Ndovu RCT: Investing the Optimal Management of Dolutegravir Resistance

Investigating the Optimal Management of Dolutegravir Resistance: an Open-label Randomised Controlled Trial of Maintaining Dolutegravir or Switch to Ritonavir-boosted Darunavir

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.

Study Overview

• Status: Recruiting
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: Dolutegravir Pill; Drug: Darunavir+Ritonavir

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 392
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Joseph Nkuranga, MBChB, MSc; Phone Number: +254737223988; Email: dnkuranga@uonbi.ac.ke

Study Locations

• Kenya
  • Kisumu, Kenya
    • Recruiting
    • Jaramogi Oginga Odinga Teaching and Referral Hospital
    • Contact: Joseph Nkuranga; Phone Number: +254737223988; Email: dnkuranga@uonbi.ac.ke
  • Mombasa, Kenya
    • Not yet recruiting
    • Bomu Hospital
    • Contact: Nashina Admani
  • Nairobi, Kenya, 00100
    • Recruiting
    • Kenyatta National Hospital
    • Contact: Joseph Nkuranga; Phone Number: +254737223988; Email: dnkuranga@uonbi.ac.ke
• Lesotho
  • Butha-Buthe, Lesotho
    • Not yet recruiting
    • Butha-Buthe District Hospital
    • Contact: Irene Ayakaka
  • Mokhotlong, Lesotho
    • Not yet recruiting
    • Mokhotlong District Hospital
    • Contact: Irene Ayakaka
• Mozambique
  • Maputo, Mozambique
    • Not yet recruiting
    • CS Machava II
    • Contact: Nalia Ismael
  • Maputo, Mozambique
    • Not yet recruiting
    • CS Ndlavela
    • Contact: Nalia Ismael
  • Sofala
    • Beira, Sofala, Mozambique
      • Not yet recruiting
      • CS Ponta Gea
      • Contact: Nalia Ismael
• Tanzania
  • Dar es Salaam, Tanzania
    • Not yet recruiting
    • MUHAS Clinical Trial Unit
    • Contact: Patricia Munseri

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Continue on DTG-based Therapy; Participants in this arm will continue their pre-randomization DTG-based ART regimen	Drug: Dolutegravir Pill; Dose will be based on weight; brand names will be as supplied through the respective national programs
Active Comparator: Switch to PI-based Therapy; Participants in this arm will be switched to ritonavir-boosted darunavir (DRV/r)-based ART regimen on the day of randomization	Drug: Darunavir+Ritonavir; Dose will be based on weight; Other Names: Durart

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with HIV-1 RNA of <200 copies/mL at 6 months	The comparative efficacy of switching to a DRV/r-based regimen after confirmed virologic failure and of remaining on DTG-based ART in achieving viral suppression of <200 copies/mL at 6 months from randomization among participants with ≥1 major DTG-associated DRM	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Superiority of switch to DRV/r	Evaluate if switching to DRV/r-based ART after virologic failure is superior to remaining on DTG-based ART in achieving viral suppression to <200 copies/mL at 6 months from randomization	6 months
Viral suppression with cut-off of 50 copies/mL	Evaluate the difference in viral suppression using HIV-RNA cut-off of <50 copies/mL at 6 and 12 months from randomization	6 and 12 months
Viral suppression with cut-off of 1,000 copies/mL	Evaluate the difference in viral suppression using HIV-RNA cut-off of <1,000 copies/mL at 6 and 12 months from randomization	6 and 12 months
Viral suppression by age strata	Viral load suppression rate by age strata: 3-9, 10-19, ≥20, 20-24, 25-34, 35-44, and ≥45 years old	6 and 12 months
Viral suppression by sex at birth	Viral load suppression based on participant's sex	6 and 12 months
Incidence of adverse events by study arm	Incidence and severity of adverse events and laboratory abnormalities	6 and 12 months
Association between adherence and suppression	Adherence levels, based on DBS TFV-DP levels, associated with suppression and selection of treatment-emergent DRMs	6 months
Incidence of drug resistant mutations (DRMs)	Incidence of treatment-emergent DRMs over 12 months of follow-up	6 and 12 months
Patient satisfaction as measured using the HIV Treatment Satisfaction Questionnaire - Status version (HIVTSQs) which scores 10 variables on a 7-point likert score ranging from 0 to 6 with a higher score representing a better outcome	Patient satisfaction (HIVTSQs) at baseline	6 months
Change in patient satisfaction as measured using the HIV Treatment Satisfaction Questionnaire - Change version (HIVTSQc) which scores 10 variables on a 7-point likert score ranging from -3 to +3 with a higher score representing a better outcome	Patient satisfaction (HIVTSQc) at month 6	Month 6
Proportion of participants with HIV-1 RNA of <200 copies/mL at 12 months	Viral suppression to HIV-RNA of <200 copies/mL at 12 months from randomization	12 months
Patterns of accumulated drug resistant mutations (DRMs)	Describe the patterns of accumulated drug resistant mutations over 12 months of follow-up	6 and 12 months
Drug resistant mutations (DRM) patterns associated with non-suppression	Evaluate drug resistant mutation patterns that are associated with sustained non-suppression	6 and 12 months
Predictors of DTG-associated drug resistant mutations (DRMs)	Investigate the predictors of selection of DTG-associated drug resistant mutations	6 and 12 months
Viral suppression by pre-enrolment nucleoside reverse transcriptase inhibitor (NRTI)	Assess viral suppression based on pre-enrolment NRTI	6 and 12 months
Viral suppression by tenofovir disoproxil fumarate versus tenofovir alafenamide	Assess viral suppression based on tenofovir disoproxil fumarate (TDF) versus tenofovir alafenamide (TAF) as the study nucleoside reverse transcriptase inhibitor	6 and 12 months
Change in cluster of differentiation 4 (CD4) Count	The impact of regimen on change in cluster of differentiation 4 (CD4) count	6 and 12 months

Collaborators and Investigators

• Sponsor: University of Nairobi
• Collaborators: London School of Hygiene and Tropical Medicine; Instituto Nacional de Saúde, Mozambique; Muhimbili University of Health and Allied Sciences; SolidarMed
• Investigators: Principal Investigator: Loice A Ombajo, MMed, MSc, University of Nairobi

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: December 18, 2024
• First Submitted That Met QC Criteria: December 18, 2024
• First Posted (Actual): December 24, 2024

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: September 4, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: HIV; Dolutegravir; Treatment failure; Drug resistant mutations; Dolutegravir resistance; Re-suppression
• Additional Relevant MeSH Terms: Viral Protease Inhibitors; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Antiviral Agents; Cytochrome P-450 Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; dolutegravir
• Other Study ID Numbers: Ndovu RCT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators will share the individual patient data (IPD) that underlie the results reported after de-identification (text, tables, figures and appendices).
• IPD Sharing Time Frame: Beginning 6 months after publication of the final manuscript and for a period of 36 months
• IPD Sharing Access Criteria: Access to IPD will be subject to the University of Nairobi data sharing requirements. Written requests should be submitted to the Chief Investigator providing a brief description of the individual or group making the request and detailing the reason for the same. Prior to sharing the data, the requestor will be required to sign a data access and sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No