FERNANDA DE MELLO MALTA
Projetos de Pesquisa
Unidades Organizacionais
LIM/07 - Laboratório de Gastroenterologia Clínica e Experimental, Hospital das Clínicas, Faculdade de Medicina
12 resultados
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- Resistance mutations are rare among protease inhibitor treatment-naive hepatitis C genotype-1 patients with or without HIV coinfection(2015) LISBOA-NETO, Gaspar; NOBLE, Caroline F.; PINHO, Joao R. Rebello; MALTA, Fernanda M.; GOMES-GOUVEA, Michele S.; ALVARADO-MORA, Monica V.; SILVA, Mariliza H. da; LEITE, Andrea G. B.; PICCOLI, Leonora Z.; RODRIGUES, Flaviane K.; CARRILHO, Flair J.; MENDES-CORREA, Maria C.Background: HCV has a high replication rate and a lack of proofreading activity, leading to a greatly diverse viral population. This diversity may lead to emergence of resistant strains in direct-acting antiviral therapy. The frequency of naturally occurring HCV protease inhibitor (PI) mutations has been addressed in many countries, but there are few data on the prevalence of these mutations in Brazilian patients. Methods: We evaluated the sequence of HCV NS3 protease gene in 247 patients (135 HCV-monoinfected and 112 HIV-HCV-coinfected patients). HCV RNA was extracted from plasma and a fragment of 765 base pairs from the NS3 region was amplified and sequenced with Sanger-based technology. Results: HIV-HCV-coinfected patients were more likely to be older than 40 years and have an HCV subtype-1a infection. Overall, 21.9% of patients had at least one amino acid substitution in the NS3 region; 14 patients (5.7%) harboured at least one resistance mutation (T54S, V55A, Q80R) and the Q80K mutation was not found in our case series. There was no difference between monoinfected and coinfected patients regarding the frequency of natural polymorphisms and resistance mutations. Conclusions: Baseline HCV NS3 amino acid substitutions identified herein are considered mostly natural polymorphisms with no clinical impact on PI-based therapy. The identified resistance mutations may be associated with low-level resistance to PIs in vitro. Q80K substitution seems to be a rare event in Brazil. HIV coinfection was not associated with a greater frequency of such substitutions in the studied sample.
- AIDS incidence and survival in a hospital-based cohort of HIV-positive patients from Sao Paulo, Brazil: The role of IFN-lambda 4 polymorphisms(2021) PRATES, Gabriela da Silva; MALTA, Fernanda M.; GONCALVES, Fernanda de Toledo; MONTEIRO, Mariana A.; FONSECA, Luiz Augusto M.; VEIGA, Ana Paula R.; MAGRI, Marcello M. C.; DUARTE, Alberto J. S.; CASSEB, Jorge; ASSONE, TatianeFew studies have reported the prognosis of human immunodeficiency virus (HIV)-positive patients followed for a long time in Brazil, particularly those including pre and post-HAART eras. The polymorphisms of interferon (IFN)-lambda 4 have been postulated as possibly associated with the pathogenesis of HIV infection. The aim of this study was to describe the incidence and mortality from a cohort of HIV-positive patients as well as whether IFN-lambda 4 gene polymorphisms (SNP rs8099917 and SNP rs12979860) were associated with HIV/acquired immune deficiency syndrome (AIDS) progression. We followed 402 patients for up to 30 years; 347 of them began follow-up asymptomatic, without any AIDS-defining opportunistic disease and/or a lymphocytes T CD4+ count of 350 cells/mm(3)or lower. We determined the probability of the asymptomatic subjects to remain AIDS-free, and the risk of death for those entering the study already with an AIDS diagnosis, as well as for subjects developing AIDS during follow-up. We compared the prognosis of patients with two different polymorphisms for the genes encoding for IFN-lambda 4, variants rs8099917 and rs12979860. The follow-up time of the 347 asymptomatic-at-entry subjects was 3687 person-years. IFN-lambda 4 rs8099917 polymorphisms were not associated with AIDS progression, but IFN-lambda 4 rs12979860 wild type genotype (CC) was associated with higher mortality compared to CT and TT, with an increased probability of death from AIDS (P = .01). In conclusion, genetic variations in IFN-lambda 4 on rs12979860 polymorphisms in HIV-infected patients may drive mortality risk.
- Prevalence of naturally occurring amino acid substitutions associated with resistance to hepatitis C virus NS3/NS4A protease inhibitors in Sao Paulo state(2018) MOREIRA, Regina Celia; SANTOS, Ana Paula de Torres; LISBOA-NETO, Gaspar; MENDES-CORREA, Maria Cassia Jacintho; LEMOS, Marcilio Figueiredo; MALTA, Fernanda Mello; SANTANA, RAbia Anita Ferraz; DASTOLI, Gregorio Tadeu Fernando; CASTRO, Vanessa Fusco Duarte de; PINHO, Joao Renato RebelloHepatitis C (HCV)-infected patients are treated with direct-acting antiviral agents (DAAs) in highly effective, well-tolerated, all-oral regimens. However, naturally occurring resistance-associated amino acid substitutions (RASs) may be selected during treatment. This study aimed to screen naturally occurring RASs NS3/NS4A inhibitors (PIs). Samples were obtained from DAA naive patients, living in Sao Paulo state, Brazil. Screening for RASs in the HCV NS3 region was conducted in 859 samples from HCV-infected patients, of which 425 and 434 samples were subtype la and lb, respectively. HCV-RNA was extracted, amplified, and sequenced. The overall prevalence of RASs to HCV PIs was 9.4%. The following RASs were observed in HCV-1a subtype infected patients: V36L (2.6%), T54S (1.6%), V55I/A (1.2% / 8.9%, respectively), Q80K (2.1%), R155K (0.5%), and D168E (0.2%); and in HCV-1b infected patients: V36L (0.7%), T54A/S (0.2% and 0.5%, respectively), V55A (0.5%), Q80K (0.2%), D168E (1.6%), and M175L (0.5%). HCV la infected subjects had higher serum viral load than that seen in patients infected with HCV 1b. There was no difference between the proportions of NS3 RASs with regards to geographic distribution within the investigated areas. These findings should be supported by additional studies in Brazil to help in the formation of local clinical guidelines for managing hepatitis C.
- HCV inter-subtype 1a/1b recombinant detected by complete-genome next-generation sequencing(2016) GASPARETO, Karine Vieira; RIBEIRO, Roberto Marques; MALTA, Fernanda de Mello; GOMES-GOUVEA, Michele Soares; MUTO, Nair Hideko; MENDES-CORREA, Maria Cassia; ROZANSKI, Andrei; CARRILHO, Flair Jose; SABINO, Ester Cerdeira; PINHO, Joao Renato RebelloNext-generation sequencing (NGS) provides a practical approach to HCV complete-genome sequencing, detecting low-frequency variants and allowing analysis of viral genetic diversity (quasispecies) in the sample, and so far, it is very useful for identifying preexisting drug-resistant mutants and emerging escape mutations, as well as detecting viral recombinants containing genomic regions from different genotypes and subtypes. The aim of this study was to analyze the complete coding region of hepatitis C virus (HCV) genotype 1 (subtypes 1a and 1b) from patients with chronic infection who were direct-acting antiviral (DAA) na < ve. Next-generation sequencing (Ion Torrent (TM) PGM) was used to determine the sequence of the complete coding region of 100 HCV-monoinfected DAA-na < ve patients (51 and 49 subtypes 1a and 1b, respectively). We report the first description of nearly complete HCV genome sequences of subtype 1a and 1b isolates from a large population of Brazilian patients with chronic hepatitis C, and HCV-1a grouped in two different clades. Using this methodology, an inter-subtype 1a/1b recombinant was identified in this study.
- Interferon lambda and hepatitis C virus core protein polymorphisms associated with liver cancer(2016) MOREIRA, Joao Paulo; MALTA, Fernanda de Mello; DINIZ, Marcio Augusto; KIKUCHI, Luciana; CHAGAS, Aline Lopes; LIMA, Livia de Souza Botelho; GOMES-GOUVEA, Michele Soares; CASTRO, Vanessa Fusco Duarte de; SANTANA, Rubia Anita Ferraz; SUMITA, Nairo Massakazu; VEZOZZO, Denise Cerqueira Paranagua; CARRILHO, Flair Jose; PINHO, Joao Renato RebelloBackground: Hepatitis C virus (HCV) infection is often persistent and gradually advances from chronic hepatitis to liver cirrhosis and hepatocellular carcinoma (HCC). Worldwide, hepatocellular carcinoma is the fifth most common neoplasm. Method of study: the Interferon lambda (IFNL) polymorphisms genotypes (rs8099917, rs12979860 and rs12980275) and the presence of mutations in HCV core protein were analyzed in 59 patients with HCC, and also in 50 cirrhotic patients (without HCC). Results: the rs12980275-AG genotype was associated with HCC on age-adjusted analysis (OR 2.42, 95% CI 1.03-5.69, P=0.043). Core substitutions R70Q and L91M were mainly found in genotype 1b isolates. Furthermore, a borderline level of statistical significance association was found among the presence of amino acid Glutamine (Q) in the position 70 and IFNL3 genotype AG (P=0.054). Conclusions: the screening of these polymorphisms and functional studies would be useful in clinical practice for identifying groups at high risk of HCC development.
- HCV Viremia Drives an Increment of CD86 Expression by Myeloid Dendritic Cells(2013) MALTA, F. M.; BRUNO, F. R.; CARVALHO, K. I.; NASTRI, A. C. S. S.; KALIL, J.; CARRILHO, F. J.; KALLAS, E. G.; PINHO, J. R. R.The host immune response, including innate and adaptive immunity, plays a critical role in determining the outcome of viral infection. Nevertheless, little is known about the exact reasons for the failure of the host immune system in controlling hepatitis C virus (HCV) infection. Impairment of dendritic cells (DCs) function is probably one of the mechanisms responsible for immune evasion of HCV. In this study, the frequency and phenotype of DCs subsets were analyzed in three groups: HCV-infected individuals who developed viral persistence (1), HCV-infected individuals who spontaneously cleared the virus (2) and HCV-seronegative uninfected subjects (3). The results showed that the frequency of DCs subsets was not statistically significant between groups. Plasmacytoid DCs circulating exhibited an immature phenotype characterized by low expression of CD86. On the other hand, CD86 expression in myeloid DCs was significantly higher in chronic infected individuals compared to healthy controls (P=0.037). A positive correlation was observed between CD86(+) myeloid DC (mDC) and HCV viral load (r=0.4121, P=0.0263). These results suggest that HCV did not have an inhibitory effect on mDC maturation and the HCV viremia drives the increase of CD86 expression in mDC. The regulation of DCs maturation and migration lies at the level of intracellular signaling. HCV can activate or block intracellular signaling pathways and alter DC function. In conclusion, the present study suggests that imbalance of DC maturation by the virus represents a mechanism of evasion of the immune system despite the fact that HCV viremia appears to exert a stimulatory effect on cell-surface immune phenotype. J Med. Virol. 85:1919-1924, 2013. (c) 2013 Wiley Periodicals, Inc.
- Association of IFNL3 and IFNL4 polymorphisms with hepatitis C virus infection in a population from southeastern Brazil(2016) NASTRI, Ana Catharina de Seixas Santos; MALTA, Fernanda de Mello; DINIZ, Marcio Augusto; YOSHINO, Alessandra; ABE-SANDES, Kiyoko; SANTOS, Sidney Emanuel Batista dos; LYRA, Andre de Castro; CARRILHO, Flair Jose; PINHO, Joao Renato RebelloHepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma (HCC). Viral and host factors are known to be predictors for antiviral therapy. Host factors that are predictors of sustained viral response (SVR) were discovered by genome-wide association studies (GWAS), including single-nucleotide polymorphisms (SNPs) in or near the interferon lambda gene (rs8099917, rs12979860 and rs368234815). The aim of the present study was to verify the genotype frequencies of SNPs rs8099917, rs12979860 and rs368234815 and to evaluate the association between SNPs and the outcome of HCV infection, taking into account the population ancestry. In this study, there was an association of the three polymorphisms with both clinical outcome and response to treatment with PEG-IFN and RBV. The polymorphisms rs12979860 and rs368234815 were associated with increased sensitivity (97.7 %, 95 % CI 87.2-100, and 93.3 %, 95 % CI 81.3-98.3; respectively) and with a greater predictive value of a positive response to treatment. In multivariable analysis adjusted by gender, age and ancestry, the haplotype G/T/Delta G was related to non-response to treatment (OR = 21.09, 95 % CI 5.33-83.51; p < 0.001) and to a higher chance of developing chronic infection (OR = 5.46, 95 % CI 2.06-14.46; p = 0.001) when compared to the haplotype T/C/TT. These findings may help to adjust our treatment policies for HCV infection based on greater certainty in studies with populations with such genetic characteristics, as well as allowing us to get to know the genetic profile of our population for these polymorphisms.
- Polymorphisms in HLA-C and KIR alleles are not associated with HAM/TSP risk in HTLV-1-infected subjects(2018) ASSONE, Tatiane; MALTA, Fernanda M.; BAKKOUR, Sonia; MONTALVO, Leilani; PAIVA, Arthur M.; SMID, Jerusa; OLIVEIRA, Augusto Cesar Penalva de; GONCALVES, Fernanda de Toledo; LUIZ, Olinda do Carmo; FONSECA, Luiz Augusto M.; NORRIS, Philip J.; CASSEB, JorgeIntroduction: Several genetic polymorphisms may be related to susceptibility or resistance to viral disease outcomes. Immunological or genetic factors may act as major triggers of the immune pathogenesis of HAM/TSP. This study investigated the association of immune related genetic polymorphisms with viral and immunological markers. Methods: 247 HTLV-1-infected volunteers, drawn from a larger group of HTLV-infected subjects followed at the Institute of Infectious Diseases ""Emilio Ribas"" (IIER) for up to 19 years, participated in this study, which ran from June 2011 to July 2016. The subjects were classified according to their neurological status into two groups: Group 1 (160 asymptomatic individuals) and Group 2 (87 HAM/TSP patients). Samples were tested for spontaneous lymphocyte proliferation (LPA) and HTLV-1 proviral load (PVL) and for IFN-lambda 4, HLA-C and KIR genotypes using qPCR. Results: We found associations between LPA (p = 0.0001) with HAM/TSP and confirmed the IFN-lambda 4 polymorphism rs8099917, allele GG, as a protective factor using a recessive model (OR = 3.22, CI = 1.10-9.47). Polymorphisms in HLA-C and KIR alleles were not associated with risk of developing HAM/TSP. Conclusion: We demonstrated that age, LPA and an IFN-lambda 4 polymorphism were associated with progression to HAM/TSP. Understanding HAM/TSP pathogenesis can provide important markers of prognostic value for clinical management, and contribute to the discovery of new therapeutic interventions in the future.
- Characterization of clinical predictors of naturally occurring NS3/NS4A protease polymorphism in genotype 1 hepatitis C virus mono and HIV co-infected patients(2017) NETO, Gaspar Lisboa; MALTA, Fernanda M.; GOMES-GOUVEA, Michele S.; NOBLE, Caroline F.; ROMANO, Camila M.; PINHO, Joao R. Rebello; SILVA, Mariliza H.; LEITE, Andrea G. B.; PICCOLI, Leonora Z.; CARRILHO, Flair J.; MENDES-CORREA, Maria C.Spontaneously occurring resistance may impair the success of protease inhibitors based regimens in HCV treatment. This study aimed to evaluate associations between amino acid substitutions in NS3/NS4A domain and clinical features of 247 HCV mono or HCV/HIV co-infected patients. Fourteen samples (5.7%) harbored at least one resistance-associated substitution (RAS). The following RASs were detected in NS3 region: T54S (6-2.4%), V55A (7-2.8%), and Q80R (2-0.8%). S122G occurred in 86.9% of HCV genotype 1b samples with either natural polymorphisms or RASs. Advanced liver fibrosis and HIV co-infection were not related to NS3/NS4A amino acid substitutions.
- Genetic diversity of HCV in Brazil(2013) LAMPE, Elisabeth; LEWIS-XIMENEZ, Lia; ESPIRITO-SANTO, Marcia P.; DELVAUX, Nathalia M.; PEREIRA, Sergio A.; PERES-DA-SILVA, Allan; MARTINS, Regina M. B.; SOARES, Marcelo A.; SANTOS, Andre F.; VIDAL, Luanna L.; GERMANO, Fabiana N.; MARTINEZ, Ana Maria B. de; BASSO, Rossana; PINHO, Joao R. Rebello; MALTA, Fernanda M.; GOMES-GOUVEA, Michele; MOLITERNO, Ricardo A.; BERTOLINI, Dennis A.; FUJISHIMA, Mayara A. T.; BELLO, GonzaloBackground: Many studies have documented the molecular epidemiological scenario of HCV within individual Brazilian states, but we still have an incomplete understanding of the dispersion dynamics of the virus in different regions throughout the country. Methods: A total of 676 HCV NS5B gene sequences of subtypes 1a (n=321), 1b (n=170) and 3a (n=185), isolated from seven different Brazilian states covering four out of five regions were analysed in the present study. We also analysed 22 HCV NS5B gene sequences of minor genetic variants including genotype 2 (n=13), genotype 4 (n=6) and subtype 5a (n=3). Brazilian HCV sequences were aligned with sequences of non-Brazilian origin and subjected to maximum likelihood phylogenetic analyses. Results: These analyses revealed that the Brazilian HCV epidemic resulted from multiple introductions and autochthonous transmission of subtypes 1a, 1b, 3a and genotypes 2, 4 and 5. Brazilian HCV subtype 1a epidemic is dominated by the dissemination of one major clade; while Brazilian HCV subtypes 1b and 3a epidemics are characterized by concurrent dissemination of several independent HCV lineages. Some HCV Brazilian lineages of subtypes 1a, 1b, 2b and 3a were successful in becoming established and disseminated through several regions in the country. Despite significant phylogenetic intermixing of Brazilian sequences, the distribution of HCV strains from different states across lineages was not completely homogeneous. Conclusions: These results demonstrate the existence of multiple introductions and local propagation of both prevalent and uncommon HCV genetic variants in Brazil and identify some major Brazilian HCV clades with nationwide dissemination. This study also suggests that the observed HCV diversity in Brazil has been shaped by both frequent viral migration among regions and in situ viral dissemination.