A Randomized Clinical Trial to Evaluate Solutions for the Management of Virologic Failure on TLD in Sub-Saharan Africa

Study Overview
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Brief Summary
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The RESOLVE trial is an open, parallel arm, randomized clinical trial which aims to determine the optimal strategy for management of virologic failure on first-line antiretroviral therapy (ART) with tenofovir, lamivudine, and dolutegravir (TLD) in sub-Saharan Africa. The primary outcome of interest will be viral suppression to <50 copies/mL at 48 weeks using the FDA snapshot definition. The study will be conducted in Uganda and South Africa.

Detailed Description
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The RESOLVE trial is an open, parallel arm, randomized clinical trial which will be conducted at public-sector HIV clinics in Uganda and South Africa. We will enroll individuals with HIV age 15 and above who have had two HIV-1 RNA viral load results >1,000 copies/mL while on TLD as first-line antiretroviral therapy and who have been on TLD for at least 12 months. Participants will be randomized using an equal allocation ratio of 1:1:1 across three study arms : 1) Maintenance on TLD with switch to protease inhibitor (PI)-based second-line ART if virologic failure persists past six months, 2) Individualized Care with regimen choice based on results of genotypic resistance tests and urine tenofovir adherence assays, or 3) Immediate Switch to PI-based second-line ART. Randomization will be stratified by clinic and prior exposure to non-nucleoside reverse transcriptase inhibitors. We will follow participants for one year with study visits at enrollment, Week 24, and Week 48. The primary outcome of interest will be viral suppression to <50 copies/mL at 48 weeks using the FDA snapshot definition.

Official Title
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A Randomized Clinical Trial to Evaluate Solutions for the Management of Virologic Failure for Individuals on Tenofovir, Lamivudine, and Dolutegravir (TLD) in Sub-Saharan Africa

Conditions
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HIV Infections, AIDS, Virologic Failure

Intervention / Treatment
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* Other: Maintenance on TLD treatment strategy
* Other: Individualized Care treatment strategy
* Other: Immediate Switch


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 15 years and above Enrolled in HIV care at one of the study clinics History of two HIV-1 RNA viral load measurements >1,000 copies/mL while on TLD On TLD as first-line ART for at least 12 months Lives within 100 kilometers of study clinic Pregnant women are eligible for enrollment. Exclusion Criteria: Plans to transfer out of the clinic within the next 48 weeks Plans to move out of the study catchment area within the next 48 weeks On TLD as second-line or third-line ART

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maintenance on TLD<br>Participants will undergo routine enhanced adherence counseling (EAC) at the enrollment visit (Week 0) and will be maintained on TLD. At Week 24, participants will undergo phlebotomy for repeat plasma HIV-1 RNA viral load testing. If the HIV-1 RNA viral load is >1,000 copies/mL, the participant will be switched to protease inhibitor (PI)-based second-line ART. Otherwise, the participant will be continued on TLD. Participants will continue to have routine care visits, EAC, and viral load monitoring at intervals determined by the clinic as per national guidelines. At study completion, participants will undergo plasma HIV-1 RNA viral load testing at Week 48. For pregnant participants randomized to the Maintenance on TLD arm, the second visit will be completed at Week 4, rather than Week 24. | Other: Maintenance on TLD treatment strategy<br>* Management of virologic failure on TLD using the Maintenance on TLD strategy<br>|
| Experimental: Individualized Care<br>Participants will undergo routine EAC, point-of-care urine tenofovir (TFV) testing, and genotypic resistance testing (GRT) at enrollment. Participants will return when GRT results are available for a treatment decision. Side effects and tolerance will also be assessed. All information will be used to make an optimal treatment recommendation with participant input. Participants will have an additional study visit at Week 24 and will continue to have routine care visits, adherence counseling by the clinic, and viral load monitoring at intervals determined by the clinic per national guidelines. Participants will undergo plasma HIV-1 RNA viral load testing at Week 48. | Other: Individualized Care treatment strategy<br>* Management of virologic failure on TLD using the Individualized Care strategy<br>|
| Experimental: Immediate Switch<br>Participants will undergo routine EAC and a switch from TLD to PI-based second-line ART at the enrollment visit (Week 0). Participants will have an additional study visit at Week 24. Participants will continue to have routine care visits and viral load monitoring at intervals determined by the clinic per national guidelines. At study completion, participants will undergo plasma HIV-1 RNA viral load testing at Week 48. | Other: Immediate Switch<br>* Management of virologic failure on TLD using the Immediate Switch strategy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral suppression at 48 weeks | A plasma HIV-1 RNA viral load <50 copies/mL (FDA-snapshot definition) | 48 weeks post-enrollment (visit window spanning 42 to 54 weeks post-enrollment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ART, Medication Adherence, Drug resistance, Dolutegravir