CD4 rate of increase is preferred to CD4 threshold for predicting outcomes among virologically suppressed HIV-infected adults on antiretroviral therapy

Autoři: Sol Aldrete aff001;  Jeong Hoon Jang aff002;  Kirk A. Easley aff002;  Jason Okulicz aff003;  Tian Dai aff004;  Yi No Chen aff005;  Maria Pino aff006;  Brian K. Agan aff007;  Ryan C. Maves aff008;  Mirko Paiardini aff006;  Vincent C. Marconi aff006
Působiště autorů: Division of Infectious Diseases, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America aff001;  Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America aff002;  Division of Internal Medicine and Infectious Disease Service, San Antonio Military Medical Center, San Antonio, Texas, United States of America aff003;  Amgen Inc, Thousands Oaks, California, United States of America aff004;  Department of Epidemiology, Emory University, Atlanta, Georgia, United States of America aff005;  Division of Microbiology and Immunology, Yerkes Non-Human Primates Research Center and Emory Vaccine Center, Atlanta, Georgia, United States of America aff006;  Department of Preventive Medicine and Biostatistics, Infectious Diseases Clinical Research Program, Uniformed Services University of the Health Sciences and Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Maryland, United aff007;  Division of Infectious Diseases, Naval Medical Center San Diego, San Diego, California, United States of America aff008;  Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, Georgia, United States of America aff009;  Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America aff010;  Atlanta Veterans Affairs Medical Center, Decatur, Georgia, United States of America aff011
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article



Immune non-responders (INR) have poor CD4 recovery and are associated with increased risk of serious events despite antiretroviral therapy (ART). A clinically relevant definition for INR is lacking.


We conducted a retrospective analysis of three large cohorts: Infectious Disease Clinic at the Atlanta Veterans Affairs Medical Center, the US Military HIV Natural History Study and Infectious Disease Program of the Grady Health System in Atlanta, Georgia. Two-stage modeling and joint model (JM) approaches were used to evaluate the association between CD4 (or CD4/CD8 ratio) slope within two years since ART initiation and a composite endpoint (AIDS, serious non-AIDS events and death) after two years of ART. We compared the predictive capacity of four CD4 count metrics (estimated CD4 slope, estimated CD4/CD8 ratio slope during two years following ART initiation and CD4 at 1 and 2 years following ART initiation) using Cox regression models.


We included 2,422 patients. Mean CD4 slope (±standard error) during two years of ART was 102 ± 2 cells/μl/year (95% confidence interval: 98–106 cells/μl/year), this increase was uniform among the three cohorts (p = 0.80). There were 267 composite events after two years on ART. Using the JM approach, a CD4 slope ≥100 cells/μL/year or CD4/CD8 ratio slope >0.1 higher rate per year were associated with lower composite endpoint rates (adjusted hazard ratio [HR] = 0.80, p = 0.04 and HR = 0.75 p<0.01, respectively). All four CD4 metrics showed modest predictive capacity.


Using a complex JM approach, CD4 slope and CD4/CD8 ratio slope the first two years after ART initiation were associated with lower rates of the composite outcome. Moreover, the uniformity observed in the mean CD4 slope regardless of the cohort suggests a common CD4 response pattern independent of age or CD4 nadir. Given the consistency observed with CD4 slope, availability and ease of interpretation, this study provides strong rationale for using CD4 gains <100 cells/μl/year to identify patients at risk for adverse events.

Klíčová slova:

Age groups – HIV – Immune response – Infectious diseases – Natural history of disease – Veteran care – Veterans – Antiretroviral therapy


1. Palella FJ Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):853–60. doi: 10.1056/NEJM199803263381301 9516219

2. Kaufmann GR, Perrin L, Pantaleo G, Opravil M, Furrer H, Telenti A, et al. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. Arch Intern Med. 2003;163(18):2187–95. doi: 10.1001/archinte.163.18.2187 14557216

3. Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48(6):787–94. doi: 10.1086/597093 19193107

4. Gaardbo JC, Hartling HJ, Gerstoft J, Nielsen SD. Incomplete immune recovery in HIV infection: mechanisms, relevance for clinical care, and possible solutions. Clin Dev Immunol. 2012;2012:670957. doi: 10.1155/2012/670957 22474480

5. Gutierrez F, Padilla S, Masia M, Iribarren JA, Moreno S, Viciana P, et al. Clinical outcome of HIV-infected patients with sustained virologic response to antiretroviral therapy: long-term follow-up of a multicenter cohort. PLoS One. 2006;1:e89. doi: 10.1371/journal.pone.0000089 17183720

6. Pacheco YM, Jarrin I, Rosado I, Campins AA, Berenguer J, Iribarren JA, et al. Increased risk of non-AIDS-related events in HIV subjects with persistent low CD4 counts despite cART in the CoRIS cohort. Antiviral Res. 2015;117:69–74. doi: 10.1016/j.antiviral.2015.03.002 25766861

7. Kelly C, Gaskell KM, Richardson M, Klein N, Garner P, MacPherson P. Discordant Immune Response with Antiretroviral Therapy in HIV-1: A Systematic Review of Clinical Outcomes. PLoS One. 2016;11(6):e0156099. doi: 10.1371/journal.pone.0156099 27284683

8. Adolescents PoAGfAa. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. [

9. Cenderello G, De Maria A. Discordant responses to cART in HIV-1 patients in the era of high potency antiretroviral drugs: clinical evaluation, classification, management prospects. Expert Rev Anti Infect Ther. 2016;14(1):29–40. doi: 10.1586/14787210.2016.1106937 26513236

10. Achhra AC, Petoumenos K, Law MG. Relationship between CD4 cell count and serious long-term complications among HIV-positive individuals. Curr Opin HIV AIDS. 2014;9(1):63–71. doi: 10.1097/COH.0000000000000017 24275674

11. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204(8):1217–26. doi: 10.1093/infdis/jir507 21917895

12. Engsig FN, Zangerle R, Katsarou O, Dabis F, Reiss P, Gill J, et al. Long-term mortality in HIV-positive individuals virally suppressed for >3 years with incomplete CD4 recovery. Clin Infect Dis. 2014;58(9):1312–21. doi: 10.1093/cid/ciu038 24457342

13. Kaufmann GR, Furrer H, Ledergerber B, Perrin L, Opravil M, Vernazza P, et al. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis. 2005;41(3):361–72. doi: 10.1086/431484 16007534

14. Gilson RJ, Man SL, Copas A, Rider A, Forsyth S, Hill T, et al. Discordant responses on starting highly active antiretroviral therapy: suboptimal CD4 increases despite early viral suppression in the UK Collaborative HIV Cohort (UK CHIC) Study. HIV Med. 2010;11(2):152–60. doi: 10.1111/j.1468-1293.2009.00755.x 19732175

15. Tan R, Westfall AO, Willig JH, Mugavero MJ, Saag MS, Kaslow RA, et al. Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2008;47(5):553–8. doi: 10.1097/QAI.0b013e31816856c5 18285713

16. Nicastri E, Chiesi A, Angeletti C, Sarmati L, Palmisano L, Geraci A, et al. Clinical outcome after 4 years follow-up of HIV-seropositive subjects with incomplete virologic or immunologic response to HAART. J Med Virol. 2005;76(2):153–60. doi: 10.1002/jmv.20352 15834865

17. Grabar S, Le Moing V, Goujard C, Leport C, Kazatchkine MD, Costagliola D, et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med. 2000;133(6):401–10. doi: 10.7326/0003-4819-133-6-200009190-00007 10975957

18. Lewden C, Chene G, Morlat P, Raffi F, Dupon M, Dellamonica P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46(1):72–7. doi: 10.1097/QAI.0b013e318134257a 17621240

19. Rodger AJ, Lodwick R, Schechter M, Deeks S, Amin J, Gilson R, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27(6):973–9. doi: 10.1097/QAD.0b013e32835cae9c 23698063

20. Lu W, Mehraj V, Vyboh K, Cao W, Li T, Routy JP. CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV-positive patients. J Int AIDS Soc. 2015;18:20052. doi: 10.7448/IAS.18.1.20052 26130226

21. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 2011;62:141–55. doi: 10.1146/annurev-med-042909-093756 21090961

22. Lim H, Mondal P, Sinner S. Joint modeling of longitudinal and event time data: application to HIV study. Journal of Medical Statistics and Informatics 2013;1.

23. Wulfsohn MS, Tsiatis AA. A joint model for survival and longitudinal data measured with error. Biometrics. 1997;53(1):330–9. 9147598

24. Guest JL, Weintrob AC, Rimland D, Rentsch C, Bradley WP, Agan BK, et al. A comparison of HAART outcomes between the US military HIV Natural History Study (NHS) and HIV Atlanta Veterans Affairs Cohort Study (HAVACS). PLoS One. 2013;8(5):e62273. doi: 10.1371/journal.pone.0062273 23658717

25. Guest JL, Moanna A, Schlueter Wirtz S, Caruth EC, Rentsch C, Marconi VC, et al. Cohort Profile: The HIV Atlanta Veterans Affairs Cohort Study (HAVACS). Int J Epidemiol. 2017;46(5):1727. doi: 10.1093/ije/dyx153 29025043

26. Marconi VC, Grandits GA, Weintrob AC, Chun H, Landrum ML, Ganesan A, et al. Outcomes of highly active antiretroviral therapy in the context of universal access to healthcare: the U.S. Military HIV Natural History Study. AIDS Res Ther. 2010;7:14. doi: 10.1186/1742-6405-7-14 20507622

27. Colasanti J, Kelly J, Pennisi E, Hu YJ, Root C, Hughes D, et al. Continuous Retention and Viral Suppression Provide Further Insights Into the HIV Care Continuum Compared to the Cross-sectional HIV Care Cascade. Clin Infect Dis. 2016;62(5):648–54. doi: 10.1093/cid/civ941 26567263

28. Zhang D, Chen MH, Ibrahim JG, Boye ME, Shen W. JMFit: A SAS Macro for Joint Models of Longitudinal and Survival Data. J Stat Softw. 2016;71(3). doi: 10.18637/jss.v071.i03 27616941

29. Castilho JL, Shepherd BE, Koethe J, Turner M, Bebawy S, Logan J, et al. CD4+/CD8+ ratio, age, and risk of serious noncommunicable diseases in HIV-infected adults on antiretroviral therapy. AIDS. 2016;30(6):899–908. doi: 10.1097/QAD.0000000000001005 26959354

30. 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):e98–106. doi: 10.1016/S2352-3018(15)00006-5 26424550

31. Song X, Davidian M, Tsiatis AA. A semiparametric likelihood approach to joint modeling of longitudinal and time-to-event data. Biometrics. 2002;58(4):742–53. doi: 10.1111/j.0006-341x.2002.00742.x 12495128

32. Rizopoulos D. Dynamic predictions and prospective accuracy in joint models for longitudinal and time-to-event data. Biometrics. 2011;67(3):819–29. doi: 10.1111/j.1541-0420.2010.01546.x 21306352

33. Brombin C, Di Serio C, Rancoita PM. Joint modeling of HIV data in multicenter observational studies: A comparison among different approaches. Stat Methods Med Res. 2016;25(6):2472–87. doi: 10.1177/0962280214526192 24671658

34. Viard JP, Mocroft A, Chiesi A, Kirk O, Roge B, Panos G, et al. Influence of age on CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: evidence from the EuroSIDA study. J Infect Dis. 2001;183(8):1290–4. doi: 10.1086/319678 11262215

35. van Lelyveld SF, Gras L, Kesselring A, Zhang S, De Wolf F, Wensing AM, et al. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS. 2012;26(4):465–74. doi: 10.1097/QAD.0b013e32834f32f8 22112603

36. Altman DG, Royston P. The cost of dichotomising continuous variables. BMJ. 2006;332(7549):1080. doi: 10.1136/bmj.332.7549.1080 16675816

37. Royston P, Altman DG, Sauerbrei W. Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med. 2006;25(1):127–41. doi: 10.1002/sim.2331 16217841

38. Takuva S, Maskew M, Brennan AT, Long L, Sanne I, Fox MP. Poor CD4 recovery and risk of subsequent progression to AIDS or death despite viral suppression in a South African cohort. J Int AIDS Soc. 2014;17:18651. doi: 10.7448/IAS.17.1.18651 24594114

39. Sax PE. Editorial commentary: can we break the habit of routine CD4 monitoring in HIV care? Clin Infect Dis. 2013;56(9):1344–6. doi: 10.1093/cid/cit008 23315314

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden