Investigating the Optimal Management of Dolutegravir Resistance

Recruiting

• Conditions: HIV-1-infection

• Registration Number: NCT06762054
• Lead Sponsor: University of Nairobi

Brief Summary

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.

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 Timeline

• Study First Submitted: 2024-12-18
• Study First Submitted QC: 2025-01-06
• Status Verified: 2025-03
• Study Start: 2025-03-03
• Last Update Submitted: 2025-03-24
• Study First Posted: 2025-03-25
• Last Update Posted: 2025-03-28
• Primary Completion: 2026-10
• Study Completion: 2026-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 6600

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Viral suppression rate	12 months	Viral suppression rate following enhanced adherence counseling

Secondary Outcome Measures

Name	Time	Method
Time to viral suppression	12 months	Time to HIV-1 viral suppression to \< 200 copies/mL
Viral suppression by age strata	12 months	Viral load suppression rate by age strata: 1-9, 10-19, ≥20, 20-24, 25-34, 35-44, and ≥45 years old
Viral suppression by viral load strata	12 months	Viral load suppression by viral load strata: 1,000-99,999, and ≥100,000 copies/mL
Viral suppression by sex at birth	12 months	Viral load suppression based on participant's sex
Viral suppression by nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)	12 months	Viral load suppression based on the NRTI component of the antiretroviral regimen
Durability of suppression	12 to 24 months	Durability of suppression at 3 months from first viral load of \<200 copies/mL
Incidence of drug resistant mutations (DRMs)	12 months	Incidence of treatment-emergent drug resistant mutations
Drug resistant mutations patterns	12 months	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
Predictors of development of dolutegravir (DTG)-associated drug resistant mutations	12 months	What are the predictors of development of dolutegravir (DTG)-associated drug resistant mutations
Time from viraemia to drug resistant mutations	12 months	Time from first detected viraemia to development of dolutegravir (DTG)-associated drug resistant mutations

Trial Locations

Locations (9)

Jaramogi Oginga Odinga Teaching and Referral Hospital; 🇰🇪 Kisumu, Kenya

Bomu Hospital; 🇰🇪 Mombasa, Kenya

Kenyatta National Hospital; 🇰🇪 Nairobi, Kenya

Butha-Buthe District Hospital; 🇱🇸 Butha-Buthe, Lesotho

Mokhotlong District Hospital; 🇱🇸 Mokhotlong, Lesotho

CS Ponta Gea; 🇲🇿 Beira, Sofala, Mozambique

CS Machava II; 🇲🇿 Maputo, Mozambique

CS Ndlavela; 🇲🇿 Maputo, Mozambique

MUHAS Clinical Trial Unit; 🇹🇿 Dar Es Salaam, Tanzania