Compromised CD4:CD8 Ratio Recovery in People Living With HIV Aged Over 50 Years

An Observational Study

A Francis-Morris; NE Mackie; J Eliahoo; F Ramzan; S Fidler; KM Pollock


HIV Medicine. 2020;21(2):109-118. 

In This Article

Abstract and Introduction


Objectives: Persistent CD4:CD8 ratio inversion (< 1) is associated with mortality in older people. We investigated the interaction of the effects of baseline CD8 count and age at HIV diagnosis on CD4:CD8 ratio recovery with antiretroviral therapy (ART).

Methods: An observational study (1 January 2007 to 31 December 2016) was carried out using routinely collected data from the HIV outpatient services at Imperial College Healthcare NHS Trust, London, UK. CD4 and CD8 counts, prior to and during ART, treatment during primary HIV infection (PHI) and HIV-1 viral load were included in univariate and multivariate analyses using Cox proportional hazard regression.

Results: Data were included for 876 patients starting ART, where HIV suppression was achieved. Of these patients, 741 of 876 (84.6%) were male and 507 of 876 (57.9%) were Caucasian. The median time on ART was 38 [interquartile range (IQR) 17–66] months. CD8 count change on ART was bidirectional; low CD8 counts (≤ 600 cells/μL) increased and high CD8 counts (> 900 cells/μL) decreased. The median pre-ART CD4:CD8 ratio was 0.41 (IQR 0.24–0.63), and recovery (≥ 1) occurred in 274 of 876 patients (31.3%). Pre- and post-ART CD4:CD8 ratios were lower in those aged > 50 years compared with young adults aged 18–30 years (P < 0.001 and P = 0.002, respectively). After adjustment, younger age at HIV diagnosis (P < 0.001) and treatment during PHI (P < 0.001) were favourable for CD4:CD8 ratio normalization.

Conclusions: Older age (> 50 years) at HIV diagnosis was associated with persistent CD4:CD8 ratio inversion, whereas treatment of PHI was protective. These findings confirm the need for testing and early treatment of people aged > 50 years, and could be used in a risk management algorithm for enhanced surveillance.


Globally, the HIV epidemic is ageing; not only are people living with HIV (PLWH) growing older, but the incidence of HIV infection remains significant in people aged 50 years and over in the United States, and has not followed the decline observed in younger age groups in the UK.[1,2] The aged immune system loses functionality, rendering older people vulnerable to infectious disease and potentially cancer (reviewed in Foster et al. and Pera et al.[3,4]). The ageing process affects T-cell subsets, particularly CD8 T-cells.[5] Loss of clonal diversity, increased CD8 count, and age-related silencing of the interleukin (IL)-7 receptor gene have been reported.[5] These changes may be reflected in CD4:CD8 ratio inversion (< 1) in older people.

The impact of acute and chronic HIV infection on the immune system in older people is not fully understood. Despite advances in life expectancy, PLWH continue to be at higher risk of all-cause mortality, and mortality from infectious and liver disease than the general population.[6] HIV infection is associated with an increased prevalence of age-related diseases, despite antiretroviral therapy (ART), and the prevalence of non-AIDS-related morbidity, such as cardiovascular disease, is higher than in the general population.[7,8] The mechanisms that drive this difference for PLWH on suppressive ART could be a consequence of persistent immune activation and inflammation.[9] Whilst most PLWH are now successfully managed on ART by nonmedical staff, development of a clinical algorithm to select those at risk of complications for additional surveillance is now required to optimize care and resources.

Monitoring the CD4:CD8 ratio may serve such a purpose.[10] The peripheral CD4 count has, for decades, been a reliable biomarker for monitoring immunosuppression and recovery with ART.[11,12] Widespread access to ART has greatly improved the prognosis in HIV infection, and, with continuous viral suppression, reduced the clinical need for CD4 count monitoring. Recovery of the CD4:CD8 ratio to normal levels (≥ 1) with ART is often incomplete, however, which could reflect chronic immune activation occurring in persistent viral infection, including cytomegalovirus (CMV) and HIV infections.[13–16] Treatment of HIV during early infection protects the CD4:CD8 ratio, improving recovery rates, but late diagnosis, when significant immune damage and viral exposure have occurred, is still commonplace.[6,16,17]

Decline of the CD4:CD8 ratio occurs in the ageing general population. This has been associated with increased mortality rates in large Swedish studies and may be linked to CMV persistence.[18,19] Age-related mechanisms underlying CD4:CD8 ratio decline include loss of thymic output, CD8 T-cell oligoclonal outgrowth and accumulation of senescent T cells, including CD8 CD28null T cells, which can be virally driven.[20,21] These changes contribute to an adaptive immune system that is less responsive and less flexible in older people. In PLWH, persistent CD4:CD8 ratio inversion can involve incomplete CD4 count recovery and/or persistently high CD8 count, and early initiation of ART supports normalization of the CD8 count.[15,22,23] The HIV reservoir could be a driver for persistent CD4:CD8 ratio abnormality.[24] Given the central role CD8 T cells play in anticancer and antiviral immunity, the recovery of this T-cell compartment is important for older people living with HIV. Identifying the associations with persistent CD4:CD8 ratio abnormality in PLWH despite ART may indicate selection criteria for those at risk of complications.

Previous studies have considered the association of CD4:CD8 ratio recovery in HIV-1 infection with morbidity and mortality outcomes, but with conflicting results regarding the utility of this as a predictive biomarker in PLWH.[25,26] In the general population, the association of CD4:CD8 ratio inversion with excess mortality affecting older people indicates that persistent inversion might be of particular importance in older people diagnosed with or living with HIV infection.[18,27] We therefore investigated the impact of age at HIV diagnosis and baseline CD8 count on CD4:CD8 ratio recovery. Here we show that treatment during primary HIV infection (PHI) was associated with recovery of the CD4:CD8 ratio to ≥ 1. Conversely, even after adjustment, older age at HIV diagnosis had a negative impact on CD4:CD8 ratio recovery, despite CD4 count gains, particularly in those aged > 50 years.