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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

1103 participants

Study Classification

OBSERVATIONAL

Study Start Date

2022-06-13

Study Completion Date

2025-08-31

Brief Summary

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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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Detailed Description

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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.

Conditions

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Hiv

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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People living with HIV

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

No interventions assigned to this group

Eligibility Criteria

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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

Minimum Eligible Age

10 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Matthias Egger, Prof. Dr.

Role: STUDY_DIRECTOR

Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland

Richard Lessells, Dr.

Role: PRINCIPAL_INVESTIGATOR

KwaZulu-Natal Research Innovation & Sequencing Platform, University of KwaZulu-Natal, South Africa

Roger Kouyos, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Switzerland

Jonathan Sterne, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

University of Bristol

Niko Beerenwinkel, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

ETH Zurich (Switzerland)

Locations

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Centro Medico Huesped

Buenos Aires, , Argentina

Site Status

Instituto Nacional de Infectiologia Evandro Chagas - Fiocruz

Rio de Janeiro, , Brazil

Site Status

Hopital de Jour du Centre Hospitalier Universitaire (CHU Souro Sanou)

Bobo-Dioulasso, , Burkina Faso

Site Status

National Centre for HIV/AIDS, Dermatology and STDs (NCHADS)

Phnom Penh, , Cambodia

Site Status

Regional Hospital Limbe

Limbe, , Cameroon

Site Status

Hospital Jamot

Yaoundé, , Cameroon

Site Status

ACONDA Centre de Prise en Charge et de Formation (CePReF)

Abidjan, , Côte d’Ivoire

Site Status

Centre médical de suivi des donneurs de sang, CNTS

Abidjan, , Côte d’Ivoire

Site Status

Moi University, AMPATH

Eldoret, , Kenya

Site Status

Lighthouse clinic

Lilongwe, , Malawi

Site Status

Martin Preuss Centre

Lilongwe, , Malawi

Site Status

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

Mexico City, , Mexico

Site Status

Centre de Traitement Ambulatoire

Brazzaville, , Republic of the Congo

Site Status

Centre de Traitement Ambulatoire

Pointe-Noire, , Republic of the Congo

Site Status

Research for Development, Einstein-Rwanda Research and Capacity Building Program

Kigali, , Rwanda

Site Status

National Institute for Medical Research (NIMR)

Kisesa, , Tanzania

Site Status

HIV-NAT/Thai Red Cross AIDS Research Center (TRCARC)

Bangkok, , Thailand

Site Status

Ramathibodi Hospital, Mahidol University

Bangkok, , Thailand

Site Status

Masaka Regional Referral Hospital / AHF Uganda Cares

Masaka, , Uganda

Site Status

Mbarara University of Science and Technology / Mbarara ISS Clinic (MUST)

Mbarara, , Uganda

Site Status

Centre for Infectious Disease Research Zambia (CIDRZ)

Lusaka, , Zambia

Site Status

Newlands Clinic

Harare, , Zimbabwe

Site Status

Countries

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Argentina Brazil Burkina Faso Cambodia Cameroon Côte d’Ivoire Kenya Malawi Mexico Republic of the Congo Rwanda Tanzania Thailand Uganda Zambia Zimbabwe