Primary and Secondary Drug Resistance Mutations (DRMs) in HIV As a Risk Factor of Failure of ART, Including Two Drugs Based Regimens.

NCT ID: NCT06661317

Last Updated: 2024-10-28

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-11-01
• Study Completion Date: 2024-12-30

Brief Summary

The presence of drug resistance mutations (DRMs) in HIV plays an important role in ART effectiveness. Despite very good results of ART, there is constant concern about the emergence of HIV strains with DRMs, what may lead to virological suppression failure. The concerns grow especially among patients treated with two drugs based regimens, including long acting therapies in injections (LAI ART) or regimens used in preexposure prophylaxis (PreP).

Detailed Description

Introduction The presence of drug resistance mutations (DRMs) in HIV plays an important role in ART effectiveness. Despite very good results of ART, there is constant concern about the emergence of HIV strains with DRMs, what may lead to virological suppression failure. Primary HIV DRMs occur in PLWH who have not previously been treated with ART. These people start treatment with a lower genetic barrier, a higher risk of virological failure and a higher risk of developing resistance to other drugs, which may lead to progression to AIDS. The concerns grow especially among patients treated with two drugs based regimens, including long acting therapies in injections (LAI ART) or regimens used in preexposure prophylaxis (PreP). The prevalence of major HIV-1 DRMs reported worldwide ranges from 5 to 25%, while in case of accessory (polymorphic) DRMs even up to 50%. It has been reported that in high-income countries the prevalence of sequences with acquired DRMs is decreasing, but the fraction of transmitted resistance is clearly increasing compared to the fraction of acquired DRMs, reaching even 70% of all cases of DRMs.

Aim of the study The choice of ART is based on epidemiological data regarding the presence of drug resistance mutations in HIV, as well on the basis of the HIV genotyping test results assessed before the start or change of the treatment. The presence of DRMs before ART initiation may be a risk factor for insufficient virological suppression, as the population of HIV is still evolving (changing due to mistakes during replication process). As well, inadequate antiretroviral therapy may drive the viral population first through a lower fitness level and then to a higher fitness level. Due to the constant changes in the pattern of HIV drug resistance (emergence of new mutations) and the introduction of new drugs into the treatment, including two drugs based regimens as LAI ART, we decided to conduct a study which determine the type and frequency of DRMs (including NRTI and NNRTI - RPV, 3TC and InSTI - CAB, DTG), in the population of previously untreated patients, as well as among patients with ART virological failure. The results may help in assessing the risk of ART failure, including LAI, and in determining ART regimens.

Methodology We aim to conduct multi-center, observational, cross sectional study. The patients' data will be extracted from the 2 year period (2023 - 2024). The site of the recruitment will be three clinical centers in Poland (two in Warsaw, one in Ostróda). Inclusion criteria are: diagnosis with HIV-1 infection, age 18 years or older. We will collect epidemiological data such as: age, gender, BMI, route of transmission also clinical and laboratory findings: HIV viral load, lymphocyte CD4 count and CD4:CD8 ratio (at the time of diagnosis/ change of therapy), presence of AIDS-defining diseases, implemented ART regimen. In all patients, before starting ART, the presence of HIV-1 DRMs to nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) protease inhibitors (PI) and integrase inhibitors (InSTI) will be evaluated, as a part of routine care.

The drug resistance genotyping of HIV-1 protease (PR) and reverse transcriptase (RT) coding region will be performed based on a Sanger sequencing method with use of commercially available ViroSeq HIV-1 Genotyping System (Abbott Molecular, Des Plains, IL, USA). The analysis procedure will be performed according to the manufacturer's instructions. HIV-1 RNA will be extracted manually from 0,5 mL of collected plasma samples by precipitation and centrifugation steps, followed by reverse transcription with MuLV reverse transcriptase. DNA products corresponding to the 1.8 kb pol region fragment will be generated in PCR with AmpliTaq Gold DNA Polymerase, after pre-incubation with Uracil-N-Glycosylase (UNG) enzyme. Where HIV-1 integrase coding region will be sequenced the ViroSeq HIV-1 Integrase Genotyping System (Celera Diagnostics, Alameda, CA, USA) will be applied with one step RT-PCR amplification reaction. Obtained PCR products will be purified enzymatically by incubation with Exo-SAP mix (Exonuclease I + Shrimp Alkaline Phosphatase), diluted if necessary, fluorescently labelled in reaction with appropriate terminators and sequenced by ABI Prism 3130 Genetic Analyzer using Data Collection Software (Applied Biosystems). The resulting sequence chromatograms will be assembled and analyzed using ViroSeq Genotyping System Software (Abbott Molecular). Drug resistance-associated mutations in protease, integrase and reverse transcriptase will be identified. The valid, quality checked pol sequences will be submitted to the Stanford University HIV Drug Resistance Database (http://hivdb.stanford.edu) in order to comparison of potential differences in the interpretation of the significance of genetic variants detected. For HIV-1 subtype and circular recombinant forms (CRFs) determination of partial pol submitted sequences REGA HIV-1 Subtyping Tool Version 3.0 will be used.

Statistical evaluation of the collected data will be performed in subgroups of PLWH with the presence of primary and secondary HIV DRMs. The analysis will also be performed in the subgroups of patients with different subtype HIV-1 infection. The Shapiro-Wilk test will be performed for the verification of the normality of the distributions in the analyzed variables. Student's t-test or Mann-Whitney U test will be used to evaluate the difference in mean value in continuous variables and χ 2 or Fisher exact tests will be performed for categorical variables. A p value of <0.05 will be considered statistically significant. Statistical analyses will be performed using Python 3.7 software and Statistica 13.1 program (StatSoft Poland, Kraków, Poland).

The clinical trial has received a positive opinion from the Bioethics Committee at the Medical University of Warsaw (number of consent: AKBE/72/2023). All analyzed patients' data will be fully anonymized. The study follows the principles of the Declaration of Helsinki.

Conditions

HIV-1-infection; DRM; DRM Gene Mutation; ART

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Study Groups

primary DRMs

patients with the presence of primary DRMs

no intervention

Intervention Type: OTHER

no intervention

secondary DRMs

patients with the presence of secondary DRMs

no intervention

Intervention Type: OTHER

no intervention

Interventions

no intervention

no intervention

Intervention Type: OTHER

Eligibility Criteria

Exclusion Criteria

Lack of HIV genotyping before ART treatment or change of ART

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medical University of Warsaw

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andrzej Załęski, PhD

Role: PRINCIPAL_INVESTIGATOR

Medical University of Warsaw

Locations

Department of Infectious Diseases, Tropical Diseases and Hepatology, Medical University of Warsaw

Warsaw, Mazowia, Poland

Countries

Poland

Central Contacts

Andrzej Załęski, PhD

Role: CONTACT

andrzejzaleski84@wp.pl

600982185

Facility Contacts

Andrzej Załęski, PhD

Role: primary

andrzejzaleski84@wp.pl

600982185

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Other Identifiers

Primary and secondary HIV DRMs

Identifier Type: -

Identifier Source: org_study_id