"Switch Either Near Suppression Or THOusand"

HIV/AIDS Clinical Trial

— SESOTHO  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03088241
• Other study ID #: P002-17-1.0
• Status: Completed
• Phase: N/A
• Start date: August 1, 2017
• Est. completion date: May 23, 2020

Study information

• Verified date: March 2022
• Source: Swiss Tropical & Public Health Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: May 23, 2020
• Est. primary completion date: May 23, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• HIV/AIDS
• Viremia

Intervention

Other:
• switch
switch to second-line ART

Locations

Country	Name	City	State
Lesotho	Butha-Buthe Hospital	Butha-Buthe
Lesotho	Muela Health Center	Butha-Buthe
Lesotho	Seboche Hospital	Butha-Buthe
Lesotho	St. Paul Health Center	Butha-Buthe
Lesotho	St. Peters Health Center	Butha-Buthe
Lesotho	Motebang Hospital, ART corner	Hlotse	Leribe
Lesotho	Senkatana ART clinic	Maseru
Lesotho	Mokhotlong Hospital	Mokhotlong

Sponsors (8)

Lead Sponsor	Collaborator
Niklaus Labhardt	Butha-Buthe Hospital, Lesotho, Ministry of Health, Lesotho, SolidarMed, Lucerne, Switzerland, SolidarMed, Maseru, Lesotho, Swiss Tropical & Public Health Institute, University Hospital, Basel, Switzerland, University of Basel

Country where clinical trial is conducted

Lesotho, 

References & Publications (2)

Amstutz A, Nsakala BL, Vanobberghen F, Muhairwe J, Glass TR, Achieng B, Sepeka M, Tlali K, Sao L, Thin K, Klimkait T, Battegay M, Labhardt ND. 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. BMC Infect Dis. 2018 Feb 12;18(1):76. doi: 10.1186/s12879-018-2979-y. — View Citation

Amstutz A, Nsakala BL, Vanobberghen F, Muhairwe J, Glass TR, Namane T, Mpholo T, Battegay M, Klimkait T, Labhardt ND. Switch to second-line versus continued first-line antiretroviral therapy for patients with low-level HIV-1 viremia: An open-label randomi — View Citation

Outcome

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

External Links

•   New coverage of the trial results
•   Research Group Webpage