Treatment eligibility and retention in clinical HIV care: A regression discontinuity study in South Africa

Abstract

Background: Loss to follow-up is high among HIV patients not yet receiving antiretroviral therapy (ART). Clinical trials have demonstrated the clinical efficacy of early ART; however, these trials may miss an important real-world consequence of providing ART at diagnosis: its impact on retention in care.

Methods and findings: We examined the effect of immediate (versus deferred) ART on retention in care using a regression discontinuity design. The analysis included all patients (N = 11,306) entering clinical HIV care with a first CD4 count between 12 August 2011 and 31 December 2012 in a public-sector HIV care and treatment program in rural South Africa. Patients were assigned to immediate versus deferred ART eligibility, as determined by a CD4 count < 350 cells/μl, per South African national guidelines. Patients referred to pre-ART care were instructed to return every 6 months for CD4 monitoring. Patients initiated on ART were instructed to return at 6 and 12 months post-initiation and annually thereafter for CD4 and viral load monitoring. We assessed retention in HIV care at 12 months, as measured by the presence of a clinic visit, lab test, or ART initiation 6 to 18 months after initial CD4 test. Differences in retention between patients presenting with CD4 counts just above versus just below the 350-cells/μl threshold were estimated using local linear regression models with a data-driven bandwidth and with the algorithm for selecting the bandwidth chosen ex ante. Among patients with CD4 counts close to the 350-cells/μl threshold, having an ART-eligible CD4 count (<350 cells/μl) was associated with higher 12-month retention than not having an ART-eligible CD4 count (50% versus 32%), an intention-to-treat risk difference of 18 percentage points (95% CI 11 to 23; p < 0.001). The decision to start ART was determined by CD4 count for one in four patients (25%) presenting close to the eligibility threshold (95% CI 20% to 31%; p < 0.001). In this subpopulation, having an ART-eligible CD4 count was associated with higher 12-month retention than not having an ART-eligible CD4 count (91% versus 21%), a complier causal risk difference of 70 percentage points (95% CI 42 to 98; p < 0.001). The major limitations of the study are the potential for limited generalizability, the potential for outcome misclassification, and the absence of data on longer-term health outcomes.

Conclusions: Patients who were eligible for immediate ART had dramatically higher retention in HIV care than patients who just missed the CD4-count eligibility cutoff. The clinical and population health benefits of offering immediate ART regardless of CD4 count may be larger than suggested by clinical trials.

Fig 1. Density of first CD4 counts.

Continuity in the density of first CD4 counts supports our interpretation that patients and providers did not systematically manipulate CD4 counts, e.g., to gain eligibility for ART.

Fig 2. Immediate ART eligibility leads to significant gains in 12-month retention.

Twelve-month retention is defined as having a CD4 count or viral load test, initiating ART, or attending a routine clinic visit within the period 6 to <18 months after first CD4 count. The sample excludes patients with <18 months of potential follow-up. Local linear regression estimated with Imbens-Kalyanaraman optimal bandwidth = 142.1 cells. The difference at the threshold was 18 percentage points (95% CI 11 to 23). The effect of interest in regression discontinuity is the difference in the local linear predictions at the threshold, i.e., in the limit, as the threshold is approached from above versus below. The bandwidth defines the region in which the relationship between first CD4 count and the outcome is assumed to be linear in our local linear regression models (Table 2).

Fig 3. ART uptake increases with an eligible CD4 count.

Local linear regression estimated with Imbens-Kalyanaraman optimal bandwidth = 96.4 cells. The difference at the threshold was 25 percentage points (95% CI 20 to 31). The effect of interest in regression discontinuity is the difference in the local linear predictions at the threshold, i.e., in the limit, as the threshold is approached from above versus below. The data-driven bandwidth refers to the region in which the relationship between first CD4 count and the outcome is assumed to be linear in our local linear regression models (Table 2).

Fig 4. The effect of immediate ART on retention is not observed in clinical trials.

Retention is reported at 2.1 years for the HPTN-052 trial [5], 3 years for the INSIGHT START trial [7], 3.5 years for the TEMPRANO trial [6], and 12 months for Hlabisa. Estimates for Hlabisa are for compliers—those patients whose treatment decision was determined by the value of their CD4 count.