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

October 24, 2024 updated by: Medical University of Warsaw

Presence of HIV-1 DRMs As a Risk Factor of Failure of Two Drugs Based ART Regimens, Including LAI ART, in Cohorts of Primary and Secondary DRMs.

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).

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Estimated)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Poland
    • Mazowia
      • Warsaw, Mazowia, Poland, 01-201
        • Department of Infectious Diseases, Tropical Diseases and Hepatology, Medical University of Warsaw
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

HIV- 1 diagnosed patient recruited in three clinical centers in Poland (two in Warsaw, one in Ostróda)

Description

Inclusion Criteria:

Inclusion criteria were: diagnosis with HIV-1 infection, age 18 years or older.

Exclusion Criteria:

Lack of HIV genotyping before ART treatment or change of ART

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
primary DRMs
patients with the presence of primary DRMs
Other: no intervention
no intervention
secondary DRMs
patients with the presence of secondary DRMs
Other: no intervention
no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
frequency of DRMs
Time Frame: 2 years
frequency of DRMs in all included patients
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
frequency of primary and secondary DRMs
Time Frame: 2 years
frequency of primary and secondary DRMs, including resistance to InSTI
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical University of Warsaw

Investigators

  • Principal Investigator: Andrzej Załęski, PhD, Medical University of Warsaw

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

November 1, 2024

Primary Completion (Estimated)

November 30, 2024

Study Completion (Estimated)

December 30, 2024

Study Registration Dates

First Submitted

October 24, 2024

First Submitted That Met QC Criteria

October 24, 2024

First Posted (Actual)

October 28, 2024

Study Record Updates

Last Update Posted (Actual)

October 28, 2024

Last Update Submitted That Met QC Criteria

October 24, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • Primary and secondary HIV DRMs

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

data extracted from medical records

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on HIV-1-infection

Clinical Trials on no intervention

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Slovenia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe