Navegando por Palavras-chave "Virological Failure"

Agora exibindo 1 - 3 de 3
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Análise de prevalência do perfil mutacional de resistência aos antirretrovirais entre indivíduos em falha ao primeiro esquema antirretroviral com ITRNN no Brasil
    (Universidade Federal de São Paulo (UNIFESP), 2020-03-05) Dias, Danilo Araujo [UNIFESP]; Diaz, Ricardo Sobhie [UNIFESP]; Universidade Federal de São Paulo
    Introduction: Antiretroviral treatment has proven to be increasingly effective and well-tolerated over time. However, drug resistance mutations have an important impact and could be a major issue especially to cases in which the first line of treatment is affected. Until recently, the first-line treatment was two (NRTI) and one (NNRTI) or efavirenz. Objective:To identify and to analyze the prevalence of resistance mutations in the reverse transcriptase (RT) region of HIV pol gene, in patients with virological failure to 2 NRTI and 1 NNRTI schemes, and with available viral genotyping. Methodology: 2934 genotyping reports made by Renageno between December/2015 to June/2017 containing evidence of first-line scheme virological failure were analyzed. The interpretation of resistance mutations was made using the Stanford University algorithm (IAS-USA database), through the Sisgeno platform, in which data such as sex, geographic location, age, viral subtype, and therapeutic scheme were extracted. Viral load and T-CD4+ counts were extracted by Siscel. Descriptive statistics and hypothesis test on categorical variables were performed by SPSS program. Graphs were prepared using Graph Pad Prisma and excel program, and multivariate analysis (ANOVA) was performed using R program. Results: The prevalence of cases was higher in the state of São Paulo (23.3%). Overall, the majority were male (69.3%), the mean of CD4 T cell count was 315 cells/mm3, the mean viral load was 154,897 copies/ml, and the mean of treatment time was 3.8 years. The most predominant subtype was B (73.2%), followed by C (15.7%) and F (11%). The predominant antiretroviral scheme was TLE (65.3%) follow by and AZT + 3TC + EFV (25.2%). The most abundant drug resistance mutations were M184I/V (59.8%) and K103N (52.5%). The accumulation of mutations in individuals exposed to EFV schemes was 78.22% in the NRTI group and 56.82% analyzing NRTI mutations and M184I/V together. In the individuals using NVP schemes, the drug resistance mutation prevalence was 76,91% and 62.74%, respectively. The number of mutations did not change the viral load according to the treatment time. The South, Southeast and Midwest regions showed similar drug resistance rates, unlike the North and Northeast, which showed higher mutations. Individuals withxx subtypes B and F presented more mutations. Men presented higher mutations than women and the prevalence of mutations was not related to age. Crossresistance to RPV showed a higher prevalence in individuals with subtype B. Regarding DOR, subtype C presented a differential mutational profile. AZT could be an alternative for a switch in schemes with EFV. Conclusion: In Brazil, the accumulation of drug resistance mutations to the first-line treatment using NNRTI is higher compared to other regions. The number of mutations in the NNRTI did not affect the viral load and treatment time. The North and Northeast regions accumulated more mutations. A proposed scheme should have DOR, RPV and ETR rescue should be evaluated regarding crossresistance.
  • Imagem de Miniatura
    Item
    Acesso aberto (Open Access)
    Inferences about fitness cost of antiretroviral drug resistance mutations: insights from the mutation dynamics during structured antiretroviral treatment interruption among individuals experiencing virological failure
    (Universidade Federal de São Paulo (UNIFESP), 2019-02-22) Hunter, James Richard [UNIFESP]; Diaz, Ricardo Sobhie [UNIFESP]; http://lattes.cnpq.br/0846508761438062; Universidade Federal de São Paulo (UNIFESP)
    This study reviews drug resistance mutation dynamics on both the pol and gag genes among individuals under antiretroviral virological failure who underwent structured treatment interruption (STI). The study involved a 12-week interruption in antiretroviral therapy (ART), monitoring of viral load, CD4+/CD8+ T cell counts, and sequencing of the pol gene to examine mutation dynamics from 38 individuals experiencing virological failure and harboring 3-class resistant HIV strains: nucleoside reverse transcriptase inhibitors (NRTI) non-nucleoside inhibitors (NNRTI) and Protease inhibitors (PI). Protease and reverse transcriptase regions of the pol gene were sequenced at baseline before STI and every 4 weeks thereafter from PBMCs and at baseline and after 12 weeks from plasma HIV RNA using population-based Sanger sequencing. Over the following 12 weeks, average viral load increased 0.568 log10 copies per milliliter. CD4+ T cell count decreased as soon as ART was withdrawn, an average loss of 99.0 cells/mL. Forty-three percent of the mutations associated with antiretroviral resistance in PBMCs disappeared and 57% of the mutations on the pol gene in plasma reverted to wild type although we had expected they would all do so. In PBMC, the PI mutations reverted more slowly than reverse transcriptase mutations. The patients are projected to need an average of 33.7 weeks against 20.9 (NRTI) or 19.8 (NNRTI) weeks. On the gag gene, patients had an average of 32.8 mutations per patient pre-STI declining to 27.2 at the end of the study (of a total of 507 codons studied) indicating that mutations did return to wild type although not as completely as previous research has indicated nor as had been shown on the pol gene. We also used our analysis of the gag gene mutation profile to drive a study of how the mutations to the gag substrates interacts with mutations directly to the protease region of the pol gene. These results suggest that gag regions outside the cleavage sites may have a larger role in drug resistance than has been previously asserted. The study is composed of two papers that are being published jointly, the first addressing the mutation dynamics on the pol gene and the second on mutations in the gag gene.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Prevalência de mutações de resistência aos antirretrovirais em pacientes com falha virológica em uso do raltegravir em regimes de terapia de resgate
    (Universidade Federal de São Paulo (UNIFESP), 2021) Nassar, Isabella Barbosa Pessoa [UNIFESP]; Diaz, Ricardo Sobhie [UNIFESP]; Universidade Federal de São Paulo
    The integrase enzyme is fundamental to the HIV virus replication process, being responsible for the integration of viral DNA into the host cell genome, andgenome and is therefore a potential target for rescue treatment among people living with HIV / AIDS. The understanding of infection and the quality of antiretroviral therapies (HAART) has been growing a lot in recent years, and the class of integrase inhibitors fits in this segment. Currently, two integrase inhibitors are in use in Brazil: raltegravir (RAL) and dolutegravir (DTG). Another three integrase inhibitors approved by the FDA and ANVISA, which have not yet arrived in Brazil, are elvitegravir, cabotegravir (CAB) in solution for injection and bictegravir (BIC), approved by ANVISA in Brazil. The low genetic barrier to RAL has favored the selection of three resistance pathways: Y43R / H / C, N155H / R and Q148H / K / R, the latter path causing cross resistance to dolutegravir. The aim of this work was to analyze the prevalence of resistance mutations to integrase inhibitors among patients with virological failure to rescue schemes containing raltegravir. To this end, 701 cases with RAL virological failure and current or previous virological failure to reverse transcriptase inhibitors similar tolike nuclei (t) ids, (ITRN) reverse transcriptase inhibitors not analogous to nuclei (t) ids were evaluated (ITRNN) and protease (IP) inhibitors. These data were collected from the Genotyping Examination Control System - SISGENO, and from the Lymphocyte Count Control System - CD4 + / CD8+ and HIV viral load - SISCEL, from January 2017 to December and 2018. From 701 patients 182 (26%) had resistance mutations to integrase inhibitors, 145 (20.7%) to IPs, 339 (48.4%) to NRTIs, and 327 (46.7%) to NRTIs and the interpretation of mutations of resistance were made by the IAS-USA algorithm. The isolated and prevalent mutations in rescue schemes containing RAL were N155H / S, and L74I / M, and among the associated mutations, the most prevalent was G140S + Q148H in 16 cases. We compared the median age, viral load and TCD4+ cells of patients with and without resistance mutations in integrase. The median age of patients with resistance mutations in to integrase was 41.0 years (p = 0.0008) with the majority being male 101 (55.5%) (p = 0.0017). The median viral load of patients with resistance mutations in integrase was 4.62 and LTCD4+ with resistance18 mutations of 171.5 (p <0.0001). When correlating viral load with the number of mutations, the results point to increase viral load in patients who had up to two mutations. However, with the presence of 3 or more mutations, the results do not show statistical significance. The patterns of resistance to integrase inhibitors (INIs) by subtype were also analyzed, with the majority having the integrase region of subtype B, followed by C and F1. In the general profile of the subtypes of the 701 genomic fragments, the most prevalent was subtype B with (74.04%) in the integrase region, followed by C with (15.41%) and F1 with (9.27%). In reverse transcriptase, subtype B with (72.90%), C (12.98%), F1 (11.13%). In protease B with (72.90%), C (12.98%) and F1 (11.13%). Loop V3 predominated B with (84.30%), C (9.87), F1 (5.83%). Gp41 B with (80%), followed by F1 with (15%) and C (5%). The longer time of exposure to rescue schemes containing RAL, revealed a higher prevalence of mutations in codon 148. In the identification of tropism, we observed that in the initial phase of HIV infection, mutational pathways 155 and 143 predominated, and in the advanced phase, via 140 and 148. When comparing the number of schemes with the number of mutations in integrase, our results demonstrate that the greater the number of accumulated mutations in integrase, the greater the number of schemes (p = 0.0007).