Utility of CD4 cell counts for early prediction of virological failure during antiretroviral therapy in a resource-limited setting

Abstract

Background: Viral load monitoring is not available for the vast majority of patients receiving antiretroviral therapy in resource-limited settings. However, the practical utility of CD4 cell count measurements as an alternative monitoring strategy has not been rigorously assessed.

Methods: In this study, we used a novel modelling approach that accounted for all CD4 cell count and VL values measured during follow-up from the first date that VL suppression was achieved. We determined the associations between CD4 counts (absolute values and changes during ART), VL measurements and risk of virological failure (VL > 1,000 copies/ml) following initial VL suppression in 330 patients in South Africa. CD4 count changes were modelled both as the difference from baseline (DeltaCD4 count) and the difference between consecutive values (CD4 count slope) using all 3-monthly CD4 count measurements during follow-up.

Results: During 7093.2 patient-months of observation 3756 paired CD4 count and VL measurements were made. In patients who developed virological failure (n = 179), VL correlated significantly with absolute CD4 counts (r = - 0.08, P = 0.003), DeltaCD4 counts (r = - 0.11, P < 0.01), and most strongly with CD4 count slopes (r = - 0.30, P < 0.001). However, the distributions of the absolute CD4 counts, DeltaCD4 counts and CD4 count slopes at the time of virological failure did not differ significantly from the corresponding distributions in those without virological failure (P = 0.99, P = 0.92 and P = 0.75, respectively). Moreover, in a receiver operating characteristic (ROC) curve, the association between a negative CD4 count slope and virological failure was poor (area under the curve = 0.59; sensitivity = 53.0%; specificity = 63.6%; positive predictive value = 10.9%).

Conclusion: CD4 count changes correlated significantly with VL at group level but had very limited utility in identifying virological failure in individual patients. CD4 count is an inadequate alternative to VL measurement for early detection of virological failure.

Figure 1

(A) Kaplan-Meier probabilities of virologic failure-free proportion. The numbers of patients followed up for 0, 12, 24, 36, 48 and 60 months were 330, 180, 123, 82, 39 and 26, respectively. (B) Kaplan-Meier probabilities of failure-free survival stratified by baseline CD4 cell count quartile range (median = 327; IQR = 205–435 cells/ul).

Figure 2

Scatter plots of (A) absolute CD4 cell count, (B) ΔCD4 cell count (change in CD4 count from baseline) and (C) CD4 cell count slope (difference between consecutive CD4 count measurements) and corresponding viral load values (log₁₀ copies/ml) measured in patients who developed virological failure. Distributions of (D) absolute CD4 counts, (E) ΔCD4 counts and (F) CD4 count slopes of patients (n = 179) at the time of virological failure (dashed lines) compared to the distribution of measurements of all patients (n = 330) at all time-points when viral load remained suppressed (solid lines).

Figure 3

Receiver Operating Characteristic (ROC) curve assessing the association between a negative CD4 cell count slope (ie a falling CD4 count) and virological failure (area under the curve = 0.59).

Figure 4

Scatter plot of the absolute CD4 count (cells/μl) and corresponding HIV RNA viral load (log₁₀ copies/ml) for the subset of patients (n = 30) who did not ever achieve virological suppression during ART (A). The distributions of ΔCD4 counts (B) and CD4 cell count slopes (C) of this group are compared with that of patients who achieved and maintained virological suppression throughout the study period (n = 151).