Evaluation of the Genotypic Prediction of HIV-1 Coreceptor Use versus a Phenotypic Assay and Correlation with the Virological Response to Maraviroc: the ANRS GenoTropism Study

Abstract

Genotypic algorithms for prediction of HIV-1 coreceptor usage need to be evaluated in a clinical setting. We aimed at studying (i) the correlation of genotypic prediction of coreceptor use in comparison with a phenotypic assay and (ii) the relationship between genotypic prediction of coreceptor use at baseline and the virological response (VR) to a therapy including maraviroc (MVC). Antiretroviral-experienced patients were included in the MVC Expanded Access Program if they had an R5 screening result with Trofile (Monogram Biosciences). V3 loop sequences were determined at screening, and coreceptor use was predicted using 13 genotypic algorithms or combinations of algorithms. Genotypic predictions were compared to Trofile; dual or mixed (D/M) variants were considered as X4 variants. Both genotypic and phenotypic results were obtained for 189 patients at screening, with 54 isolates scored as X4 or D/M and 135 scored as R5 with Trofile. The highest sensitivity (59.3%) for detection of X4 was obtained with the Geno2pheno algorithm, with a false-positive rate set up at 10% (Geno2pheno10). In the 112 patients receiving MVC, a plasma viral RNA load of <50 copies/ml was obtained in 68% of cases at month 6. In multivariate analysis, the prediction of the X4 genotype at baseline with the Geno2pheno10 algorithm including baseline viral load and CD4 nadir was independently associated with a worse VR at months 1 and 3. The baseline weighted genotypic sensitivity score was associated with VR at month 6. There were strong arguments in favor of using genotypic coreceptor use assays for determining which patients would respond to CCR5 antagonist.During the entry process of HIV-1 in the target cell, the interaction of the viral surface glycoprotein gp120 with a cellular chemokine receptor, the coreceptor, is an essential step, besides attachment to the CD4 receptor, and precedes the fusion of the viral envelope to the cell membrane. The V3 hypervariable loop of gp120 is involved in coreceptor binding. Two coreceptors are most commonly used in vivo: CCR5 and CXCR4 (1). Viral coreceptor use (i.e., usage of either CCR5 or CXCR4) differs between viral isolates. If CCR5-using isolates (R5 isolates) are by far predominant at the early stage of early infection and seem to be selected during HIV-1 transmission, CXCR4 usage (X4 tropism) will become more prevalent as the infection progresses, with approximately half of X4 or dual or mixed (D/M) tropism in antiretroviral-experienced patients with advanced HIV-1 disease (10).Maraviroc (MVC), a CCR5 inhibitor, binds specifically to CCR5 and blocks HIV-1 binding to this coreceptor (5). MVC has shown a potent antiviral effect in antiretroviral-experienced patients with R5 HIV-1 infection in a placebo-controlled trial (7) and is currently prescribed in this indication. As MVC has shown little activity in patients with X4 viruses, the determination of HIV-1 coreceptor use has become mandatory before the prescription of CCR5 inhibitors (8).

Antiretroviral-Experienced HIV-1-Infected Patients Treated with Maraviroc: Factors Associated with Virological Response

“…The coreceptor usage was determined from the V3 env region sequence by geno2pheno before the introduction of MVC (false-positive rate 10%). 4 The reverse transcriptase, protease, and integrase resistance mutations were interpreted with the last ANRS genotypic algorithm (www.hivfrenchresistance .org). According to the ANRS algorithm, the genotypic susceptibility score of treatment (GSS) of the MVC cotreatment received by the patient was calculated as follows: 1 for a sensitive drug and 0 for a resistant or possibly resistant drug.…”

Prediction of HIV-1 Coreceptor Usage (Tropism) by Sequence Analysis using a Genotypic Approach

“…The V3 sequence permits a reliable viral tropism prediction, as shown in clinical studies [3][4][5][6][7][8][9] . In fact, genotypic determination is contemplated in the current European and German-Austrian guidelines 10 .…”

HIV-1 Diversity and Its Implications in Diagnosis, Transmission, Disease Progression, and Antiretroviral Therapy

“…A study found integrase gene polymorphisms present in more than 10% of the 97 analyzed sequences (subtype B and non-B) from patients treated with RAL but these polymorphisms showed no impact on virological outcome either at week 24 or at week 48 (Charpentier et al, 2010). N155H, Q148H/R/K with G140S/A, and Y143R/C are the described mutational patterns that confer resistance to RAL, with or without secondary mutations (Garrido et al, 2010).…”

“…In general, the enhanced sensitivity Trofile (ESTA) assay (phenotypic assay) and V3 population genotyping are the recommended methods. A multicenter prospective study evaluated the performance of genotypic algorithms for prediction of HIV-1 coreceptor usage in comparison with a phenotypic assay for the determination of coreceptor usage (Recordon-Pinson et al, 2010). Researchers reported important differences between 13 algorithms in the sensitivity of detection of X4 isolates.…”