South African HIV treatment guidelines call for patients who fail first-line antiretroviral therapy
(ART) to be switched to second-line ART, yet logistical issues, clinician decisions and
patient preferences make delay in switching to second-line likely. We explore the impact of
delaying second-line ART after first-line treatment failure on rates of death and virologic
We include patients with documented virologic failure on first-line ART from an observational
cohort of 9 South African clinics. We explored predictors of delayed second-line
switch and used marginal structural models to analyze rates of death following first-line failure
by categorical time to switch to second-line. Cox proportional hazards models were
used to examine virologic failure on second-line ART among patients who switched to second-
5895 patients failed first-line ART, and 63% switched to second-line. Among patients who
switched, median time to switch was 3.4 months (IQR: 1.1–8.7 months). Longer time to
switch was associated with higher CD4 counts, lower viral loads and more missed visits
prior to first-line failure. Worse outcomes were associated with delay in second-line switch
among patients with a peak CD4 count on first-line treatment 100 cells/mm3. Among these patients, marginal structural models showed increased risk of death (adjusted HR for switch in 6–12 months vs. 0–1.5 months = 1.47 (95% CI: 0.94–2.29), and Cox models
showed increased rates of second-line virologic failure despite the presence of survivor
bias (adjusted HR for switch in 3–6 months vs. 0–1.5 months = 2.13 (95% CI: 1.01–4.47)).
Even small delays in switch to second-line ART were associated with increased death and
second-line failure among patients with low CD4 counts on first-line. There is opportunity for
healthcare providers to switch patients to second-line more quickly.
S1 Fig. Illustration of allocation of person time in marginal structural models. Hypothetical
person time contributed to each of the 6 exposure groups in marginal structural models.
S1 Table. Alternative stratifications for adjusted marginal structural models for hazard
ratios of death after first-line failure.
S2 Table. Adjusted marginal structural model hazard ratios for death after first-line failure,
limiting to patients with 2 weeks to <8 months between failing viral loads on first-line
(n = 4908).
S3 Table. Adjusted Cox proportional hazards ratios for alternative virologic outcomes on
second-line ART, stratified by peak CD4 count prior to first-line failure.
S4 Table. Adjusted marginal structural models for hazard ratios of death after first-line failure
(a) and adjusted Cox proportional hazards ratios for confirmed failure on second-line ART
(b), with weighting by inverse probability of censoring after second-line switch to account for
loss to follow-up.