SESOTHO trial (Switch Either near Suppression Or THOusand) - switch to second-line versus WHO-guided standard of care for unsuppressed patients on first-line ART with viremia below 1000 copies/mL: protocol of a multicenter, parallel-group, open-label, randomized clinical trial in Lesotho, Southern Africa

Background: 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 new WHO guidelines 2016 continue to define 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 is 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 assesses a lower threshold for switch to second-line ART in patients with sustained unsuppressed VL. Methods: In this multicenter, parallel-group, open-label, randomized controlled trial conducted in Lesotho, patients on first-line ART with two consecutive unsuppressed VL measurements >= 100 copies/mL, where the second VL is between 100 and 999 copies/mL, will either be switched to second-line ART immediately (intervention group) or not be switched (standard of care, according to WHO guidelines). The primary endpoint is viral resuppression (VL < 50 copies/mL) 9 months after randomization. We will enrol 80 patients, giving us 90% power to detect a difference of 35% in viral resuppression between the groups (assuming two-sided 5% alpha error). For our primary analysis, we will use a modified intention-to-treat set, with those lost to care, death, or crossed over considered failure to resuppress, and using logistic regression models adjusted for the prespecified stratification variables. Discussion: The SESOTHO trial challenges the current WHO guidelines, assessing an alternative, lower VL threshold for patients with unsuppressed VL on first-line ART. This trial will provide data to inform future WHO guidelines on VL thresholds to recommend switch to second-line ART.