Changing mortality risk associated with CD4 cell response to antiretroviral therapy in South Africa

Abstract

Objective: To determine the relationship between mortality risk and the CD4 cell response to antiretroviral therapy (ART).

Design: Observational community-based ART cohort in South Africa.

Methods: CD4 cell counts were measured 4 monthly, and deaths were prospectively ascertained. Cumulative person-time accrued within a range of updated CD4 cell count strata (CD4 cell-strata) was calculated and used to derive CD4 cell-stratified mortality rates.

Results: Patients (2423) (median baseline CD4 cell count of 105 cells/microl) were observed for up to 5 years of ART. One hundred and ninety-seven patients died during 3155 person-years of observation. In microltivariate analysis, mortality rate ratios associated with 0-49, 50-99, 100-199, 200-299, 300-399, 400-499 and at least 500 cells/microl updated CD4 cell-strata were 11.6, 4.9, 2.6, 1.7, 1.5, 1.4 and 1.0, respectively. Analysis of CD4 cell count recovery permitted calculations of person-time accrued within these CD4 cell-strata. Despite rapid immune recovery, high mortality in the first year of ART was related to the large proportion of person-time accrued within CD4 cell-strata less than 200 cells/microl. Moreover, patients with baseline CD4 cell counts less than 100 cells/microl had much higher cumulative mortality estimates at 1 and 4 years (11.6 and 16.7%) compared with those of patients with baseline counts of at least 100 cells/microl (5.2 and 9.5%) largely because of greater cumulative person-time at CD4 cell counts less than 200 cells/microl.

Conclusion: Updated CD4 cell counts are the variable most strongly associated with mortality risk during ART. High cumicrolative mortality risk is associated with person-time accrued at low CD4 cell counts. National HIV programmes in resource-limited settings should be designed to minimize the time patients spend with CD4 cell counts less than 200 cells/microl both before and during ART.

Fig. 1. Kaplan–Meier plots showing cumulative mortality risk over 48 months

(a) Cumulative mortality estimates for the whole cohort at 1 2 and 48 months of ART were 8.4 and 1 3.2%, respectively, (b) Cumulative mortality estimates al 12 and 48 months from enrolment were 11.6 and 16.7%, respectively, in those with baseline CD4 cell counts of less than 100 cells/μl (―) compared with 5.2 and 9.5% in those wilth baseline counts more than 100 cells/μl (----).

Fig. 2. Graph showing the mortality rates (95% confidence interval, deaths/100 person-years) according to updated CD4 cell counts during antiretroviral therapy

CD4 cell counts (cells/μl) were measured at baseline and 4 monthly during ART. Follow-up time intervals were defined by the CD4 cell count at the start of each interval and categorized into one of six different CD4 cell count strata. Cumulative person-time accruing within those strata was determined and used to derive the CD4 cell-stratum-specific mortality rates. Unadjusted mortality rates during person-time accrued within the 0–49, 50–99, 100–199, 200–299, 300–399, 400–499 and at least 500 cells/μl CD4 cell-strata were 38.6 (30.3–48.6), 12.8 (8.9–17.9), 5.4 (3.9–7.2), 2.7(1.6–4.1), 2.0(1.0–3.6), 2.0(0.7–4.3) and 1.2 (0.3–3.2) deaths/100 person-years, respectively.

Fig. 3. Graph showing smoothed changes in distribution of CD4 cell counts in the cohort over time during 48 months of antiretroviral therapy

The proportions (percentage) of patients with CD4 cell counts lying below thresholds of 100, 200, 300, 400, 500, 600, 700, 800, 900 and 1000 cells/μl are shown. The proportions of patients with CD4 cell counts less than 100 and 200cells/μl decreased steeply over the 1st and 2nd years of ART, respectively. The proportion of patients with CD4 cell counts more than 500 cells/μl steadily increased throughout follow-up, indicating ongoing immune recovery. Median CD4 cell counts at 0, 12,24,36 and 48 months of ART were 101,261, 355,417 and 483 cells/μl, respectively.