From 1982 to 1989, 705 infants born to HBsAg-positive mothers entered the Dutch neonatal hepatitis B vaccination program and received passive-active hepatitis B immunization in three randomized controlled trials testing variations in time of starting active vaccination, dose and type of vaccine, and number of hepatitis B immunoglobulin (HBIg) injections. A meta-analysis of individual patient data of the three randomized trials was performed to determine which independent host and vaccination related factors influence protective efficacy and long-term immunogenicity, and to assess whether hepatitis B vaccination concomitant with standard DKTP vaccination provides optimal protection. Statistical methodology included multivariate logistic regression analysis. Eight infants (1.1%), all born to HBeAg-positive mothers, became HBsAg carriers within the first year of life. The protective efficacy rate (PER) of passive-active immunization at 12 months follow-up was 92% for the total group of children from 114 HBeAg-positive mothers with no significant differences between children starting active immunization at birth or at 3 months of age, between infants starting at 3 months of age receiving one or two doses of HBIg or between those receiving plasma derived or recombinant vaccine. The only factor that affected the PER significantly was the level of maternal HBV DNA; PER was 100% if maternal HBV DNA was < 150 pg ml-1 and 68% for HBV DNA levels > 150 pg ml-1. After 5 years of follow-up, the group that started active immunization at birth had significantly more infants with loss of seroprotection (anti-HBs levels < 10 IU l-1, 15%) than the corresponding group starting at 3 months of age (anti-HBs < 10 IU l-2, 2%). One of 35 children with loss of seroprotection at 2 years became a HBsAg carrier in the fifth year of follow-up. This meta-analysis shows that the protective efficacy of passive-active hepatitis B vaccination is mainly influenced by material HBV DNA levels, and independent of the time of starting active vaccination at birth or at 3 months of age; long-term immunity was enhanced by starting active vaccination concomitant with DKTP vaccination. These findings allow incorporation of hepatitis B vaccine into the standard infant immunization programs for countries with a passive-active immunization strategy for the control of hepatitis B. Additional measures are needed to protect neonates of highly viremic women.

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Interferon alfa (IFN-␣) is the primary treatment for chronic hepatitis B. The standard duration of IFN-␣ therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-␣ treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in which all patients were treated with a standard regimen of 10 million units IFN-␣ 3 times per week over 16 weeks. Patients who were still HBeAgpositive after 16 weeks of therapy were randomized to prolongation of the identical regimen up to 32 weeks (prolonged therapy) or discontinuation of treatment (standard therapy). Among the 162 patients who entered the study, 27 (17%) were HBeAg-negative after the first 16 weeks of treatment, and 118 were randomized to standard or prolonged therapy. After randomization, a response Worldwide, chronic hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma. Clearance of hepatitis B e antigen (HBeAg) indicates transition to a state of low-level viral replication that is accompanied by biochemical remission of liver disease and prolonged survival. 1-3 Interferon alfa (IFN-␣) has emerged as one of the most effective treatments for chronic hepatitis B, inducing HBeAg seroconversion in about one third of the patients. 4,5 Many attempts to enhance this response rate have been unsuccessful. Treatment with nucleoside analogues, such as lamivudine, or combination of these agents with IFN-␣, does not yet appear to significantly increase the HBeAg seroconversion rate, 6-8 whereas the use of priming therapy with prednisone has not been generally accepted as a result of a lack of consistent results and the risk of hepatic decompensation. 4,9 How long we should treat chronic HBV patients with IFN-␣ is still not established. The standard duration of treatment is considered 16 weeks. In several studies, IFN-␣ was given for a longer period, and some suggest additional benefit of prolonged therapy. 10,11 However, these studies contain a small number of patients, show considerable heterogeneity in patient population and response rates, and the results should therefore be interpreted with caution. In an uncontrolled pilot study, we successfully prolonged IFN-␣ treatment in those patients who approximated HBeAg seroconversion, as demonstrated by a continuous decrease of quantified serum HBV-DNA and HBeAg values, at the end of standard IFN-␣ therapy. 12 Therefore, we initiated a large, prospective, randomized, controlled trial investigating the efficacy of treatment prolongation with an additional 16 weeks in those patients who did not respond with HBeAg seroconversion during a standard 16-week IFN-␣ course. PATIENTS AND METHODSPatients. One hundred sixty-two patients from 16 European hepatologic centers (EUROHEP) 13 were enrolled after central evaluation of their eligibility. Th...

The inhibitory effects of the 9-(2-phosphonylmethoxyethyl)adenine-related compounds (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine, (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine, (R)-9-(2-phosphonylmethoxypropyl)adenine, (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine, and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine on human hepatitis B virus replication in the human hepatoma cell line HepG2 2.2.15 and duck hepatitis B virus infection in primary duck hepatocytes were investigated. (R)-9-(2-phosphonylmethoxypropyl-2,6-diaminopurine had the lowest 50%o inhibitory concentrations against hepatitis B virus and duck hepatitis B virus, 0.22 and 0.06 ,iM, respectively, i.e., two-to fivefold lower concentrations than required for (R)-9-(2-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxyethyl)adenine. All compounds were not toxic in vitro at a concentration of 100 ,uM.In chronic hepatitis B virus (HBV) infection the basic therapy is the administration of interferon, although complete disappearance of virus markers is seldom observed. Hepatitis B e antigen seroconversion, reflecting a drastic decline of viral replication, is seen in only 20 to 40% of patients with HBV infections.More potent antiviral drugs are eagerly awaited, and in light of this, the acyclic nucleoside phosphonates described earlier (3, 4) were considered adequate candidates to be further pursued for the treatment of HBV infections.In an earlier study (6) we investigated the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in two hepatoma cell lines and primary duck hepatocytes. The 50% inhibitory concentrations (IC50) for human HBV and duck HBV (DHBV) were found to be 1.2 and 0.2 ,uM as measured in HepG2 2.2.15 cells and primary duck hepatocytes, respectively.Among the acyclic nucleoside phosphonates several other derivatives were found to have high anti-DNA virus activity (herpes group) or antiretrovirus (human immunodeficiency virus [HIV] and Moloney murine sarcoma virus) activity (1). The most effective HIV inhibitors among the acyclic nucleoside phosphonates were evaluated for their anti-HBV activities in the human hepatoma cell line HepG2 2.2.15. Two of the compounds, candidates for application with humans, were also assayed in primary duck hepatocytes infected with DHBV, in anticipation of studies with chronically DHBV-infected ducklings and chronic hepatitis B patients.PMEA, (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine [(S)-FPMPA], (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine [(R)-PMPDAP], (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (R)-9-(2-phosphonylmethoxypropyl)adenine [(R)-PMPA], and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine were synthesized by

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