Parameters Influencing Baseline HIV-1 Genotypic Tropism Testing Related to Clinical Outcome in Patients on Maraviroc

Abstract

ObjectivesWe analysed the impact of different parameters on genotypic tropism testing related to clinical outcome prediction in 108 patients on maraviroc (MVC) treatment.Methods87 RNA and 60 DNA samples were used. The viral tropism was predicted using the geno2pheno[coreceptor] and T-CUP tools with FPR cut-offs ranging from 1%-20%. Additionally, 27 RNA and 28 DNA samples were analysed in triplicate, 43 samples with the ESTA assay and 45 with next-generation sequencing. The influence of the genotypic susceptibility score (GSS) and 16 MVC-resistance mutations on clinical outcome was also studied.ResultsConcordance between single-amplification testing compared to ESTA and to NGS was in the order of 80%. Concordance with NGS was higher at lower FPR cut-offs. Detection of baseline R5 viruses in RNA and DNA samples by all methods significantly correlated with treatment success, even with FPR cut-offs of 3.75%-7.5%. Triple amplification did not improve the prediction value but reduced the number of patients eligible for MVC. No influence of the GSS or MVC-resistance mutations but adherence to treatment, on the clinical outcome was detected.ConclusionsProviral DNA is valid to select candidates for MVC treatment. FPR cut-offs of 5%-7.5% and single amplification from RNA or DNA would assure a safe administration of MVC without excluding many patients who could benefit from this drug. In addition, the new prediction system T-CUP produced reliable results.

Pretreatment resistance mutations and treatment outcomes in adults living with HIV-1: a cohort study in urban Malawi

“…Nucleic acid extraction from 500 µL of serum was performed using the DNA and viral NA large volume kit (Roche Diagnostics, Mannheim, Germany) for the automated MagNA Pure 96 system (Roche Diagnostics, Rotkreuz, Switzerland). The protease and reverse transcriptase regions were amplified for resistance analysis as described by Lübke et al [8], and the envelope region for tropism determination as described by Sierra et al [9]. For HIV subtyping, the COMET tool version 2.2 [10] was used.…”

Genotypic Prediction of Co-receptor Tropism of HIV-1 Subtypes A and C

“…support vector machines 11 , artificial neural networks 12 , structural models 13 and position specific scoring matrices (PSSM) 14 . The most commonly used tools today are geno2pheno 15 and WebPSSM 14 , which deliver high levels of sensitivity 16 . Nevertheless, the performance of computational models in tropism prediction of HIV-1 strongly depends on the database that has been used for algorithm development.…”

Genotypic tropism testing of proviral DNA to guide maraviroc initiation in aviraemic subjects: 48‐week analysis of results from the PROTEST study

“…However, the data reported to date are scarce. A number of retrospective analyses have evaluated the feasibility of HIV tropism determination from proviral DNA to guide the use of MVC in the clinical setting [17][18][19][20][21][22]. In a small pilot prospective randomized trial, switching the third drug to MVC was shown to be safe and efficacious and improved lipid parameters [24].…”

“…To date, only retrospective analyses have evaluated the feasibility of HIV tropism determination from proviral DNA to guide the use of MVC in the clinical setting. A re‐analysis of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment‐Experienced Patients (MOTIVATE)/A4001029 trials in antiretroviral‐experienced patients and some data obtained outside clinical trials in cohorts of patients in which MVC was initiated based on genotypic results suggest that HIV tropism determination from proviral DNA is a predictor of virological response to MVC, similar to determinations obtained using Trofile ™ and Enhanced Sensitivity Trofile Assay (ESTA) .…”