatitis B vaccine for 15 years, but those who did not were more likely to have received HBIG at birth, suggesting that passive antibody may interfere with the induction of immunological memory.

Antenatal screening for HIV; are those who refuse testing at higher risk than those who accept testing?

BACKGROUND: The UK Department of Health recommends that all pregnant women are offered screening for infection with human immunodeficiency virus (HIV) and had encouraged maternity units to achieve uptake targets of 90 per cent by the end of 2002. Many maternity units fail to meet this target and there is concern that those women who are still refusing testing may include a higher proportion of women at high risk of infection. In consequence, those infected with HIV are not being identified and are not receiving the antiviral treatment, which would be of benefit to them and reduce the risk of transmission of HIV to their babies. METHODS: A retrospective audit of HIV screening uptake in women who were found to be infected with hepatitis B virus (HBV) and in those who were not infected with HBV was carried out in order to explore further the characteristics of 'acceptors' and 'refusers' of HIV screening. RESULTS: The overall uptake rate of HIV screening in the West Midlands population served by the National Blood Service was 60 per cent in 2001 and 74 per cent in 2002. The prevalence of HBV infection was found to be twice as high (0.39 per cent) in those who had refused an HIV test compared with those who had accepted a test (0.21 per cent) (p = 0.022). CONCLUSION: There is good evidence that women refusing HIV antenatal screening have a higher prevalence of another blood-borne virus, indicating clearly that further effort must be made to increase the screening uptake and fully integrate HIV screening with other antenatal tests.

Evaluation of a line probe assay for identification of hepatitis B virus precore variants in serum from chronic hepatitis B carriers.

A prototype line probe assay (LiPA) for identifying hepatitis B virus (HBV) precore variants (INNO-LiPA HBV precore) was evaluated using a panel of 50 sera from 46 patients with HBV infection. The assay detected sequence variations detected commonly in the precore promoter region and in amino acid codons 28 and 29 of the precore gene. There was strong agreement between INNO-LiPA HBV precore results and those of a codon 28 point mutation assay (PMA), with identical results obtained in 40 of 43 sera (93%) typeable by both assays (kappa coefficient (kappa)=0.90). In addition, the precore codon 29 sequence identified by the INNO-LiPA HBV precore was confirmed by nucleotide sequencing in all seven samples analysed. However, the INNO-LiPA HBV precore identified precore promoter sequences much less efficiently. The prototype assay could identify codon 28/29 sequences from as little as 10 HBV genome equivalents in 10 microl serum, and in experiments using artificially prepared mixtures of variants could identify a minor component constituting 2.5% of the total viral DNA population. The INNO-LiPA HBV precore was also straightforward technically and rapid, and is therefore likely to be useful for epidemiological investigations into the prevalence, distribution and clinical significance of HBV precore variants.

Evidence for a dynamic host-parasite relationship in e-negative hepatitis B carriers.

Anti-hepatitis Be (HBe) carriers are perceived as having low infectivity, with hepatitis B virus (HBV) DNA levels far below those seen in the HBeAg carrier. However, the temporal stability of HBV DNA in anti-HBe carriers remains poorly characterised. UK Department of Health guidelines use HBV DNA levels to define whether HBV-infected health care workers may perform exposure-prone procedures. Two samples separated by 1-23 years available from 147 carriers were analysed for precore variants and HBV DNA levels. Among 15 HBeAg carriers, HBV DNA was maintained at high levels. There was a 5 log(10) fold reduction in DNA in 11 individuals who developed anti-HBe during follow-up evaluation. Proportional changes in HBV DNA levels in anti-HBe carriers were similar to those in HBeAg carriers, although there was a trend for changes in viral DNA to be more marked in anti-HBe carriers followed up for longer periods. Closer sampling in 20 anti-HBe carriers demonstrated large fluctuations of DNA levels over short periods. Serum transaminases and precore mutant status at the outset failed to predict those in whom HBV DNA levels fluctuated. HBV DNA was below the detection threshold (<400 copies/ml) in 36 anti-HBe carriers at first sampling and remained so in all but 5 of these carriers. Twelve individuals who were previously viraemic lost detectable HBV DNA during follow-up evaluation. While HBV DNA levels are found to fluctuate in carriers, our results indicate that once below the threshold of detectability, levels are unlikely to rise. This is an important factor when assessing health care workers for exposure-prone procedures.