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

Hiv Clinical Trial

— DTG-Resist  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06285110
• Other study ID #: DTG Resist
• Status: Recruiting
• Start date: June 13, 2022
• Est. completion date: August 31, 2025

Study information

• Verified date: February 2024
• Source: University of Bern
• Contact: Matthias Egger, Prof.Dr.
• Phone: +41 31 684 35 11
• Email: matthias.egger[@]unibe.ch
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2600
• Est. completion date: August 31, 2025
• Est. primary completion date: August 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hiv

Locations

Country	Name	City	State
Argentina	Centro Medico Huesped	Buenos Aires
Brazil	Instituto Nacional de Infectiologia Evandro Chagas - Fiocruz	Rio De Janeiro
Burkina Faso	Hopital de Jour du Centre Hospitalier Universitaire (CHU Souro Sanou)	Bobo-Dioulasso
Cambodia	National Centre for HIV/AIDS, Dermatology and STDs (NCHADS)	Phnom Penh
Cameroon	Regional Hospital Limbe	Limbe
Cameroon	Hospital Jamot	Yaounde
Congo	Centre de Traitement Ambulatoire	Brazzaville
Congo	Centre de Traitement Ambulatoire	Pointe Noire
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	Abidjan
Kenya	Moi University, AMPATH	Eldoret
Malawi	Lighthouse clinic	Lilongwe
Malawi	Martin Preuss Centre	Lilongwe
Mexico	Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán	Mexico City
Rwanda	Research for Development, Einstein-Rwanda Research and Capacity Building Program	Kigali
Tanzania	National Institute for Medical Research (NIMR)	Kisesa
Thailand	HIV-NAT/Thai Red Cross AIDS Research Center (TRCARC)	Bangkok
Thailand	Ramathibodi Hospital, Mahidol University	Bangkok
Uganda	Masaka Regional Referral Hospital / AHF Uganda Cares	Masaka
Uganda	Mbarara University of Science and Technology / Mbarara ISS Clinic (MUST)	Mbarara
Zambia	Centre for Infectious Disease Research Zambia (CIDRZ)	Lusaka
Zimbabwe	Newlands Clinic	Harare

Sponsors (5)

Lead Sponsor	Collaborator
University of Bern	ETH Zurich, University of Bristol, University of KwaZulu, University of Zurich

Countries where clinical trial is conducted

Argentina,  Brazil,  Burkina Faso,  Cambodia,  Cameroon,  Congo,  Côte D'Ivoire,  Kenya,  Malawi,  Mexico,  Rwanda,  Tanzania,  Thailand,  Uganda,  Zambia,  Zimbabwe, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Type of Integrase Drug Resistance Mutations (INSTI DRMs) at the time of failing a DTG-based regimen.	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
Primary	Prevalence of Integrase Drug Resistance Mutations (INSTI DRMs) at the time of failing a DTG-based regimen.	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
Primary	Time to virologic failure	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
Primary	Number of INSTI DRMs per patient	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
Primary	DTG drug resistance	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
Primary	Phenotypic resistance levels of novel DRMs	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