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      Incidence of CXCR4 tropism and CCR5-tropic resistance in treatment-experienced participants receiving maraviroc in the 48-week MOTIVATE 1 and 2 trials

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          Abstract

          Maraviroc blocks HIV-1 entry into CD4+ cells by interrupting the interaction between viral gp120 and cell-surface CCR5. Resistance to CCR5 antagonist–mediated inhibition can develop by unmasking pre-existing CXCR4-using virus or through selection of CCR5-tropic resistant virus, characterized by plateaus in maximum percent inhibition <95%. Here, we examine viral escape in maraviroc-treated participants during virologic failure through Week 48 in the MOTIVATE 1 and 2 trials. Resistance was assessed relative to number of active drugs in participants’ optimized background therapy, pharmacokinetic adherence markers, Baseline demographic data, HIV-1 RNA and CD4+ counts. For participants with R5 virus confirmed ( post hoc) at Screening, Baseline genotypic weighted optimized background therapy susceptibility scores (gwOBTSS) were assigned where possible. Through Week 48, 219/392 (56%) participants with an assigned gwOBTSS achieved a virologic response. Of those remaining, 48/392 (12%) had CXCR4-using virus; 58/392 (15%) had R5 virus (maraviroc sensitive: n = 35/392, 9%; maraviroc resistant: n = 18/392, 5%; undeterminable: n = 5/392, 1%) and 67/392 (17%) had no failure tropism result. When optimized background therapy provided limited support to maraviroc (gwOBTSS <2), 143/286 (50%) responded to therapy, while 76/106 (72%) participants with gwOBTSS ≥2 responded ( p < 0.001). Resistance rates were highest for participants with gwOBTSS <2, accounting for 45/48 (94%) of total CXCR4-using emergence and 18/18 (100%) of total CCR5-tropic resistance. R5 viruses from participants with gwOBTSS ≥2 ( n = 10) were exclusively maraviroc sensitive; five of these participants had pharmacokinetic and/or pill-count markers of non-adherence. When co-administered with a fully active background regimen, maraviroc did not readily generate resistance in the clinical setting.

          Trial registry name:

          ClinicalTrials.gov ( https://clinicaltrials.gov/), NCT00098722 and NCT00098306

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          Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity.

          Patrick Dorr, Mike Westby, Susan Dobbs … (2005)
          Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 microM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.
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            Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex.

            Qiuxiang Tan, Ya Zhu, Jian LI … (2013)
            The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom-resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor-gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.
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              Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.

              Daria J. Hazuda, David Cooper, Christine Katlama … (2008)
              We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.) 2008 Massachusetts Medical Society
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antivir Chem Chemother
                Journal ID (iso-abbrev): Antivir. Chem. Chemother
                Journal ID (publisher-id): AVC
                Journal ID (hwp): spavc
                Title: Antiviral Chemistry & Chemotherapy
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 0956-3202
                ISSN (Electronic): 2040-2066
                Publication date (Electronic): 19 December 2019
                Publication date Collection: 2019
                Volume: 27
                Electronic Location Identifier: 2040206619895706
                Affiliations
                [1 ]Pfizer Inc, Clinical Group, Rare Disease, Groton, CT, USA
                [2 ]The Research Network, Sandwich, UK
                [3 ]Pfizer Inc, Pharmacometrics, Sandwich, UK
                Author notes
                [*]Charles Craig, Pfizer Inc Global Research and Development, 600 Discovery Park House, Ramsgate Road Sandwich, Kent CT12 9ND, UK. Email: charles.craig@ 123456pfizer.com
                Author information
                https://orcid.org/0000-0003-3276-9925
                Article
                Publisher ID: 10.1177_2040206619895706
                DOI: 10.1177/2040206619895706
                PMC ID: 6931239
                PubMed ID: 31856576
                SO-VID: cb72ed55-3594-4292-935f-5a2eb5e08605
                Copyright © © The Author(s) 2019
                License:

                Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 19 August 2019
                Date accepted : 14 November 2019
                Funding
                Funded by: Pfizer, FundRef https://doi.org/10.13039/100004319;
                Funded by: ViiV Healthcare, FundRef https://doi.org/10.13039/100010877;
                Categories
                Subject: Original Article
                Custom metadata
                cover-date January-December 2019
                typesetter ts2

                Keywords: aids,drug resistance,hiv,mutations
                Data availability:
                Keywords: aids, drug resistance, hiv, mutations

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