Delayed switch of antiretroviral therapy after virologic failure associated with elevated mortality among HIV-infected adults in Africa

Abstract

Objective: Routine monitoring of plasma HIV RNA among HIV-infected patients on antiretroviral therapy (ART) is unavailable in many resource-limited settings. Alternative monitoring approaches correlate poorly with virologic failure and can substantially delay switch to second-line therapy. We evaluated the impact of delayed switch on mortality among patients with virologic failure in Africa.

Design: A cohort.

Methods: We examined patients with confirmed virologic failure on first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from four cohorts with serial HIV RNA monitoring in Uganda and South Africa. Marginal structural models aimed to estimate the effect of delayed switch on mortality in a hypothetical trial in which switch time was randomly assigned. Inverse probability weights adjusted for measured confounders including time-updated CD4+ T-cell count and HIV RNA. Results: Among 823 patients with confirmed virologic failure, the cumulative incidence of switch 180 days after failure was 30% [95% confidence interval (CI) 27-33]. The majority of patients (74%) had not failed immunologically as defined by WHO criteria by the time of virologic failure. Adjusted mortality was higher for individuals who remained on first-line therapy than for those who had switched [odds ratio (OR) 2.1, 95% CI 1.1-4.2]. Among those without immunologic failure, the relative harm of failure to switch was similar (OR 2.4; 95% CI 0.99-5.8) to that of the entire cohort, although of borderline statistical significance.

Conclusion: Among HIV-infected patients with confirmed virologic failure on first-line ART, remaining on first-line therapy led to an increase in mortality relative to switching. Our results suggest that detection and response to confirmed virologic failure could decrease mortality.

Fig. 1. Cumulative incidence of switch to second-line antiretroviral therapy (ART) (a) and mortality (b) following confirmed virologic failure on first-line NNRTI-based ART, among 823 patients with confirmed virologic failure, overall and stratified by WHO immunological failure at or before time of virologic failure

N refers to full cohort (not stratified by immunologic failure).

Fig. 2. Counterfactual mortality curves following confirmed virologic failure on first-line NNRTI-based ART, estimated using inverse probability weighting of marginal structural models

(a) Among all patients with confirmed virological failure (N=823) under a range of hypothetical delays before switching to second-line antiretroviral therapy, ranging from immediate switch (within 30 days of confirmed virologic failure) to never switch, (b) Among all patients with confirmed virological failure (N=823) and only those patients without WHO immunological failure at or before time of virologic failure (N=610), under immediate switch (within 30 days of confirmed virologic failure) and never switch.