Clinical trial NCT06762054: Investigating the Optimal Management of Dolutegravir Resistance
Official title: Investigating the Optimal Management of Dolutegravir Resistance: a Multi-country Cohort Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: HIV-1-infection
Keywords: HIV
Dolutegravir
Treatment failure
Drug resistant mutations
Dolutegravir resistance
Re-suppression
Lead sponsor: University of Nairobi
Sponsor class: OTHER
Collaborators: name: Instituto Nacional de Saúde, Mozambique
name: Muhimbili University of Health and Allied Sciences
name: SolidarMed
name: London School of Hygiene and Tropical Medicine
First posted: 2025-01-07
Enrollment: 6600
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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).

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).

Eligibility criteria: 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

Primary outcomes:
measure: Viral suppression rate
timeFrame: 12 months
Secondary outcomes:
measure: Time to viral suppression
timeFrame: 12 months
measure: Viral suppression by age strata
timeFrame: 12 months
measure: Viral suppression by viral load strata
timeFrame: 12 months
measure: Viral suppression by sex at birth
timeFrame: 12 months
measure: Viral suppression by nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)
timeFrame: 12 months
measure: Durability of suppression
timeFrame: 12 to 24 months
measure: Incidence of drug resistant mutations (DRMs)
timeFrame: 12 months
measure: Drug resistant mutations patterns
timeFrame: 12 months
measure: Predictors of development of dolutegravir (DTG)-associated drug resistant mutations
timeFrame: 12 months
measure: Time from viraemia to drug resistant mutations
timeFrame: 12 months
Other outcomes:
Locations:
city: Kisumu
country: Kenya
facility: Jaramogi Oginga Odinga Teaching and Referral Hospital
city: Mombasa
country: Kenya
facility: Bomu Hospital
city: Nairobi
country: Kenya
facility: Kenyatta National Hospital
city: Butha-Buthe
country: Lesotho
facility: Butha-Buthe District Hospital
city: Mokhotlong
country: Lesotho
facility: Mokhotlong District Hospital
city: Beira
country: Mozambique
facility: CS Ponta Gea
state: Sofala
city: Maputo
country: Mozambique
facility: CS Machava II
city: Maputo
country: Mozambique
facility: CS Ndlavela
city: Dar Es Salaam
country: Tanzania
facility: MUHAS Clinical Trial Unit
Study officials:
affiliation: University of Nairobi
name: Loice A Ombajo, MMed, MSc
role: PRINCIPAL_INVESTIGATOR
References: