Hepatitis B is a serious infectious disease causing substantial morbidity and mortality worldwide. It is estimated that more than two billion people have evidence of previous hepatitis B infection, resulting in more than 350 million individuals with chronic hepatitis B virus (HBV) infection. In turn, this leads to an estimated one million deaths each year due to chronic end-stage liver disease and hepatocellular carcinoma. Liver transplantation is effective therapy for fulminant hepatitis B or chronic hepatitis B with decompensation and/or hepatocellular carcinoma. From 1987-2002, 3,403 liver transplants were performed in the United States for adults with liver disease due to hepatitis B.1
Patients undergoing transplantation for hepatitis B have a high risk of recurrence without effective adjuvant therapy. Many centers use both hepatitis B immune globulin (HBIG) and antiviral agents to prevent recurrence. HBIG is expensive, and stimulation of the patient's own immune system with hepatitis B vaccine has been attempted to eliminate the need for additional therapy after liver transplantation. Multiple trials of hepatitis B vaccination after transplantation for hepatitis B have recently been reported.2–6 Interpretation and comparison of the numerous studies available is complicated by different methodologies and end points. Anti-HBs levels ranging from >10 IU/L to >500 IU/L have been used to define response in the posttransplant setting. In addition, these studies have differed with regard to vaccine antigens, vaccination schedules and routes of administration, and approaches to the use of antivirals and HBIG. Overall, an anti-HBs level >500 IU/L, without the use of hepatitis B immune globulin, was achieved in 5.9-80% of treated patients in these studies, emphasizing the certainty that other variables are involved.
The highest response rates were reported by Bienzle et al., who studied 20 patients who were HBeAg and HBV DNA negative prior to transplantation, were on stable doses of HBIG, and received hepatitis B vaccine combined with the novel adjuvant system composed of 3-deacylated monophosphoryl lipid A and Quillaja saponaria Molina, a purified natural saponin molecule in an oil/water emulsion.2 Patients received from 2-8 vaccinations. Four patients also received antiviral therapy, three with lamivudine and one with famciclovir. Eighty percent of patients achieved anti-HBs levels >500 IU/L and were free of HBIG use after being followed for 10-27 months.
In this issue, Starkel et al. present the results of a small, nonrandomized clinical study of a new hepatitis B vaccine adjuvanted by monophosphoryl lipid A. Fifteen adult patients stable for at least three years after liver transplantation were studied. Ten subjects were transplanted for HBV-related disease (mean age 49 years), and 5 subjects were transplanted for liver disease of nonviral etiology (mean age 65 years). Two of the hepatitis B patients were transplanted for fulminant hepatic failure. Of the 8 chronic HBV subjects in the study, all were negative for HBV DNA by bDNA assay prior to transplantation. Six of 8 were infected with an HBV precore mutant prior to liver transplantation, and two subjects had been infected with wild-type HBV. It is not clear if any of the patients had received antiviral therapy prior to or after transplantation. All subjects were receiving low-level immunosuppression (tacrolimus or cyclosporine) and HBIG prophylaxis (5,000 IU every 6 weeks intravenously). No subjects had concomitant viral infection (human immunodeficiency virus [HIV], hepatitis C virus [HCV], hepatitis D virus [HDV]), and all were seronegative for HBsAg and HBV-DNA at study entry.
The vaccine used in this study was recombinant purified HBsAg (20 mcg/0.5 mL) formulated with sucrose and adjuvanted with MPL. The vaccine was administered as double doses (i.e., two 20 mcg doses) intramuscularly in the deltoid on a schedule of 0, 4, and 8 weeks (primary schedule) followed by a booster schedule at 26 and 52 weeks. HBIG prophylaxis was continued during the primary immunization schedule if anti-HBs titers dropped below 150 IU/L. Vaccine response was predefined as anti-HBs antibody levels >500 IU/L persisting for ≥12 months after primary immunization and where HBIG prophylaxis was stopped.
Other than self-resolving local inflammatory effects (redness, pain, swelling at site of injection) and transient low-level transaminase elevations (<2-fold), no serious adverse events were identified. No evidence of transplant rejection occurred, and no breakthrough HBV (detectable HBsAg or HBV-DNA) was observed. Fifty-three percent (8/15) of subjects developed anti-HBs antibody levels >500 IU/L. Both subjects transplanted for fulminant HBV responded to the vaccine. Only two of the 8 subjects transplanted for chronic HBV responded. Reasons for the lower response rates in this study compared with that of Bienzle et al. are not clear but may be due to differences in patient population, vaccine, or vaccine schedule. Among the non-HBV subjects, 80% (4/5) responded to the vaccine. This number is encouraging compared with the response rates of 20-40% reported in other studies for non-HBV patients vaccinated after liver transplantation.
Several caveats are appropriate in considering the results of this study. First, it must be acknowledged that this was a small, nonrandomized clinical trial from which definitive conclusions cannot be established. Vaccine lot numbers were not reported and hence comparison across vaccine lots is not possible for this vaccine.7 In addition, the needle length used to administer vaccine was not reported, and short needles adversely influence antibody response.8 Notably, study subjects were all nonsmokers, and all were clinically stable on low doses of immunosuppressives for at least three years after transplantation. Whether and how well this vaccine would work in the acute posttransplant setting is speculative, and no data are available. Despite these caveats, the data from this article add to the available information that a proportion of stable posttransplant patients can benefit from hepatitis B immunization, preventing HBV recurrence and reducing or eliminating the need for regular (and expensive) HBIG infusions. Further studies of this vaccine, involving larger numbers of study subjects across the spectrum of relevant clinical variables and at varying vaccine doses and dose schedules, are urgently needed.
Although the outcome of liver transplantation for hepatitis B has improved in the United States,1 the care of the post-liver transplant patient requires more immunogenic vaccines. Hepatitis B vaccine nonresponse can be due to a variety of factors including administration into the buttock,9–12 male gender,10–12 cigarette smoking, obesity,13 increasing age, certain human leukocyte antigen (HLA) haplotypes,14 and immunocompromised conditions.15, 16 These factors are important concomitant issues for the post-solid organ transplant patient, where age, body mass index, smoking, and immunosuppressive medications all conspire to prevent seroconversion in response to HBV vaccines.
For the 6,000 persons who receive liver transplants annually, we must continue to advance the science by developing even more immunogenic vaccines and immunization regimens. Although progress is being made in devising newer vaccines,17, 18 more funding and more research into novel vaccines and vaccine adjuvants will be essential in achieving the desired clinical goals. In particular, the current study by Starkel et al., as well as that by Bienzle et al., suggests that hepatitis B vaccination can be successfully achieved and suggests an opportunity to increase the immunogenicity of hepatitis B vaccines by the addition of MPL and/or QS21 adjuvants and an increased dose of HBsAg to the vaccine.2 Finally, it should be emphasized that the most compelling argument is that delivery of hepatitis B vaccine prior to exposure to the virus is the most effective strategy of all.