ABSTRACT
BACKGROUND: There is very little data on long-term immune recovery responses in patients on suppressive antiretroviral therapy (ART) in the setting of sub-Saharan Africa (SSA). Thus, we sought to determine CD4+ T-cell, CD8+ T-cell and CD4/CD8 ratio responses in a cohort of HIV infected individuals on sustained suppressive ART followed up for more than a decade. METHODS: The cohort comprised adult patients who started ART between 2001 and 2007 and followed for up to 14 years. Trends in median CD4+ T-cells, CD8+ T-cells and CD4/CD8 ratio were reviewed retrospectively. Poisson regression models were used to identify factors associated with achieving normalized T-cell biomarkers. Kaplan-Meier curves were used to estimate the probability of attaining normalized counts while on suppressive ART. RESULTS: A total of 227 patients with a median duration of follow-up on ART of 12 (IQR: 10.5-13.0) years were included. CD4 cell count increased from baseline median of 138 cells (IQR: 70-202) to 555 cells (IQR: 417-830). CD4 cell increased continuously up until 5 years, after which it plateaued up until 14 years of follow up. Only 69.6% normalized their CD4 cell count within a median of 6.5 (IQR: 3.0-10.5) years. In addition, only 15.9% of the cohort were able to achieve the median reference CD4+ T-cell threshold count in Ethiopians (≈760 cells/µL). CD8+ T-cell counts increased initially until year 1, after which continuous decrease was ascertained. CD4/CD8 ratio trend revealed continuous increase throughout the course of ART, and increased from a median baseline of 0.14 (IQR: 0.09-0.22) to a median of 0.70 (IQR: 0.42-0.95). However, only 12.3% normalized their ratio (≥ 1.0) after a median of 11.5 years. In addition, only 8.8% of the cohort were able to achieve the median reference ratio of healthy Ethiopians. CONCLUSION: Determination of both CD4+ and CD8+ T-cells, along with CD4/CD8 ratio is highly relevant in long-term follow-up of patients to assess immune recovery. Monitoring ratio levels may serve as a better biomarker risk for disease progression among patients on long-term ART. In addition, the findings emphasize the relevance of initiation of ART at the early stage of HIV-1 infection.
Subject(s)
Anti-HIV Agents/administration & dosage , Antiretroviral Therapy, Highly Active/methods , CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/drug effects , HIV Infections/drug therapy , Adult , Anti-HIV Agents/pharmacology , CD4 Lymphocyte Count , CD4-CD8 Ratio , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Ethiopia , Female , HIV Infections/immunology , HIV Infections/virology , HIV-1/drug effects , HIV-1/physiology , Humans , Male , Middle Aged , Retrospective Studies , Sustained Virologic Response , Viral Load/drug effectsABSTRACT
BACKGROUND: The role of CD4/CD8 ratio on the incidence of tuberculosis (TB) in patients on antiretroviral therapy (ART) is unknown. Thus, we sought to determine whether the CD4/CD8 ratio was associated with development of TB in a cohort of HIV infected individuals on ART followed up for more than a decade in the setting of sub-Saharan Africa (SSA). METHODS: The cohort comprised adult patients who started ART between 2001 and 2007 and followed for up to 15 years. Clinical data were collected in retrospective manner. Patients with an AIDS defining illness or a CD4 count <200 cell/µL were started with a combination of ART. The participants have clinic visits every 6 months and/or as needed. Poisson regression models were used to identify factors associated with development of incident TB. Kaplan-Meier curves were used to estimate the probability of incident TB while on ART. RESULTS: A total of 347 patients with a median duration of follow-up on ART of 11.5 (IQR: 10.0-12.5) years were included. Incident TB developed in 47 patients during the 3259 person-years of follow-up, the majority (76.6%) occurred within five year of ART initiation. On univariate analysis, poor ART adherence (RR:2.57, 95% CI: 1.28-5.17), time-updated CD4 cell count of lower than 200 (RR: 4.86, 95%CI 2.33-10.15), or CD4 cell count between 200 and 500 (RR: 4.68, 95% CI: 2.17-10.09), time-updated CD8 cell count lower than 500 (RR: 2.83 95% CI 1.31-6.10), or CD8 cell count over 1000 (RR: 2.23, 95% CI: 1.12-4.45), time-updated CD4/CD8 ratio of less than 0.30 (RR: 6.00, 95% CI: 2.96-12.14), lack of normalization of CD4 T-cell count (RR: 6.13, 95% CI: 2.20-17.07), and virological failure (RR: 2.35 (95% CI: 1.17-4.71) were all associated with increased risk of incident TB. In multivariate analysis, however, time-updated CD4/CD8 ratio of less than 0.30 (adjusted RR: 4.08, 95% CI: 1.31-12.68) was the only factor associated with increased risk of developing incident TB (p = 0.015). Similar results were obtained in a sensitivity analysis by including only those virally suppressed patients (n = 233, 69% of all patients). In this group, CD4/CD8 ratio of less than 0.30 was associated with development of incident TB (adjusted RR: 4.02, 95% CI: 1.14-14.19, p = 0.031). Overall, the incidence rate of TB in patients with an updated CD4/CD8 ratio of less than 0.30 was more than 5-fold higher when compared with those with a ratio more than 0.45. CONCLUSION: Low CD4/CD8 ratio is independently associated with an increased risk of incident TB despite viral suppression. CD4/CD8 ratio may serve as a biomarker for identifying patients at risk of TB in patients on ART in the setting of SSA.
