HIV-1 Subtype-specific Drug Resistance in Patients Failing Dolutegravir (DTG) Based Regimen (DTG-Resist)

November 24, 2025 updated by: University of Bern

HIV-1 Subtype-specific Drug Resistance in Patients Failing Dolutegravir-based 1st, 2nd or 3rd Line Regimens: the International Epidemiological Databases to Evaluate AIDS (IeDEA)

This is a prospective observational study enrolling People Living with HIV (PLHIV) who are on a Dolutegravir-based AntiRetroviral Treatment (ART) regimen and experiencing virologic failure. Virologic failure is defined as two consecutive viral load measurements of >1000 copies/mL of blood. The main aim of the study is to identify the drug-resistance mutations in the viral genome that are associated with this failure.

To achieve this goal, patients fulfilling the eligibility criteria will be invited for a single study visit for the collection of blood. The extracted HIV virus will be sequenced through whole genome sequencing methods to identify the drug-resistance mutations. The study is conducted in 15-20 countries within six regions of the IeDEA cohort (International epidemiology Databases to Evaluate AIDS).

Study Overview

Status

Completed

Conditions

Detailed Description

With the expansion of access to Anti-Retroviral Treatment (ART) in Low and Middle-Income Countries (LMIC), there is an increase in HIV drug resistance. The previously recommended 1st-line regimen of Tenofovir, Emtricitabine and Efavirenz (TEE) contains three drugs with a low genetic barrier to resistance. As a result, acquired drug resistance mutations are detected in the majority of people on TEE across different regions and HIV-1 subtypes. There has also been a steady increase in Pre-treatment Drug Resistance (PDR) as ART coverage has expanded in LMIC. WHO now recommends the use of Dolutegravir (DTG) in 1st -, 2nd and 3rd-line ART for adults and adolescents. Therefore, in most countries, PLHIV are transitioned to a DTG-based regimen. DTG is a potent Integrase Strand Transfer Inhibitor (InSTI) which has better efficacy and safety profile than Efavirenz in 1st-line therapy and Lopinavir/Ritonavir in 2nd-line therapy. DTG has a high genetic barrier to resistance, and resistance in ART-naïve individuals treated with combination ART has so far been rare. However, when used as monotherapy, or in people with pre-existing InSTI resistance, DTG is associated with a higher risk of virologic failure and resistance.

In this study, the investigators aim to -

  1. Identify novel mutations or novel combinations of DTG Drug Resistance Mutations (DRMs).
  2. Identify risk factors for virologic failure, development of InSTI DRMs and InSTI drug resistance.
  3. Check the correlations between novel resistance genotypes and phenotypic DTG resistance across HIV-1 subtypes.

Adults (≥18 years) and adolescents (10-17 years) with virologic failure (viral load ≥1000 copies/mL) on any DTG-based anti-retroviral treatment (1st-line, 2nd-line and 3rd-line) at 20-30 clinical sites within six regions of the IeDEA cohort will be recruited into the study. There is only one study visit per participant and the study is observational and embedded in routine care, with no additional interventions. After obtaining informed consent, a blood specimen will be taken from the study participants. Whole genome sequencing will be performed using the Illumina MiSeq platform to identify the Drug Resistance Mutations. In addition, new DRMs and mutation pathways will be explored by viral genome-wide association study and conjunctive Bayesian network approaches.

Study Type

Observational

Enrollment (Actual)

1103

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Argentina
      • Buenos Aires, Argentina
        • Centro Medico Huesped
  • Brazil
      • Rio de Janeiro, Brazil
        • Instituto Nacional de Infectiologia Evandro Chagas - Fiocruz
  • Burkina Faso
      • Bobo-Dioulasso, Burkina Faso
        • Hopital de Jour du Centre Hospitalier Universitaire (CHU Souro Sanou)
  • Cambodia
      • Phnom Penh, Cambodia
        • National Centre for HIV/AIDS, Dermatology and STDs (NCHADS)
  • Cameroon
      • Limbe, Cameroon
        • Regional Hospital Limbe
      • Yaoundé, Cameroon
        • Hospital Jamot
  • Côte d’Ivoire
      • Abidjan, Côte d’Ivoire
        • ACONDA Centre de Prise en Charge et de Formation (CePReF)
      • Abidjan, Côte d’Ivoire
        • Centre médical de suivi des donneurs de sang, CNTS
  • Kenya
      • Eldoret, Kenya
        • Moi University, AMPATH
  • Malawi
      • Lilongwe, Malawi
        • Lighthouse clinic
      • Lilongwe, Malawi
        • Martin Preuss Centre
  • Mexico
      • Mexico City, Mexico
        • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
  • Republic of the Congo
      • Brazzaville, Republic of the Congo
        • Centre de Traitement Ambulatoire
      • Pointe-Noire, Republic of the Congo
        • Centre de Traitement Ambulatoire
  • Rwanda
      • Kigali, Rwanda
        • Research for Development, Einstein-Rwanda Research and Capacity Building Program
  • Tanzania
      • Kisesa, Tanzania
        • National Institute for Medical Research (NIMR)
  • Thailand
      • Bangkok, Thailand
        • Ramathibodi Hospital, Mahidol University
      • Bangkok, Thailand
        • HIV-NAT/Thai Red Cross AIDS Research Center (TRCARC)
  • Uganda
      • Masaka, Uganda
        • Masaka Regional Referral Hospital / AHF Uganda Cares
      • Mbarara, Uganda
        • Mbarara University of Science and Technology / Mbarara ISS Clinic (MUST)
  • Zambia
      • Lusaka, Zambia
        • Centre for Infectious Disease Research Zambia (CIDRZ)
  • Zimbabwe
      • Harare, Zimbabwe
        • Newlands Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Patients routinely treated at the local HIV care clinics.

Description

Inclusion Criteria:

  • Adults aged 18 years or older and adolescents (10-17 years)
  • On any DTG-based ART regimen
  • Who develop virologic failure (VF) defined as a VL >1000 copies/mL (single or confirmed measurement),
  • and have signed the informed consent.

Exclusion Criteria:

  • No Informed Consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
People living with HIV
People living with HIV and on a Dolutegravir-based ART regimen, and experiencing treatment failure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Type of Integrase Drug Resistance Mutations (INSTI DRMs) at the time of failing a DTG-based regimen.
Time Frame: 4 years
The investigators define INSTI DRMs as all mutations associated with INSTIs by the Stanford HIVdb algorithm (https://hivdb.stanford.edu/). The identified mutations will be classified into major, accessory and other mutation types. New mutations will also be assessed. Analyses will be cross-sectional and differences between groups (for example, HIV-1 subtypes) tested using Pearson's chi-squared tests.
4 years
Prevalence of Integrase Drug Resistance Mutations (INSTI DRMs) at the time of failing a DTG-based regimen.
Time Frame: 4 years
Prevalence of the identified mutations will be expressed as the proportion of the study population showing INSTI DRMs compared to the total number of study participants experiencing treatment failure (Viral load > 1000 copies/mL and successfully sequenced). Analyses will be cross-sectional and differences between groups (for example, HIV-1 subtypes) tested using Pearson's chi-squared tests.
4 years
Time to virologic failure
Time Frame: 4 years
The Investigators define virologic failure as two consecutive viral load measurements of >1000 copies/mL of blood. The time to virologic failure will be analysed using survival models, stratified by country to account for heterogeneity, including all individuals who started Antiretroviral Therapy (ART) on a dolutegravir-based regimen or switched to such a regimen.
4 years
Number of INSTI DRMs per patient
Time Frame: 4 years
The Investigators define INSTI DRMs as all mutations associated with INSTIs by the Stanford HIVdb algorithm, including major and accessory mutations (HIV Drug Resistance Database (https://hivdb.stanford.edu/)). All individuals who developed virologic failure on any dolutegravir-based regimen will be analysed using a negative binomial generalised linear model for the number of major/accessory INSTI DRMs per patient.
4 years
DTG drug resistance
Time Frame: 4 years
The Investigators will use the Stanford HIV Database and the Stanford HIVdb algorithm (HIV Drug Resistance Database (https://hivdb.stanford.edu/)) to categorise drug resistance levels as susceptible (score below 10), potential low (10-14), low (15-29), intermediate (30-59), or high (≥60). An ordinal logistic regression model will be used to analyse the drug resistance levels.
4 years
Phenotypic resistance levels of novel DRMs
Time Frame: 1 year
Selected samples will undergo phenotypic testing to identify any correlations between the observed DRMs on HIV phenotype, which is quantified as the fold change of IC50 to DTG, i.e. the concentration at which viral replication is reduced by 50%.
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Bern

Collaborators

University of Zurich
University of Bristol
ETH Zurich
University of KwaZulu

Investigators

  • Study Director: Matthias Egger, Prof. Dr., Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland
  • Principal Investigator: Richard Lessells, Dr., KwaZulu-Natal Research Innovation & Sequencing Platform, University of KwaZulu-Natal, South Africa
  • Principal Investigator: Roger Kouyos, Prof. Dr., Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Switzerland
  • Principal Investigator: Jonathan Sterne, Prof. Dr., University of Bristol
  • Principal Investigator: Niko Beerenwinkel, Prof. Dr., ETH Zurich (Switzerland)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 13, 2022

Primary Completion (Actual)

August 31, 2025

Study Completion (Actual)

August 31, 2025

Study Registration Dates

First Submitted

May 8, 2023

First Submitted That Met QC Criteria

February 26, 2024

First Posted (Actual)

February 29, 2024

Study Record Updates

Last Update Posted (Actual)

November 25, 2025

Last Update Submitted That Met QC Criteria

November 24, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DTG Resist

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The Investigators are open to share any type of study data upon reasonable request, pending approval by local sites.

IPD Sharing Time Frame

Within 1 year of study conclusion, for about 1 year.

IPD Sharing Access Criteria

Upon reasonable request, pending approval by local sites.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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