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: a multicenter, open-label, randomized clinical trial

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 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.

Methods

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.

Main funding

Swiss National Science Foundation (IZ07Z0_160876/1; PCEFP3_181355; 323530_177576)

Trial registration

ClinicalTrials.gov (NCT03088241), registered May 05, 2017

Publications

Study protocol: BMC Infectious Diseases, 12 February 2018
Primary outcomes: PLOS Medicine, 16 September 2020
Resistance data: Journal of Antimicrobial Chemotherapy, 13 April 2021

Amstutz A, Nsakala B.L, Vanobberghen F, Muhairwe J, Glass T.R, Achieng B, Sepeka M, Tlali K, Sao L, Thin K, Klimkait T, Battegay M, Labhardt N.D. 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, r. BMC Infect Dis. 2018;18:76. DOI: 10.1186/s12879-018-2979-y

Amstutz A, Nsakala B.L, Vanobberghen F, Muhairwe J, Glass T.R, Namane T, Mpholo T, Battegay M, Klimkait T, Labhardt N.D. Switch to second-line versus continued first-line antiretroviral therapy for patients with low-level HIV-1 viremia: an open-label randomized controlled trial in Lesotho. PLoS Med. 2020;17(9):e1003325. DOI: 10.1371/journal.pmed.1003325

Brown J.A, Amstutz A, Nsakala B.L, Seeburg U, Vanobberghen F, Muhairwe J, Klimkait T, Daniel Labhardt N. Extensive drug resistance during low-level HIV viraemia while taking NNRTI-based ART supports lowering the viral load threshold for regimen switch in resource-limited settings: a pre-planned analysis from the SESOTHO trial. J Antimicrob Chemother. 2021;76(5):1294-1298. DOI: 10.1093/jac/dkab025

Capacity Building
Medical Interventions

Contact

Niklaus Labhardt

Prof. Dr. Niklaus Labhardt, MD, DTM&H, MIH
Guest Scientist

+41612848692
n.labhardtswisstph.ch

Project Facts