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
doi: 10.1371/journal.pone.0227124



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


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