Double-dose hepatitis B vaccination in cirrhotic patients on a liver transplant waiting list

ORIGINAL PAPERS

Double-dose hepatitis B vaccination in cirrhotic patients on a liver transplant waiting list

Patricia R. Bonazzi^{I, II}; Telesforo Bacchella^I; Angela C. Freitas^II; Karina T. Osaki^I; Marta H. Lopes^II; Maristela P. Freire^I; Marcel C.C. Machado^I; Edson Abdala^{I, II}

^ILiver Transplantation Division, Department of Gastroenterology

^IIDepartment of Infectious Diseases – Clinical Hospital University of São Paulo Medical School; São Paulo, SP, Brazil

^{Address for correspondence}

ABSTRACT

Development of immunity to hepatitis B virus in cirrhotic patients waiting for liver transplantation is highly desirable. Though a double-dose regimen is available, little is know about its effectiveness. We examined the efficacy of double-dose hepatitis B virus vaccination in cirrhotic patients waiting for liver transplantation. We studied 43 patients who were waiting for liver transplantation. They were vaccinated with three doses of 40 mg hepatitis B vaccine at 0, 1 and 6 months; the normal dose is 20 mg. Efficacy was measured based on seroconversion of anti-HBs. Global response to the primary vaccination scheme was 67.5% (29 patients). Forty-one per cent of responders had anti-HBs titers above 1,000 IU/mL. No factors were associated with response, based on multivariate analysis. The vaccination scheme of 40 mg at 0, 1 and 6 months was superior to conventional vaccination doses (20 mg) for cirrhotic patients on a waiting list for liver transplantation.

Key-Words: Vaccine, cirrhotic, hepatitis B, liver transplant.

Hepatitis B virus (HBV) is transmitted through sexual and parenteral routes, including blood transfusion and organ donation [1,2]. Cirrhotic patients and those submitted to transplant procedures are potentially exposed to these risk factors [3], and infection may lead to hepatic decompensation [4-6] or shorter graft survival [2]. In order to reduce this risk, it is desirable to induce immunity to HBV in this type of patient.

The conventional vaccination scheme consists of three doses of recombinant vaccine against HBV (20 µg), applied at 0, 1 and 6 months, which gives immunity in 95% of the general population [1,5]. However, these high rates are not seen in HIV-infected patients [7], in patients undergoing dialysis [6,8,9], or in cirrhotic patients [2,4,6]. A double-dose regimen (40 µg) has been used in HIV-infected patients and hemodialysis patients, giving an improved response [6,7]. This higher dose was subsequently test on other groups of immunocompromised patients [10]; we adopted the double-dose regimen for cirrhotic patients on a waiting list for liver transplantation.

We examined the efficacy of double-dose hepatitis B vaccination in cirrhotic patients waiting for liver transplantation and evaluated factors associated with seroconversion.

Material and Methods

Two hundred and eight patients waiting for liver transplantation at the Clinical Hospital of the University of São Paulo Medical School were retrospectively evaluated. The following inclusion criteria were required: cirrhotic patient more than 18 years old; the HBV vaccine was given from January 2003 to August 2004; the vaccination scheme had been completed and a anti-HBs level measurement was made between one and two months after vaccination. The exclusion criteria were: HIV patients, dialysis patients and patients with any serological marker of previous hepatitis B infection.

The HBV vaccine consisted of three 40 µg doses, applied into the deltoid muscle, at 0, 1 and 6 months. Efficacy was measured by the seroconversion of anti-HBs (negative to positive). Anti-HBs levels were analyzed by ELISA one to two months after the last vaccine dose. The titers above 10IU/mL were considered positive.

The following factors were analyzed as variables for vaccine response: age, gender, Child-Turcotte-Pugh classification [11], MELD (Model for End Stage Liver Disease) classification [12] and etiology of hepatic disease at first vaccination dose. The data was analyzed using the EpiInfo 3.3.2 computer program. Univariate analysis was made by χ² test or Fischer's exact test. Multivariate analysis was made by stepwise logistic regression. Independent variables were introduced, depending on p values. The significance level adopted was 0.05.

Results

Forty-eight patients were selected based on the inclusion and exclusion criteria. Five of them had incomplete information and were excluded afterwards. Among these 43 patients, 24 were female (56%). Age varied between 22 and 63 years (mean of 44.2 years). Predominant etiologies were hepatitis C virus (35%), alcohol use (12%) and autoimmune hepatitis (19%). Child-Turcotte-Pugh score varied from A5 to C11; most were classified as Child B (58%).

Global response to the primary vaccination scheme was 67.5% (29 patients, Table 1). Forty-one per cent of responders had anti-HBs titers above 1000 IU/mL, 35% between 100 and 1,000 IU/mL and 24% between 10 and 100 IU/mL. Three of 14 non-responders were submitted to a new vaccination scheme of three more double doses of 40 µg (0, 1 and 6 months); anti-HBs levels rose to above 10 IU/mL one month after the sixth dose.

Based on univariate analysis, Child-Turcotte-Pugh C patients had better seroconversion rates (p=0.03; CI=1.2 to 185, Table 1). When we used multivariate analysis, no significant differences were identified.

Discussion

Recombinant vaccine against HBV is responsible for a reduction in rates of chronic hepatic disease and hepatocellular carcinoma secondary to HBV [1]. The conventional dose regimen recommended for immunocompetent adults is 20 µg at 0, 1 and 6 months, resulting in approximately 95% of seroconversion rates [1,5]. Factors such as male gender, tobacco use, age (more than 40 years old), place of vaccine application and obesity are associated with lower vaccine response rates [2,4,8]. Low response rates are also found in immunocompromised patients. Improved seroconversion rates were obtained when double-doses (40 µg) were administered to patients under hemodialysis [6] and to HIV-infected patients with T-CD4 lymphocyte counts above 350 cells/mm³ [7], using the same application intervals of 0, 1 and 6 months.

Cirrhotic patients waiting for liver transplants are particularly exposed to contamination risk [2]. Vaccine efficacy in this population is not as high as in immunocompetent individuals. Some studies show rates of seroconversion varying from 16% [13] to 70% [14]; in the face of these results, we examined the efficacy of vaccination with higher doses (Table 2).

A controlled randomized trial was conducted using a double-dose regimen of vaccine (40 µg) at 0, 1 and 6 months in a group of alcohol-abuse patients, some of whom had hepatic disease; improved results were obtained with this higher dose. However, no consistent conclusion was obtained due to the reduced number of cirrhotic patients in this study [10]. There have been few studies comparing doses of 20 and 40 µg in cirrhotic patients. Engler et al. compared 20 and 40 µg, but used application intervals of 0, 7 and 21 days; they found no difference between the treatment groups [2]. Accelerated vaccination schemes, reducing the application interval to 0, 7 and 21 days or 0, 1 and 2 months have been used in countries where the waiting time for an organ is less than six months. However, seroconversion was not satisfactory [2,4,6,15,16].

Using doses of 40 µg at 0, 1 and 6 months, we obtained 67.5% seroconversion, which is above what is generally observed in studies with this type of patient. Mattos et al. [14] obtained 70% response with a conventional scheme, but they only included patients with Child-Tuscotte-Pugh A classification. Our elevated response rates could be explained by the dose and scheme utilized; however, ours was a young cohort, which is associated with improved responses, and there were few cases of alcohol etiology, which otherwise negatively affects response [2,8,10].

Based on univariate analysis, we found better response to vaccine in Child-Turcotte-Pugh C patients, different from published reports [4,8]. However, this conclusion was not confirmed by multivariate analysis.

Our study had some limitations, including a retrospective design, a relatively small number of patients and absence of a control group. However, the high seroconversion rates lead us to suggest that a prospective evaluation would be worthwhile, including testing of shorter schemes.

We conclude that the a double dose of 40 µg HBV vaccine at 0, 1 and 6 months is superior to a conventional 20 µg dose at the same intervals, for cirrhotic patients on waiting lists for liver transplants; however, controlled and comparative studies using 20 versus 40 µg are needed before such a treatment scheme can be recommended.

Acknowledgments

We thank Aurea Aparecida Silva Garibaldi for reviewing this manuscript.

Received on 20 March 2008; revised 3 August 2008.

• 1. Poland G.A., Jacobson R.M. Prevention of hepatitis B with the hepatitis B vaccine. N Engl J Med 2004;351:2832-8.
• 2. Engler S.H., Sauer P.W., Golling M., et al. Immunogenicity of two accelerated hepatitis B vaccination protocols in liver transplant candidates. Eur J Hepato 2001;13:363-7.
• 3. Horlander J.C., Boyle N., Manam R., et al. Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation. Am J Med Sci 1999;318:304-7.
• 4. De Maria, Idilman, Calantoni, Van Thiel. Increased effective immunogenicity to high-dose and short-interval hepatitis B virus vaccination in individuals with chronic hepatitis without cirrhosis. Journal of Viral Hepatitis 2001;8:372-6.
• 5. Arguedas M.R., McGuire B.M., Fallon M.B. Implementation of vaccination in patients with cirrhosis. Dig Dis Sci 2002;47:384-7.
• 6. Idilman R, Colantoni A, De Maria N et al. Impaired antibody response rates after high dose short interval hepatitis B virus vaccination of immunosuppressed individuals. Hepatogastroenterol 2003;50:217-21.
• 7. Fonseca M.O., Pang L.W., de Paula Cavalheiro N., et al. Randomized trial of recombinant hepatitis B vaccine in HIV infected adult patients comparing a standard dose to a double dose. Vaccine 2005;23:2902-8.
• 8. Castells L., Esteban R. Hepatitis B vaccination in liver transplant candidates. Eur J Hepato 2001;13:359-61.
• 9. Leroy V., Bourliere M., Durand M., et al. The antibody response to hepatitis B virus vaccination is negatively influenced by the hepatitis C virus viral load in patients with chronic hepatitis C: a case-control study. Eur J Gastroenterol Hepatol 2002;14:485-9.
• 10. Rosman A.S., Basu P., Galvin K., Lieber C.S. Efficacy of a high and accelerated dose of hepatitis B vaccine in alcoholic patients: a randomized clinical trial. Am J Med 1997;103:217-22.
• 11. Pugh R.N.H., Murray-Lyon I.M., Dawson J.L., et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9.
• 12. Kamath O.S., Wiesner R.H., Malinchoc M., et al. A model predict survivalin patients with end-stage liver disease. Hepatology 2001;33:464-70.
• 13. Chalasani N., Smallwood G., Halcomb H.J., et al. Is vaccination against hepatitis B infection indicated in patients waiting for or after orthotopic liver transplantation? Liver Transplant Surg 1998;4:128-32.
• 14. Mattos A.A., Gomes E.B., Tovo C.V., et al. Hepatitis B vaccine efficacy in patients with chronic liver disease by hepatitis C virus. Gastroenterol 2004;41:180-4.
• 15. Kallinowski B., Benz C., Buchholz L., Stremmel W. Accelerated schedule of hepatitis B vaccination in liver transplant candidates. Transplant Proc 1998;30:797-9.
• 16. Idilman R., De Maria N., Colantoni A., et al. The effect of high dose and short interval HBV vaccination in individuals with chronic hepatitis C. Am J Gastroenterol 2002;97:435-9.
• 17. Domínguez M., Bárcena R., García M., et al. Vaccination against hepatitis B vírus in cirrhotic patients on liver transplant waiting list. Liver Transpl 2000;6:440-2.
• 18. Macedo G., Maia J.C., Gomes A., et al. Efficacy of a reinforced protocol of HBV vaccination in cirrhotic patients waiting for orthotopic liver transplantation. Transplant Proc 2000;32:2641.

Publication Dates

• Publication in this collection
  13 Nov 2008
• Date of issue
  Aug 2008

History

• Reviewed
  03 Aug 2008
• Received
  20 Apr 2008