Ndovu RCT: Investing the Optimal Management of Dolutegravir Resistance

University of Nairobi

Status and phase: Not yet enrolling; Phase 3

Conditions: HIV-1-infection

Treatments: Drug: Darunavir+Ritonavir; Drug: Dolutegravir Pill

Study type: Interventional

Funder types: Other

Identifiers

NCT06747507

Ndovu RCT

Details and patient eligibility

About

This clinical trial will address the gap in published data on the effect of dolutegravir (DTG)-associated drug-resistant mutations on viral suppression among people remaining on DTG-based antiretroviral therapy. It will also address the gap in the optimal management strategy for this population.

Full description

BACKGROUND:

The majority of people living with HIV (PLWH) on first-line antiretroviral therapy (ART) in low- and middle-income countries are on dolutegravir (DTG)-containing regimens. Different countries have adopted different approaches in the management of people on DTG-based first-line ART with repeat HIV viral load (VL) of > 1,000 copies/mL after 3 months of enhanced adherence counselling. For example, Kenya recommends a drug resistance test (DRT) to guide on switch and the optimal second-line regimen; Mozambique and Tanzania recommend switch to 2 nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) without drug resistance testing; South Africa does not recommend switch from DTG or DRT for those who are on first-line DTG-containing regimens within the first 2 years of treatment, after which management is guided by possible DRT and expert opinion. The World Health Organization has recognised the role of drug resistance testing (DRT) in a treatment failure algorithm for people living with HIV receiving DTG-based treatment to minimise unnecessary switches from this regimen. The switch to PI has disadvantages including higher cost, higher pill burden, less convenient administration (often should be taken with food), more potential drug-drug interactions, poorer tolerability and more long-term toxicities.

GOAL:

To assess the efficacy and safety of remaining on DTG compared to switching to DRV/r among people failing DTG-based ART with at least one major DTG DRM.

METHODS:

This is a phase 3b, multi-country, open-label, two-arm, active-controlled randomized clinical trial (RCT) over 12 months describing the efficacy and safety of switching from DTG to DRV/r among PLWH age ≥ 3 years who are failing DTG-based ART with HIV-1 RNA ≥ 200 copies/mL and ≥ 1 major DTG-associated DRM (and most recent prior HIV-1 RNA ≥ 1,000 copies/mL after at least 6 months on DTG-based ART). The primary efficacy endpoint is the proportion of participants with HIV-1 RNA < 200 copies/mL at month 6. The study will be conducted in 9 sites in Kenya, Mozambique, Tanzania and Lesotho targeting 392 participants including 30 children aged between 3 and 14 years old. The primary efficacy analysis will assess the difference in the proportion of participants with viral suppression at month 6 using the Cochran-Mantel-Haenszel method. This RCT is nested within an observational cohort study describing HIV-1 viral suppression of people with HIV-1 RNA value of ≥ 1,000 copies/mL after at least six months on DTG-based ART.

Enrollment: 392 estimated patients

Sex: All

Ages: 3+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Enrolled in the Ndovu cohort study
• Able and willing to understand and comply with the protocol requirements, instructions and restrictions
• Able and willing to provide informed consent for the nested clinical trial (assent as appropriate and legal guardian consent if < 18 years)
• Age ≥ 3 years
• Most recent HIV-1 RNA ≥ 200 copies/mL
• At least one major DTG-associated DRM (substitution at codon 66K, 92Q, 118R, 138K/A/T, 140S/A/C, 148H/R/K, 155H or 263K)

Exclusion criteria

• Pregnant or breastfeeding
• Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs
• WHO stage 3 or 4 opportunistic infection which would prevent randomisation to either arm (e.g. due to drug interactions or significant liver or renal injury) within 4 weeks prior to RCT screening
• Investigator opinion that the potential participant should discontinue DTG immediately for clinical reasons
• Investigator opinion that the potential participant should not switch to DRV/r for clinical reasons

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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392 participants in 2 patient groups

Continue on DTG-based Therapy

Experimental group

Description:

Participants in this arm will continue their pre-randomization DTG-based ART regimen

Treatment:

Drug: Dolutegravir Pill

Switch to PI-based Therapy

Active Comparator group

Description:

Participants in this arm will be switched to ritonavir-boosted darunavir (DRV/r)-based ART regimen on the day of randomization

Treatment:

Drug: Darunavir+Ritonavir