Uganda: very late ART start increases risk of death by 60%

Starting ART at CD4 cell counts below 50 cells/mm³ increased the relative risk of death by approximately 60% compared to starting at 150-249 cells/mm³ or more Edward J Mills and colleagues reported in an observational study of 22,315 patients in ten clinics in Uganda over a ten year period 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 sub-Saharan Africa in HIV patients on ART.

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

The concern, raised by funders, note the authors, given resource limitations in resource-poor settings is a potential inability to manage the increased workload that will come with starting ART earlier. So, they add, some international funders are hesitant about supporting programmes that start ART at CD4 cell counts above 200 cells/mm³.

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

Patients were followed until death or the end of the study. Age, gender, and baseline CD4 cell count (divided by categories: below 50, 50-99, 100-149, 150-249, 250-299 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/mm³with over 70% starting with a CD4 cell count under 200 cells/mm³.

60% of patients started 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 as in this study. TASO they note have adherence counsellors and database managers at each of their sites. In addition peer support groups and psychosocial support have played an important role in their 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 300cells/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 under 50 cells/mm³ the risk of mortality was 0.75 (95% CI: 0.65-0.88) at 50-99 cells/mm³; 0.60 (95% CI: 0.51-0.70) at 100-149 cells/mm³; 0.43 (95% CI: 0.37-0.50) at 150-249 cells/mm³ and 0.41 (95% CI: 0.33-0.51) at ≥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 reflects a lack of resources. In addition they note 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 as 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 getting 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.”