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NCT Number: NCT06285110

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

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).

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Key information

Conditions

HIV Acquired Immunodeficiency Syndrome Blood-Borne Infections Communicable Diseases Genital Diseases HIV Infections Immune System Diseases Immunologic Deficiency Syndromes Infections Lentivirus Infections RNA Virus Infections Retroviridae Infections Sexually Transmitted Diseases Sexually Transmitted Diseases, Viral Slow Virus Diseases Urogenital Diseases Virus Diseases

Age range

10 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Centro Medico Huesped, Buenos Aires, Argentina

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About this study

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 -

  • Identify novel mutations or novel combinations of DTG Drug Resistance Mutations (DRMs).
  • Identify risk factors for virologic failure, development of InSTI DRMs and InSTI drug resistance.
  • 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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Primary outcomes

  1. 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.

  2. 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.

  3. 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. 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.

  5. 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.

  6. 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%.

Sponsors and collaborators

Lead sponsor

University of Bern

Other

Collaborators

  • ETH Zurich
  • University of Bristol
  • University of KwaZulu
  • University of Zurich

Registry information

Official study title

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)

Acronym: DTG-Resist

Important dates

Study start
2022
Primary completion
2025
Study completion
2025
First posted
Feb 29, 2024
Registry last updated
Nov 25, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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