"Switch Either Near Suppression Or THOusand" (SESOTHO)

March 20, 2022 updated by: Niklaus Labhardt

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, Parallel-group, Open-label, Randomized Clinical Study in Rural Lesotho

This trial addresses the question of the viral load (VL) threshold for switching from first-line to second-line antiretroviral therapy (ART). The WHO currently sets the threshold at 1000 copies/mL. However, the optimal threshold for defining virological failure and the need to switch ART regimen has not been determined. In fact, people with VL levels of less than 1000 copies/mL, however, not fully suppressed, are at increased risk for drug resistance mutations (DRM) and subsequent virological failure. In resource-limited settings where VL monitoring is not as frequent as in high-income countries, this could have serious implications and patients may continue on a failing regimen for a long period. Our research consortium will conduct a multicenter, parallel-group, open-label, randomized clinical trial in a resource-limited setting to assess whether a threshold of 100 copies/mL compared to the WHO-defined threshold of 1000 copies/mL for switching to second-line ART among unsuppressed HIV-positive patients on first-line ART will lead to better outcomes.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Study background & rational:

The Joint United Nations Programme on HIV/AIDS (UNAIDS) launched the 90-90-90 targets for 2020 based on the result of newly-acquired scientific evidence that - irrespective of CD4 count - early antiretroviral treatment (ART) for HIV-positive individuals is beneficial to them and prevents HIV transmission. UNAIDS expects that the 90-90-90 targets will lead to a reduction in the yearly global HIV incidence from 2 million currently to 500,000 by 2020.

A crucial step to achieve the third pillar of the UNAIDS 90-90-90 targets - 90% viral suppression among HIV-positive individuals on treatment - and thus ensure a successful treatment outcome is the monitoring and management of first-line ART failure.

Since 2013, the WHO recommends routine viral load (rVL) measurement as the preferred monitoring strategy in resource-limited settings and defines virological failure as confirmed VL 1000 copies/mL despite good adherence. Specifically, the guidelines recommend that in case of a VL ≥ 1000 copies/mL the patient should undergo enhanced adherence support and a second VL test 3 months later. A second VL ≥ 1000 copies/mL with confirmed good adherence would trigger the switch to a second-line regimen, whereas if the VL is < 1000 copies/mL the patient should continue unaltered first-line ART. However, the optimal threshold for defining virological failure and the need for switching ART regimen has not yet been determined. In fact, people with VL levels of less than 1000 copies/mL, but not fully suppressed (usually defined as 50-100 copies/mL), are at a increased risk for drug resistance mutations (DRM) and subsequent virological failure. A recently published study from our research consortium in Lesotho indicates similar findings, demonstrating a significant accumulation of drug resistance mutations in patients with VL levels of less than 1000 copies/mL.

The VL threshold of 1000 copies/mL recommended by the WHO and the Lesotho national guidelines for the switch to second-line ART is likely to miss a substantial number of patients on first-line ART with persisting virus replication below 1000 copies/mL with DRM. In resource-limited settings where VL monitoring is not as frequent as in high-income countries, this could have serious implications: after a VL below 1000 copies/mL the patient may not receive a follow-up VL for up to a year, and thus may continue on a failing regimen for a long period of time. In conclusion, such patients are at increased risk for DRM, accumulation of further resistance mutations, drug-resistant virus transmission, and subsequent virological failure.

Study hypothesis:

Our research consortium hypothesizes that in patients on first-line ART with two consecutive unsuppressed VL measurements equal/more than 100 copies/mL, where the second VL is between 100 and 999 copies/mL, switch to second-line ART (intervention group) will lead to a higher rate of viral resuppression (VL < 50 copies/mL) and is therefore superior compared to not switching to second-line ART according to WHO guidelines (control group, standard of care).

Study design:

Multicenter (2-12 centers), parallel-group (1:1 allocation), open-label, superiority, prospective randomized clinical study.

Study Type

Interventional

Enrollment (Actual)

80

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Butha-Buthe, Lesotho, 400
        • Butha-Buthe Hospital
      • Butha-Buthe, Lesotho, 400
        • Seboche Hospital
      • Butha-Buthe, Lesotho
        • Muela Health Center
      • Butha-Buthe, Lesotho
        • St. Paul Health Center
      • Butha-Buthe, Lesotho
        • St. Peters Health Center
      • Maseru, Lesotho
        • Senkatana ART clinic
      • Mokhotlong, Lesotho
        • Mokhotlong Hospital
    • Leribe
      • Hlotse, Leribe, Lesotho
        • Motebang Hospital, ART corner

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • On NNRTI-based first-line ART with two consecutive unsuppressed VL equal/more 100 copies/mL, with the second VL between 100 and 999 copies/mL.
  • Lives and/or works in the district of Butha-Buthe and declares to seek follow-up at one of the study-facilities
  • Signed written informed consent. For children aged <16 years, a main caregiver, and for illiterate a literate witness, has to provide oral and written informed consent.

Exclusion Criteria:

  • On ART less than 6 months
  • On protease-inhibitor containing ART or any other second-line ART
  • Bad adherence (self-reported at least 1 dose missing in the last 4 weeks, resp. 2 doses of a twice-daily-regimen)
  • Clinical WHO stage 3 or 4 at enrolment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intervention
switch to second-line ART
switch to second-line ART
No Intervention: Control
Standard of care: no switch to second-line ART

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
viral suppression
Time Frame: 9 months after randomization
Proportion of virologically suppressed (VL < 50 copies/mL) participants 9 months after randomization.
9 months after randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of participants with different VL thresholds (VL <100, <200, <400, <1000 copies/mL) at 9 months after randomization
Time Frame: 9 months after randomization
9 months after randomization
Adherence at 3, 6, 9 months, assessed by self-reported dose omission
Time Frame: 3, 6, 9 months after randomization
3, 6, 9 months after randomization
Change in values (versus values at baseline) of body-weight (kg) at 9 months
Time Frame: 9 months after randomization
9 months after randomization
Change in values (versus values at baseline) of haemoglobin (g/dL) at 9 months
Time Frame: 9 months after randomization
9 months after randomization
Change in values (versus values at baseline) of CD4 count (cells/mL) at 9 months
Time Frame: 9 months after randomization
9 months after randomization
Change in values (versus values at baseline) of lipids (total cholesterol, LDL, HDL, triglycerides; mmol/l) at 9 months
Time Frame: 9 months after randomization
9 months after randomization
Change in values (versus values at baseline) of new clinical WHO 3 or 4 events (proportion) count at 9 months
Time Frame: 9 months after randomization
9 months after randomization
Change in values (versus values at baseline) of deaths (all-causes) (proportion) at 9 months
Time Frame: 9 months after randomization
9 months after randomization
Proportion of patients with adverse events and serious adverse events at 9 months after randomization
Time Frame: 9 months after randomization
9 months after randomization
Long-term follow-up endpoint: Proportion of patients that are alive, retained in care and virologically suppressed (VL < 50 copies/mL) at 24 months
Time Frame: 24 months after randomization
24 months after randomization
Proportion of virologically suppressed (VL < 50 copies/mL) participants by demographic groups (children vs pregnant women vs adults)
Time Frame: 9 months after randomization
9 months after randomization
Proportion of virologically suppressed (VL < 50 copies/mL) participants by different VL groups at enrolment (VL 100-599 vs 600-999 copies/mL copies/mL)
Time Frame: 9 months after randomization
9 months after randomization
Proportion of participants with viral resuppression (<50 copies/mL)
Time Frame: 6 months after randomization
6 months after randomization
Sustained virologic failure
Time Frame: 6 and 9 months after randomization
Proportion of participants with unsuppressed VL >50 copies/mL at 6 and 9 months
6 and 9 months after randomization

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Direct costs of each treatment arm
Time Frame: 9 months and 24 months after randomization
9 months and 24 months after randomization
Prevalence of major viral resistance mutations to first-line regimen in each treatment arm for all samples for which an RT-PCR amplification is successful
Time Frame: 9 months after randomization
9 months after randomization
pre-specified subgroup: Log-drop
Time Frame: 9 months after randomization
Viral resuppression among individuals with a >0.5 drop in log10 VL between the first screening VL and the second screening VL (i.e. VL at enrolment)
9 months after randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2017

Primary Completion (Actual)

May 23, 2020

Study Completion (Actual)

May 23, 2020

Study Registration Dates

First Submitted

March 12, 2017

First Submitted That Met QC Criteria

March 17, 2017

First Posted (Actual)

March 23, 2017

Study Record Updates

Last Update Posted (Actual)

March 22, 2022

Last Update Submitted That Met QC Criteria

March 20, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

IPD Plan Description

IPD (baseline characteristics, outcomes, follow-up data) will eventually be shared after completion of the study upon request.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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