Long-Term Persistence of Humoral Immunity After Hepatitis A Vaccination in HIV-Infected Adults (2011)

To the Editors: INTRODUCTION HIV-infected patients exposed to hepatitis A virus (travelers to countries with high endemicity, men who have sex with men, users of illicit drugs) are targeted by vaccination.1 Hepatitis A vaccine is less immunogenic in HIV-infected adults than in immunocompetent persons: both seroconversion rates and antibody titers are lower, especially in patients with CD4 counts <500 cells per cubic millimeter.2,3 In immunocompetent subjects, protective anti-HAV (Hepatitis A Virus) titers persist for decades after vaccination in most subjects,4 and booster doses are generally not recommended. Impaired immunogenicity can shorten the duration of protection provided by vaccination, and a crucial question is to state on the need and optimal timing of such booster vaccination in immunocompromised persons, such as HIV-infected patients. To date, few data exist on long-term persistence of immunity after hepatitis A vaccination in HIV-infected adults.3,5,6 We reported previously the results of a randomized controlled trial comparing the immunogenicity of a 3-dose to a standard 2-dose schedule of HAV in 99 HIV-infected adults.3 Four weeks after last vaccine dose, 71 over 90 evaluable patients had reached the protective anti-HAV antibody level (88% and 72% in the 3-dose and 2-dose groups, respectively, P = 0.11). Here, we describe long-term antibody responses 3.7 years (±0.5) after last vaccine dose and predictors of loss of seroprotection. METHODS From June 2003 to May 2005, 99 HIV-1-infected patients with CD4-T cells between 200 and 500 cells per cubic millimeter, HIV-1 RNA level <50,000 copies per milliliter and negative anti-HAV IgG antibodies were included in a study conducted in 7 French university sites. Patients were randomized to receive either a standard 2 dose (at weeks 0 and 24, n = 50) or a reinforced 3-dose regimen (at weeks 0, 4 and 24, n = 49) of HAV (HAVRIX 1440; GlaxoSmithKline, Marly le Roi, France). Serum samples were centralized and tested for anti-HAV antibodies at weeks 4, 24, 28, 72 after the first vaccine dose. Anti-HAV antibody titers were determined with an enzyme-linked immunosorbent assay method (ETI-AB-HAVK PLUS; DiaSorin, Saluggia, Italy). Patients who had reach the protective level of antibody titers (≥20 mIU/mL) at week 28 were defined as “responders” and tested for anti-HAV antibodies 3.7 years (±0.5) after last vaccination. Predictors of loss of HAV seroprotection were assessed by logistic regression in participants who had received at least 2 vaccine doses and were responders at week 28. Variables analyzed in the univariable analysis were as follows: age, gender, smoking habits, CDC clinical stage at inclusion, time from diagnosis of HIV infection, nadir of CD4+ T-cell count, maximal HIV viral load, titer of anti-VHA antibodies 1 month after last vaccine dose, and CD4+ T-cell count and HIV viral load at study entry, at time of second (or third) injection, and at the end of follow-up. Continuous and categorical covariates were compared using Wilcoxon and Fisher exact tests, respectively. Factors achieving a P value <0.20 in the univariable analysis were included in the multivariable analysis. A backward stepwise variable selection procedure was used to remove factors with P value >0.05. Sta tistical analyses were done using R 2.11.1 statistical package (http://www.R-project.org). RESULTS Ninety-nine patients were randomized in the study and 91 received at least 2 vaccine doses. Seventy-one were responders at week 28, and among them, 52 provided blood sample 3.7 years (±0.5) after last vaccine dose (26 in both arms). Baseline characteristics of these 52 responders did not differ from those initially randomized: 44 men (85%), median age 39.5 years (interquartile range: 33.9-43.3), 17 smokers (33%), 14 with CDC stage C disease (27%), median CD4 T-cell count of 362 cells per cubic millimeter (interquartile range: 295-405), and 32 (62%) with median HIV-1 RNA level <50 copies per milliliter at baseline. At the end of follow-up, 85% (95% CI = 74% to 95%) of initial responders had maintained protective anti-HAV titers (85% in both groups). As presented in Figure 1, anti-HAV titers reached their maximum 4 weeks after last vaccine dose and experienced a rapid decline followed by a long-term plateau. Geometric Mean Titers (GMTs) did not significantly differ between the 2 groups at week 4 [GMTs (95% CI) mIU/mL = 451.5 (296.4 to 687.7) and 532.6 (335.1 to 846.7) in the 2-dose and 3-dose groups, respectively, P = 0.34], week 48 [172.0 (101.2 to 292.3) vs. 162.3 (93.1 to 283.1), P = 1], nor at the end of follow-up [46.3 (33.3 to 64.2) vs. 76.5 (50.8 to 115.2), P = 0.06].FIGURE 1: Anti-HAV GMTs measured 4 weeks, 48 weeks, and 3.7 years (196 weeks)after last vaccine dose in 52 HIV-1-infected adults who received either 2 (solid line) or3 doses (dashed line) of HAV.Predictors of loss of seroprotection in the univariable analysis were as follows: a long duration of HIV infection (P = 0.04), a detectable HIV-1 viral load at time of last vaccine dose (P = 0.001), and a low titer of anti-HAV antibodies 1 month after last vaccine dose (P = 0.008). CD4+ T-cell count at baseline also tended to be higher among long-term responders, but the difference was not significant [370 cells/mm3 (315 to 420) versus 303/mm3 (285 to 356), P = 0.11]. In the multivariable analysis, only a detectable HIV-1 viral load at time of last vaccine dose [OR (95% CI) = 28.7 (2.8 to infinity)] and a long duration of HIV infection [OR (95% CI) = 2.9 (1.2 to 19.4) per 5 years] remained significantly associated with loss of protective antibody titers. DISCUSSION In our population of 52 HIV-1-infected adults who initially responded to 2 or 3 doses of HAV, 85% (95% CI = 74 to 95) were able to maintain protective anti-HAV titers 3.7 years (±0.5) after last vaccine dose. However, anti-HAV antibody titers decreased by approximately 90% during follow-up. After adjustment, predictors of long-term maintenance of protective antibody titers were a shorter duration of HIV infection at inclusion and an undetectable HIV viral load at time of last vaccine dose. Anti-HAV GMTs were somewhat, although not significantly, more elevated in the 3 doses group at the end of follow-up, but sample sizes were small. Our results are consistent with the other two studies on long-term immunologic responses (>6 months) to HAV in HIV-positive patients.5,6 Among initial vaccine responders, 90% at 18 months (n = 108)5 and 90% at 3 years (n = 116)6 maintained protective antibody titers. High responders (antibody titers ≥250 mIU/mL) were more likely to maintain seroprotection at 18 months5 and lower log10 HIV RNA level at the time of vaccination was associated with higher anti-HAV GMTs over time (b = −0.068, P = 0.005).6 Postvaccination anti-HAV titers seem to decline more rapidly in HIV-infected individuals compared with healthy persons, as previously shown for other vaccines such as hepatitis B7 and Pneumococcus vaccines.8 High antibody titers during the first months after vaccination and low HIV viral load at time of vaccination seem to be strong predictors of long-term maintenance of antibodies.7,8 Our report also underlines the role of duration of HIV infection as an independent cofactor. This suggests that in HIV-infected persons, HAV should be administered as early as possible in the course of the disease and more importantly, in patients with undetectable HIV viral load. Conversely, the 3-dose vaccine scheme does not seem to be strongly associated with long-term maintenance of protective antibodies. In healthy subjects, protective anti-HAV titers have been estimated to persist for decades after vaccination.4 Considering the rapid decline of anti- HAV antibody titers in HIV-positive patients, it would certainly be useful to check achievement of seroconversion at the end of vaccine scheme and repeat dosage of anti-HAV every 2 or 3 years, especially in low responders or patients with uncontrolled HIV infection to propose booster injections. The optimal timing for repeated measurements of anti-HAV is not clear and would require additional studies beyond 10 years and statistical modeling to try to obtain reliable predictions at an individual level. ACKNOWLEDGMENTS The authors thank all patients, nurses, and physicians in investigation centres. HEPAVAC Study Group: OL (coordinator), C.D., L.B., S.G., B. Silbermann, J. Dimet, C. Guérin, D. Jégou, A. Krivine, V. Lebault, D. Salmon, and M. P. Piétri (Hôpital Cochin, Paris); O.L., R. Lahoulou, and B. Dupont (Hôpital Necker, Paris); D.R., P. Fischer, and J. M. Lang (Strasbourg); S.A., E.G., O. Bouchaud, S. Abad, and V. Williams (Bobigny); PMG., D. Bollens, B. Lefèvre, J. L. Meynard, and P. Roussard (Hôpital Saint-Antoine, Paris); C. Piketty and M. Kahramann (Hôpital Européen Georges Pompidou, Paris); and J. Beytout (Clermont Ferrand). Solen Kernéis, MD*† Corinne Desaint, PhD* Ségolène Brichler, PharmD‡ David Rey, MD§ Linda Belarbi, MD* Emmanuel Gordien, MD, PhD‡ Jérôme Pacanowski, MD‖ Olivier Lortholary, MD, PhD¶ Sophie Abgrall, MD, PhD# Pierre-Yves Boëlle, PhD† Sophie Grabar, MD, PhD** Odile Launay, MD, PhD* *Université Paris Descartes, Faculté de Médecine; Inserm, CIC BT505; Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, CIC Vaccinologie de Vaccinologie Cochin Pasteur, Paris, France †INSERM, UMR-S 707; Université Pierre et Marie Curie-Paris 6, UMR-S 707, F-75012, Paris, France ‡Université Paris 13; Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service de bactériologie, virologie—hygiène, Bobigny, France §Le Trait d'Union, Centre de Soins de l'Infection par le VIH, Hôpitaux Universitaires, Strasbourg, France ‖Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Service des maladies infectieuses et tropicales, Paris, France ¶Université Paris Descartes, Faculté de Médecine; Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Centre d'Infectiologie Necker Pasteur, Paris, France #Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service des maladies infectieuses et tropicales, Bobigny, France **Université Paris Descartes; INSERM U943; Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Unité de Biostatistique et Epidémiologie, Paris, France