Abstract

BackgroundThe 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.MethodsIn 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.DiscussionThe 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.Trial registrationClinicalTrials.gov (NCT03088241), registered May 05, 2017

Highlights

  • The World Health Organization (WHO) recommends viral load (VL) measurement as the preferred monitoring strategy for Human Immunodeficiency Virus (HIV)-infected individuals on antiretroviral therapy (ART) in resource-limited settings

  • 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

  • By the end of 2016, an estimated 11.7 million individuals, representing 60% of all people living with HIV in Eastern and Southern Africa, were receiving ART [31]

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Summary

Methods

Setting and design The SESOTHO trial will be conducted in the district of Butha-Buthe, in northern Lesotho, Southern Africa. Primary endpoint The primary endpoint is viral resuppression (VL < 50 copies/mL) 9 months after randomization The rationale for this time-point is that, according to national guidelines, VL should be measured 6 months after switch to second-line ART. Due to the limited published data, our sample size assumptions were primarily based on our own data from a previous cohort study in Lesotho, the sample size of that study was small and the confidence intervals of our estimates were wide [17] Based on those data, we expect 9month viral resuppression rates of 25% in the control arm and 60% in the intervention arm, assuming a lost-to-follow-up (LTFU) rate of 10% in each arm, and counting participants who are LTFU as failures, Fig. 2 SPIRIT Flow Diagram of the SESOTHO trial. We anticipate identifying approximately 14 eligible participants/month and a 10% refusal rate, we project a total recruitment period of 7 months to achive our target sample size of 80 patients

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