Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa

Abstract

Objective: To determine the short-term and long-term risks of tuberculosis (TB) associated with CD4 cell recovery during antiretroviral therapy (ART).

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

Methods: TB incidence was determined among patients (n = 1480) receiving ART for up to 4.5 years in a South African community-based service. Updated CD4 cell counts were measured 4-monthly. Person-time accrued within a range of CD4 cell count strata (CD4 cell strata) was calculated and used to derive CD4 cell-stratified TB rates. Factors associated with incident TB were identified using Poisson regression models.

Results: Two hundred and three cases of TB were diagnosed during 2785 person-years of observation (overall incidence, 7.3 cases/100 person-years). During person-time accrued within CD4 cell strata 0-100, 101-200, 201-300, 301-400, 401-500 and more than 500 cells/microl unadjusted TB incidence rates were 16.8, 9.3, 5.5, 4.6, 4.2 and 1.5 cases/100 person-years, respectively (P < 0.001). During early ART (first 4 months), adjusted TB rates among those with CD4 cell counts 0-200 cells/microl were 1.7-fold higher than during long-term ART (P = 0.026). Updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk.

Conclusion: Updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. Among those with baseline CD4 cell counts less than 200 cells/microl, the excess adjusted risk of TB during early ART was consistent with 'unmasking' of disease missed at baseline screening. TB incidence rates at CD4 cell counts of 200-500 cells/microl remained high and adjunctive interventions are required. TB prevention would be improved by ART policies that minimized the time patients spend with CD4 cell counts below a threshold of 500 cells/microl.

Fig. 1. Graph of tuberculosis incidence rates (95% confidence interval, cases/100 person-years) plotted against serially updated CD4 cell counts measured during total duration (early and late) of antiretroviral therapy

CD4 cell counts (cells/µl) were measured at baseline and 4-monthly during antiretroviral therapy (ART). Tuberculosis (TB) incidence rates are seen to decrease with increasing CD4 cell counts. Data used to derive these rates are displayed in the table beneath. Median CD4 cell counts within 0–100, 101–200, 201–300, 301–400, 401–500 and more than 500 CD4 cell strata were 60, 157, 250, 345, 446 and 700 cells/µl, respectively. CI, confidence interval.

Fig. 2. CD4 cell-stratified tuberculosis incidence rates during first 4 months of antiretroviral therapy (early antiretroviral therapy) and during person-time thereafter (late antiretroviral therapy)

Within each of the CD4 cell strata 0–100, 101–200 and 201–300 cells/µl, tuberculosis (TB) incidence rates during early antiretroviral therapy (ART) are compared with rates during late ART [cases/100 person-years, 95% confidence interval (CI)]. Incidence rates and incidence rate ratios (IRRS) for these CD4 cell strata are shown. Within the two lowest strata (0–100 and 101–200 cells/µl), TB incidence rates during early ART were approximately double the rates during long-term ART in unadjusted analyses and 1.7-fold higher in adjusted analyses (P = 0.026).

Fig. 3. Changes in CD4 cell counts during 4 years of antiretroviral therapy

The graph shows the changes in the proportions (%) of patients with CD4 cell counts lying below thresholds of 200, 500 and 1000 cells/µl with increasing duration of antiretroviral therapy (ART). During the first year of ART, the proportion of patients with a CD4 cell count less than 200 cells/µl decreased steeply from 89% at baseline, eventually accounting for less than 10% of patients. In contrast, the proportion of patients with CD4 cell counts more than 500 cells/µl increased steadily over time reaching 48% after 47 years. Only data from patients with at least two serial measurements were included and the numbers of patients represented at 0, 48, 96, 144 and 208 weeks were 1313, 1129, 595, 237 and 97, respectively.