The World Health Organization (WHO) recommends viral load (VL) measurement as the preferred monitoring strategy for HIV-infected individuals on antiretroviral therapy (ART) in resource-limited settings. The 2016 WHO guidelines defined virologic failure as two consecutive VL ≥1000 copies/mL (at least 3 months apart) despite good adherence, triggering switch to second-line therapy. However, the threshold of 1000 copies/mL for defining virologic failure was based on low-quality evidence. Observational studies have shown that individuals with low-level viremia (measurable but below 1000 copies/mL) are at increased risk for accumulation of resistance mutations and subsequent virologic failure. The SESOTHO trial assessed a lower threshold for switch to second-line ART in patients with sustained unsuppressed VL.
In this multicenter, parallel-group, open-label, randomized controlled trial conducted in Lesotho, patients on first-line, non-nucleoside reverse transcriptase inhibitor-based ART with two consecutive unsuppressed VL measurements ≥100 copies/mL, where the second VL is between 100 and 999 copies/mL, were either switched to second-line ART immediately (intervention group) or not switched (standard of care, according to guidelines at the time). The primary endpoint was viral resuppression (VL < 50 copies/mL) 9 months after randomization. The sample size comprised 80 patients, allowing 90% power to detect a difference of 35% in viral resuppression between the groups (assuming two-sided 5% alpha error). Primary analysis followed a modified intention-to-treat set with loss from care, death, or crossing over considered as failure to resuppress, using logistic regression models adjusted for the prespecified stratification variables.
Results and discussion
Switching led to significantly increased rates of viral suppression to < 50 copies/mL. Viral suppression was also significantly improved using several other thresholds (<20, <100, <200, <400, and <600 copies/mL), but not for <1,000 copies/mL. Post-hoc analysis demonstrated extensive drug resistance to first-line ART. These findings support lowering the virologic threshold for switching to second-line ART.
Swiss National Science Foundation (IZ07Z0_160876/1; PCEFP3_181355; 323530_177576)
ClinicalTrials.gov (NCT03088241), registered May 05, 2017
Study protocol: BMC Infectious Diseases, 12 February 2018
Primary outcomes: PLOS Medicine, 16 September 2020
Resistance data: Journal of Antimicrobial Chemotherapy, 13 April 2021