Blunted response to combination antiretroviral therapy in HIV elite controllers: an international HIV controller collaboration

Faroudy Boufassa, Jérome Lechenadec, Laurence Meyer, Dominique Costagliola, Peter W Hunt, Florencia Pereyra, Steve Deeks, Gianfranco Pancino, Olivier Taulera, Mathias Lichterfeld, Pierre Delobel, Asier Saez-Cirion, Olivier Lambotte, ANRS CO18 HIV Controllers Cohort, Cascade Collaboration in Eurocoord, SCOPE Cohort, International HIV Controllers Study, Faroudy Boufassa, Jérome Lechenadec, Laurence Meyer, Dominique Costagliola, Peter W Hunt, Florencia Pereyra, Steve Deeks, Gianfranco Pancino, Olivier Taulera, Mathias Lichterfeld, Pierre Delobel, Asier Saez-Cirion, Olivier Lambotte, ANRS CO18 HIV Controllers Cohort, Cascade Collaboration in Eurocoord, SCOPE Cohort, International HIV Controllers Study

Abstract

Objective: HIV "elite controllers" (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs).

Methods: ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models.

Results: After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63√CD4/month), followed by +0.19√CD4/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm(3), the estimated mean CD4 T-cell gain during the first 12 months was 139/mm(3) in VIRs and 80/mm(3) in ECs (p = 0.048).

Conclusions: cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Estimated CD4 cell count dynamics…
Figure 1. Estimated CD4 cell count dynamics in viremic patients (VIRs: n = 478) and elite controllers (ECs: n = 34) in mixed-effect linear models (mean CD4 T cells gain after 12 months of cART was significantly lower in ECs than in VIRs (p = 0.048)).

References

    1. Touloumi G, Pantazis N, Stirnadel HA, Walker S, Boufassa F, et al. (2008) Rates and determinants of virologic and immunological response to HAART resumption after treatment interruption in HIV-1 clinical practice. J Asquir Immune Defic Syndr 49(5): 492–498.
    1. Hunt PW, Deeks SG, Rodriguez B, Valdez H, Shade SB, et al. (2003) Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 17: 1907–15.
    1. Bosch RJ, Wang R, Vaida F, Lederman MM, Albrecht MA (2006) for the AIDS Clinical Trial Group 364 Study Team. Changes in slope of the CD4 cell count increase after initiation of potent antiretroviral treatment. J Acquir Immune Defic Syndr 43(4): 433–435.
    1. Grabar S, Koussignian I, Sobel A, Le Bras P, Gasnault J, et al. (2004) Immunologic and clinical responses to HAART over a 50 years of age. Results from the French Hospital Database on HIV. AIDS 18(15): 2009–2038.
    1. Wood E, Yip B, Hogg RS, Sherlock CH, Jahnke N, et al. (2000) Full suppression of viral load is needed to achieve an optimal CD4 cell count response among patients on triple drug antiretroviral therapy. AIDS 14: 1955–1960.
    1. Smith CJ, Sabin CA, Youle MS, Kinlock-de Loes S, Lampe FC, et al. (2004) Factors influencing increases in CD4 cell counts of HIV-positive persons receiving long-term highly active antiretroviral therapy. JID 190: 1860–1868.
    1. Lifson AR, Krantz EM, Eberly LE, Dolan MJ, Marconi VC, et al. (2011) Long-term CD4+ lymphocyte response following HAART initiation in a U.S. military prospective cohort. AIDS Research and Therapy 8: 2–11.
    1. Bailey JR, Williams TM, Siliciano RF, Blankson JN (2006) Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. J Exp Med. 203: 1357–1369.
    1. Blankson JN, Bailey JR, S Thayil HC, Yang HC, Lassen K, et al. (2007) Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J Virol. 81: 2508–2518.
    1. Sáez-Cirión A, Pancino G, Sinet M, Venet A (2007) Lambotte (2007) O for the ANRS EP36 HIV CONTROLLERS study group. HIV Controllers: how do they tame the virus? Trends Immunol. 28(12): 532–540.
    1. Deeks SG, Walker BD (2007) Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27: 406–416.
    1. Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, et al. (2008) Genetic and Immunologic Heterogeneity among Persons Who Control HIV Infection in the Absence of Therapy. J Infect Dis 197: 563–571.
    1. Madec Y, Boufassa F, Porter K, Meyer L on behalf of the CASCADE Collaboration (2005) Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters. AIDS 19: 2001–2007.
    1. Lambotte O, Boufassa F, Madec Y, Nguyen A, Goujard C, et al. (2005) HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. CID 41: 1053–1056.
    1. Okulicz JF, Marconi VC, Landrum ML, Wegner S, Weintrob AC, et al. (2009) Clinical outcomes of elite controllers, viremic controllers, and long-term non progressors in the US Department of Defense HIV Natural History study. J Infect Dis 200: 1714–1723.
    1. Okulicz JF, Grandits GA, Weintrob AC, Landrum ML, Ganesan A, et al. (2010) CD4 T cell reconstitution in HIV controllers after highly active antiretroviral therapy. CID 50: 1187–1191.
    1. Hatano H, Yukl SA, Ferre AL, Graf EH, Somosouk M, et al. (2013) Prospective antiretroviral treatment of asymptomatic HIV-1 infected controllers. PLOS Pathogens 9(10): e1003691.
    1. Vingert B, Benati D, Lambotte O, de Truchis P, Slama L, et al. (2012) HIV controllers maintain a population of highly efficient Th1 effector cells in contrast to patients treated in the long term. J Virol 86(19): 10661–10674.
    1. Hunt PW, Landay AL, Sinclair E, Martinson JA, Hatano H, et al. (2011) A Low T Regulatory Cell Response May Contribute to Both Viral Control and Generalized Immune Activation in HIV Controllers. PLoS ONE 6(1): e15924 doi:
    1. The International HIV Controllers Study (2010) The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330: 1551–1557.
    1. Madec Y, Boufassa F, Porter K, Prins M, Sabin C, et al. (2013) Natural History of HIV control since seroconversion: Experience from the CASCADE collaboration. AIDS 27(15): 2451–2460.
    1. Pereyra F, Palmer S, Miura T, Block BL, Wiegand A, et al. (2009) Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J Infect Dis 200: 984–990.
    1. Hatano H, Delwart EL, Norris PJ, Lee TH, Dunn-Williams J, et al. (2009) Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol 83: 329–335.
    1. Sauce D, Larsen M, Fastenackels S, Pauchard M, Ait-Mohand H, et al. (2011) HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood 117(19): 5142–5151.
    1. Yang Y, Al-Mozaini M, Buzon MJ, Beamon J, Ferrando-Martinez S, et al. (2012) CD4 T-cell regeneration in HIV-1 elite controllers. AIDS 26: 701–706.
    1. Sajadi MM, Pulijala R, Redfield RR, Talwani R (2012) Chronic immune activation and decreased CD4 counts associated with hepatitis C infection in HIV-1 natural viral suppressors. AIDS 26(25): 1879–1884.
    1. Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, et al. (2000) Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV cohort study. Lancet 356: 1800–1805.
    1. De Luca A, Bugarini R, Cozzi Lepri A, Puoti M, Girardi E, et al. (2002) Coinfection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects. Arch Intern Med. 162: 2125–2132.
    1. Rockstroh JK, Mocroft A, Soriano V, Tural C, Losso MH, et al. (2005) Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. JID 192: 992–1002.
    1. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, et al. (1997) Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277(5322): 112–116.
    1. Hunt PW, Brenchley J, Sinclair E, Mc Cune JM, Roland M, et al. (2008) Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. JID 197: 126–133.
    1. Mocroft A, Furrer HJ, Miro JM, Reiss P, Mussini C, et al. (2013) The incidence of AIDS-defining illnesses at a current CD4 count ≤200 cells/mm3 in the post-combination antiretroviral therapy era. CID 57: 1038–1047.
    1. Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, et al. (2013) Post-treatment HIV-1 controllers with a long term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211 Doi:

Source: PubMed

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