Adherence to hepatitis A virus vaccination in HIV-infected men who have sex with men

Abstract

Although vaccination against hepatitis A virus (HAV) is essential for human immunodeficiency virus (HIV)-infected patients, the uptake of HAV vaccine is reported to be very low. From 2007 to 2012, 912 HIV-infected men in Athens, Greece were screened for exposure to HAV. Two doses of an HAV vaccine were recommended to 569 eligible patients. Reminder cards with scheduled vaccination visits were given to each patient. Among eligible patients, 62.2% (354/569) received both doses. Patients who were fully vaccinated compared with non-adherent patients were natives, older, had undetectable HIV viral load, higher CD4 T cell counts and lower nadir CD4 T cell counts. Multivariate logistic regression revealed that the patient’s country of origin (p = 0.024; OR = 2.712; 95% CI, 1.139–6.457), CD4 T cell count (p < 0.001) and nadir CD4 T cell count (p < 0.001) were factors directly associated with adherence. In conclusion, adherence to HAV vaccination was better than in previously published data. Because many of the factors related to vaccination completion are parameters of HIV infection, it appears that physician interest in HIV care and vaccination planning is crucial to enhancing vaccine uptake.

Keywords

HIV AIDS treatment vaccination HAV vaccine adherence hepatitis A MSM

Introduction

Hepatitis A is generally a self-limited disease with minimal public health impact in countries with low hepatitis A virus (HAV) endemicity. In recent years, however, acute hepatitis A outbreaks have been reported among men who have sex with men (MSM) and intravenous drug users in the USA, Europe and Australia.^1–3 These epidemics are often a source of HAV dispersion in the general population. This reminds us of the necessity for widespread vaccination of high-risk groups, both for protecting high-risk individuals and for maintaining increased immunity among the general population.

Hepatitis A and its prevention is a particular concern for human immunodeficiency virus (HIV)-infected patients, especially those with underlying liver disease.⁴ In hepatitis B or C co-infected patients, HAV infection can be a serious disease with complications such as fulminant hepatitis.⁵ Furthermore, hepatitis A may cause prolonged illness in HIV patients, which can increase the excretion time of the virus and hence the transmissibility.⁶

The guidelines for the clinical care of HIV-infected patients recommend vaccination against HAV in those at increased risk of exposure or complications from HAV such as MSM, injection drug users, international travellers, and persons with chronic liver disease, including chronic hepatitis B or C.^4,7–9

Few studies of HAV vaccination coverage in HIV patients exist.^10–14 These studies indicate that uptake of HAV vaccine and screening rates for exposure to HAV are low.

In this study, an HAV immunization schedule was recommended to HIV patients receiving care in a tertiary-care hospital in Athens, Greece, after systematic screening for exposure to HAV and consultation. The aim of the study was to evaluate the adherence to HAV vaccination and the factors influencing adherence. Understanding the parameters associated with vaccine adherence is essential to recognizing the difficulties with immunization against HAV and to implement new practices in HIV patient preventive care.

Methods

This retrospective study was conducted in the HIV/AIDS Unit of the Andreas Sygros University Hospital (Athens, Greece) and was reviewed and approved by the hospital’s ethics committee. The study included MSM with HIV infection who were seen at the HIV/AIDS Unit from 2007 to 2012. Since 2007, there has been an effort to screen all HIV-infected MSM for exposure to HAV and to vaccinate those patients without HAV immunity. Patients with documented past vaccination or history of acute hepatitis A were excluded from the screening.

From 2007 to 2012, 912 of 1131 HIV-infected MSM who were seeking care during this same period were tested for HAV-specific IgG antibodies (anti-HAV). Among these patients, 592 had no immunity to hepatitis A (anti-HAV IgG negative). Patients with a negative serologic test were considered eligible for an HAV vaccination if they had a CD4 T cell count >200 cells/mm³ (n = 569). Vaccination of patients with a CD4 T cell count >200 cells/mm³ is thought to result in a better immune response. Greece is a country with low hepatitis A endemicity, so deferring vaccination until immune reconstitution has a very low risk of HAV infection.

All 569 patients were informed about their anti-HAV test results and the importance of vaccination, and an immunization schedule was recommended (baseline visit). Two doses of inactive HAV vaccine (Havrix 1440 IU per dose, GlaxoSmithKline, Rixensart, Belgium or Vaqta 50 IU per dose, Merck & Co., NJ, USA) were scheduled to be administered 6–12 months apart. A reminder card with the scheduled dates for vaccine administration was given to each patient. The interval between anti-HAV testing and the administration of the first dose of the vaccine was up to 30 days.

The study included all patients eligible for vaccination who were followed for ≥1.5 years after the baseline visit. Data were extracted through a review of the medical records. The investigators were also the treating physicians and were responsible for the patients’ medical files, vaccination and follow-up. Adherence to vaccination was acknowledged if a patient had received both doses of the vaccine. Patients who received ≤1 dose were counted as non-adherent.

Additional data included demographic characteristics, time since HIV diagnosis, CD4 T cell counts and nadir CD4 T cell counts, plasma HIV viral load, administration of combination antiretroviral therapy (cART), co-infection with hepatitis B or C, number of office visits per year, adherence to cART and history of sexually transmitted infections (STIs). All parameters were based on the patient’s status as of the baseline visit.

Patients were termed highly adherent to cART if it was reported that they had taken ≥95% of their prescribed medication the year prior to their baseline visit. Patients with at least one diagnosis of early syphilis or gonorrhoea were considered to have an STI. Early syphilis and gonorrhoea were chosen as these diseases have a well-documented diagnosis and are indicators of high-risk sexual behaviour.

A patient’s economic status was not reported in the study data because HAV vaccine is free for high-risk individuals in Greece (MSM, injection drug users, international travellers, persons with chronic liver disease, laboratory animal practitioners, food processing/handling professionals and cleaning staff). The stage of HIV infection was also excluded from the data because it is strongly associated with nadir CD4 T cell count.

Statistical analyses were conducted using PASW Statistics 18 software.

Logistic regression models were used to explore the factors associated with adherence to vaccination against hepatitis A.

Results

The study included 569 patients who had a mean age of 39.0 years, and the vast majority (95.3%) were of Greek origin. Among the foreign patients, 18 of 27 were of African origin and the rest were from Asia or Eastern Europe.

Among the 569 patients, 354 (62.2%) were adherent to vaccination, receiving both doses of the HAV vaccine. The remaining 215 patients (37.8%) were non-adherent: 73 (12.8%) received only one dose and 142 (25%) received no vaccine. Only 37% of the foreign patients (10/27) were adherent, compared to 63.4% (344/542) of Greek patients.

Twenty-two patients (4%) received the second dose of the vaccine 12 months after the first dose.

Baseline characteristics of the patients are summarized in Table 1. Patients who were fully vaccinated were natives, older, had plasma HIV RNA levels of <40 copies/ml, higher CD4 T cell counts, and lower nadir CD4 T cell counts (Table 1).

Table 1.

Patients’ characteristics.

Characteristics	All patients (n = 569)	Adherent to vaccination patients (n = 354)	Non-adherent to vaccination patients (n = 215)	P-Value
Age (years)	39.00 (±8.36)	39.56 (±7.94)	38.09 (±8.98)	0.029
Origin (natives), n	542 (95.3%)	344 (97.17%)	198 (92.09%)	0.006
Education
Primary	99 (17.4%)	57 (16.1%)	42 (19.5%)	0.272
Secondary	339 (59.6)	220 (62.14%)	119 (55.34%)
Tertiary	131 (23.0)	77 (21.75%)	54 (25.11%)
Time of HIV diagnosis (years)	4.22 (±3.16)	4.02 (±2.93)	4.57 (±3.48)	0.052
STIs, n	170 (29.9)	111 (31.35%)	59 (27.44%)	0.323
Hepatitis B/C co-infection, n	54 (9.5%)	33 (9.32%)	21 (9.76%)	0.860
Antiretroviral therapy, n	407 (71.5%)	261 (73.72%)	146 (67.90%)	0.136
Adherence to ART, n	282 (49.6%)	162 (45.76%)	87 (40.46%)	0.22
Visits ≥ 2/year, n	363 (63.9%)	235 (66.38%)	128 (59.53%)	0.125
CD4 T-cells (cells/mm³)	619.65 (±585.54)	653.31 (±716.57)	563.88 (±240.40)	0.033
HIV RNA (copies/ml) <40 copies/ml, n	12582.27 (±48580.19) 320 (56.23%)	12174.13 (±42775.14) 224 (63.27%)	12969 (±30903.21) 96 (44.64%)	0.790 0.001
nadir CD4 T-cells (cells/mm³)	317.42 (±182.04)	297.55 (±173.76)	350.40 (±190.90)	0.001

Note: Categorical variables are shown as numbers [percentages] and continuous as means (± standard deviation). STIs: sexually transmitted infections; ART: antiretroviral therapy.

Univariate analysis showed that vaccination was significantly affected by the origin of the patients (p = 0.006; OR = 0.339; 95% CI, 0.152–0.754) and the undetectable plasma HIV viral load (p = 0.001; OR = 2.136; 95% CI, 1.512–3.015). In addition, patients who adhered to the vaccination had a statistically significant difference in age (p = 0.029), CD4 T cell count (p = 0.033) and nadir CD4 T cell count (p = 0.001) compared to non-adherent patients.

No association was observed between adherence to HAV vaccination and history of STIs, hepatitis B or C co-infection, high education level, administration of cART and adherence to cART.

A multiple logistic variation model was created that fits well to the available data. The Nagelkerke R² value was 0.107, while the correct classification rate was 66.4%. Parameters that were evaluated included origin, age, HIV RNA, CD4 and nadir CD4 T cell counts. Multivariate analysis (Table 2) showed that adherence to vaccination was significantly affected by, the patient’s origin (p = 0.024; OR = 2.712; 95% CI, 1.139–6.457), CD4 T cell count (p < 0.001), and CD4 T cell count nadir (p < 0.001).

Table 2.

Factors associated with adherence to HAV vaccination (multivariate analysis).

	p-Value	OR (95% CI)
Origin
Foreigners		1.000
Natives (Greek)	0.024	2.712 (1.139–6.457)
CD4 T-cells	<0.001	0.998 (0.997–0.999)
Nadir CD4 T-cells	<0.001	1.003 (1.002–1.005)

Discussion

In this study, 62.2% of HIV-infected MSM eligible for HAV vaccination completed the full, two-dose series of the HAV vaccine. For the patients non-adherent to vaccination, 12.8% of the total eligible population received only one dose and 25% received no vaccine. Although the vaccine uptake is not satisfactory, it is much better than the vaccination coverage that was reported from other relevant studies.^10,11,13

Data from eight HIV clinics (USA) showed that there can be substantial variation by clinic in the percentage of patients screened for exposure to HAV and the percentage of those subsequently vaccinated against HAV. Overall, the screening rate for exposure to HAV was 49%, and only 29% of the eligible patients were vaccinated against HAV.¹⁰

Another study by Tedaldi et al.(USA) involving 1071 HIV patients similarly reported a low screening rate for exposure to HAV (57.2%) and a low rate of HAV vaccination (23.3% received ≥1 dose).¹¹

Garvey et al. studied patients with HIV and hepatitis B or/C co-infection in the UK and concluded that 13% were neither vaccinated nor immune to hepatitis A.¹²

A report of HIV patients co-infected with hepatitis C virus (France, 2011) found that 31.3% of the participants were screened for exposure to HAV and only 6% were vaccinated against HAV.¹³

HAV vaccine uptake in HIV-negative high-risk individuals is also reported to be low. In the USA in 2011, it was reported that there was low HAV vaccination coverage (17%) among those with chronic liver conditions.¹⁵ In 2010, HAV vaccination among adult travellers to endemic countries was 26.6% for one dose and 16.9% for a two-dose series completion.¹⁶

The higher vaccination rates recorded in this study compared to those mentioned above likely can be attributed to differences in the study group and to the planning of the screening and vaccination strategy. In addition, some of the above studies included intravenous drug users (IVDU), who are patients with difficulties adhering to medical care instructions.

Compared to HIV-negative high-risk individuals (e.g. travellers or MSM), patients with HIV infection have regular medical care; therefore, somewhat higher rates of vaccination adherence can be expected.

Considering the factors associated with adherence, it was found that the patient’s country of origin was related to vaccination adherence. This result was expected as the vast majority of the foreign-born patients were refugees from Africa, who generally have difficulty with communication and compliance with doctors' instructions. The association between adherence to vaccination and HIV-infection parameters is interesting. Patients who had undetectable HIV viral load, higher CD4 T cell counts and lower nadir CD4 T cell counts were more adherent to HAV vaccination. These patients are likely more aware of their illness and the need for medical care. They might also more regularly contact their physicians.

The results from separate studies concerning factors associated with vaccination adherence are variable, e.g. data on the relationship between age and vaccination are conflicting.^17,18 Among demographic factors, education level was reported to be directly related to adherence to HAV vaccination.¹³ In addition, for HIV-negative MSM, HAV vaccination was associated with behavioural factors (e.g. greater number of lifetime partners).^17,18

Data on the relationship between HIV-infection parameters and adherence to HAV vaccination are very limited. Univariate analysis in HIV/HCV co-infected patients showed that lower CD4 T cell count nadirs were associated with the absence of HAV vaccination. In that study population, mainly drug users, low CD4 T cell count nadirs may be related to late presentation of HIV infection and the lack of seeking health care.¹³

Despite various published study results, almost all investigators agree about the importance of physician awareness and vaccine recommendation for effective vaccine uptake. Low uptake of HAV vaccine in some studies may reflect not only the patients’ poor adherence but also the providers’ apathetic recommendations. Incomplete medical records, postponement of vaccination due to low CD4 T cell counts and considering a given patient to be at low risk for infection might be reasons for a provider not to recommend HAV vaccination. Reports concerning the cost-effectiveness of HAV vaccination in hepatitis C-infected patients also may lead physicians to not recommend the HAV vaccine.^19,20

In the current study, there was a systematic effort to screen all HIV patients for exposure to HAV and provide the immunization-eligible patients with a scheduled vaccination programme. In addition, reminder cards might have played an important and beneficial role.

Limitations of this study include it being retrospective, performed at a single site and the lack of a control group of HIV-negative MSM. In addition, having had the justifications from the patients as to why they were non-adherent to the vaccination regimen may have been informative.

In conclusion, uptake of HAV vaccine is better when there is a systematic effort for vaccination planning. Because adherence to HAV vaccination is often associated with HIV-infection parameters and care, physicians should pay attention to screening and implementing new strategies to increase vaccine uptake. Vaccination as soon as immune reconstitution is achieved or provision of translation services or reminder cards in different languages for foreigners might also improve adherence. Immunization against HAV and preventive care, in general, should be key priorities for HIV patients, especially MSM.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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