MARIA CASSIA JACINTHO MENDES CORREA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Moléstias Infecciosas e Parasitárias, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/52 - Laboratório de Virologia, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/52 - Laboratório de Virologia, Hospital das Clínicas, Faculdade de Medicina - Líder
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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.
conferenceObject HIV CO-INFECTION IS AN INDEPENDENT FACTOR IN DETERMINING VACCINE SCAPE MUTANTS AMONG HEPATITIS B CHRONIC PATIENTS IN BRAZIL(2012) MENDES-CORREA, M. C.; PINHO, J. R. R.; GOMES-GOUVEA, M. S.; CHACHA, S.; MARTINELLI, A. L. C.; GUASTINI, C. F.; SANTOS, A. C. S.; SOARES, M. C. P.; LEITE, O. H. M.; UIP, D. E.Background: Prolonged lamivudine (LAM) therapy has been associated with different mutations in the hepatitis B virus (HBV) genome. The aims of this study were: (1) to compare lamivudine-resistance mutation patterns after prolonged LAM use between patients with chronic hepatitis B infection (CHB) with or without human immunodeficiency virus (HIV) co-infection; (2) to evaluate the incidence and factors associated with the presence of mutations in the envelope gene among these patients. Methods: We included patients with CHB treated with LAM and with detectable HBV-DNA (>50IU/mL) after at least six months of LAM use. HBV load was determined using an “in-house” real-time polymerase chain reaction. HBV mutation status analysis were carried out by amplification and sequencing the complete HBV RT-domain. Results: Ninety-one patients infected only with HBV and 34 HIV-HBV co-infected patients were included. The time of exposure to LAM varied from 7 to 140 months among HBV infected patients and from 12 to 182 months among co-infected patients. Mutations associated with resistance to LAM were observed in 42.9% of HBV infected patients and in 67.6% of HIV-HBV co-infected patients. In this latter group, the frequency of the rtV173L + rtL180M + rtM204V triple mutation was 32.0% versus 7.6% observed among patients infected only with HBV. All patients with this triple mutational pattern also showed sE164D + sI195M changes in the envelope gene. Multivariate analysis demonstrated that time of exposure to lamivudine superior of 32 months (adjusted PR 1.51, 95%CI 1.10–2.06) was an independent variable associated with the chance of harboring mutations in the polymerase gene. Multivariate analysis also demonstrated that HIV co-infection (adjusted PR 1.40, 95%CI 1.10–1.78) was the only independent variable associated with the chance of harboring sE164D or I195M changes in the envelope gene (vaccine escape phenotype). Conclusions: Prolonged use of LAM may be associated with multiple changes in the pol gene, among mono or co-infected patients; 2-HIV co-infection is an independent factor in determining sE164D and I195M changes in the envelope gene, a vaccine escape phenotype.- 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.
conferenceObject Absence of anti-HBc in HIV/HBV coinfected individuals with advanced immunosuppression(2012) AVELINO-SILVA, Vivian I.; GOMES-GOUVEA, Michele S.; MIRAGLIA, Joao Luiz; GUASTINI, Cristina; PINHO, Joao R.; MENDES-CORREA, Maria CassiaHBV chronic infection is frequent among HIV carriers but serological markers may present atypical profiles among these patients. HBsAg reactivity in anti-HBc negative patients is a rare event that has been described in HIV co-infected patients. This pattern was related to mutations in the coding region of the viral core protein, to aberrant host immune response or to both factors. The aim of this study was to evaluate the occurrence of anti-HBc negative/HBsAg positive profile in HIV/HBV coinfected patients and to identify possible associations with clinical variables and HBV mutations. This is a case control study based in medical reports and laboratorial records from the studied patients. For each anti-HBc negative/HBsAg positive identified case, 2 anti-HBc positive/HBsAg positive controls matched by sex and age were selected. HBVDNA was detected by real time PCR. Patients with detectable viral load were further analyzed by amplification and sequencing of precore/core and S regions for genotyping and identification of mutations possibly involved with this anomalous serological pattern. Our study population was selected from 2412 anti-HIV positive patients. Among them, 120 were HBsAg reactive. Patients were followed up for a mean time of 5 years, utilizing from 1 to 5 samples for serological evaluations. We identified 12 patients (11 male and one female) who were negative for anti-HBc but positive for HBsAg in at least one sample during follow up, Compared with controls, anti-HBc negative / HBsAg positive cases had lower mean count of CD4 + T lymphocytes (349.2 vs. 455 cells/mm3, P = 0.048). There was no correlation between anti-HBc negative/HBsAg positive serological profile and the analyzed clinical variables (time of diagnosis, history of opportunistic infections, nadir CD4 + T cells, use of medications effective against HBV or advanced liver disease). Serum samples from 7 patients were submitted to the HBV viral load detection and HBV DNA was detected in only 3 of these patients, with a mean viral load of 5.67 log. These three cases were infected by HBV subgenotype A1 and the analysis of the precore/core region of these viruses did not identify any mutation that could explain the anomalous serological profile. In our series of HBV/HIV co-infected patients, 10% of them were concomitantly HBsAg reactive but anti-HBc nonreactive. No mutation in the precore/core regions was identified that could explain this profile. As these patients showed a lower mean CD4+T cells count compared to the control group, our findings may suggest that advanced immunosuppression may be involved, determining the loss of anti-HBc at least in detectable levels.bookPart Hepatite B(2017) GOUVêA, Michele Soares Gomes; PINHO, João Renato Rebello; MENDES, Maria Cássia Jacintho Corrêa- Hepatitis delta in HIV/HBV co-infected patients in Brazil: is it important?(2011) MENDES-CORREA, Maria Cassia; GOMES-GOUVEA, Michele S.; ALVARADO-MORA, Monica V.; SILVA, Mariliza H. Da; LAZARI, Carolina; CAVALCANTI, Norma C. S.; ALONSO, Flaviane K.; CARPINELLI, Catia C.; UIP, David E.; PINHO, Joao R. R.Objectives: This study was carried out to evaluate the prevalence of hepatitis delta virus (HDV) among human immunodeficiency virus (HIV)/hepatitis B virus (HBV) co-infected patients from Sao Paulo, in the Southeast Region of Brazil. Methods: A total of 3259 HIV patients with serological markers for HBV were initially enrolled in the study. Among these patients, 154 (4.7%) were hepatitis B surface antigen (HBsAg)-reactive. Serum samples were obtained from 86 HBsAg-positive patients and were submitted to anti-HDV serological assay. Results: One (1.2%) HIV/HBV patient was found to be anti-HDV-positive, and the HDV infection was confirmed by PCR. Phylogenetic analysis showed that this HDV sequence grouped with other HDV genotype 1 sequences from Mediterranean European countries, suggesting that this virus has a common ancestor with HDV from that region. This patient was probably infected by sexual transmission, as he reported unprotected sexual intercourse with multiple partners over the course of many years but denied intravenous drug use or any travel to the Brazilian Amazon, an area known to have a high HDV prevalence. Conclusions: HDV infection is infrequent in the Southeast Region of Brazil, however there have been a few cases in this region. HIV/HBV patients are at potential risk for HDV infection, therefore investigations for the presence of HDV infection must be carried out in these patients.
conferenceObject CHARACTERIZATION OF CLINICAL PREDICTORS OF NATURALLY OCCURRING NS3/NS4A PROTEASE POLYMORPHISM IN GENOTYPE 1 HEPATITIS C VIRUS INFECTED PATIENTS(2015) LISBOA NETO, G.; NOBLE, C.; PINHO, J. R. R.; MALTA, F. M.; GOMES-GOUVEA, M. S.; ALVARADO-MORA, M. V.; SILVA, M. H.; LEITE, A. G.; PICCOLI, L. Z.; CARRILHO, F. J.; MENDES-CORREA, M. C.conferenceObject Clinical and virological characterization of chronic hepatitis B in the state of Minas Gerais, Brazil(2012) ANDRADE, Jose R.; SILVA, Luciano D.; BASSETTI-SOARES, Eric; GUIMARAES, Camila M.; GOMES-GOUVEA, Michele S.; MENDES-CORREA, Maria Cassia; CARVALHO, Vitor O. Botelho de; TEIXEIRA, RosangelaIntroduction/Aim: Although chronic HBV infection is a global health problem, there are geographical differences in endemicity and virological characteristics of infection even in the same country. The increasing prevalence of HBeAg-negative hepatitis has been observed in some areas in Brazil. The aim of this study was to investigate the clinical and virological characteristics of patients with chronic hepatitis B in Minas Gerais, the second Brazilian state in population. Methods: In a retrospective cross-sectional study, 235 patients with confirmed chronic hepatitis B monoinfection in replicative phase (HBsAg positive >6 months, HBVDNA > 2000 UI/mL) admitted at the University Hepatitis Reference Center between 1998 and 2011 were included. Demographic, clinical and virological characteristics were analyzed. This study was approved by the Ethics Committee of UFMG. Results: Overall, 169 (71.9%) patients were male, with mean age of 44.1± 12.4 years. The known ways of transmission were vertical in 32 (13.6%), sexual in 27 (11.5%) and blood transfusion in 26 (11.1%). In 143 (60.9%), the transmission mode could not be confirmed. The HBV genotype A was identified in 88/96 (91.7%), followed by genotypes D(3.1%), F (3.1%), B (1.0%) and G (1.0%). 156 (66.4%) and 79 (33.6%) patients were HBeAg negative and positive, respectively, with median age of 46.0± 11.2 and 42.0± 14.6 years (p=0.12), male/female 102/54 and 67/12 (p=0.002), respectively. ALT levels were lower in HBeAg-negative compared with HBeAg positive patients (median of 46.0+/- 73.0 IU/mL vs. 80.0± 104.2 IU/mL, p<0.001). The HBV viremia was lower in HBeAg negative compared with HBeAg positive patients (4.51 log10 IU/mL vs. 6.85 log10 IU/mL, p<0.001). The confirmed diagnostics of cirrhosis and HCC in HBeAg-negative and positive patients were: 60/156 (38.5%) vs. 46/79 (58.2%) (p=0.004) and 11/156 (7.1%) and 8/79 (6.7%) (p=0.41), respectively. The risk of cirrhosis was independently associated with age > 50 years (OR=5.45, 95% CI = 2.88 to 10.36, p<0.001) and male gender (OR=3.21, 95% CI = 1.64 to 6.32, p<0.001), but not with HBeAg status (p=0.21) or high HBV viremia (p=0.92). 18/19 (94.7%) patients with HCC were cirrhotic. Age >50 years was associated with development of HCC (OR=3.90, CI 95% = 1.35 to 11.54, p=0.008) independently of HBeAg status or HBV load. Conclusions: High prevalence of chronic hepatitis B HBeAg-negative and genotype A can be observed in Minas Gerais (Brazil). HBeAg-negative patients had lower ALT and HBV viral load as compared with HBeAg-positive patients. Cirrhotic patients over 50 years had higher risk of development of HCC regardless the status of HBeAg.- The role of PNPLA3 and TM6SF2 polymorphisms on liver fibrosis and metabolic abnormalities in Brazilian patients with chronic hepatitis C(2021) OLIVEIRA, Arthur Ivan N.; MALTA, Fernanda M.; ZITELLI, Patricia Momoyo Y.; SALLES, Ana Paula M.; GOMES-GOUVEA, Michele S.; NASTRI, Ana Catharina S.; PINHO, Joao Renato R.; CARRILHO, Flair J.; OLIVEIRA, Claudia P.; MENDES-CORREA, Maria Cassia; PESSOA, Mario G.; MAZO, Daniel F.BackgroundDespite the growing body of knowledge about TM6SF2 and PNPLA3 polymorphisms in non-alcoholic fatty liver disease, their influence in the spectrum of HCV liver disease is not yet fully defined. Besides that, admixed populations, such as Brazilians, were not included in most of the studies.MethodsThis cross-sectional study enrolled 365 treatment-naive patients with HCV and 134 healthy individuals. TM6SF2 (rs58542926 c.499C>T) and PNPLA3 (rs738409 c.444C>G) polymorphisms were evaluated regarding their association with clinical and laboratory data, histological liver steatosis and fibrosis, and with components of the metabolic syndrome.ResultsIn HCV subjects, the frequencies of TM6SF2 CC and CT+TT were 89% and 11%, while PNPLA3 frequencies of CC and CG+GG were 51.4% and 48.6%. In the univariate logistic regression analysis, the TM6SF2 CT+TT genotype in HCV was associated with significant liver fibrosis (p=0.047; OR 1.953; 95% CI 1.009-3.788). In comparison to the CT+TT genotype, the TM6SF2 CC genotype in HCV was associated with older age (p=0.002), higher frequency of arterial hypertension (p=0.032), obesity (p=0.030), metabolic syndrome (p=0.014) and lower total cholesterol levels (p=0.036). The PNPLA3 GG subjects had lower body mass index than CG/ CC individuals (p=0.047). None of the polymorphisms, or their combinations, was independently associated with hepatic steatosis or fibrosis. On the other hand, older age, lower serum levels of total cholesterol, and higher serum levels of alanine aminotransferase and alkaline phosphatase were associated with liver fibrosis in the multivariate logistic regression analysis.ConclusionIn this evaluation of an admixed HCV population, neither TM6SF2 nor PNPLA3 polymorphisms were independently associated with hepatic steatosis or fibrosis. Other factors seem more influential than these specific polymorphisms in isolation. More studies are warranted to clarify the role of the TM6SF2 and PNPLA3 polymorphisms in Brazilians with HCV.
conferenceObject HBV resistance frequency in nucleos(t)ide analogue-untreated patients from different Brazilian regions(2012) GOMES-GOUVEA, Michele S.; MENDES-CORREA, Maria Cassia; FERREIRA, Ariana C.; TEIXEIRA, Rosangela; ANDRADE, Jose R.; BARROS, Lena Maria F.; FERREIRA, Adalgisa S.; REZENDE, Rosamar F.; NASTRI, Ana Catharina S.; LEITE, Andrea G.; PICCOLI, Leonora Z.; GALVAN, Josiane; CONDE, Simone Regina S.; SOARES, Manoel C.; CARRILHO, Flair J.; PINHO, Joao R.Background - Presence of viral variants with drug-resistance mutations in drug-naïve hepatitis B virus (HBV) infected patients can seriously compromise response to antiviral treatment. Therefore, our study aimed to determine the prevalence of HBV with drug-resistance in 557 untreated chronic hepatitis B (CHB) patients with nucleos(t)ide analogues (NA) from five different geographic regions of Brazil. Methods – HBV reverse-tran-scriptase (RT) region was sequenced and mutations associated with resistance to NA inhibitors were analyzed. Amino acid changes potentially associated with resistance were also investigated. Furthermore, HBV genotypes and subgenotypes were determined by phylogenetic analysis of the sequences. Results – HBV genotypes A [A1 (66.8%), A2 (2.3%)] and D [D1 (0.5%), D2 (4.3%), D3 (11.8%), D4 (6.6%)] were the most prevalent in Brazil, but genotypes B1 (0.2%), B2 (0.2%), C2 (0.7%), E (0.7%), F2a (4.5%), F4 (0.4%) and G (0.5%) were also found. Overall, 1.8% (10/557) of the patients carried HBV variants with primary drug-resistance mutations [rtM204V/I (0.4%); rtM204V + rtS202G (0.4%); rtA181S/T (0.4%); rtM250I (0.2%); rtA194T (0.4%)]. The four strains with mutation at position 204 also had compensatory mutations [rtL180M (3/4); rtL180M + rtV207I (1/4). One patient was infected with HBV variant only with compensatory mutations (rtV173L + rtL180M). Thirty (5%) patients were infected with strain harboring some of that mutation potentially associated with Adefovir resistance [rtS85A (n=1), rtV214A (n=6), rtQ215S (n=14), rtI233V (n=6), rtN238T (n=4), rtN238D (n=5)]. Additionally, we observed in 18 (3.2%) patients the presence of variants with novel amino acid substitutions at positions reported to be potentially associated with Adefovir resistance: rtV214G (n=2), V214E (n=1), Q215H (n=6), Q215P (n=1), E218D (n=2), I233L (n=1), T237A (n=1), N238H (n=3), N238A (n=1). Conclusions – HBV variability is high in Brazil, thirteen HBV subgenotypes were found. The rate of important drug resistance mutations was low (1.8%) among the drug-naïve HBV infected patients studied, indicating the high potential to full efficacy of nucleos(t)ide analogue therapy in these patients. The high frequency of mutations potentially associated with Adefovir resistance among untreated patients suggests that these mutations are not really associated to resistance.