Safety and efficacy of hepatitis A vaccine in children with chronic liver disease

Abstract

AIM: To study the safety and efficacy of hepatitis A vaccine (HAV) in children with chronic liver disease of various etiologies.

METHODS: Eleven children with chronic liver disease and thirteen age- and sex-matched controls negative for HAV antibodies were vaccinated against hepatitis A after they gave their informed consent. Children with uncontrolled coagulopathy or signs of hepatic decompensation were excluded. The vaccine (Havrix: 720 ELISA units in 0.5 mL, from GlaxoSmithKline Biologicals) was given intramuscularly in the deltoid in 2 doses 6 mo apart. Children were tested for HAV antibodies one and six months after the 1^st dose and one month after the 2^nd dose. Total serum bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were determined immediately before and after one month of the 1st dose of the vaccine.

RESULTS: Only 7 out of the 11 patients were positive for HAV antibodies after the 1^st dose of the vaccine, as compared to 100% of the controls. One month after the 2^nd dose, all patients tested were positive for HAV antibodies. No deterioration in liver functions of patients was noted after vaccination. No adverse events, immediate or late, were reported by the mothers after each dose of the vaccine.

CONCLUSION: Hepatitis A vaccine is both safe and effective in this small studied group of children with chronic liver disease. Given the high seroconversion rate, post-vaccination testing for HAV antibodies is not needed.

INTRODUCTION

Hepatitis A virus (HAV) infection is common. In general, hepatitis A is a self-limited illness with a recovery time measured in months[1]. Young children are often asymptomatic, whereas adults are more likely to be symptomatic and may present with jaundice. Although most patients have a relatively quick recovery without long-term sequelae, about 15% may have a prolonged cholestatic syndrome or a relapsing course over 6-9 mo. A smaller subset will progress to fulminant hepatic failure and death or transplantation, with estimated case fatality rates ranging from 0.01%-0.03% to 0.2% of cases among hospitalized patients[2,3]. Two major risk factors have been identified in patients who developed fulminant hepatic failure: age over 40 years and the presence of underlying chronic liver disease (CLD)[2-4].

Apart from the growing evidence that acute hepatitis A has a more severe clinical course and a higher death rate in individuals with chronic hepatitis B[4-6], and that there is an increased risk of fulminant hepatitis A in patients with chronic hepatitis C[7], patients with other chronic liver diseases also appear to be at an increased risk of developing more severe disease[4,5,8,9].

As the pool of patients with CLD grows, and acute viral hepatitis continues to occur with only a slightly reduced incidence, it is inevitable that a greater number of individuals with CLD will be at risk of developing superimposed acute and chronic hepatitis[1]. To minimize the occurrence of acute hepatitis in patients with CLD, a variety of organizations have recommended hepatitis A and B vaccination in these patients[10,11].

Given the growing evidence that hepatitis A super-infection is probably worse in at least some and probably most patients with CLD, vaccination seems reasonable. In evaluating HAV vaccination in patients with CLD, an effective strategy should include choice of vaccines, in addition to issues related to safety and efficacy of the vaccine[1].

The issue of pre-vaccination screening for hepatitis A in children with chronic liver disease has been discussed in details in a previous report[12]. The aim of the present study was to evaluate the safety and efficacy of hepatitis A vaccine (Havrix, GlaxoSmithKline Biologicals) in a group of Egyptian children suffering from CLD of various etiologies.

MATERIALS AND METHODS

Patients

We included 172 children: 101 children having CLD and 71 healthy age- and sex- matched brothers, sisters and contacts of the patients as a control group. Their age ranged between 2 and 18 years, with a mean of 7.8 ± 4 years. Parental consent was obtained for medical examination, venepuncture and vaccination. The etiological diagnoses of the 101 children with CLD included autoimmune hepatitis (14 children, 14%), cholestatic disorders of infancy (16 children, 16%), hepatitis B virus (HBV) infection (4 children, 4%) and hepatitis C virus (HCV) infection (9 children, 9%). The remaining 58 children (57%) had miscellaneous causes for their CLD.

Inclusion criteria of children with CLD were willingness to participate in the study, any CLD regardless of etiology, no previous history of vaccination against hepatitis A, children of both sexes. Exclusion criteria were children with uncontrolled coagulopathy, children with decompensated liver disease (hepatic coma, massive ascites, frequent bleeders from esophageal varices, repeated spontaneous bacterial peritonitis), children with known immunological deficiency, and infants below 2 years of age (those who will not be vaccinated).

All children were tested for anti-HAV antibodies by a competitive enzyme immunoassay (ELISA) using commercially available kits (Dia. Pro. Diagnostic Bioprobes Srl., Milano, Italy).

The test results were calculated by means of a cut-off value determined by the following formula: Cut-off = (NC + PC)/3 (NC: negative control; PC: positive control), and interpreted as a ratio of cut-off value and optical density (A_{450 nm}) of the sample (or Co/S) (Table 1).

Table 1.

Ratio of cut-off value and optical density (A₄₅₀ nm) of the sample (or Co/S)

Co/S	Interpretation
< 0.9	Negative
0.9-1.1	Equivocal
> 1.1	Positive

Out of the 101 children with CLD, only 15 cases were negative for hepatitis A (15%) and 11 consented to be vaccinated. Among the controls, only 16 were negative for hepatitis A (22.5%) and 13 consented to receive the vaccine. Among the 11 cases, 4 were diagnosed as cholestatic disorder of infancy, 3 as HCV infection, 2 as glycogen storage disease, 1 as HBV infection and 1 as Wilson’s disease.

Two doses of the vaccine (Havrix: 720 ELISA units in 0.5 mL, from GlaxoSmithKline Biologicals) given intramuscularly in the deltoid 6 mo apart. The mothers were asked to report any immediate or late reactions after the vaccine was given.

Total serum bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were determined immediately before and one month after the 1^st dose of the vaccine. Testing for anti-HAV antibodies was done at 3 occasions: one and six months after the 1^st dose of the vaccine and one month after the 2^nd dose of the vaccine.

Statistical analysis

All patients’ data were collected, tabulated and processed using SPSS 12.0 for Windows XP. Categorical variables were compared using Fischer’s exact test. Continuous data were expressed as mean ± SD, range and median if appropriate. Repeated measures for HAV IgG were followed in the same group using Freidman test. These variables were compared in both cases and controls by analysis of variance of repeated measures using the general linear model. Paired variables before and after the vaccine was given were compared using Wilcoxon-Signed Rank test, while unpaired data were compared by Mann-Whitney U test. In all tests, P < 0.05 was considered statistically significant.

RESULTS

Testing for HAV antibodies in children with CLD, revealed that only 7 out of the 11 children with CLD were positive for HAV antibodies while 100% of the controls were positive for HAV antibodies one and six months after the 1^st dose of the vaccine (P = 0.07 and 0.09 respectively) (Table 2). However, all the children with CLD were positive for HAV antibodies one month after the second dose (booster).

Table 2.

Rate of seroconversion in patients and controls 1 and 6 mo after 1^st dose and 1 mo after 2^nd dose of HA vaccine

Time	Patients (n = 11)	Controls (n = 13)	P
	n (%)	n (%)
1 mo after the 1st dose of HA vaccine
Positive	7 (63.6)	13 (100)	0.07
Equivocal	2 (18.2)	0
Negative	2 (18.2)	0
6 mo after the 1st dose of HA vaccine
Positive	7 (63.6)	13 (100)	0.09
Equivocal	3 (27.3)	0
Negative	1 (9.1)	0
1 mo after the 2nd (booster) dose of HA vaccine
Positive	11 (100)	13 (100)	0.63
Equivocal	0	0
Negative	0	0

HA: Hepatitis A.

According to the interpretation of results in Table 1, a significant rise in HAV antibodies (Co/S) was noted both in the children with CLD and in the controls over the 3 readings (P = 0.003 and 0.02 respectively) (Table 3).

Table 3.

Comparison of the mean value of seroconversion (Co/S) between patients and controls

Time	Patients (n = 11)		Controls (n = 13)
	Range	Mean ± SD	Range	Mean ± SD
1 mo after the 1st dose of HA vaccine	0.6-1.6	1.1 ± 0.4	1.5-3.6	2.5 ± 0.97
6 mo after the 1st dose of HA vaccine	0.9-4.8	3 ± 1.3	2.3-6.9	4.7 ± 1.8
1 mo after the 2nd (booster) dose of HA vaccine	3.2-5.3	4.6 ± 0.8	4.2-5.7	4.9 ± 0.7
P	bP = 0.003		aP = 0.02

^aP = 0.02 within controls by Friedman test;

^bP = 0.003 within patients by Friedman test.

No changes in liver function were noted after vaccination except for an insignificant rise in AST of the children with CLD (P = 0.07) and a significant rise in AST of the controls (P = 0.01), although which was within the normal AST range. No adverse events, immediate or late, were reported by the mothers after each dose of the vaccine (Table 4).

Table 4.

Comparison of liver function tests before and after vaccination

	Before vaccination		After vaccination		P
	Range	Median	Range	Median
Patients
Total Serum Bilirubin (mg/L)	4-210	7	3-250	7.5	9.5
ALT (IU/L)	19-163	42	19-136	27.5	0.11
AST (IU/L)	28-299	38	30-288	43	0.07
Controls
Total Serum Bilirubin (mg/L)	3-6	5	1-6	4	4.8
ALT (IU/L)	9-21	18	10-27	17	0.93
AST (IU/L)	21-39	27	21-57	31	0.01b

^bP < 0.01 vs controls before and after vaccination (Wilcoxon Signed Ranks Test). ALT: alanine aminotransferase; AST: aspartate aminotransferase.

Comparison of the difference in liver functions before and after vaccination revealed a significant decrease in ALT of the children with CLD after vaccination as compared to the controls (Table 5).

Table 5.

Comparison of differences in liver functions before and after vaccination between patients and controls (mean ± SD)

	Bilirubin (mg/L)	ALT (IU/L)	AST (IU/L)
Patients	0.8 ± 17	-11.3 ± 26	14.8 ± 23.8
Controls	-0.18 ± 0.9	0.54 ± 7.3	5.1 ± 6.8
P	0.92	0.03a	0.58

^aP < 0.05 vs controls before and after vaccination (Mann-Whitney U test). ALT: alanine aminotransferase; AST: aspartate aminotransferase.

DISCUSSION

HAV vaccine is currently recommended for three groups: communities with endemic HAV infection (> 20/100 000), individuals at an increased risk of HAV exposure, and individuals with an increased risk of developing severe disease[11]. Patients with CLD are considered to be at risk of developing severe disease, and also at an increased risk of HAV exposure. Patients with serological evidence of previous hepatitis A are considered to have probable lifelong immunity. As such, the seroprevalence of HAV markers plays a central role in determining a vaccination strategy[1]. To determine the need of our children with CLD for hepatitis A vaccination, pre-vaccination screening for HAV antibodies was carried out and vaccination was planned for those negative for HAV antibodies. Because of the high seroprevalence of HAV antibodies among our patients and controls, it seems cost-effective to pretest those above 5 years of age, while pre-vaccination screening would be cost-ineffective in those below 5 years of age[12]. In general, targeted vaccination strategies have been found to be the most cost-effective[13]. Even at the lowest estimated anti-HAV be seroprevalenced rates, selective or deferred vaccination is the most cost-effective strategy in patients with CLD, if the recommended HAV vaccination schedule is to be used[14]. The prevalence of anti-HAV must decrease to below 12% before universal vaccination becomes a more cost-effective strategy[1].

Among our studied children with CLD and controls, no immediate or late adverse effects after vaccination were noticed by the mothers. Liver functions were assessed immediately before and one month after the 1^st dose of the vaccine. No significant changes were noted in the children with CLD apart from a significant decrease in ALT as assessed by comparing the mean difference (Table 5). Patients with CLD can receive HAV vaccination with little worry about the vaccine-related adverse effects. Since 1980s, hepatitis A vaccine has been studied extensively in individuals of all ages, and has been known to be safe[15-18]. No significant adverse events have been found to be associated with the use of hepatitis A vaccine in patients with CLD[19].

Only 7 out of 11 children with CLD were positive for HAV antibodies while 100% of the controls were positive for HAV antibodies one and six months after the 1^st dose of the vaccine. However, one month after the booster dose all the children with CLD (100%) were positive for HAV antibodies. A rise in antibody level as calculated by Co/S was noted in both the children with CLD and the controls over the 3 readings. Similar seroconversion rates have been reported in children with chronic hepatitis B and C[20] and other chronic liver diseases[18]. A booster dose could induce seroprotection in all children[20]. Keeffe and co-workers[19] reported that the mean geometric titer of anti-HAV is significantly lower in patients with CLD than in healthy controls. However, seroconversion to an immune state has been found in approximately 95% of patients with CLD and 98% of healthy controls (seronegative patients can achieve anti-HAV titers of ≥ 30 kIU/L as previously defined). A smaller trial in Chinese patients also noted that the seroconversion rates are similar in 65 chronic HBV infection patients given HAV vaccine and healthy controls, although the anti-HAV titer is lower in patients with CLD[21]. Seroconversion in all patients after the 1^st dose of the vaccine has been reported by Giacchino et al[22] in a group of children with a variety of metabolic liver diseases.

Although studies have demonstrated the immu-nogeni-city of HAV vaccine in mild and moderate CLD, the efficacy of HAV vaccines in advanced or decompensated liver disease has not been thoroughly investigated. Smallwood et al[23] found that seroconversion can be achieved in only 48.6% of patients with end-stage liver disease awaiting liver transplantation following a normal HAV vaccination schedule. Patients with end-stage liver disease with uncontrolled coagulopathy and signs of hepatic decompensation were not included in our study.

In conclusion, hepatitis A vaccine is indicated for patients with CLD who are negative for HAV antibodies, and should be provided as early as possible in the course of CLD, as the immunogenicity is poor in advanced liver disease and after liver transplantation. In view of the high seroconversion rate for patients with mild to moderate disease, post-vaccination testing is not needed. The vaccine is both safe and effective in children with mild to moderate liver disease.