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      Short-term maraviroc exposure, a clinical approach to decide on maraviroc prescription in HIV-1-infected treatment-naïve patients

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          Abstract

          Dear editor Woollard and Kanmogne1 have generated an exhaustive review on maraviroc and its use in human immunodeficiency virus (HIV) infection. Within their interesting dissertation, they discuss about the maraviroc clinical test (MCT), a clinical approach developed in our group in order to decide candidate patients to receive maraviroc as part of a further combined antiretroviral therapy, as an alternative to genotypic and phenotypic tropism assays.2 Based on our results, they state that MCT could help to determine/confirm the genotypic/phenotypic HIV-1 tropism, particularly in patients with nonreportable results by Trofile®. Subsequently, they note that “no concordance” between standard V3-based genotypic tropism assays and virological response to maraviroc monotherapy was found, according to previous results generated by our group.3 Finally, based on the results of Hernández-Novoa et al,4 they conclude that short-term maraviroc exposure cannot predict viral tropism in treatment-naïve patients. In our opinion, MCT is an alternative tool to be used in clinical practice to decide CCR5-antagonist prescription in HIV-infected subjects, both in treatment-experienced and -naïve patients. Discordances between phenotypic and genotypic methods have been found.5 Moreover, our group developed MCT, a drug sensitivity test but not a tropism assay, and again discordances between MCT and different tropism methods including deep-sequencing were found.5,6 Hence, it has not been established as a “gold standard” to be used in clinical practice before prescribing maraviroc. We consider that the virological response to the drug should be the most important criteria in order to decide maraviroc prescription, and not a categorical tropism result. Therefore, we use MCT not just to confirm a genotypic/phenotypic tropism result and not particularly in patients with a nonreportable result by Trofile® but in all patients. Regarding the naïve scenario, our group has explored this issue in a recently published work,7 confirming that MCT is a reliable tool to decide maraviroc prescription in naïve HIV-infected subjects. In this work, most patients showed a significant viral load reduction during MCT and an excellent immunovirological evolution was shown once the subsequent cART was started after MCT; again, discordance rates were found between MCT and different tropism methods, similar to those found in treatment-experienced patients.2,5,6 Unfortunately, the review by Woollard and Kanmogne1 was accepted for publication just before the publication of this work, so they probably did not have time to include our data in their study. Additionally, Woollard and Kanmogne consider that MCT cannot be used in naïve HIV-infected subjects based on data from Hernández-Novoa et al,4 because these authors concluded that this clinical test cannot be used as a surrogate marker of viral tropism in naïve patients. We agree with the conclusion of Hernández-Novoa et al, since MCT is not a surrogate marker of viral tropism but a clinical test based on the virological response to a short-term exposure to the drug, and provides discordant results with different tropism assays as previously reported.2,5,6 Hernández-Novoa et al show that patients with R5 or dual/mixed viral tropism according to Trofile® have similar virological responses to maraviroc monotherapy, reflecting the previously described discordance between the clinical approach and the phenotypic tropism method, as expected. Analyzing their data, we can see that 32/37 (85%) of their patients had virological response according to MCT (viral load reduction >1 log RNA copies/mL) while 5/37 (15%) did not, exactly the R5 and non-R5 expected percentages in HIV-1 treatment-naïve patients.8 In addition, given the MCT criteria, 9/37 (24%) of the patients had discordant results with Trofile® in their study, similar to previous studies.2,5–7 Besides, unlike Hernández-Novoa et al, in these mentioned studies we performed a follow-up of the patients proving the safety of the test according to the excellent immunovirological evolution after long-term cART started after MCT. Therefore, we consider that a misclassification by Trofile® and genotypic methods would be the more plausible explanation for the discordances observed with the virological response during maraviroc monotherapy exposure, probably due to the presence of low-level X4 variants with no clinical relevance. Taken altogether, we think that MCT remains a very promising strategy to decide maraviroc prescription in HIV-infected patients, both treatment-experienced and -naïve subjects, independent of the viral tropism result once the presence of low-level X4 variants seem to be clinically irrelevant.

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          Most cited references 20

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          The CCR5 and CXCR4 coreceptors--central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection.

          In this review, we will discuss what is known, what is suspected, and what still remains obscure about the central role played by coreceptor expression and usage in the transmission and pathogenic consequences of human immunodeficiency virus type 1 (HIV-1) infection. An emphasis will be on the HIV-1 phenotypic variants that are defined by their usage of the CCR5 or CXCR4 coreceptors, and how the different cellular tropism of these variants influences how and where HIV-1 replicates in vivo. We will also review what might happen when coreceptor antagonists are used clinically to treat HIV-1 infection.
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            Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir.

            Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log(10) copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope (Env) clones from pre- and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on Env clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.
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              Detection of low-frequency pretherapy chemokine (CXC motif) receptor 4 (CXCR4)-using HIV-1 with ultra-deep pyrosequencing.

              Identification of low-frequency variants is of clinical importance in the identification of preexisting drug resistance. Using 'ultra-deep' sequencing, we address the detection of potential resistance to the chemokine (C-C motif) receptor 5 (CCR5) antagonist, maraviroc, due to the pretreatment presence of low levels of chemokine (CXC motif) receptor 4 (CXCR4)-using virus. We present a novel protocol for the phenotyping of HIV based on '454' pyrosequence data and apply this to two large data sets comprised of 104 628 (before treatment, day 1) and 191 637 (after treatment, day 11) reads from the envelope region. We study resistance in the context of the evolutionary history of the intrapatient viral population. Variation was also investigated both within and outside the V3 region, the region associated with the receptor switch. CXCR4-using virus can be detected at low frequency prior to maraviroc treatment ( approximately 0.5%) and at high frequency after failure of monotherapy ( approximately 81%). Inferring an evolutionary tree from the 1674 unique reads that span the V3 region confirms that the CXCR4-using population emerged from low-frequency CXCR4-using variants present before treatment. Changes in the frequency of amino acid residues used at individual sites were found in regions outside the V3 region, indicative of other potential sites associated with receptor usage. We have provided a high-resolution snapshot of intrapatient viral variation, prior and after treatment with maraviroc, and detected preexisting CXCR4-using variants present at an extremely low frequency. The evolutionary analysis demonstrates the extent of diversity present at a single time point within an infected individual and the rapid effect of drug pressure on the structure of a viral population.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                18 January 2016
                : 10
                : 353-356
                Affiliations
                [1 ]Laboratory of Molecular Immunobiology, Hospital General Universitario Gregorio Maranon, Madrid, Spain
                [2 ]Laboratory of Immunovirology, Institute of Biomedicine of Seville, Seville, Spain
                Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
                Author notes
                Correspondence: Alejandro Gonzalez-Serna, Laboratory of Molecular Immunobiology, Hospital General Universitario Gregorio Maranon, C/Dr. Esquerdo 46, 28007 Madrid, Spain, Tel +34 91 586 8000, Fax +34 91 586 8018, Email alextantalo@ 123456gmail.com
                Miguel Genebat, Laboratory of Immunovirology, Institute of Biomedicine of Seville, C/Avenida Manuel Siurot s/n, 41013, Seville, Spain, Tel +34 95 592 3109, Fax +34 95 592 3101, Email mgenebat@ 123456yahoo.es
                Correspondence: Georgette D Kanmogne, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE, USA, Tel +1 402 559 4084, Fax +1 402 559 7495, Email gkanmogne@ 123456unmc.edu
                Article
                dddt-10-353
                10.2147/DDDT.S100639
                4723024
                26848259
                © 2016 Gonzalez-Serna et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed

                Categories
                Letter

                Pharmacology & Pharmaceutical medicine

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