Brief Report: Response to Hepatitis A Virus Vaccine in HIV-Infected Patients Within a Retrospective, Multicentric Cohort: Facing Hepatitis A Outbreaks in the Clinical Practice

Abstract

Background: 

Various recent outbreaks of hepatitis A virus (HAV) have been described in men who have sex with men despite the availability of an effective vaccine. This study aimed to determine the current rates of seroconversion after receiving HAV vaccine (HAV-V) in HIV-infected patients under real-life conditions.

Setting: 

Patients were selected from a Southern Spanish multicentric cohort of HIV-infected subjects.

Methods: 

Retrospective analysis of all patients who received 2 doses (standard scheme) from April 2008 to May 2016 or from June 2016 to February 2018 facing an HAV outbreak with shortage of HAV-V, 1 single dose of HAV-V. Response to HAV-V was defined as positive anti-HAV IgG between 1 and 12 months after the last vaccination dose.

Results: 

A total of 522 patients were included, mainly men who have sex with men (86.2%). In the standard-dose group, 303/343 [88.3%; 95% confidence interval (CI): 84.5 to 91.5] patients showed seroconversion as compared with 149/179 (83.2%; 95% CI: 76.9 to 88.4) of the single-dose group (P = 0.107). Undetectable baseline HIV-RNA (adjusted odds ratio: 4.86; 95% CI: 1.86 to 12.75; P = 0.001) and a CD4⁺ T-cell count ≥350/μL (adjusted odds ratio, 3.96; 95% CI: 1.26 to 12.49; P = 0.019) were independently associated with response to both regimens. A higher CD4/CD8⁺ ratio was also associated with response after a single dose.

Conclusions: 

HIV-infected patients should be encouraged to undergo HAV-V with 2 standard doses 6 months apart; a single dose achieves a high rate of seroconversion in those patients with favorable response factors and may be enough to limit future outbreaks in case of HAV-V shortage until supply is reestablished.

INTRODUCTION

Hepatitis A virus (HAV) infection is a widespread disease, mainly affecting developing countries because its transmission depends on sanitary and food processing conditions. Owing to the fecal–oral transmission route, HAV is also a potentially sexually transmissible disease in those who practice oral–anal sex contacts, affecting mainly men who have sex with men (MSM), who moreover show poor vaccine uptake, and, to a lesser extent, heterosexual individuals. In addition, injecting drug users have been identified as risk group for HAV acquisition. Acute hepatitis A does not develop to chronicity and is rarely fatal in healthy adults.¹ However, settings such as HIV infection are associated with prolongation of HAV viremia and fecal shedding.² Given the high proportion of MSM practicing sexual risk behavior among the HIV-infected population, sexual outbreaks of hepatitis A are potentially favored in the HIV-1–infected population.

Moreover, patients with chronic liver disease, including hepatitis C, as often observed in HIV infection, are at elevated risk of complications^3,4 and severity of hepatitis A is increased.⁵ For approximately 2 decades, an effective and safe HAV vaccine (HAV-V) composed of inactivated HAV is available. The most common vaccination scheme comprises 2 doses administered at 0 and 6–12 months, resulting in up to 100% seroprotection in healthy subjects.⁶ Unlike vaccination against hepatitis B virus (HBV), HAV-V does not form part of universal mass immunization programs in children in most Western countries,⁷ including Spain, but is recommended for risk groups.⁸ Nonetheless, an alarming number of hepatitis A outbreaks, mainly affecting MSM, have been reported from 16 European countries since June 2016.⁹ This is of special concern because MSM are also at high risk for HIV infection, which negatively impacts on the effectiveness of HAV-V.¹⁰ Unfortunately, supplies of HAV-V ran short in some endemic regions, and management of resources came to the force.^11,12 Thus, knowing the efficacy of 1 and 2 doses of HAV-V in the HIV-infected population in the current clinical practice is crucial to develop strategies that effectively manage supplies in case of HAV-V shortage, apart from preventing further spreading of HAV.

PATIENTS AND METHODS

Study Population and Vaccination Schemes

HAV-seronegative HIV-infected adults included in a cohort conducted at the infectious disease units of 5 university hospitals in Southern Spain were retrospectively analyzed. All patients who received 2 standard doses of HAV-V 6 months apart (Havrix 1440; GlaxoSmithKline, S.A., Madrid, Spain; 1440 units/dose) from April 2008 to May 2016 were included in the standard-dose group. In 2016, when HAV-V supply ran short due to a hepatitis A outbreak that took place among MSM in Spain, HAV-seronegative HIV-infected adults at risk of HAV infection were prioritized to receive a single dose of HAV-V (a single-dose group). To be included in the study, patients had to have an available determination of anti-HAV IgG between 1 and 12 months after the last vaccination dose. Subjects with signs or symptoms of active infection or fever, or active HIV-related opportunistic infections or malignancies, were excluded from the analysis.

Laboratory Determinations

HIV-RNA was quantified by real-time polymerase chain reaction (COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, Roche Diagnostics, Basel, Switzerland). Qualitative plasma anti-HAV IgM and IgG determinations were performed by electrochemiluminescence immunoassay (Elecsys Anti-HAV Cobas e 100 V2; Roche Diagnostics GmbH, Mannheim, Germany).

Statistical Analysis

The outcome variable was the response rate to HAV-V, defined as a positive detectable anti-HAV IgG between 1 and 12 months after the last dose of HAV-V. Categorical variables were analyzed using the χ² test or the Fisher exact test, when applicable, whereas the Student t test or the Mann–Whitney test was used to analyze continuous variables, which were expressed as median [interquartile range (IQR)] [range]. Those factors showing an association with a P < 0.2 in the univariate analysis, and those with a potential clinical impact, were tested in multivariate logistic regression models. Statistical analysis was performed using the SPSS statistical software package release 23.0 (IBM, Chicago, IL) and STATA 9.0 (StataCorp LP, College Station, TX).

Ethical Aspects

The study was designed and performed according to the Helsinki declaration and was approved by the Ethics Committee of the Virgen del Rocío University Hospital (Seville, Spain). All patients gave their written informed consent before being included in the cohort.

RESULTS

Study Population

A total of 522 patients were included, of whom 343 patients received the standard dose, from April 2008 to May 2016, while from June 2016 to February 2018, 179 individuals received a single dose due to shortage of HAV-V supply. The majority (86.2%) were MSM. Detailed baseline characteristics and comparisons between the 2 study populations are shown in Table 1. The most notable differences were the number of patients receiving antiretroviral therapy (ART) and the proportion of those with an undetectable viral load (VL) and a better immune status as measured by the CD4⁺ T-cell count and CD4⁺/CD8⁺ ratio in the single-dose group.

TABLE 1.: Baseline Characteristics of the Population Who Received Two Standard Doses of Hepatitis A Virus Vaccine (HAV-V) With a 6-Month Interval (Standard-Dose Group) and Those Who Received a Single Dose of HAV-V

Response to HAV-V

In the standard-dose group, the seroprotection rate was 88.3% [95% confidence interval (CI): 84.5 to 91.5] as achieved by 303 patients evaluated after a median, (IQR), [range] time from the last dose of 139 (56–184) [30–364] days. In the univariate analysis, HIV-RNA undetectability and a CD4⁺ T-cell count ≥350/μL were associated with seroconversion (Fig. 1A). All (100%; 95% CI: 86 to 100) of the 25 women vs. 278 (87.4%; 95% CI: 83.3 to 90.9) of the men showed response (P = 0.059). The median age was higher among responders {36.8 (29.4–43.6) [18.3–43.6] vs. 32.7 (26.7–38.4) [20–55.9] years (P = 0.035)}, although this probably has no clinical significance.

FIGURE 1.: Response rates to hepatitis A virus vaccine (HAV-V) between 1 and 12 months after 2 standard doses (A) and 1 single dose (B) according to the HIV viral load (VL) and CD4⁺ T-cell count at the moment of the first dose.

A lower CD4⁺/CD8⁺ ratio {0.67 (0.45–0.094) [0.14–2.34] vs. 0.54 (0.4–0.8) [0.25–2.25] (P = 0.149)} and tobacco smoking tended to negatively impact on response {174 (90.6%; 95% CI: 85.6 to 94.3) vs. 123 (84.8%; 95% CI: 77.9 to 90.2) patients, P = 0.126}, although without reaching statistical significance. There was no association between response to HAV-V and hepatitis C virus (HCV) coinfection, concomitant vaccination against HBV, or alcohol consumption in the standard-dose group. In the multivariate analysis adjusted for age and sex, a baseline HIV VL below 50 copies/mL (adjusted odds ratio (AOR): 4.86; 95% CI: 2.06 to 11.46; P < 0.001) and a CD4⁺ T-cell count >350/µL (AOR: 4.75; 95% CI: 1.84 to 12.3; P = 0.001) were the only variables independently associated with response, whereas tobacco smoking tended to negatively affect the response to HAV-V (AOR: 0.52; 95% CI: 0.26 to 1.06; P = 0.071).

In the single-dose group, 149 (83.2%; 95% CI: 76.9 to 88.4) individuals showed response to HAV-V evaluated after 175 (127–203) [32–363] days. Response rates, according to HIV-RNA undetectability and to CD4⁺ T-cell counts, are presented in Figure 1B. Median CD4⁺ T-cell counts were 694/µL, (513–861) [117–1620] in responders vs. 537/µL, (312–839) [81–1812] vs. nonresponders, P = 0.021. Corresponding numbers for the CD4⁺/CD8⁺ ratio were 0.85 (0.62–1.08) [0.08–2.83] vs. 0.54 (0.28–0.8) [0.14–1.39], P < 0.001). Age, HCV coinfection, concomitant vaccination against HBV, and alcohol consumption or tobacco smoking showed no influence on seroconversion. This group only included 2 women; both showed response to the HAV-V.

The response rates to HAV-V between the standard-dose and the single-dose groups were similar [Δ 5.1% (95% CI: 1.07 to 11.2), P = 0.107], despite them differing from the virological and immunological point of view.

One hundred twenty-nine patients of the standard-dose group had a response evaluation after the first dose. Of these, 53 patients (41.1%; 95% CI: 32.5 to 50.1) showed seroconversion evaluated after a median time of 97 (78–170) [30–184] days, accounting for a difference of 42.1% as compared with the single-dose group (P < 0.001) After completing the standard-dose scheme, seroconversion was achieved by 102/129 (79.1%; 95% CI: 71 to 85.7), P < 0.001. In the univariate analysis, an HIV VL below 50 copies/mL [33 (47.8%; 95% CI: 35.6 to 60.2) vs. 20 (33.3%; 95% CI: 21.7 to 46.7) patients, P = 0.109] and a higher age {39.2 (30.2–46.3) [21.3 − 68.1] vs. 34.7 (28.8–40.2) [20–68] years, P = 0.04} positively impacted on seroconversion rates. In those patients with an HIV VL <50 copies/mL and a CD4⁺ >350/µL (n = 182), the response rate was 73.1% (95% CI: 61.7 to 73.3) vs. 54.8% (95% CI: 46.2 to 63.4; P = 0.001) in those subjects with detectable VL and CD4⁺ <350/µL (n = 126). Two multivariate analyses were performed to identify the independent predictors of seroconversion to a single dose. In the first one, CD4⁺ T-cell count >350/µL (AOR: 2.12; 95% CI: 1.03 to 4.39, P = 0.042), HIV VL below 50 copies/mL (AOR: 1.92, 95% CI: 1.16 to 3.16, P = 0.011], and age (AOR: 1.03; 95% CI: 1.001 to 1.06, P = 0.044) were independently associated with seroconversion. In the second adjusted for age and HIV VL, the CD4⁺ T-cell count was substituted by the CD4⁺/CD8+ ratio and was the only variable independently associated with response to HAV-V (AOR: 2.99; 95% CI: 1.49 to 5.07, P = 0.002).

DISCUSSION

In this large real-life cohort of HIV-infected patients, a response rate higher than 95% to the standard double dose HAV-V was observed when plasma HIV-RNA was undetectable and the CD4⁺ T-cell count was ≥350/µL, 2 factors classically associated with response to the HAV-V.¹³

Before the widespread use of the triple ART, 2 clinical trials reported a seroconversion rate of 88% and 52% in 76 and 48 adult patients, who received 2 doses of 1140 inactivated HAV Units with a mean CD4⁺ of 555 and 380/μL, respectively, compared with a rate of 100% in HIV-negative subjects.^14,15 Afterward, in 2008, Launay et al¹⁶ observed a seroconversion rate as low as 72% among 49 patients who received the same vaccination scheme with a median CD4⁺ of 355/μL (IQR, 290–415) and an undetectable VL only in 56% of them. In more recent studies, the response rates to the standard scheme of vaccination were between 75% and 81%,^17–19 although less than two-thirds of the subjects were receiving ART.

In the context of an outbreak with shortage of HAV-V, we gave priority to vaccinate with a single dose of HVA-V to HIV-infected patients, mostly MSM, achieving seroconversion up to 83.2% of the cases, and we once again observed that an undetectable HIV viremia and a CD4⁺ T-cell count ≥350/µL were factors associated with the best response to HAV-V to which the CD4⁺/CD8⁺ ratio should be added, as demonstrated in this study. This high rate of seroconversion after a single HVA-V dose after 2016 merely reflects a better immunologic status of those subjects as result of earlier ART following international recommendations. In a subpopulation derived from the standard-dose group with only 67% on ART and 54% of them with an undetectable VL, the seroconversion rate after a single HAV-V dose fell to 41%.

The main limitation of this study is that only qualitative anti-HAV analysis was conducted. However, there is evidence from clinical experience suggesting that protection after HAV vaccination may be present even if there are no detectable HAV antibodies.⁶ Therefore, the rate of seroprotection after standard HAV-V scheme may rather be underrated than overestimated and thus support the results of this analysis. Furthermore, in this study, no long-term follow-up was analyzed and the median time to response evaluation differed significantly. Still, the longer duration to response evaluation was observed in the single-dose group, so a loss of seroprotection over time would have had more negative impact on the single-dose group and thus does not explain the considerably high protection rates in this group as compared with the standard-dose group. Still, studies on the long-term effect of a single dose as compared with the addition of a second dose in patients with favorable characteristics regarding the plasma HIV VL and CD4⁺ T-cell count are warranted. Finally, the number of patients with ≤ 200 CD4⁺/µL was very low and did not allow deeper analysis of the efficacy of HAV-V under this cutoff value.

As reflected in the present population, fecal–oral contact is one of the main transmission routes for HIV in Western countries, and, as a consequence, a high proportion of HIV-infected individuals are candidates for HAV-V. To avoid future hepatitis A outbreaks, MSM should still be considered as a risk group and, accordingly, should be candidates for the hepatitis A vaccine.

In conclusion, given the high overall response rates in the current clinical practice, HIV-infected patients should be encouraged to undergo HAV-V with 2 standard doses 6 months apart; a single dose achieves a high rate of seroconversion in those patients with favorable response factors, and it may be enough to limit and HAV outbreak in case of HAV-V shortage. However, once the supply is reestablished, patients are likely to benefit from a booster dose. In subjects without this favorable factors, others vaccination schemes, such as double dose or 2 doses in a shorter interval, must be investigated to obtain a higher response rate in a shorter period of time.