CD4/CD8 ratio normalization rates and low ratio as prognostic marker for non-AIDS defining events among long-term virologically suppressed people living with HIV

Win Min Han, Tanakorn Apornpong, Stephen J Kerr, Akarin Hiransuthikul, Sivaporn Gatechompol, Tanya Do, Kiat Ruxrungtham, Anchalee Avihingsanon, Win Min Han, Tanakorn Apornpong, Stephen J Kerr, Akarin Hiransuthikul, Sivaporn Gatechompol, Tanya Do, Kiat Ruxrungtham, Anchalee Avihingsanon

Abstract

Background: Immune restoration is often incomplete after ART in HIV patients, both quantitatively and qualitatively. We studied the incidence and probability of CD4/CD8 normalization in an adult Thai HIV cohort and explored the predictive value of the ratio for developing of non-AIDS defining events (NAEs).

Methods: We analyzed data from HIV-infected Thai adults between 1996 and 2017 in the HIV-NAT 006 prospective long-term cohort in Bangkok, Thailand. Normalization was defined as CD4/CD8 ratio ≥ 1 on two consecutive visits, and normalization probability was calculated using the Kaplan-Meier method. NAEs were a composite endpoint including cardiovascular or cerebrovascular diseases, chronic kidney diseases, non-AIDS defining malignancies and death. Multivariate Cox regression was used to evaluate demographic, disease and treatment characteristics associated with CD4/CD8 ratio normalization and NAEs.

Results: A total of 800 ART-naïve patients with baseline CD4/CD8 ratio of < 0.8 who started combination ART, and had sustained virological suppression were enrolled. Participants were on ART for a median of 8.9 years and virologically suppressed for 6.1 years. The probabilities of CD4/CD8 normalization at 2, 5 and 10 years after virological suppression were 5.1%, 18.6% and 39.1%, respectively. Factors associated with normalization in multivariate analysis were female sex (hazard ratio [HR]: 2.47, 95% CI 1.71-3.56, p < 0.001) and baseline CD4 counts ≥ 350 cells/mm3 (HR: 3.62, 95% CI 2.36-5.55), p < 0.001) vs. < 200 cells/mm3 as reference. The second analysis explored the predictive value of CD4/CD8 ratio for NAEs. Older age (HR: 1.09, 95% CI 1.05-1.13, p < 0.01) and current CD4/CD8 ratio < 0.3 (HR: 3.02, 95% CI 1.27-7.21, p = 0.01) or between 0.3 and 0.45 (HR: 2.03, 95% CI 1.03-3.98, p = 0.04) vs. > 0.45 were independently associated with higher risk of progression to NAEs in the multivariate analysis.

Conclusions: Our findings showed that complete immune recovery is uncommon in an Asian setting and earlier ART initiation at higher CD4 counts may have increased the ratio sooner. The findings demonstrate the use of CD4/CD8 ratio as a prognostic marker for clinical progression of NAEs. Trial registration HIV-NAT 006 cohort, clinical trial number: NCT00411983.

Keywords: Asia; CD4/CD8 ratio; Immune restoration; Long-term virological suppression; Non-AIDS events.

Figures

Fig. 1
Fig. 1
Flow diagram for patients for inclusion to study analysis
Fig. 2
Fig. 2
Kaplan–Meier curve showing probabilities of CD4/CD8 ratio normalization
Fig. 3
Fig. 3
Kaplan–Meier curves showing probabilities of composite end point with CD4/CD8 ratio

References

    1. Low A, Gavriilidis G, Larke N, B-Lajoie MR, Drouin O, Stover J, et al. Incidence of opportunistic infections and the impact of antiretroviral therapy among HIV-infected adults in low- and middle-income countries: a systematic review and meta-analysis. Clin Infect Dis. 2016;62(12):1595–1603. doi: 10.1093/cid/ciw125.
    1. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog. 2014;10(5):e1004078. doi: 10.1371/journal.ppat.1004078.
    1. Leung V, Gillis J, Raboud J, Cooper C, Hogg RS, Loutfy MR, et al. Predictors of CD4:CD8 ratio normalization and its effect on health outcomes in the era of combination antiretroviral therapy. PLoS ONE. 2013;8(10):e77665. doi: 10.1371/journal.pone.0077665.
    1. Mocroft A, Reiss P, Gasiorowski J, Ledergerber B, Kowalska J, Chiesi A, et al. Serious fatal and nonfatal non-AIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr. 2010;55(2):262–270. doi: 10.1097/QAI.0b013e3181e9be6b.
    1. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–1371. doi: 10.1038/nm1511.
    1. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol. 2008;214(2):231–241. doi: 10.1002/path.2276.
    1. Dock JN, Effros RB. Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging Dis. 2011;2(5):382–397.
    1. Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, Jacobson MA, et al. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011;203(10):1474–1483. doi: 10.1093/infdis/jir060.
    1. Hadrup SR, Strindhall J, Kollgaard T, Seremet T, Johansson B, Pawelec G, et al. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol. 2006;176(4):2645–2653. doi: 10.4049/jimmunol.176.4.2645.
    1. Wikby A, Maxson P, Olsson J, Johansson B, Ferguson FG. Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev. 1998;102(2–3):187–198. doi: 10.1016/S0047-6374(97)00151-6.
    1. Guiguet M, Kendjo E, Carcelain G, Abgrall S, Mary-Krause M, Tattevin P, et al. CD4+ T-cell percentage is an independent predictor of clinical progression in AIDS-free antiretroviral-naive patients with CD4+ T-cell counts > 200 cells/mm3. Antivir Ther. 2009;14(3):451–457.
    1. Mussini C, Lorenzini P, Cozzi-Lepri A, Lapadula G, Marchetti G, Nicastri E, et al. CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study. Lancet HIV. 2015;2(3):e98–e106. doi: 10.1016/S2352-3018(15)00006-5.
    1. Serrano-Villar S, Perez-Elias MJ, Dronda F, Casado JL, Moreno A, Royuela A, et al. Increased risk of serious non-AIDS-related events in HIV-infected subjects on antiretroviral therapy associated with a low CD4/CD8 ratio. PLoS ONE. 2014;9(1):e85798. doi: 10.1371/journal.pone.0085798.
    1. Caby F, Guihot A, Lambert-Niclot S, Guiguet M, Boutolleau D, Agher R, et al. Determinants of a low CD4/CD8 ratio in HIV-1-infected individuals despite long-term viral suppression. Clin Infect Dis. 2016;62(10):1297–1303. doi: 10.1093/cid/ciw076.
    1. Petoumenos K, Choi JY, Hoy J, Kiertiburanakul S, Ng OT, Boyd M, et al. CD4:CD8 ratio comparison between cohorts of HIV-positive Asians and Caucasians upon commencement of antiretroviral therapy. Antivir Ther. 2017;22(8):659–668. doi: 10.3851/IMP3155.
    1. Putcharoen O, Wattanachanya L, Sophonphan J, Siwamogsatham S, Sapsirisavat V, Gatechompol S, et al. New-onset diabetes in HIV-treated adults: predictors, long-term renal and cardiovascular outcomes. AIDS. 2017;31(11):1535–1543. doi: 10.1097/QAD.0000000000001496.
    1. Durier N, Ananworanich J, Apornpong T, Ubolyam S, Kerr SJ, Mahanontharit A, et al. Cytomegalovirus viremia in Thai HIV-infected patients on antiretroviral therapy: prevalence and associated mortality. Clin Infect Dis. 2013;57(1):147–155. doi: 10.1093/cid/cit173.
    1. Edwards-Jackson N, Kerr S, Tieu H, Ananworanich J, Hammer S, Ruxrungtham K, et al. Cardiovascular risk assessment in persons with HIV infection in the developing world: comparing three risk equations in a cohort of HIV-infected Thais. HIV Med. 2011;12(8):510–515. doi: 10.1111/j.1468-1293.2011.00916.x.
    1. Tinago W, Coghlan E, Macken A, McAndrews J, Doak B, Prior-Fuller C, et al. Clinical, immunological and treatment-related factors associated with normalised CD4+/CD8+ T-cell ratio: effect of naive and memory T-cell subsets. PLoS ONE. 2014;9(5):e97011. doi: 10.1371/journal.pone.0097011.
    1. Falster K, Petoumenos K, Chuah J, Mijch A, Mulhall B, Kelly M, et al. Poor baseline immune function predicts an incomplete immune response to combination antiretroviral treatment despite sustained viral suppression. J Acquir Immune Defic Syndr. 2009;50(3):307–313. doi: 10.1097/QAI.0b013e3181945ed4.
    1. Trickey A, May MT, Schommers P, Tate J, Ingle SM, Guest JL, et al. CD4:CD8 ratio and CD8 count as prognostic markers for mortality in human immunodeficiency virus-infected patients on antiretroviral therapy: the antiretroviral therapy cohort collaboration (ART-CC) Clin Infect Dis. 2017;65(6):959–966. doi: 10.1093/cid/cix466.
    1. Serrano-Villar S, Gutierrez C, Vallejo A, Hernandez-Novoa B, Diaz L, Abad Fernandez M, et al. The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression. J Infect. 2013;66(1):57–66. doi: 10.1016/j.jinf.2012.09.013.
    1. Sainz T, Serrano-Villar S, Diaz L, Gonzalez Tome MI, Gurbindo MD, de Jose MI, et al. The CD4/CD8 ratio as a marker T-cell activation, senescence and activation/exhaustion in treated HIV-infected children and young adults. AIDS. 2013;27(9):1513–1516. doi: 10.1097/QAD.0b013e32835faa72.
    1. Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011;203(6):780–790. doi: 10.1093/infdis/jiq118.
    1. Barrett L, Stapleton SN, Fudge NJ, Grant MD. Immune resilience in HIV-infected individuals seronegative for cytomegalovirus. AIDS. 2014;28(14):2045–2049. doi: 10.1097/QAD.0000000000000405.
    1. Freeman ML, Mudd JC, Shive CL, Younes SA, Panigrahi S, Sieg SF, et al. CD8 T-cell expansion and inflammation linked to CMV coinfection in ART-treated HIV infection. Clin Infect Dis. 2016;62(3):392–396. doi: 10.1093/cid/civ840.

Source: PubMed

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