Investigating the Optimal Management of Dolutegravir Resistance

Investigating the Optimal Management of Dolutegravir Resistance: a Multi-country Cohort Study

The goal of this study is to address the gap in published data on viral suppression among people meeting the criteria for virologic failure on dolutegravir (DTG)-based ART regimens without a change in regimen. The study will also assess the emergence of DTG-associated drug-resistant mutations and their impact on viral suppression.

Study Overview

• Status: Recruiting
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: Continue DTG-based antiretroviral therapy; Behavioral: Enhanced adherence counselling

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 counseling. 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.

OBJECTIVE:

To assess viral suppression rate following enhanced adherence counseling among people on DTG-based ART who have sustained viraemia (≥ 1,000 copies/mL) after at least six months on ART.

METHODS:

This is a multi-country observational prospective cohort study over 12 months describing HIV-1 viral suppression in people with high viral load (≥ 1,000 copies/mL) after at least six months on DTG-based ART. The Study targets to enrol 6,600 participants in Kenya, Mozambique, Tanzania and Lesotho. Study visits and VL testing will take place at enrolment and then every 3 months for up to 12 months during the active follow-up period for participants who do not achieve viral suppression < 200 copies/mL. During each visit, protocol-specified enhanced adherence counseling and assessment/management of other causes of viremia will continue for at least 3 sessions. For participants who achieve the primary outcome of HIV-1 RNA < 200 copies/mL during the active follow-up period, a repeat VL will be performed after 3 months; outcomes from routinely collected program data (viral load, loss to follow-up, death) will be collected 12-24 months from enrolment to assess durability of suppression among this group. The investigators will estimate the viral suppression at 6 and 12 months using a generalized linear regression model with binomial distribution as well as assess for predictors of achieving suppression, development of DTG-associated drug resistance mutations (DRMs), and development of opportunistic infections using logistic regression models. Participants will also be assessed for eligibility to enrol into a nested randomized clinical trial (RCT) on management of people who develop DRMs during the cohort study (Ndovu RCT; see separate protocol).

• Study Type: Observational
• Enrollment (Estimated): 6600

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
    • Recruiting
    • Butha-Buthe District Hospital
    • Contact: Irene Ayakaka
  • Mokhotlong, Lesotho
    • 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

• Sampling Method: Probability Sample

Study Population

Participants will be recruited without advertisement from the pool of patients receiving routine outpatient HIV care at the study sites and at surrounding HIV clinics in 8 central study sites in Kenya, 1 central study site in Tanzania (enrolling from surrounding care and treatment centres in Dar es Salaam), 6 study sites in Mozambique, and 5 study sites in Lesotho. The target sample size for this study is 6,600 participants. Participants who develop DTG-associated DRMs during cohort follow-up will be assessed for eligibility into a clinical trial assessing the optimal management of people who develop drug resistance to DTG-based ART (Ndovu RCT).

Description

Inclusion Criteria:

• Able and willing to provide informed consent (assent as appropriate and legal guardian consent if < 18 years)
• Age ≥ 1 years
• Documented HIV-1 infection as confirmed by national HIV testing standards at the respective study sites
• On a DTG-based ART regimen for at least six months
• Most recent HIV-1 RNA ≥ 1,000 copies/mL within 3 months prior to enrolment, taken after at least 6 months on current ART regimen

Exclusion Criteria:

• Has switched ART regimen for confirmed or suspected HIV treatment failure while on a PI- or INSTI-based regimen
• Any reason which, in the investigator's opinion, will significantly prevent the collection of viral load levels such as relocation to another area outside of the trial sites or imminent death
• Concomitant NNRTI or PI while on DTG

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Viral suppression rate	Viral suppression rate following enhanced adherence counseling	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to viral suppression	Time to HIV-1 viral suppression to < 200 copies/mL	12 months
Viral suppression by age strata	Viral load suppression rate by age strata: 1-9, 10-19, ≥20, 20-24, 25-34, 35-44, and ≥45 years old	12 months
Viral suppression by viral load strata	Viral load suppression by viral load strata: 1,000-99,999, and ≥100,000 copies/mL	12 months
Viral suppression by sex at birth	Viral load suppression based on participant's sex	12 months
Viral suppression by nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)	Viral load suppression based on the NRTI component of the antiretroviral regimen	12 months
Durability of suppression	Durability of suppression at 3 months from first viral load of <200 copies/mL	12 to 24 months
Incidence of drug resistant mutations (DRMs)	Incidence of treatment-emergent drug resistant mutations	12 months
Drug resistant mutations patterns	Drug resistant mutations (DRM) patterns (dolutegravir (DTG)-associated DRMs with or without concomitant nucleoside reverse transcriptase inhibitors drug resistant mutations) associated with sustained non-suppression or viral rebound after suppression	12 months
Predictors of development of dolutegravir (DTG)-associated drug resistant mutations	What are the predictors of development of dolutegravir (DTG)-associated drug resistant mutations	12 months
Time from viraemia to drug resistant mutations	Time from first detected viraemia to development of dolutegravir (DTG)-associated drug resistant mutations	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): March 3, 2025
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: December 18, 2024
• First Submitted That Met QC Criteria: January 6, 2025
• First Posted (Actual): January 7, 2025

Study Record Updates

• Last Update Posted (Estimated): September 5, 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: Anti-Infective Agents; Antiviral Agents; Anti-Retroviral Agents
• Other Study ID Numbers: Ndovu Cohort Study

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 Principal 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