| Grant number: | 11/21958-2 |
| Support type: | Regular Research Grants |
| Duration: | April 01, 2012 - March 31, 2014 |
| Field of knowledge: | Health Sciences - Medicine - Medical Clinics |
| Principal researcher: | Luís Fernando de Macedo Brígido |
| Grantee: | Luís Fernando de Macedo Brígido |
| Home Institution: | Instituto Adolfo Lutz (IAL). Coordenadoria de Controle de Doenças (CCD). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil |
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)
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