Vertical transmission of hepatitis B virus (HBV) can occur occasionally despite vaccination of the child. This vaccination breakthrough has been associated with high maternal viraemia. We treated eight highly viraemic (HBV-DNA >/= 1.2 x 10(9) geq/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. HBV-DNA, hepatitis B surface antigen (HBsAg), anti-HBs and anti-HBc of their offspring were measured at birth and at 3, 6 and 12 months, respectively. Twenty-four children, born to untreated HBsAg-positive mothers with HBV-DNA levels >/=1.2 x 10(9) geq/mL served as historical controls. All children received passive-active immunization at birth and were followed-up for 12 months. In the lamivudine group one of the eight children (12.5%) was still HBsAg and HBV-DNA positive at the age of 12 months. All other children seroconverted to anti-HBs and maintained seroprotection. In three children, HBV-DNA was temporarily detected by polymerase chain reaction. In the untreated historical control group, perinatal transmission occurred in seven of 25 children (28%). In highly viraemic HBsAg-positive mothers, reduction of viraemia by lamivudine therapy in the last month of pregnancy may be an effective and safe measure to reduce the risk of child vaccination breakthrough. This approach should be evaluated in a large controlled trial.

Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

Background and aims: Interferon (IFN) induced hepatitis B e antigen (HBeAg) seroconversion is durable in 80-90% of chronic hepatitis B patients. Preliminary reports on the durability of HBeAg seroconversion following lamivudine are contradictory. We investigated the durability of response following IFN, lamivudine, or IFN-lamivudine combination therapy in a meta-analysis of individual patient data. Patients and methods: Twenty four centres included 130 patients in total with an HBeAg seroconversion (HBeAg negative, antibodies to hepatitis B e antigen positive) at the end of antiviral therapy: 59 with lamivudine, 49 with interferon, and 22 with combination therapy. Relapse was defined as confirmed reappearance of HBeAg. Results: The three year cumulative HBeAg relapse rate by the Kaplan-Meier method was 54% for lamivudine, 32% for IFN, and 23% for combination therapy (p=0.01). Cox regression analysis identified pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and therapy as independent predictive factors of post-treatment relapse; Asian race, previous therapy, centre, and type of study were not predictive of relapse. The relative HBeAg relapse risk of lamivudine compared with IFN therapy was 4.6 and that of combination therapy to IFN therapy 0.7 (p overall =0.01). Conclusions: The durability of HBeAg seroconversion following lamivudine treatment was significantly lower than that following IFN or IFN-lamivudine combination therapy. The risk of relapse after HBeAg seroconversion was also related to pretreatment levels of serum ALT and HBV DNA, but independent of Asian race.

Currently, the best option for patients with hepatitis delta is interferon alpha therapy for at least one year. To evaluate the effect of the combination lamivudine-high-dose interferon alpha therapy, we first treated eight patients with chronic hepatitis delta infection with lamivudine for at least 24 weeks; then lamivudine was combined with a high dose of interferon alpha followed by a regular dose (9 MU tiw). Follow-up was 12 weeks. Virological, biochemical and histological features were evaluated for response to therapy. At baseline, all patients were HBsAg positive in serum and HDV RNA-(PCR)positive in plasma; HBV DNA was undetectable with the Digene Hybrid Capture assay (limit of detection 1.5 x 10(6) geq ml-(1)) in all cases. Transaminases were elevated in all patients; median ALT 68 (range 48-143) IU l(1). Seven of eight patients completed the course; one patient with a pre-existing sickle cell trait was withdrawn from the trial due to the development of a nephrotic syndrome. The HBsAg-concentration in serum decreased in two out of seven patients (29%). However, there was no significant decrease in the HBsAg-concentration in serum during treatment (median 3654 PEU l(-1) (range 548-7,684) to 5300 PEU l(-1) (range 168-19,639)). The drop of HDV RNA in plasma from baseline during treatment was not significant. Decrease of HDV RNA was observed in three out of seven patients (43%) (median 10(5) geq ml(-1); range 10(3)-10(6) to median 10(3) geq ml(-1); range 10(2)-10(7)). Serum ALT did not change as reflected by a median of 68 IU l(-1) (range 48-143) at start of therapy to 63 IU l(-1) (range 20-171) at the end of therapy. At the end of treatment transaminases had normalised in one patient and decreased in three other patients (improvement in 57%). However, three of these four patients showed a rebound after withdrawal of therapy. The Histology Activity Index (HAI) indicated a drop from a median score of 7 (range 5-9) at baseline to 5 (range 3-8) at the end of treatment, but an increase in fibrosis from a median grade of 2 (range 1-3) at baseline to 3 (range 1-4) at the end of treatment was observed. In conclusion, this study does not yield support for the combination of an HBV suppressor and 16 weeks of high-dose interferon for therapy aimed at eradicating the hepatitis delta virus.

In view of the limited efficacy of lamivudine monotherapy for chronic hepatitis B (HBV) infection, combination with other drugs seems logical. Intravenous neutralization of circulating HBsAg by specific hepatitis B immunoglobulin (HBIg) has been shown to protect hepatocytes against (re-)infection with HBV in the setting of liver transplantation and postexposure prophylaxis. Large controlled vaccination trials have revealed that HBV can be prevented by HBIg therapy in the majority of newborns after perinatal infection. A benefit of anti-HBs in HBV patients has so far only been investigated in three small studies. In this pilot study we investigated the effects of polyclonal i.v. HBIg (HepatectR, Biotest) administration in HBV-infected patients. Six liver biopsy-proven HBV-infected patients, all on lamivudine treatment and HBV DNA negative by PCR, were investigated. Pre-treatment HBsAg levels varied between 120 and 9760 ng/mL. On day 1, 10.000 IU HBIg was given, followed by 10.000 IU once, twice or three times on day 29. Long-term follow-up lasted at least 4 months. HBsAg and anti-HBs were measured quantitatively by standard MEIA and also by an experimental EIA. In vitro neutralization of HBsAg by Hepatect was mimicked in an 'inhibition in solution assay'. Complete neutralization of HBsAg by HBIg in vitro was possible, 50% inhibition concentrations varied between 100 and 250 IU/L HBIg with HBsAg levels of 68 and 120 ng/mL. No HBIg-related side-effects were observed. In two patients with low pretreatment HBsAg levels HBsAg reached levels below the detection limit of the assay, which persisted a maximum of 31 and 7.5 h, respectively. Peak anti-HBs concentrations were 5100 and 4648 IU/L. In the other four patients, with higher pretreatment HBsAg levels, HBsAg concentrations in serum hardly changed. For the whole population, the drop in HBsAg did not reach statistical significance. However, in four of the six patients a further decrease in HBsAg [18%-66%] was observed. In conclusion, HBIg was well tolerated; however, efficacy was limited due to high HBsAg levels in spite of maximum inhibition of virion production. 'Neutralization' was achieved only in two patients with low HBsAg levels. Passive immunization in HBV-DNA negative patients is not a feasible option. This strategy seems only feasible if agents inhibiting both the production of viral proteins and Dane particles more selectively, become available.