Effect of maraviroc on non-R5 tropic HIV-1: refined analysis of subjects from the phase IIb study A4001029.

M Surdo, C Alteri, M C Puertas, P Saccomandi, L Parrotta, L Swenson, D Chapman, G Costa, A Artese, E Balestra, S Aquaro, S Alcaro, M Lewis, B Clotet, R Harrigan, H Valdez, V Svicher, C F Perno, J Martinez-Picado, F Ceccherini-Silberstein

Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 2015;21(1):103.e1-6

PMID: 25636934

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Abstract

We characterized maraviroc susceptibility of dual/mixed tropic viruses from subjects enrolled onto phase IIb study A4001029. Maraviroc baseline plasma samples from 13 multidrug-experienced subjects were sequenced and the HIV-1-env gene cloned into pNL4.3Δenv to obtain recombinant viruses. The V3 region was sequenced by the Sanger method and ultradeep sequencing. By analysing subjects having a weighted optimized background therapy susceptibility (wOBT) score of <1, 3/7 subjects were characterized by good in vivo and in vitro response to maraviroc therapy. Molecular docking simulations allowed us to rationalize the maraviroc susceptibility of dual/mixed tropic viruses. A subset of subjects with dual/mixed tropic viruses responded to maraviroc. Further investigations are warranted of CCR5 antagonists in subjects carrying dual/mixed tropic virus that explore the feasible use of maraviroc in subjects that is potentially larger than those infected with a pure R5 virus.

Address: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.; Institut de Recerca de la SIDA irsiCaixa, Hospital Universitari 'Germans Trias i Pujol', Badalona, Universitat Autònoma de Barcelona (UAB), Catalonia, Spain.; Department of Pharmacobiological Sciences, University of Catanzaro 'Magna Græcia', Catanzaro, Italy.; BC Centre for Excellence in HIV/AIDS, Vancouver, Canada.; Pfizer, New York, NY, USA.; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.; Pfizer, UK.; Institut de Recerca de la SIDA irsiCaixa, Hospital Universitari 'Germans Trias i Pujol', Badalona, Universitat Autònoma de Barcelona (UAB), Catalonia, Spain; Universitat de Vic (UVic), Catalonia, Spain.; Institut de Recerca de la SIDA irsiCaixa, Hospital Universitari 'Germans Trias i Pujol', Badalona, Universitat Autònoma de Barcelona (UAB), Catalonia, Spain; Universitat de Vic (UVic), Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.; Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy. Electronic address: [email protected].

DOI: 10.1016/j.cmi.2014.08.002

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MeSH Terms: CCR5 Receptor Antagonists, Cyclohexanes, HIV Infections, HIV-1, Humans, Maraviroc, Mutation, Triazoles, Viral Tropism