Clinical trial NCT06285110: HIV-1 Subtype-specific Drug Resistance in Patients Failing Dolutegravir (DTG) Based Regimen
Official 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)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Hiv
Keywords: HIV
Dolutegravir drug resistance mutations
Virologic failure
DTG based regimen
Lead sponsor: University of Bern
Sponsor class: OTHER
Collaborators: name: University of Zurich
name: ETH Zurich
name: University of KwaZulu
name: University of Bristol
First posted: 2024-02-29
Enrollment: 2600
Sex: ALL
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients routinely treated at the local HIV care clinics.

Brief summary: 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Type of Integrase Drug Resistance Mutations (INSTI DRMs) at the time of failing a DTG-based regimen.
timeFrame: 4 years
measure: Prevalence of Integrase Drug Resistance Mutations (INSTI DRMs) at the time of failing a DTG-based regimen.
timeFrame: 4 years
measure: Time to virologic failure
timeFrame: 4 years
measure: Number of INSTI DRMs per patient
timeFrame: 4 years
measure: DTG drug resistance
timeFrame: 4 years
measure: Phenotypic resistance levels of novel DRMs
timeFrame: 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Centro Medico Huesped
city: Rio De Janeiro
country: Brazil
facility: Instituto Nacional de Infectiologia Evandro Chagas - Fiocruz
city: Bobo-Dioulasso
country: Burkina Faso
facility: Hopital de Jour du Centre Hospitalier Universitaire (CHU Souro Sanou)
city: Phnom Penh
country: Cambodia
facility: National Centre for HIV/AIDS, Dermatology and STDs (NCHADS)
city: Limbe
country: Cameroon
facility: Regional Hospital Limbe
city: Yaounde
country: Cameroon
facility: Hospital Jamot
city: Brazzaville
country: Congo
facility: Centre de Traitement Ambulatoire
city: Pointe Noire
country: Congo
facility: Centre de Traitement Ambulatoire
city: Abidjan
country: Côte D'Ivoire
facility: ACONDA Centre de Prise en Charge et de Formation (CePReF)
city: Abidjan
country: Côte D'Ivoire
facility: Centre médical de suivi des donneurs de sang, CNTS
city: Eldoret
country: Kenya
facility: Moi University, AMPATH
city: Lilongwe
country: Malawi
facility: Lighthouse clinic
city: Lilongwe
country: Malawi
facility: Martin Preuss Centre
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
city: Kigali
country: Rwanda
facility: Research for Development, Einstein-Rwanda Research and Capacity Building Program
city: Kisesa
country: Tanzania
facility: National Institute for Medical Research (NIMR)
city: Bangkok
country: Thailand
facility: HIV-NAT/Thai Red Cross AIDS Research Center (TRCARC)
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital, Mahidol University
city: Masaka
country: Uganda
facility: Masaka Regional Referral Hospital / AHF Uganda Cares
city: Mbarara
country: Uganda
facility: Mbarara University of Science and Technology / Mbarara ISS Clinic (MUST)
city: Lusaka
country: Zambia
facility: Centre for Infectious Disease Research Zambia (CIDRZ)
city: Harare
country: Zimbabwe
facility: Newlands Clinic
Study officials:
affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland
name: Matthias Egger, Prof. Dr.
role: STUDY_DIRECTOR
affiliation: KwaZulu-Natal Research Innovation & Sequencing Platform, University of KwaZulu-Natal, South Africa
name: Richard Lessells, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Switzerland
name: Roger Kouyos, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Bristol
name: Jonathan Sterne, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: ETH Zurich (Switzerland)
name: Niko Beerenwinkel, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: