Late HIV treatment increases risk of death three-fold in Uganda

Starting ART at CD4 cell counts below 50 cells/mm³ increased the relative risk of death by approximately 60%, compared to starting at 150 to 249 cells/mm³ or more, and more than tripled the risk of death when compared to starting at a CD4 count above 300 cells/mm³. These findings were reported by Edward J Mills and colleagues in an observational study of 22,315 patients in ten clinics in Uganda, studied over a ten-year period, and published in the advance online edition of AIDS.

The lower the CD4 cell count at the start of ART, the greater the risk of death. Death rates were highest in the first year.

Over a median follow-up period of 31 months ((IQR: 19-45), 6.7% died and 6.4% were lost to follow-up.

This is, note the authors, the largest study to look at the effects of baseline CD4 cell count on mortality in HIV patients on ART in sub-Saharan Africa, and to quantify the relative risk of very late initiation of antiretroviral therapy. 

CD4 cell count at the start of ART is one of the most important predictors of survival. Patients in most resource-poor settings start ART late in the course of their illness, often with very low CD4 cell counts

Current World Health Organization guidelines recommend that ART is started at 350 cells/mm³ or below; the International AIDS Society guidelines recommend starting at 500 cells/mm³ or below. Guidance is based on limited and conflicting data from resource-rich settings.

Data from The AIDS Support Organisation (TASO) clinics in Uganda, from patients aged 14 or over who had started ART between 1 January 2000 and 1 February 2010, were analysed.

Patients were followed until death or the end of the study. Age, gender, and baseline CD4 cell count (divided by categories: below 50, 50 to 99, 100 to 149, 150 to 249, 250 to 299, and at or above 300 cells/mm³) were noted. Survival was assessed according to these categories.

Median age was 37 years (IQR: 31-43) and 70% of patients were female.

Median CD4 cell count at the start of ART was 142 cells/mm³ (IQR: 70-206 cells/mm³), with more than 70% starting with a CD4 cell count under 200 cells/mm³.

Sixty per cent of patients started treatment at an advanced stage of their illness (WHO disease stage II or III).  Adherence was maintained at 95% and over for 85.8% of patients.

The authors note that, unlike many programmes in Africa, TASO programmes have a relatively low loss-to-follow-up rate, as shown in this study. They explain that TASO clinics provide adherence counsellors and database managers at each of their sites. In addition, peer support groups and psychosocial support have played an important role in TASO programmes, from the beginnings of the epidemic in Uganda.

Crude mortality rates ranged from 53.8 per 1000 patient-years (95% CI: 48.8-58.8) among those starting ART with CD4 cell counts below 50 cells/mm³, to 15.7 per 1000 patient-years (95% CI: 12.1-19.3) for those with CD4 cell counts over 300 cells/mm³.

Adjusting for gender, WHO disease stage and year when starting ART, the risk of death increased significantly as the CD4 cell count decreased. However, the authors stress that the best time to start ART cannot be determined from this study.

Relative to a CD4 cell count at baseline of under 50 cells/mm³, the risk of mortality was 0.75 (95% CI: 0.65-0.88)at 50 to 99 cells/mm³; 0.60 (95% CI: 0.51-0.70) at 100 to 149 cells/mm³; 0.43 (95% CI: 0.37-0.50) at 150 to 249 cells/mm³and 0.41 (95% CI: 0.33-0.51) at more than 250 cells/mm³, p=<0.001.

Even when taking into account the missing baseline CD4 cell counts of 3817 patients (17.1%), the differences remained significant.

The authors note that the missing data, as in other resource-poor settings, reflect a lack of resources. In addition, they note that routine patient data – such as viral load or resistance testing data – are not available, so it is not possible to understand how these factors may have affected mortality in this cohort. 

The authors caution against drawing conclusions about causality as this was an observational study.

The authors note their study did not take into account patients, in any of the CD4 cell-count categories, who died before receiving ART.

Uganda guidelines recommend patients start ART at or below 250 cells/mm³. In the interests of improved access to treatment and health, the Ugandan Ministry of Health is considering an increase in the threshold for starting treatment to 300 cells/mm³.

The authors conclude that starting ART earlier is associated with increased survival benefits and “may extend beyond mortality alone to decreased co-infections, decreased resource costs and possibly even prevention efforts”.