Durability of response to vaccination against viral hepatitis A in HIV-infected patients: a 5-year observation

Abstract

The aim of this study was to estimate the prevalence of total antibodies to hepatitis A virus (anti-HAV-T) in the group of HIV-positive adults in Lodz region of Poland, and to evaluate the response and long-term immunity after vaccination against hepatitis A virus. In the group of 234 HIV-infected patients, 72 persons (30.8%) were anti-HAV-T positive (>20 IU/L). In multivariate analysis, two independent factors associated with the presence of anti-HAV-T were identified: the age of patients (OR = 1.07) and the presence of antibodies to hepatitis C virus (OR = 2.87). Vaccination was completed in 83 patients. Good response (anti-HAV-T >20 IU/L one month after the booster dose) was obtained in 79.5% of patients. In patients with CD4 >200 cells/µL in multivariate analysis only presence of antibodies to hepatitis C virus was a prognostic factor for the response to vaccination (OR = 0.13). Among responders available for the follow-up, 82% (50 out of 61) had detectable anti-HAV-T at 1 year and 75.5% (37 out of 49) at 5 years. Our results demonstrate that most of the studied HIV-positive patients were susceptible to hepatitis A virus infection. Most HIV-infected adults with high CD4 counts had a durable response even up to 5 years after vaccination. Patients with a HIV/hepatitis C virus coinfection displayed a worse response to vaccination.

Keywords

HIV AIDS hepatitis A virus vaccination prognostic factors response hepatitis C

Introduction

Hepatitis A virus (HAV) is mainly transmitted through the faecal-oral route, but infection by blood transfusion and sexual intercourse is also possible. Due to their lifestyle, injection drug users (IDUs) and men who have sex with men (MSM) run a higher risk of acquiring this virus.¹ Numerous outbreaks of HAV infection have been reported in these groups of patients.

HAV infection does not progress to chronic hepatitis and liver cirrhosis but acute viral hepatitis A poses a risk of acute liver insufficiency or even death. The risk is higher in patients who already have chronic liver disease.² Such threat is higher in HIV-positive patients, especially in IDUs, because they are frequently co-infected with hepatitis B virus (HBV) and hepatitis C virus (HCV).³

HIV infection may also affect the course of acute HAV disease. Prolonged time to normalization of alanine aminotransferase (ALT) level and prolonged HAV viraemia were observed in HIV-positive patients with hepatitis A.^4,5

In Poland, vaccination against hepatitis A is not state-funded in patients with chronic liver diseases and in HIV-positive persons with a higher risk of HAV infection (drug users, MSM), which is one of the reasons why HIV-infected patients are not frequently vaccinated. Thus, their response to vaccination against hepatitis A in HIV-positive persons also remains unknown.

Aim of the study

The aim of the study was to estimate the prevalence of total antibodies to hepatitis A virus (anti-HAV-T) in the group of HIV-positive adults in Lodz region as well as to evaluate the response after vaccination against viral hepatitis A. In the vaccinated group, we particularly focused on the effect of CD4 count, HIV viral load, HCV coinfection and use of antiretroviral therapy (ART) on the response to HAV vaccine. Our special interest was to determine the long-term immunity after this vaccination in HIV-infected patients in the area of combination antiretroviral therapy (cART).

Material and methods

Routine screening of HIV-positive patients for anti-HAV-T was introduced in the Outpatient HIV/AIDS Department in Lodz in 2004. No person had been vaccinated against hepatitis A in the past. Patients without detectable anti-HAV-T belonging to the risk category were eligible for vaccination with Hepatitis A Vaccine (Havrix 1440 vaccine, SmithKline Beecham). The risk categories included: hepatitis B or C infection, MSM, IDUs, high-risk heterosexuals and travellers to countries with high or intermediate rates of hepatitis A.

The vaccine was administered intramuscularly with a booster dose after 6 months. Serum anti-HAV-T was determined 1 month, 1 year and 5 years after the booster dose (electrochemiluminescence method Cobas – Roche). Test result 20 IU/L or higher was considered positive.

Age, gender, route of transmission, CD4 count, HIV viraemia, body mass index (BMI), smoking status and history of ART were noted for each patient. CD4 count and HIV viraemia results were determined no later than 3 months prior to vaccination.

Statistical methods

For the quantitative parameters the results are presented as arithmetic mean–standard deviation (mean–SD). An independent samples t-test was conducted to compare the normally distributed unpaired data sets. Statistical comparisons of non-normally distributed variables were performed with the Mann-Whitney U test. In order to evaluate the frequency of non-quantitative parameters (according to the size of the studied group), the Chi square test, the Chi square test with Yates’ correction or Fischer’s exact test were used. Univariate and multivariate logistic regression were applied in order to establish which predictors determined the prevalence of anti-HAV and the response to vaccination. P values less than 0.05 were interpreted as statistically significant.

Results

Prevalence of anti-HAV

The study group consisted of 234 HIV-positive patients with no prior vaccination against hepatitis A, in whom anti-HAV-T have been determined. There were 162 men and 72 women in the group. All individuals were Caucasian.

In the whole study group anti-HAV-T were found in 72 patients (30.8%). In univariate and multivariate analyses two independent factors associated with the prevalence of anti-HAV-T were identified: the age of patients and the presence of anti-HCV (Tables 1 and 2).

Table 1.

Predictors determining the prevalence of anti-HAV – results of univariate regression.

	OR	95% CI	p
Age	1.04	1.01–1.08	<0.01
Women	0.94	0.52–1.75	>0.05
Drug users	1.71	0.97–3.01	>0.05
CD4a	1.04	0.94–1.15	>0.05
Anti-HCV	2.00	1.12–3.58	<0.02

OR: odds ratio; CD4a: CD4 within 3 months before anti-HAV assessment.

According to this analysis age and presence of anti-HCV were the variables of a statistical significance with respect to the occurrence of anti-HAV.

Table 2.

Predictors determining the prevalence of anti-HAV – results of multivariate regression.

	OR	95% CI	p
Age	1.07	1.02–1.11	<0.002
Women	1.04	0.53–2.07	>0.05
Drug users	1.15	0.48–2.75	>0.05
CD4a	1.05	0.94–1.17	>0.05
Anti-HCV	2.87	1.11–7.41	<0.03

CD4a: CD4 within 3 months before anti-HAV assessment; OR: odds ratio (adjusted for all variables used in this model).

According to this analysis age and presence of anti-HCV were the variables of a statistical significance with respect to the occurrence of anti-HAV.

The group of patients eligible for anti-HAV vaccination

One hundred sixty two patients with no anti-HAV-T were eligible for vaccination. So far the observation has been completed in 93 patients. In this group, five individuals were given only one dose of vaccine (they missed the booster dose).

In five persons who received two doses of vaccine the presence of anti-HAV-T after vaccination was not assessed (they missed the scheduled visit).

Further analysis involved the group of 83 individuals who were given two doses of vaccine and in whom at least one assay of anti-HAV-T was performed after vaccination. The mean age of vaccinated patients was 30.7 ± 7.1 years, the mean CD4 count at the time of vaccination was 450.1 ± 174.1 cells/uL. The group involved 38 patients with anti-HCV and 45 patients without these antibodies. HBsAg was present in seven persons (8.4%). In the vaccinated group 33 patients were on cART, in 2 persons ART was introduced within 6 months of the first dose of vaccine and 48 patients were not treated either before, or during the vaccination period.

Response to vaccination at 1 month

Tables 3 and 4 present the occurrence of anti-HAV-T in the study group one month after the booster dose. Response to vaccination (anti-HAV-T present ≥20 IU/mL) was found in 79.5% of persons. Response was statistically more frequent in the group of patients with CD4 count prior to vaccination above 200 cells/µL as compared to patients with CD4 count 200 cells/µL or lower. No statistically significant differences in response were found between the groups depending on gender, age, route of transmission, BMI (mean value for responders 23.19 vs for non-responders 23.41), smoking status or HIV viraemia. Patients on cART responded to vaccination less frequently, had lower CD4 count (mean 363 vs 496 cells µL; p = 0.001) and lower CD4 nadir (mean 206 vs 368 cells/µL; p = 0.0001). Among HIV/HCV co-infected patients 27 of 38 (71.1%) responded to vaccination, while in the group without coinfection a response occurred in 39 out of 45 (86.7%) individuals.

Table 3.

Presence of anti-HAV-T in the group of 83 persons 1 month after administering the second dose of vaccine.

		Study group n	Anti-HAV +		p
		Study group n	n	%	p
		83	66	79.5
Women		29	23	79.3	>0.05
Men		54	43	79.6	>0.05
Age ≤35 years		66	54	81.8	>0.05
Age >35 years		17	12	70.6	>0.05
Anti-HCV (+)		38	27	71.1	>0.05
Anti-HCV (−)		45	39	86.7	>0.05
Route of Transmission	IDU	35	26	74.3	>0.05
	Hetero	24	19	79.2
	Homo/bi	22	19	86.4
	Unknown	2	2
CD4a >200 cells/µL		78	66	84.6	<0.001
CD4a ≤200 cells/µL		5	0		<0.001
CD4n >200 cells/µL		47	37	78.7	>0.05
CD4n ≤200 cells/µL		18	15	83.3	>0.05
CD4n >100 cells/µL		59	49	83.1	>0.05
CD4n ≤100 cells/µL		6	3	50.0	>0.05
ARV treatment (+)		33	23	69.7	>0.05
ARV treatment (−)		50	43	86.0	>0.05
HBsAg (+)		7	6		>0.05
HBsAg (−)		76	60	78.9	>0.05
HIV viraemia >400 copies/mL		53	44	83.0	>0.05
HIV viraemia ≤400 copies/mL		30	22	73.3	>0.05
Smoking (+)		40	28	70.0	>0.05
Smoking (−)		43	38	88.4	>0.05

IDUs: injection drug users; CD4a: CD4 within 3 months before vaccination; CD4n: CD4 nadir; ARV: antiretroviral treatment.

Table 4.

Predictors of response to anti-HAV vaccination in patients with CD4 count>200 cells/µL – results of univariate regression.

	OR	95% CI	p
Gender	0.93	0.25–3.52	>0.05
Age	1.20	0.08–18.92	>0.05
CD4a	1.06	0.03–33.24	>0.05
Anti-HCV	0.14	0.03–0.70	<0.02
ARV	0.50	0.14–1.77	>0.05
BMI	0.17	0.01–5.16	>0.05
HBsAg	1.10	0.12–10.42	>0.05
HIV viraemia >400 copies/mL	1.00	0.27–3.76	>0.05
Smoking	0.15	0.03–0.75	<0.03

OR: Odds ratio; CD4a: CD4 within 3 months before vaccination; ARV: antiretroviral treatment; BMI: body mass index.

According to this analysis presence of anti-HCV was the only variable of a statistical significance with respect to the response to anti-HAV vaccination.

In the group of patients who had CD4 >200 cells/µL before vaccination (n = 78), an analysis of prognostic factors for the response to vaccination was performed using univariate and multivariate logistic regression (Tables 4 and 5). Presence of anti-HCV was found to be the only predictor which independently affected the response to vaccination (OR = 0.13).

Table 5.

Predictors of response to anti-HAV vaccination in patients with CD4 count >200 cells/µL – results of multivariate regression.

	OR	95% CI	p
Gender	1.02	0.19–5.38	>0.05
Age	1.03	0.91–1.18	>0.05
CD4a	1.00	0.99–1.00	>0.05
Anti-HCV	0.13	0.02–0.99	<0.05
ARV	0.11	0.01–1.88	>0.05
BMI	0.86	0.68–1.08	>0.05
HBsAg	2.29	0.18–28.4	>0.05
HIV viraemia >400 copies/mL	0.21	0.01–4.35	>0.05
Smoking	0.26	0.04–1.79	>0.05

CD4a: CD4 within 3 months before vaccination; ARV: antiretroviral treatment; BMI: body mass index; OR: odds ratio (adjusted for all variables used in this model).

According to this analysis presence of anti-HCV was the only variable of a statistical significance with respect to the response to anti-HAV vaccination.

Persistence of anti-HAV-T at 1 year

One year after the booster dose anti-HAV-T could be assessed in 61 persons who responded to vaccination. This group involved 25 patients with an HIV/HCV coinfection and 36 without HIV/HCV coinfection. Persistence of anti-HAV-T was found in 50 of 61 individuals (81.9%): in 30/36 (83.3%) patients without HIV/HCV coinfection and in 20/25 (80.0%) patients with HIV/HCV coinfection. Among these 50 patients, 38 had anti-HAV-T >60 IU/L and in 12 individuals this value ranged between 20 and 60 IU/L.

At 18 months anti-HAV-T were still present in 17 (85%) and absent in three (15%) of 20 responders on cART.

Among 41 responders not on cART at the time of vaccination, presence of anti-HAV-T at 18 months was found in 33 individuals (80.5%) and not found in eight persons (19.5%).

Persistence of anti-HAV-T at 5 years

Among HAV-seropositive persons 1 year after vaccination, available for the follow-up, 75.5% (37/49) remained seropositive at 5 years. Five years after vaccination protective levels of anti-HAV-T were found in 16/20 patients with HIV/HCV coinfection and in 21/29 patients without HIV/HCV coinfection. All individuals who had anti-HAV-T >60 IU/L at 1 year had anti-HAV-T above 20 IU/L at 5 years. Mean CD4 count in patients with persistent anti-HAV-T at 5 years was 472 cells/µL ± 161.7 (205–863).

Discussion

Since about 1997 prevalence of acute hepatitis A in Poland is low. As the vaccination is uncommon, one can observe an increasing percentage of individuals susceptible to HAV infection and occurrence of a compensatory epidemic is possible.^6–8 This observation is confirmed by the results of our study: anti-HAV-T were absent in 79.2% of persons aged below 30 years. The study conducted in our AIDS centre showed that the prevalence of anti-HAV-T was higher in the group of IDUs compared to the group of patients infected through a sexual route. More frequent occurrence of these antibodies in IDUs is in all probability associated with a more often direct person-to-person transmission related to crowding and hygiene factors. Our results remain in accordance with other studies in this respect.^9,10

Consequently, the group of sexually-infected patients is more susceptible to the occurrence of a compensatory epidemic. This applies especially to MSM who run a higher risk of acquiring HAV infection.

Pre-vaccination anti-HAV testing is only recommended in specific circumstances in order to reduce the costs of vaccinating people who are already immune to hepatitis A.¹¹ The study performed in our centre showed that the prevalence of anti-HAV-T increases with age. In the group of patients older than 40 years almost 50% were HAV seropositive, which leads to the conclusion that in this age group testing for anti-HAV-T before vaccination will likely be cost-effective.

Younger patients, especially those sexually infected, could be vaccinated with no prior testing. In Poland vaccination against hepatitis A is recommended in the following groups of inhabitants: persons in contact with food (production and distribution), public utility workers, health care workers, children and teenagers, travelers to the countries with high hepatitis A incidence, MSM, IDUs, individuals with clotting disorders and patients with hepatic disorders. Despite these recommendations vaccination is not commonly performed. This is mainly due to the cost of the vaccine – the procedure is not state-funded so patients have to bear the costs. Problems concerning vaccination are observed also in other parts of the world. A retrospective study conducted in the USA showed that 66.8% of HIV-infected patients were eligible for vaccination but only 23.3% of them received at least one dose of vaccine.¹²

There are no other Polish studies concerning the response to vaccination against hepatitis A in HIV-infected patients and that is why we have compared our results with those of foreign researchers. Unlike our study, most data come from retrospective studies in which the presence of anti-HAV was checked in a variable time span after vaccination.

Both our results and those observed by other authors in the groups of HIV-infected patients^13–18 are worse than the results obtained by vaccination of healthy volunteers. In the healthy population seropositivity rate after vaccination was higher than 99%.¹⁹

A worse response to vaccination against hepatitis A in the group of HIV-positive patients was observed by Weissman et al.¹⁷ The authors of this study have found the presence of post-vaccination anti-HAV-T in 48% of patients. Similarly, low efficacy of vaccination (49.6%) was obtained by Overton et al.¹⁴ In our study group 1 month after the booster dose anti-HAV-T were found in 79.5% of patients and 1 year after vaccination anti-HAV-T were present in 82% of patients. Similar results were obtained by other authors who have found the presence of anti-HAV-T in 74%–89% of vaccinated individuals.^{13,15,16,20,21} These discrepancies are probably due to the differences in the studied groups. In some studies only patients with higher CD4 counts were eligible for vaccination. Like us, many other authors assessed factors affecting the response to vaccination against hepatitis A. In the study by Overton et al.,¹⁴ the efficacy of vaccination was not influenced by race, CD4 nadir and CD4 count at the time of vaccination, only by HIV viraemia level and gender. Better response to vaccination was obtained in men and in individuals with low HIV viraemia. But in most studies the response to vaccination was affected by the CD4 count. In the study by Weissman et al.,¹⁷ the response to vaccine was not related to race, age and CD4 nadir but was more frequent in women and in persons with higher CD4 counts prior to vaccination. Better response in patients with higher CD4 counts was also obtained by Neilsen et al.¹³ Like other authors, we also found the presence of anti-HAV-T after vaccination in patients with higher CD4 counts (above 200 cells/uL) more frequently. The results of vaccination were affected by HCV coinfection – in the group of coinfected patients the response to vaccine was worse (71.1%) as compared to the monoinfected individuals (86.7%), but this difference was not statistically significant. Weinberg et al.²² have presented an interesting study: in the group of HIV-positive children on ART with CD4 counts ≥20% a better response to vaccination was observed in children with negative HIV viraemia. Therefore, it might be concluded that ART may improve the results of vaccination even in individuals with relatively good immunity. However, in our study the response to vaccination was not statistically significantly higher in ART-naive patients compared to patients on cART. We think that a worse response to vaccination in patients on cART was caused by the differences in the compared groups at baseline. Patients off treatment not only had higher CD4 counts and higher CD4 nadir but also belonged to the category A according to the Centers for Disease Control and Prevention (CDC),²³ which was the reason why they were not on ART. Crum-Cianflone et al.²⁰ observed a sustained response to vaccination against hepatitis A in HIV-infected individuals: they found anti-HAV-T 3 years after vaccination in 90% of patients tested and after 6–10 years in 85% of individuals. Unlike our study, in their vaccinated group only 2% of patients were HIV/HCV coinfected. This fact might have resulted in a better response to vaccination in their study.

Because of the worse response in HIV-infected patients some authors propose the use of three instead of two doses of vaccine.²² In any case, in the era of cART, when reconstruction of immune system is possible, it is important to start vaccination at the proper time when patients have optimal CD4 count, because this is the main factor affecting the response to vaccination. Based on our results three-dose vaccination regimen could be considered in patients with low CD4 counts and HIV/HCV coinfection as this schedule proved to be safe and generated higher antibody titres.^22,24 However in the study conducted by Tseng et al.,²⁵ serologic response rate to three and to two doses of HAV vaccine was similar and only higher CD4 counts and suppression of HIV replication increased the seroconversion rate.

A limitation of this paper is the lack of the control group and of quantitative titres for results of anti-HAV-T higher than 60 IU/L, which resulted in our inability to analyse the Geometric Mean Titers of anti-HAV-T. Small sample size is also a limitation, but a relatively high percentage of patients with HIV/HCV coinfection is worth noting.

Conclusions

Our results demonstrate that most of studied HIV-positive patients were susceptible to HAV infection. Most HIV-infected adults with CD4 >200 cells/µL had a durable response even up to 5 years after vaccination. Patients with a HIV/HCV coinfection displayed a worse response to vaccination.

Footnotes

Conflict of interest

The authors declare no conflict of interest.

Funding

The study was supported by internal grant of the Medical University of Lodz (502-11-724)

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