.

A Randomized Clinical Trial of Immunization With Combined Hepatitis A and B Versus Hepatitis B Alone for

Hepatitis B Seroprotection inHemodialysis Patients

Jennifer Tung et al.

Preceptor-Dr.WahidSpeaker- Basavaraj.Utagi

American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp 713-719

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):452-456.

Background

Combined vaccination of hepB and hep A improves

immunogenicity to hepatitis B in healthy individuals

Knoll A et al.Vaccine. 2000;18(19):2029-2032.

Czeschinski PA et al. Vaccine. 2000;18(11-12):1074-1080

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 injectionsPatients 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 40Engerix

20+Twintrix

96 patients randomised

Month 3 blood work

Month 3 blood work

Engerix 40Engerix 40

Engerix 40Engerix

20+Twintrix

Month 7 blood work

Month 7 blood work

Engerix 40

Engerix 20+Twintri

x

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, 34-91 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

THANK YOUThank you