. A Randomized Clinical Trial of Immunization With Combined Hepatitis A and B Versus Hepatitis B Alone for Hepatitis B Seroprotection in Hemodialysis Patients Jennifer Tung et al. Preceptor-Dr.Wahid Speaker- Basavaraj.Utagi American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp

INTRODUCTION 350million people are chronically infected worldwide(WHO) with hepatitis B About 20 million new cases reported annually First large-scale outbreaks of Hepatitis B in dialysis centers in the 1970s The prevalence and incidence of the hepatitis B infections are very high about 7.6% and 3.2 % respectively among dialysis patients in India

INTRODUCTION(CONTD) CDC recomends immunisation of dialysis patients with Hepatitis B vaccine After a primary series of hepatitis B vaccination, 90%-95% of healthy immunocompetent adults develop protective anti–hepatitis B surface antigen(HBsAg) antibodies Protective antibody titer defined as  10 mIU/mL 1.MMWR Recomm Rep. 2001;50(RR-5):1-43.

INTRODUCTION(CONTD)  However, the efficacy of the vaccine in hemodialysis patients is much lower,with a median of 64% 1 (range, 34%-88%)  Various approaches to increase the immunogenicity vaccine  variations in dose and frequency  use of novel adjuvants  coadministration of immunomodulators (IL2,IFN,levamisole)  However all these approaches had varying results

Background Mean of anti-HBsAg titers at month 6, patients receiving the combined Hepatitis A and Hepatitis B vaccine showed a statistically significant higher response than with monovalent vaccines in healthy adults Ambrosch et al. J Med Virol. 1994;44(4):

Background Combined vaccination of hepB and hep A improves immunogenicity to hepatitis B in healthy individuals Knoll A et al.Vaccine. 2000;18(19): Czeschinski PA et al. Vaccine. 2000;18(11-12):

Need for this Study? Effect of combined vaccination on anti-HBsAg antibody response in hemodialysis patients is unknown

Methods  Randomized controlled trial in outpatient hemodialysis patients St. Joseph’s Healthcare  Inclusion criteria  Receiving hemodialysis treatment  18 years or older  Undetectable antibody to HBsAg  Able and willing to give informed consent

Methods(contd..)  Exclusion criteria  Presence of HBsAg and antibody to hepatitis B core antigen  Treatment with intravenous immune globulin within the last 6 months  Hypersensitivity to components of either vaccine  Contraindication to intramuscular injections  Patients were not excluded based on pre-existing antibodies to hepatitis A

Methods(contd..) Patients were randomly assigned starting in February 2005 Vaccination began in March 2005, and the vaccination schedules were completed by November 2005 Ethics approval was obtained from the St. Joseph’s Healthcare Research Ethics Board

Study Design  Patients were given 4 doses at 0, 1, 2, and 6 months according to the vaccine schedule  Randomly assigned to receive one of the following regimens  Engerix-B, 20 mcg (1 mL), and Twinrix (720 ELISA units of inactivated hepatitis A virus and 20 mcg of recombinant HBsAg protein) at 0, 1, and 6 months plus Engerix-B, 40 mcg,at month 2 or  Engerix-B, 40 mcg (2 mL), at 0, 1, 2, and 6 months

 Both groups received a total dose of 160 mcg of hepatitis B vaccine  The route of administration was intramuscular injection

Methods(contd..) The primary outcome was the difference in proportion of patients achieving seroprotection against hepatitis B virus between the 2 arms Seroprotection defined as an anti-HBsAg antibody titer  10 mIU/mL at month 7 The secondary end point was the frequency of adverse events associated with vaccine administration

Methods(contd..) Blood samples were drawn at baseline and months 3 and 7 to determine antibodies to HBsAg Neither patients nor clinical study personnel were blinded with respect to the vaccine administered The laboratory personnel performing tests for antibody levels and the independent statistician assessing clinical outcomes were blinded

Adverse events were recorded after each dose Patients were interviewed to obtain ratings for pain and swelling, which were evaluated using a visual analogue scale Temperatures were measured 1 hour after vaccination and on days 2and 4

Engerix 40 Engerix 20+Twintrix 96 patients randomised Month 3 blood work Engerix 40 Engerix 20+Twintrix Month 7 blood work Engerix 40 Engerix 20+Twintrix TwintrixEngerix Month 0 Month 1 Month 2 Month 6 Month 7

Statistical Analysis Descriptive statistics are expressed in terms of mean standard deviation for continuous variables and percentages for categorical variables Standard statistical tests for comparing mean values, unpaired t test, and unpaired proportion tests were used to assess treatment differences

RESULTS

Results Overall,mean age was 67 years (range, years), and 63% were men Duration of dialysis therapy ranged from 10 days to 9 years, with a mean of 3 years At Month-3 there was no statistically significant difference in seroprotection rates for hepatitis B between the 2 groups(25% vs 27%) (P =0.4)

Results At Month-7 there was a statistically significant difference in anti- HBsAg antibody response between the groups using either per- protocol or ITT analyses At month 7, using per-protocol analysis, 68% and 49% of patients had experienced seroconversion in the treatment and control groups, respectively(P 0.05; RR, 1.4; absolute abatement, 19%). Using ITT analysis, 58% and 38% of patients had experienced seroconversion in the treatment and control groups, respectively(P 0.02; RR, 1.5; absolute abatement,20%).

Results There were no significant differences between groups in adverse events(pain scores or swelling scores)

DISCUSSION The study’s main outcome,hepatitis B seroconversion at 7 months,showed a statistically significant and clinically important improvement in the combined-vaccination arm In comparison to healthy persons, who have a reported 89% seroprotection rate at month 3 and 90%-95% at month 7 with standard dosing, seroprotection rates in this study population were much lower

The seroprotection rate in control group also was lower compared with previous studies of hemodialysis patients, in which median seroprotection rates of 64%-86% were reported

Limitations Small sample size Study had a power of 80% The short study period The duration of a patient’s seroprotection status couldn’t be assessed The need for future booster shots or revaccination couldnot de determined

Mean age of patients was 67yrs,so efficacy of vaccine in young dialysis patients could not be assessed Study was done in mainly western population

Conclusion Vaccination of hemodialysis patients with a combined hepatitis A and hepatitis B regimen may be more effective than hepatitis B monovalent vaccine in providing seroprotection against hepatitis B virus

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