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Genetic resistance to HIV-1 in the salvage therapy with new antiretroviral drug classes

Abstract

The introduction of highly active antiretroviral therapy (HAART) has brought a significant decline in morbidity and an increased survival of people living with HIV/AIDS. However, during therapy, due to numerous factors, there may be selection of resistant viral strains, which compromises the action of drugs. This is a major cause of non-suppression in patients that are adherent to HAART. The first targets of antiretroviral therapy were the reverse transcriptase and protease enzymes of HIV. The search for drugs with a higher genetic barrier, with other resistance patterns, as well as the development of new therapeutic targets is a complex process, and although three new classes and new generations of drugs are already in use, these need to be combined with drugs recycled from previous regimens for an compose an effective regimen able to suppress plasma viremia. This project will help in designing therapeutic strategies to rescue patients with therapeutic failures with genotypic resistance profiles to two or more classes, where the construction of regimens that have more active drugs can be facilitated by new classes of medications, necessary to maximize the activity of drug combinations. The study will provide genotypic analysis of viral genomic regions associated with antiretroviral medication on 200 volunteers, 80 of those before the introduction of new classes of drugs and another 120 enrolled during use of new class medications. These medications include inhibitors of gp41, integrase inhibitors and CCR5 coreceptor antagonists. By determining the profile of genetic susceptibility to antiretroviral drugs and prediction of genotypic viral tropism, in the case of CCR5 antagonists, the study will identify molecular signatures in the viral genome and its association with the susceptibility of these drugs. We will analyze the profiles of genetic diversity in these regions, especially the presence of primary resistance and polymorphisms that may favor the evolution of the profile of mutations during treatment. In cases of failure to treatment the profile of mutations of both recycled drugs and new classes will be evaluated in the sample near the time of virologic failure, supporting the clinical management and maximizing the potential effectiveness of these salvage regimens. The study of proviral DNA in cases without treatment failure during follow-up (viral load below 1000 copies / mL at week 48) will allow the delineation of the profile of polymorphisms that may have a minor impact on therapeutic success that will be compared to that observed among cases failing therapy. As information on HIV-1 non subtype B are less available, priority will be given the recruitment of cases with evidence of non-B genome or mosaics (such as recombinant pol region in previous genotyping). These molecular data will be analyzed in the context of the history of therapies previously used, the levels of CD4 cells, plasma viremia and clinical aspects contributing to the understanding of mutational pathways of resistance to new classes and subsidizing drug recycling in the composition of subsequent salvage regimens. (AU)

Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE SOUZA GUIMARAES, PAULA MORENA; DE PAULA FERREIRA, JOAO LEANDRO; OZORIO COELHO, LUANA PORTES; CAVALCANTI, JAQUELINE DE SOUZA; SILVA LOPEZ LOPES, GISELLE IBETTE; MATSUDA, ELAINE MONTEIRO; ALMEIDA, FLAVIA JACQUELINE; ALMEIDA, VALERIA CORREIA; CAMPEAS, ALEXANDRE ELY; PEREIRA JUNIOR, LUIZ CARLOS; DE MACEDO BRIGIDO, LUIS FERNANDO; WORKGRP, SAO PAULO SALVAGE. Transmitted Drug Resistance Among Recently Diagnosed Adults and Children in Sao Paulo, Brazil. AIDS Research and Human Retroviruses, v. 31, n. 12, p. 1219-1224, DEC 1 2015. Web of Science Citations: 6.
JOLY, MARCEL; PINTO, JOSE M.; RONDO, PATRICIA H. C.; RODRIGUES, ROSANGELA; FERREIRA, JOAO L. P.; CAVALCANTI, JAQUELINE S.; BRIGIDO, LUIS F. M.; ODLOAK, DARCI. Combine operations research with molecular biology to stretch pharmacogenomics and personalized medicine-A case study on HIV/AIDS. Computers & Chemical Engineering, v. 80, p. 114-129, SEP 2 2015. Web of Science Citations: 4.
CAVALCANTI, JAQUELINE DE SOUZA; DE PAULA FERREIRA, JOAO LEANDRO; DE SOUZA GUIMARAES, PAULA MORENA; VIDAL, JOSE ERNESTO; DE MACEDO BRIGIDO, LUIS FERNANDO. High frequency of dolutegravir resistance in patients failing a raltegravir-containing salvage regimen. Journal of Antimicrobial Chemotherapy, v. 70, n. 3, p. 926-929, MAR 2015. Web of Science Citations: 7.
MATSUDA, ELAINE MONTEIRO; OZORIO COELHO, LUANA PORTES; PIMENTEL, VICTOR FIGUEIREDO; ONIAS, HUMBERTO BARJUD; DE MACEDO BRIGIDO, LUIS FERNANDO. An HIV-1 Transmission Case Possibly Associated with Manicure Care. AIDS Research and Human Retroviruses, v. 30, n. 11, p. 1150-1153, NOV 1 2014. Web of Science Citations: 5.
OZORIO COELHO, LUANA PORTES; DE PAULA FERREIRA, JOAO LEANDRO; CABRAL, GABRIELA BASTOS; DE SOUZA GUIMARAES, PAULA MORENA; DE MACEDO BRIGIDO, LUIS FERNANDO. Genotypic Tropism Prediction from Paired Cell and Plasma Using Single and Replicate Sequences. AIDS Research and Human Retroviruses, v. 30, n. 7, p. 711-716, JUL 2014. Web of Science Citations: 0.
ALMEIDA, FLAVIA JACQUELINE; ZAPAROLI, MAYRA SIMIONI; MOREIRA, DENISE HELENA; CAVALCANTI, JAQUELINE DE SOUZA; RODRIGUES, ROSANGELA; BEREZIN, EITAN NAAMAN; DE PAULA FERREIRA, JOAO LEANDRO; PALAZZI SAFADI, MARCO AURELIO; DE MACEDO BRIGIDO, LUIS FERNANDO. Association of X4 tropism with disease progression in antiretroviral-treated children and adolescents living with HIV/AIDS in Sao Paulo, Brazil. Brazilian Journal of Infectious Diseases, v. 18, n. 3, p. 300-307, Jun. 2014. Web of Science Citations: 3.
CAVALCANTI, JAQUELINE DE SOUZA; DE PAULA FERREIRA, JOAO LEANDRO; VIDAL, JOSE ERNESTO; DE SOUZA GUIMARAES, PAULA MORENA; MOREIRA, DENISE HELENA; DE MACEDO BRIGIDO, LUIS FERNANDO; WORKGRP, SAO PAULO SALVAGE. HIV-1-infected patients with advanced disease failing a raltegravir-containing salvage regimen in Sao Paulo, Brazil. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, v. 43, n. 3, p. 287-291, MAR 2014. Web of Science Citations: 2.
SILVA LOPEZ-LOPES, GISELLE IBETTE; LANCA, ANDRE MINHOTO; DE PAULA FERREIRA, JOAO LEANDRO; SOUZA, LUCIANA OLIVEIRA; DE MACEDO BRIGIDO, LUIS FERNANDO. Discrepancies of HIV-1 Reverse Transcriptase Resistance Interpretation of Insertions and Deletions between Two Genotypic Algorithms. Intervirology, v. 56, n. 4, p. 217-223, 2013. Web of Science Citations: 1.
CAVALCANTI, JAQUELINE SOUZA; LANCA, ANDRE MINHOTO; DE PAULA FERREIRA, JOAO LEANDRO; DA EIRA, MARGARETH; DE SOUZA DANTAS, DANIEL SOARES; DE MACEDO BRIGIDO, LUIS FERNANDO. In-vivo selection of the mutation F121Y in a patient failing raltegravir containing salvage regimen. Antiviral Research, v. 95, n. 1, p. 9-11, JUL 2012. Web of Science Citations: 6.

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