The Impact of Different CD4 Cell-Count Monitoring and Switching Strategies on Mortality in HIV-Infected African Adults on Antiretroviral Therapy: An Application of Dynamic Marginal Structural Models

Abstract

In Africa, antiretroviral therapy (ART) is delivered with limited laboratory monitoring, often none. In 2003-2004, investigators in the Development of Antiretroviral Therapy in Africa (DART) Trial randomized persons initiating ART in Uganda and Zimbabwe to either laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). CD4 cell counts were measured every 12 weeks in both groups but were only returned to treating clinicians for management in the LCM group. Follow-up continued through 2008. In observational analyses, dynamic marginal structural models on pooled randomized groups were used to estimate survival under different monitoring-frequency and clinical/immunological switching strategies. Assumptions included no direct effect of randomized group on mortality or confounders and no unmeasured confounders which influenced treatment switch and mortality or treatment switch and time-dependent covariates. After 48 weeks of first-line ART, 2,946 individuals contributed 11,351 person-years of follow-up, 625 switches, and 179 deaths. The estimated survival probability after a further 240 weeks for post-48-week switch at the first CD4 cell count less than 100 cells/mm(3) or non-Candida World Health Organization stage 4 event (with CD4 count <250) was 0.96 (95% confidence interval (CI): 0.94, 0.97) with 12-weekly CD4 testing, 0.96 (95% CI: 0.95, 0.97) with 24-weekly CD4 testing, 0.95 (95% CI: 0.93, 0.96) with a single CD4 test at 48 weeks (baseline), and 0.92 (95% CI: 0.91, 0.94) with no CD4 testing. Comparing randomized groups by 48-week CD4 count, the mortality risk associated with CDM versus LCM was greater in persons with CD4 counts of <100 (hazard ratio = 2.4, 95% CI: 1.3, 4.3) than in those with CD4 counts of ≥100 (hazard ratio = 1.1, 95% CI: 0.8, 1.7; interaction P = 0.04). These findings support a benefit from identifying patients immunologically failing first-line ART at 48 weeks.

Keywords: Africa; HIV; antiretroviral therapy; drug switching; dynamic marginal structural models; monitoring.

Figure 1.

Directced acyclic graph illustrating associations between randomized trial group (R), time-dependent covariates at time t (C_t, e.g., CD4 cell count), switch to second-line antiretroviral therapy (ART) before/at time t (E_t), death before/at time t (D_t), and unmeasured common causes of C and D (U) among human immunodeficiency virus–positive patients on ART. Arrows represent direct causal relationships between variables. Time-dependent covariates (C) at a given time point influence whether treatment is switched to second-line ART at that time point or subsequently (E) and influence time-dependent covariates (C) at later time points and mortality (D). Switching treatment regimens (E) influences time-dependent covariates (C), switching (E), and mortality at later time points (D). The following assumptions are made: R has no effect on C other than via E; R has no effect on D other than via E; there are no unmeasured common causes of E and C or E and D; and R is randomized. Different line styles and colors are used only to distinguish the effects of randomized group, different covariates, exposures, and death: Effects of R are shown by solid black lines; effects of C₀ by dashed gray lines; effects of E₀ by dashed black lines; effects of D₁ by solid gray lines; effects of C₁ by dotted black lines; effects of E₁ by dashed-dotted gray lines; and effects of U by dotted gray lines.

Figure 2.

Survival among human immunodeficiency virus–positive patients on antiretroviral therapy (ART) for different CD4 cell-count monitoring strategies, all assuming a switch in treatment regimen (to second-line ART) at the first observed CD4 count less than 100 cells/mm³ or the first non-Candida World Health Organization stage 4 event (with CD4 count <250), estimated by means of dynamic marginal structural models, Development of Antiretroviral Therapy in Africa (DART) Trial, Uganda and Zimbabwe, 2003–2008. Baseline was 48 consecutive weeks on first-line ART.

Figure 3.

Survival among human immunodeficiency virus–positive patients on antiretroviral therapy (ART), by randomized trial group (laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM)) and CD4 cell count at 48 consecutive weeks on first-line ART (baseline), Development of Antiretroviral Therapy in Africa (DART) Trial, Uganda and Zimbabwe, 2003–2008.