Background Whether seroresponse to a vaccine such as hepatitis B virus (HBV) vaccine can provide a measure of the functional immune status of HIV-infected persons is unknown.This study evaluated the relationship between HBV vaccine seroresponses and progression to clinical AIDS or death. Methods and Findings From a large HIV cohort, we evaluated those who received HBV vaccine only after HIV diagnosis and had anti-HBs determination 1–12 months after the last vaccine dose. Non-response and positive response were defined as anti-HBs <10 and ≥10 IU/L, respectively. Participants were followed from date of last vaccination to clinical AIDS, death, or last visit. Univariate and multivariable risk of progression to clinical AIDS or death were evaluated with Cox regression models. A total of 795 participants vaccinated from 1986–2010 were included, of which 41% were responders. During 3,872 person-years of observation, 122 AIDS or death events occurred (53% after 1995). Twenty-two percent of non-responders experienced clinical AIDS or death compared with 5% of responders (p<0.001). Non-response to HBV vaccine was associated with a greater than 2-fold increased risk of clinical AIDS or death (HR 2.47; 95% CI, 1.38–4.43) compared with a positive response, after adjusting for CD4 count, HIV viral load, HAART use, and delayed type hypersensitivity skin test responses (an in vivo marker of cell-mediated immunity). This association remained evident among those with CD4 count ≥500 cells/mm3 (HR 3.40; 95% CI, 1.39–8.32). Conclusions HBV vaccine responses may have utility in assessing functional immune status and risk stratificating HIV-infected individuals, including those with CD4 count ≥500 cells/mm3.
References
[1]
Centers for Disease Control and Prevention (2009) Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR 58: 1–94.
[2]
Mellors JW, Munoz A, Giorgi JV, Margolick JB, Tassoni CJ, et al. (1997) Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Annals of Internal Medicine 126: 946–954.
[3]
O'Brien WA, Hartigan PM, Martin D, Esinhart J, Hill A, et al. (1996) Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. New England Journal of Medicine 334: 426–431.
[4]
The INSIGHT-ESPRIT Study Group and SILCAAT Scientific Committee (2009) Interleukin-2 therapy in patients with HIV infection. New England Journal of Medicine 361: 1548–1559.
[5]
Rodriguez B, Sethi AK, Cheruvu VK, Mackay W, Bosch RJ, et al. (2006) Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 296: 1498–1506.
[6]
Dolan MJ, Kulkarni H, Camargo JF, He W, Smith A, et al. (2007) CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. Nature Immunology 8: 1324–1336.
[7]
Maas JJ, Roos MT, Keet IP, Mensen EA, Krol A, et al. (1998) In vivo delayed-type hypersensitivity skin test anergy in human immunodeficiency virus type 1 infection is associated with T cell nonresponsiveness in vitro. J Infect Dis 178: 1024–1029.
[8]
Jones-Lopez EC, Okwera A, Mayanja-Kizza H, Ellner JJ, Mugerwa RD, et al. (2006) Delayed-type hypersensitivity skin test reactivity and survival in HIV-infected patients in Uganda: should anergy be a criterion to start antiretroviral therapy in low-income countries? Am J Trop Med Hyg 74: 154–161.
[9]
Dolan MJ, Clerici M, Blatt SP, Hendrix CW, Melcher GF, et al. (1995) In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus. Journal of Infectious Diseases 172: 79–87.
[10]
Anastos K, Shi Q, French AL, Levine A, Greenblatt RM, et al. (2004) Total lymphocyte count, hemoglobin, and delayed-type hypersensitivity as predictors of death and AIDS illness in HIV-1-infected women receiving highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 35: 383–392.
[11]
Blatt SP, Hendrix CW, Butzin CA, Freeman TM, Ward WW, et al. (1993) Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients. Annals of Internal Medicine 119: 177–184.
[12]
Birx DL, Brundage J, Larson K, Engler R, Smith L, et al. (1993) The prognostic utility of delayed-type hypersensitivity skin testing in the evaluation of HIV-infected patients. Journal of Acquired Immune Deficiency Syndromes 6: 1248–1257.
[13]
Meroni L, Marchetti G, Gatti N, d'Arminio Monforte A, Galli M (2003) Delayed-type hypersensitivity skin testing can predict CD4 count increase in HIV patients with poor immunologic response to HAART. J Acquir Immune Defic Syndr 33: 277–278.
[14]
Aberg JA, Gallant JE, Anderson J, Oleske JM, Libman H, et al. (2004) Primary care guidelines for the management of persons infected with human immunodeficiency virus: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 39: 609–629.
[15]
Landrum ML, Huppler Hullsiek K, Ganesan A, Weintrob AC, Crum-Cianflone NF, et al. (2010) Hepatitis B vaccination and risk of hepatitis B infection in HIV-infected individuals. AIDS 24: 545–555.
[16]
Bauer T, Jilg W (2006) Hepatitis B surface antigen-specific T and B cell memory in individuals who had lost protective antibodies after hepatitis B vaccination. Vaccine 24: 572–577.
[17]
Egea E, Iglesias A, Salazar M, Morimoto C, Kruskall MS, et al. (1991) The cellular basis for lack of antibody response to hepatitis B vaccine in humans. J Exp Med 173: 531–538.
[18]
Filion LG, Saginur R, Szczerbak N (1988) Humoral and cellular immune responses by normal individuals to hepatitis B surface antigen vaccination. J Exp Immunol 71: 405–409.
[19]
Goncalves L, Albarran B, Salmen S, Borges L, Fields H, et al. (2004) The nonresponse to hepatitis B vaccination is associated with impaired lymphocyte activation. Virology 326: 20–28.
[20]
Valdez H, Smith KY, Landay A, Connick E, Kuritzkes DR, et al. (2000) Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. AIDS 14: 11–21.
[21]
Loke RH, Murray-Lyon IM, Coleman JC, Evans BA, Zuckerman AJ (1990) Diminished response to recombinant hepatitis B vaccine in homosexual men with HIV antibody: an indicator of poor prognosis. Journal of Medical Virology 31: 109–111.
[22]
Chun HM, Fieberg AM, Hullsiek KH, Lifson AR, Crum-Cianflone NF, et al. (2010) The epidemiology of hepatitis B virus infection in a U.S. cohort of HIV-infected individuals during the last 20 years. Clinical Infectious Diseases 50: 426–436.
[23]
Landrum ML, Fieberg AM, Chun HM, Crum-Cianflone NF, Marconi VC, et al. (2010) The effect of human immunodeficiency virus on hepatits B virus serological status in co-infected adults. PLoS One 5: e8687.
[24]
Landrum ML, Hullsiek KH, Chun HM, Crum-Cianflone NF, Ganesan A, et al. (2011) The timing of hepatitis B virus (HBV) immunization relative to human immunodeficiency virus (HIV) diagnosis and the risk of HBV infection following HIV diagnosis. American Journal of Epidemiology 173: 84–83.
[25]
Landrum ML, Huppler Hullsiek K, Ganesan A, Weintrob AC, Crum-Cianflone NF, et al. (2009) Hepatitis B vaccine responses in a large U.S. military cohort of HIV-infected individuals: Another benefit of HAART in those with preserved CD4 count. Vaccine 27: 4731–4738.
[26]
Brodine SK, Starkey MJ, Shaffer RA, Ito SI, Tasker SA, et al. (2003) Diverse HIV-1 subtypes and clinical, laboratory and behavioral factors in a recently infected US military cohort. AIDS 17: 2521–2527.
[27]
Centers for Disease Control and Prevention (1992) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 41: Available: http://www.cdc.gov/mmwr/preview/mmwrhtml？/00018871.htm. Accessed Jan 4, 2008.
[28]
Alper CA, Kruskall MS, Marcus-Bagley D, Craven DE, Katz AJ, et al. (1989) Genetic prediction of nonresponse to hepatitis B vaccine. New England Journal of Medicine 321: 708–712.
[29]
Craven DE, Awdeh ZL, Kunches LM, Yunis EJ, Dienstag JL, et al. (1986) Nonresponsiveness to hepatitis B vaccine in health care workers: results of revaccination and genetic typings. Annals of Internal Medicine 105: 356–360.
[30]
Wang C, Tang J, Song W, Lobashevsky E, Wilson CM, et al. (2004) HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination. Hepatology 39: 978–988.
[31]
Moir S, Fauci AS (2008) Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J Allergy Clin Immunol 122: 12–19.
[32]
Moir S, Ogwaro KM, Malaspina A, Vasquez J, Donoghue ET, et al. (2003) Pertubations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals. PNAS 100: 6057–6062.
[33]
Pessoa SD, Miyamoto M, Ono E, Gouvea AFTB, de Moraes-Pinto MI, et al. (2010) Persistence of vaccine immunity against hepatitis B virus and response to revaccination in vertically HIV-infected adolescents on HAART. Vaccine 28: 1606–1612.
[34]
del Mar del Pozo Balado M, Leal M, Lagares GM, Mata RC, Lopez-Cortes LF, et al. (2010) Increased regulatory T cell counts in HIV-infected nonresponders to hepatitis B virus vaccine. Journal of Infectious Diseases 202: 362–369.
[35]
Holmes D, Jiang Q, Zhang L, Su L (2008) Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis. Immunology Research 41: 248–266.
[36]
Yang Z, Wang L, Niu W, Wu Y, Zhang J, et al. (2008) Increased CD4+CD25+FoxP3+ regulatory T cells in the blood of nonresponders after standard hepatitis B surface antigen vaccine immunization. Clinical Immunology 127: 256–266.
Appay V, Rowland-Jones SL (2002) Premature ageing of the immune system: the cause of AIDS? Trends in Immunology 23:
[39]
Effros RB (2007) Role of T lymphocyte replicative senescence in vaccine efficacy. Vaccine 25: 599–604.
[40]
Lange CG, Lederman MM, Medvik K, Asaad R, Wild M, et al. (2003) Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS 17: 2015–2023.
[41]
Hunt PW (2007) Role of immune activation in HIV pathogenesis. Current HIV/AIDS Reports 4: 42–47.
[42]
Effros RB, Dagarag MD, Spaulding CC, Man J (2005) The role of CD8 T cell replicative senescence in human aging. Immunology Reviews 205: 147–157.
[43]
Marconi VC, Grandits GA, Weintrob AC, Chun H, Landrum ML, et al. (2010) Outcomes of highly active antiretroviral therapy in the context of universal access to healthcare: the U.S. military HIV natural history study. AIDS Research and Therapy 7: 14.
