Low CD4/CD8 ratio is associated with increased morbidity and mortality in late and non-late presenters: results from a multicentre cohort study, 2004–2018

Abstract

Background To study whether the association between the CD4/CD8 ratio variation over time and the development of clinical outcomes vary in late presenters (CD4 count < 350/µL or AIDS event at enrolment) or advanced presenters (CD4 count < 200/µL or AIDS event at enrolment). Methods We included ART-naïve adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) enrolled between January 2004 up to November 2018 and with at least 6 months of follow-up. We used extended Cox proportional hazard models to estimate the hazard ratios (HRs) for the association between CD4/CD8 ratio over time and a composite endpoint of the occurrence of the first AIDS event, first serious non-AIDS event or overall mortality occurring from 6 months after enrolment. HRs in non-late, late and advanced presenters were obtained by including an interaction term between late presentation status and CD4/CD8 ratio over time. Results Of 10,018 participants, 55.6% were late presenters and 26.5% were advanced presenters. Compared with CD4/CD8 ratio > 0.4, CD4/CD8 ratio ≤ 0.4 over time was associated with an increased risk of experiencing the composite endpoint in non-late (HR 1.90; 95%CI 1.48, 2.43), late (HR 1.94; 1.46, 2.57) and advanced presenters (HR 1.72; 1.26, 2.34). Similarly, CD4/CD8 ratio ≤ 0.4 over time was associated with a higher risk of developing an AIDS event (HR 3.31; 2.23, 4.93 in non-late; HR 2.75; 1.78, 4.27 in late and HR 2.25; 1.34, 3.76 in advanced presenters) or serious non-AIDS event (HR 1.39; 0.96, 2.02 in non-late, HR 1.62; 1.10, 2.40 in late and HR 1.49; 0.97, 2.29 in advanced presenters) as well as with a higher risk of overall mortality (HR 1.49; 0.92, 2.41 in non-late, HR 1.80; 1.04, 3.11 in late and HR 1.61; 0.92, 2.83 in advanced presenters) compared to CD4/CD8 > 0.4, regardless of the late presentation status. Conclusions A low CD4/CD8 measured over time is associated with increased risk of morbidity and mortality in people living with HIV independently of their late presentation status. These data support the prognostic role of CD4/CD8 over time and can help defining a subgroup of patients who need closer monitoring to avoid comorbidities.

CD4/CD8 ratio and CD8+ T-cell count as prognostic markers for non-AIDS mortality in people living with HIV. A systematic review and meta-analysis

“…A detailed description of the data adjustment to these cut-offs is included in Supplementary 3 . Six studies ( 28 – 33 ) were excluded from the meta-analysis due to deviations from our study protocol but were accounted for in the systematic review based on follow-up after ART initiation and reported outcomes. Reasons for exclusion are reported in Supplementary 4 .…”

“…Items assessing study attrition showed the highest risk of bias. The overall risk of bias in the included studies was high (n=7; 35%) ( 28 , 30 , 31 , 36 , 37 , 40 , 43 ), moderate (n=11: 55%) ( 9 , 18 , 19 , 21 , 29 , 32 , 33 , 35 , 38 , 39 , 41 ), or low (n=2; 10%) ( 20 , 42 ). Nearly all included studies (n=18; 90%) ( 9 , 18 , 19 , 21 , 28 – 33 , 35 – 41 , 43 ) lacked a description of the lost and censored participants, their characteristics, and the methodology for statistical imputation of the missing values.…”

“…The overall risk of bias in the included studies was high (n=7; 35%) ( 28 , 30 , 31 , 36 , 37 , 40 , 43 ), moderate (n=11: 55%) ( 9 , 18 , 19 , 21 , 29 , 32 , 33 , 35 , 38 , 39 , 41 ), or low (n=2; 10%) ( 20 , 42 ). Nearly all included studies (n=18; 90%) ( 9 , 18 , 19 , 21 , 28 – 33 , 35 – 41 , 43 ) lacked a description of the lost and censored participants, their characteristics, and the methodology for statistical imputation of the missing values. Time definition, including the timing of CD4/CD8 ratio measurement (n=7; 35%) ( 19 , 28 , 33 , 36 , 38 , 39 , 41 ), as well as the definition of the time to the event, were penalized in most of the studies (n=16; 80%) ( 9 , 18 , 19 , 21 , 28 – 33 , 36 , 37 , 39 , 41 – 43 ).…”

“…Nearly all included studies (n=18; 90%) ( 9 , 18 , 19 , 21 , 28 – 33 , 35 – 41 , 43 ) lacked a description of the lost and censored participants, their characteristics, and the methodology for statistical imputation of the missing values. Time definition, including the timing of CD4/CD8 ratio measurement (n=7; 35%) ( 19 , 28 , 33 , 36 , 38 , 39 , 41 ), as well as the definition of the time to the event, were penalized in most of the studies (n=16; 80%) ( 9 , 18 , 19 , 21 , 28 – 33 , 36 , 37 , 39 , 41 – 43 ). Eight studies (40%) ( 19 , 21 , 28 , 33 , 36 , 38 , 39 , 41 ) reported CD4/CD8 ratio measurement at the baseline evaluation of the cohorts, with subsequent updating of the data during follow-up, but without specifying the frequency of determination.…”

Expanding HIV Clinical Monitoring: The Role of CD4, CD8, and CD4/CD8 Ratio in Predicting Non-AIDS Events

“…In addition to the different CD4/CD8 ratios and CD8 counts used in previous literature to define associations with SNAEs risk, another important source of heterogeneity across studies is the timing of CD4 and CD8 measurements relative to ART initiation, including time-varying variables [11,12,15,27,28] These variables are less interpretable and more challenging to translate to the clinic [29]. Furthermore, measurements taken proximal to the event can make the role of the CD4/CD8 as a predictor less clear [13,25,30].…”