Publications by authors named "Ana de Lourdes Candolo Martinelli"

36 Publications

Bone loss in hepatitis B virus-infected patients can be associated with greater osteoclastic activity independently of the retroviral use.

Sci Rep 2021 May 13;11(1):10162. Epub 2021 May 13.

Department of Clinical Medicine, Ribeirão Preto Medical School, University of São Paulo - FMRP/USP, São Paulo, Brazil.

Nucleoside/nucleotide analogs such as tenofovir, have been used as long-term therapy for the treatment of hepatitis B and side effects such as the reduction in bone mineral density have been associated with their use. To determine the relationships between bone, hormonal, biochemical, and mineral parameters in patients with hepatitis B treated with nucleoside/nucleotide antiviral. A cross-sectional study was conducted with 81 adult patients with chronic hepatitis B infection. Dual-energy X-ray absorptiometry (DXA) was performed to assess bone mineral density. Biochemical analyses were performed for osteocalcin, deoxypyridinoline, parathyroid hormone, vitamin D, IGF-1, TSH, testosterone, estradiol, FSH, transaminases, urea, creatinine, calcium, serum and urinary phosphorus, magnesium, and FGF-23, body composition was performed by DXA. Participants, both gender, were divided according to the use of antiretrovirals: Group1: 27 inactive virus carriers without medication; Group2: 27 patients using tenofovir; and Group3: 27 patients using lamivudine or entecavir. DXA readings diagnosed osteopenia in the lumbar spine for 7.4% of individuals in Group1, 15% in Group2, and 3.7% in Group3. For all groups, we observed normal values in bone formation markers, osteocalcin levels as well as parathyroid hormone, insulin growth factor 1, and FGF-23. In all groups, we found increased levels of urinary deoxypyridinoline, a bone resorption marker. Increased levels in the bone resorption markers indicated a high resorptive activity of bone tissue. These data suggested high resorption activity of bone tissue in hepatitis B virus-infected patients independent of the use of antiretrovirals.
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http://dx.doi.org/10.1038/s41598-021-89486-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119499PMC
May 2021

Corrigendum: A novel substitution in NS5A enhances resistance of hepatitis C virus genotype 3 to daclatasvir.

J Gen Virol 2021 Mar;102(3)

School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.

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http://dx.doi.org/10.1099/jgv.0.001582DOI Listing
March 2021

A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir.

J Gen Virol 2021 01 3;102(1). Epub 2020 Nov 3.

School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.

Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs.
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http://dx.doi.org/10.1099/jgv.0.001496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116786PMC
January 2021

Unexpected findings of hepatitis B and delta infection in northeastern Brazil: A public health alert.

Ann Hepatol 2021 May-Jun;22:100272. Epub 2020 Oct 16.

Department of Medicine, Federal University of Maranhão, Maranhão, Brazil.

Introduction And Objectives: Research has shown that hepatitis B (HBV) and Delta virus (HDV) are a worldwide public health problem. This study aims to estimate the prevalence rates of HBV and HDV infection in five municipalities of Maranhão, Northeastern Brazil.

Materials And Methods: A total sample between 3856 and 4000 individuals. Questionnaires were used to register sociodemographic characteristics and factors associated with transmission. Patients were tested for hepatitis B virus surface antigen (HBsAg), anti-hepatitis B core antigen (anti-HBc), and antibodies against hepatitis Delta virus (anti-HDV). Factors associated with HBV were detected by means of multivariate Poisson regression.

Results: Overall, 3983 subjects were included. Ninety-two of the participants were HBsAg-positive (2.30%, 95% CI 1.80-2.80), and anti-HBc was detected in 1535 (38.50%, 95% CI 37-40). The factors associated with the presence of anti-HBc were: (1) Municipality (P<0.001); Age (P<0.001); School education (P<0.001); Illicit drug use (P=0.001); non-HBV vaccine (P=0.041). Among the HBsAg carriers, eight were anti-HDV-positive (8.69%, 95% CI 2.90-14.40). The most frequent HBV genotype was D4. The only HDV genotype was HDV-8.

Conclusion: HBV exhibited intermediate endemicity in the studied region. Traditional factors were associated with exposure to the virus. The presence of the HDV was confirmed. The most frequent HBV and HDV genotypes were unlike the ones currently described in Brazil.
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http://dx.doi.org/10.1016/j.aohep.2020.09.016DOI Listing
October 2020

HLA-G liver expression and HLA-G extended haplotypes are associated with chronic hepatitis C in HIV-negative and HIV-coinfected patients.

Clin Immunol 2020 08 27;217:108482. Epub 2020 May 27.

Commissariat à l'Energie Atomique et aux Energies Alternatives, Direction de la Recherche Fondamentale, Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris, France; Université Paris-Diderot, UMR 976 HIPI, Institut de Recherche Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris, France. Electronic address:

Chronic hepatitis C virus (HCV) infection induces liver damage and the HCV/Human Immunodeficiency Virus (HIV)-coinfection may further contribute to its progression. The HLA-G molecule inhibits innate and adaptive immunity and may be deleterious for chronically virus-infected cells. Thus we studied 204 HCV-mono-infected patients, 142 HCV/HIV-coinfected patients, 104 HIV-mono-infected patients and 163 healthy subjects. HLA-G liver expression was similarly induced in HCV and HCV/HIV specimens, increasing with advanced fibrosis and necroinflammatory activity, and with increased levels of liver function-related enzymes. Plasma soluble HLA-G (sHLA-G) levels were higher in HCV/HIV patients compared to HCV, HIV and to healthy individuals. sHLA-G continued to be higher in coinfected patients even after stratification of samples according to degree of liver fibrosis and necroinflammatory activity when compared to mono-infected patients. Some HLA-G gene haplotypes differentiated patient groups and presented few associations with liver and plasma HLA-G expression. HLA-G thus may help to distinguish patient groups.
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http://dx.doi.org/10.1016/j.clim.2020.108482DOI Listing
August 2020

Cost-effectiveness analysis is a mandatory strategy for health systems: evidence from a study involving therapies for hepatitis C.

Cad Saude Publica 2020 31;36(2):e00036619. Epub 2020 Jan 31.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brasil.

Cost-effectiveness analysis is essential in health decision making. Several countries use it as synthesis of evidence to incorporate health technologies. The protease inhibitors (PI) boceprevir (BOC) and telaprevir (TVR) are indicated for chronic hepatitis C treatment and were incorporated in guidelines worldwide. Pre-marketing clinical trials showed higher sustained virological response rates in relation to previous therapies, but the incorporation of PIs generated a significant financial impact. The aim of this study was to discuss the relevance of cost-effectiveness analysis through a study that involved the inclusion of PIs in a clinical protocol. The analysis was part of a real-life study that included patients infected with hepatitis C virus genotype 1 treated in a tertiary university hospital in Brazil. Triple therapies (TT) with ribavirin (RBV), peginterferon α-2a (Peg-INF α-2a) and BOC or TVR were compared to dual therapy with RBV and Peg-INF α-2a. Sensitivity analysis of the cost-effectiveness ratio indicated an 88.2% chance of TTs presenting a higher cost per cure. The incremental cost-effectiveness ratios (ICER) exceeded the Brazilian gross domestic product (GDP) per capita by three times in all proposed scenarios. The sensitivity of ICER showed an 88.4% chance of TT not being cost-effective. The impact of PI incorporation was negative and the conduct about this could have been different if a previous cost-effectiveness analysis had been conducted.
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http://dx.doi.org/10.1590/0102-311X00036619DOI Listing
July 2020

Baseline resistance associated substitutions in HCV genotype 1 infected cohort treated with Simeprevir, Daclatasvir and Sofosbuvir in Brazil.

Clin Res Hepatol Gastroenterol 2020 06 12;44(3):329-339. Epub 2019 Sep 12.

FCFRP-USP - University of São Paulo, Ribeirão Preto Faculty of Pharmaceutical Sciences-Café avenue, 14040-903 Ribeirão Preto, SP, Brazil. Electronic address:

Background: The World Health Organization estimates that 1% of the world population (71 million) is infected with hepatitis C virus (HCV). In 2015, three direct-acting antivirals (DAAs), simeprevir (SMV), sofosbuvir (SOF) and daclatasvir (DCV) were included in the Brazilian protocol for the treatment of chronic hepatitis C. Despite the fact that the use of these drugs is associated with higher treatment response rates and with lower incidence of side effects, studies have shown the association between the presence of viral resistance mutations and the failure of pharmacological treatment.

Aim: This way, this study aimed to evaluate the safety and effectiveness of treatment for HCV genotypes 1a and 1b infected patients with these DAAs, also analyzing the occurrence and prevalence of baseline resistance associated substitutions (RAS), observing the impact of these mutations into the treatment success.

Methods: Clinical data were collected from all the 262 HCV infected patients included for comparative analysis, while serum samples collected from 144 of these individuals, before treatment, were submitted to molecular biology approaches for mutation analysis into NS3, NS5A and NS5B regions.

Results: Regarding the treatment regimens, 49.6% of the patients received SOF+DCV±ribavirin and 50.4% used SOF+SMV±ribavirin. The sustained virological response at 12 weeks post-treatment (SVR12) rate was 92.7% (93.9% for SOF plus DCV and 91.7% for SOF plus SMV). No clinical or laboratorial factor was statistically associated with SVR. The most common adverse reactions were haematological events, nausea/vomiting, headache and asthenia. Out of 144 blood samples, 70 (48.6%) had detected RAS, 34.8% treated with SOF+DCV±ribavirin and 61.3% SOF+SMV±ribavirin. The resistance mutations against SMV were detected into NS3: substitutions G122S (28%), I170V (22.7%), Y56F (17.3%) and V132I (14.7%). The mutations against DCV R30Q (9.1%), P58H (6.1%) and Q62E (6.1%) were observed into NS5A, and for SOF the mutations A421V (10.6%), L159F (6.4%) and C316N (6.4%) were present inside NS5B viral protein. Four patients did not reach SVR, three of them presented viruses carrying RAS (1 treated with SOF+DCV and 2 with SOF+SMV). Some of these mutations, like R30Q (present in relapsing samples) and L159F, are well known by their influence on antiviral resistance, while others, like C316N, have a compensatory effect on viral fitness, maintaining these baseline RAS.

Conclusion: The use of treatment regimens composed of SOF and DCV or SOF and SMV showed a high SVR rate, despite of a high rate of RAS, and a good tolerability profile in patients with HCV genotype 1. However, the high occurrence of baseline RAS observed in this casuistic is still a concern and studies like this show the necessity to understand how they are maintained in the population and to direct more efficiently the use of DAAs.
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http://dx.doi.org/10.1016/j.clinre.2019.07.015DOI Listing
June 2020

Comprehensive analysis of gene in hereditary hemochromatosis and in diseases associated with acquired iron overload.

World J Hepatol 2019 Feb;11(2):186-198

Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil.

Background: Patients with hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may or not develop iron overload (IO), which is associated with worst prognosis, because can cause serious damage to organs. gene controls the iron uptake from gut, particularly in patients with hereditary hemochromatosis (HH).

Aim: To identify associations between coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO.

Methods: We sequenced exons 2 to 5 and boundary introns of gene, evaluating all polymorphic sites in patients presenting hereditary (hemochromatosis) or acquired iron overload HCV and HCC) and in healthy controls, using Sanger sequencing. We also determined the ensemble of extended haplotype in healthy control individuals, including several major histocompatibility complex loci, using sequence specific probes. Haplotype reconstruction was performed using the Arlequin and Phase softwares, and linkage disequilibrium (LD) between histocompatibility loci and gene was performed using the Haploview software.

Results: The *003 allele was overrepresented ( = 71%) and *001 allele was underrepresented ( = 14%) in HH patients compared to all groups. A strong linkage disequilibrium was observed among the , and gene variants, particularly in HH; however, the mutation was not directly associated with HH susceptibility. The *001/*002 genotype conferred susceptibility to HCC in HCV patients exhibiting IO ( = 0.02, OR = 14.14). Although is telomeric to other histocompatibility genes, the ( ≤ 0.00001/ ≤ 0.0057) combination was in LD with *44 allele group in healthy controls. No LD was observed between alleles and other major histocompatibility loci.

Conclusion: A differential association was observed for HH and for diseases associated with acquired IO (HCV, HCC). Since is very distant from other histocompatibility loci, only weak associations were observed with these alleles.
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http://dx.doi.org/10.4254/wjh.v11.i2.186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393716PMC
February 2019

First-wave protease inhibitors for hepatitis C genotype 1 treatment: a real-life experience in Brazilian patients.

Rev Soc Bras Med Trop 2018 Mar-Apr;51(2):146-154

Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.

Introduction: Licensed for chronic hepatitis C treatment in 2011, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), which have high sustained viral responses (SVR), ushered a new era characterized by the development of direct-action drugs against the hepatitis C virus (HCV). The aim of this study was to analyze the effectiveness and safety of BOC and TVR administered with pegylated interferon and ribavirin and to share the experience of a Brazilian reference center.

Methods: A retrospective descriptive study was conducted in patients with HCV genotype 1 infection who started treatment between July 2013 and December 2015. Data were collected using a computerized system.

Results: A total of 115 subjects were included, of which 58 (50.4 %) had liver cirrhosis and 103 (89.6 %) used TVR. The overall SVR rate was 61.7 % (62.1 % for TVR and 58.3 % for BOC). The presence of cirrhosis was associated with a lower SVR rate, whereas patients who relapsed after prior therapy had a greater chance of showing SVR than did non-responders. The incidence of adverse drug reactions (ADRs) was high. Almost all patients (~100 %) presented with hematologic events. Furthermore, treatment had to be discontinued in 15 subjects (13 %) due to severe ADRs.

Conclusions: In conclusion, the SVR rates in our study were lower than those reported in pre-marketing studies but were comparable to real-life data. ADRs, particularly hematological ADRs, were more common compared to those in previous studies and resulted in a high rate of treatment discontinuity.
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http://dx.doi.org/10.1590/0037-8682-0153-2017DOI Listing
May 2018

Peginterferon still has a place in the treatment of hepatitis C caused by genotype 3 virus.

Rev Inst Med Trop Sao Paulo 2017 Nov 6;59:e67. Epub 2017 Nov 6.

Universidade de São Paulo, Faculdade de Medicina, Departamento de Doenças Infecciosas e Parasitárias, São Paulo, São Paulo, Brazil.

Despite recent advances in therapy for chronic hepatitis C (CHC), the disease caused by genotype 3 virus (GEN3) is still considered a treatment challenge in certain patient subgroups. The aim of this retrospective study was to evaluate the effectiveness and safety of the peginterferon (Peg-IFN) and ribavirin (RBV) combination treatment for GEN3/CHC patients, and to evaluate sustained virological response (SVR) indicators and early treatment interruption due to serious adverse events (SAE). This was a retrospective observational study of GEN3/CHC patients, co-infected or not by HIV and treated with Peg-IFN/RBV in nine Brazilian healthcare centers. The study sample included 184 GEN3/CHC patients; 70 (38%) were co-infected with HIV. The overall SVR rate was 57.1% (95% CI 50-64). Among co-infected and mono-infected patients, the SVR rate was 51.4% (36/70) and 60.5% (69/114), respectively (p=0.241). Thirty-four (18.5%) patients experienced SAE and interrupted treatment. SVR was negatively associated with the use of Peg-IFN alpha 2b (PR 0.75; 95% CI 0.58-0.99; p=0.045) and to early treatment interruption due to SAE (PR 0.36; 95% CI 0.20-0.68; p=0.001). Early treatment interruption due to SAE was associated with age (PR 1.06; 95% CI 1.02-1.10; p<0.001) and occurrence of liver cirrhosis (PR 2.06; 95% CI 1.11-3.83; p=0.022). In conclusion, Peg-IFN/RBV might represent an adequate treatment option, mainly in young patients without advanced liver disease or when the use of direct-action drugs is limited to specific patient groups.
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http://dx.doi.org/10.1590/S1678-9946201759067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679679PMC
November 2017

Basal core promoter and precore mutations among hepatitis B virus circulating in Brazil and its association with severe forms of hepatic diseases.

Mem Inst Oswaldo Cruz 2017 Sep;112(9):626-631

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Divisão de Gastroenterologia, Ribeirão Preto, SP, Brasil.

Background: In Brazil, few studies have investigated the prevalence of infection with the precore (PC) and basal core promoter (BCP) mutants of the hepatitis B virus (HBV).

Objectives: This study aimed to analyse the frequency of PC and BCP mutations among patients infected with HBV and to evaluate the association between the variants and advanced hepatic disease.

Methods: A total of 161 patients infected with HBV were studied. To identify PC and BCP mutations, a 501-bp fragment of HBV DNA was amplified and sequenced.

Findings: PC and BCP regions from HBV strains were successfully amplified and sequenced in 129 and 118 cases, respectively. PC and BCP mutations were detected in 61.0% and 80.6% of the cases, respectively. The A1762T/G1764A variant was identified in 36.7% of the patients with grade 1 and 2 liver fibrosis (29/79) and in 81.8% of the patients with grade 3 and 4 liver fibrosis (9/11) (p < 0.01); in 76.9% of the patients with cirrhosis (10/13) and in 38.1% of the patients without cirrhosis (40/105) (p = 0.01); and in 77.8% of the patients with hepatocellular carcinoma (HCC) (7/9) and in 39.4% of the patients without HCC (43/109) (p = 0.03).

Main Conclusions: A high prevalence of HBV PC and BCP mutants was found. The A1762T/G1764A variant was independently associated with advanced forms of liver fibrosis, hepatic cirrhosis, and HCC.
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http://dx.doi.org/10.1590/0074-02760160540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572448PMC
September 2017

Effectiveness and safety of first-generation protease inhibitors in real-world patients with hepatitis C virus genotype 1 infection in Brazil: a multicenter study.

Clinics (Sao Paulo) 2017 Jun;72(6):378-385

Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina, Universidade de Sao Paulo (USP), SP, BR.

Objective:: To evaluate the effectiveness and safety of first-generation protease inhibitors for the treatment of genotype 1 hepatitis C virus-infected patients at Brazilian reference centers.

Methods:: This multicenter cross-sectional study included hepatitis C virus genotype 1 monoinfected patients treated with Peg-interferon, ribavirin, and either boceprevir (n=158) or telaprevir (n=557) between July 2013 and April 2014 at 15 reference centers in Brazil. Demographic, clinical, virological, and adverse events data were collected during treatment and follow-up.

Results:: Of the 715 patients, 59% had cirrhosis and 67.1% were treatment-experienced. Based on intention-to-treat analysis, the overall sustained viral response was 56.6%, with similar effectiveness in both groups (51.9% for boceprevir and 58% for telaprevir, p=0.190). Serious adverse events occurred in 44.2% of patients, and six deaths (0.8%) were recorded. Cirrhotic patients had lower sustained viral response rates than non-cirrhotic patients (46.9% vs. 70.6%, p<0.001) and a higher incidence of serious adverse events (50.7% vs. 34.8%, p<0.001). Multivariate analysis revealed that sustained viral response was associated with the absence of cirrhosis, viral recurrence after previous treatment, pretreatment platelet count greater than 100,000/mm3, and achievement of a rapid viral response. Female gender, age>65 years, diagnosis of cirrhosis, and abnormal hemoglobin levels/platelet counts prior to treatment were associated with serious adverse events.

Conclusion:: Although serious adverse events rates were higher in this infected population, sustained viral response rates were similar to those reported for other patient cohorts.
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http://dx.doi.org/10.6061/clinics/2017(06)08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463255PMC
June 2017

Distribution of HBV subgenotypes in Ribeirão Preto, Southeastern Brazil: a region with history of intense Italian immigration.

Braz J Infect Dis 2017 Jul - Aug;21(4):424-432. Epub 2017 May 6.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil.

Hepatitis B virus (HBV) is distributed worldwide, with geographical variations regarding prevalence of the different genotypes. The aim of this study was to determine the HBV genotypes and subgenotypes circulating in Southeast Brazil and compare the genetic sequences found with HBV sequences previously described in the world. Sequences from 166 chronic HBV carriers were analyzed using the fragment constituted by 1306 base pairs comprising surface and polymerase regions of the HBV genome. The sequences obtained were submitted to phylogenetic analysis. HBV subgenotypes A1, A2, D1-D4, F2a, and F4 were found. HBV genotype D was the most frequent, found in 99 patients (58.4%). Within this group, subgenotype D3 was the most prevalent, in 73 patients (42.9%). HBV genotype A was identified in 58 (36%) patients, subgenotype A1, in 48 (29.8%) subjects. Genotype F was identified in 9 (5.4%). According to the phylogenetic analysis, the sequences found were grouped with sequences from Europe, Asia and Middle East (subgenotypes D1, D2, D3) and sequences from Latin America and Africa (subgenotype A1). HBV D3 grouped in different clusters inside D3 clade, several of them with sequences isolated in Italy. We also identified eight families whose relatives were infected with the same HBV subgenotype, most with high similarity between sequences. In conclusion, the distribution of the HBV sequences obtained interweaved with sequences from other continents, corresponding to regions from where many immigrants came to this region, in accordance to the hypothesis that the HBV detected over there were brought during the colonization times.
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http://dx.doi.org/10.1016/j.bjid.2017.01.011DOI Listing
August 2017

The HLA-G 14-base pair deletion allele and the deletion/deletion genotype are associated with persistent HBe antigenemia in chronic hepatis B infection.

Hum Immunol 2017 Feb 29;78(2):166-171. Epub 2016 Dec 29.

Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil.

Background And Aims: HLA-G has well-recognized immunomodulatory properties, and this molecule is frequently expressed in the livers of hepatitis B virus (HBV)-infected patients. Because the HLA-G 14 bp-insertion/deletion polymorphism (rs371194629) has been associated with the magnitude of HLA-G expression, we evaluated this polymorphism in the recognized evolutionary forms of chronic HBV infection.

Methods: We studied 196 chronic HBV-infected patients (118 HBeAg-negative chronic hepatitis, 53 HBeAg-positive chronic hepatitis and 25 inactive carriers exhibiting low levels of serum HBVDNA and persistently normal ALT levels), and 202 healthy individuals. Chronic hepatitis HLA-G typing was performed using PCR-amplified DNA hybridized with specific primers.

Results: The frequencies of the insertion/deletion alleles and genotypes were very similar in patients and controls. After patient stratification according to the evolutionary form of the chronic HBV infection, the frequencies of the deletion allele (P=0.0460; OR=1.26; 95%CI=1.01-1.45) and of the deletion/deletion genotype (P=0.0356; OR=2.08; 95%CI=1.05-4.09) were overrepresented in HBeAg-positive patients when compared to HBeAg-negative patients. No differences were observed when HBV inactive carriers were compared to HBeAg-negative chronic hepatitis patients.

Conclusions: Because the 14-bp deletion allele has been associated with increased HLA-G production and because HLA-G may down regulate the cytotoxic activity of TCD8 and NK cells, patients exhibiting the 14-bp deletion allele at single or double doses are at increased risk for developing chronic forms of HBV associated with persistent viremia and worse prognoses.
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http://dx.doi.org/10.1016/j.humimm.2016.12.011DOI Listing
February 2017

A Day-4 Lille Model Predicts Response to Corticosteroids and Mortality in Severe Alcoholic Hepatitis.

Am J Gastroenterol 2017 02 6;112(2):306-315. Epub 2016 Dec 6.

Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Objectives: Prednisolone therapy increases the risk of infections in patients with severe alcoholic hepatitis (SAH). We evaluated whether the use of the Lille Model at day 4 (LM4) is useful to predict response to prednisolone compared with the classic day 7 (LM7) in order to limit a futile exposure to corticosteroids.

Methods: We performed a retrospective analysis of a large multinational cohort of patients with SAH with Maddrey's discriminant function (DF) ≥32. Response to corticosteroids was assessed with LM4 and LM7, according to the validated cutoff value (CUV>0.45). Receiver operating characteristics (ROC) curves were constructed to determine the optimal CUV for LM4 and to compare accuracy between LM4, LM7, MELD (Model for End-Stage Liver Disease), and ABIC (age, bilirubin, international normalized ratio, and creatinine). Logistic regression models were constructed to predict 28- and 90-day mortality. Cox regression analysis was performed to assess long-term survival.

Results: A total of 163 (62.7%) out of 260 patients received corticosteroids. The median DF for the patients treated with corticosteroids was 64.1 (47.9-81.3). Overall 90-day mortality was 35.9%. The median LM4 and LM7 for the patients who received treatment was 0.39 (0.19-0.83) and 0.36 (0.13-0.77). LM4 was a strong independent predictor of 28-day mortality (OR 25.4, (95% confidence interval (CI) 5.1-126.8), P<0.001). By using LM4 with a CUV>0.45, 28- and 90-day survival was significantly higher for responders (90% and 76%) than non-responders (66% and 40%), P<0.001. Importantly, the area under the ROC curve for predicting mortality for LM4 was similar than the classic LM7 (0.77 vs. 0.75, respectively: P=0.558).

Conclusions: LM4 is as accurate as LM7 in predicting response to corticosteroids, as well as 28- and 90-day mortality. Assessing the efficacy of prednisolone at an earlier time point can avoid a more prolonged futile use of this therapy.
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http://dx.doi.org/10.1038/ajg.2016.539DOI Listing
February 2017

Addition of n-butyl cyanoacrylate to classic transarterial chemoembolization may improve the radiological response in patients with hepatocellular carcinoma.

Clinics (Sao Paulo) 2015 Dec;70(12):781-9

Divisão de Radiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.

Objective: Transarterial chemoembolization is the treatment of choice for intermediate-stage hepatocellular carcinoma. However, there are no clear data supporting transarterial chemoembolization vs . transarterial embolization or regarding the best chemotherapeutic agent, which may suggest a preponderant role of ischemia over chemotherapeutic action. This study sought to evaluate the radiological response and outcome of transarterial chemoembolization modified by n-butyl cyanoacrylate addition compared to conventional transarterial chemoembolization in hepatocellular carcinoma patients.

Materials And Methods: A retrospective review identified forty-seven patients who underwent modified chemoembolization and thirty-three who underwent conventional chemoembolization between June 2006 and December 2011. The radiological response was reassessed using the modified Response Evaluation Criteria in Solid Tumors. The sustained complete response, time to progression and overall survival rates were also analyzed.

Results: Complete response rates were significantly higher in patients who had undergone modified chemoembolization compared to those who had undergone conventional treatment (61.7% and 24.3%, respectively; p < 0.001). The rate of sustained complete response was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 236 and 37 days, respectively; p < 0.001). Time to progression was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 424 and 201 days, respectively; p = 0.042). Overall survival rates revealed no difference between patients who received modified chemoembolization and conventional chemoembolization (median of 483 and 399 days, respectively; p = 0.316).

Conclusion: Transarterial chemoembolization modified by n-butyl cyanoacrylate addition was superior to conventional transarterial chemoembolization in terms of the radiological response in the first imaging control. Although the sustained complete response and time to progression rates were higher for the modified chemoembolization group, no differences in overall survival rates were observed.
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http://dx.doi.org/10.6061/clinics/2015(12)04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676315PMC
December 2015

Epidemiological study of hepatitis B and C in a municipality with rural characteristics: Cássia dos Coqueiros, State of São Paulo, Brazil.

Rev Soc Bras Med Trop 2015 Nov-Dec;48(6):674-81

Departamento de Medicina Social, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.

Introduction: Hepatitis B and C viral infections remain an important cause of global morbidity and mortality. Studies have been conducted in population groups of large cities, leaving gaps in the knowledge regarding the situation in small municipalities. We aimed to measure the prevalence of hepatitis B and C markers and presence of infection-associated factors.

Methods: All inhabitants of Cássia dos Coqueiros aged ≥18 years who agreed to participate in the research were included. We collected blood as well as information via a questionnaire between March 2011 and December 2013. Univariate and multivariate analyses were conducted.

Results: Among the 1,001 participants, 41 (4.1%) participants had a serological profile of hepatitis B viral exposure, and only one (0.1%) participant was considered a virus carrier. The frequency of isolated antibody to hepatitis B virus surface antigen (anti-HBs) markers was 17.8% for the overall population. In the multivariate analysis, hepatitis B virus (HBV) infection was associated with age, birth outside the State of São Paulo, history of hepatitis, ≥2 sexual partners in the last 6 months, and tattoos. Four (0.4%) participants had a serological profile of hepatitis C viral exposure. However, after confirmation using viral ribonucleic acid (RNA) evaluation, only one (0.1%) individual remained positive.

Conclusions: The positivity rates for hepatitis B and C were low, despite greater sexual freedom and the recent emergence of illicit drugs, as observed by the health personnel working in Cássia dos Coqueiros.
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http://dx.doi.org/10.1590/0037-8682-0222-2015DOI Listing
May 2016

IL-18, TNF, and IFN-γ alleles and genotypes are associated with susceptibility to chronic hepatitis B infection and severity of liver injury.

J Med Virol 2015 Oct 7;87(10):1689-96. Epub 2015 May 7.

Gastroenterology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.

This study evaluated the association of polymorphisms in the IL-18 (-607C/A and -137C/G), IFNγ (+874 A/T), and TNF (-238 A/G and -308 A/G) genes with susceptibility to HBV infection and severity of liver injury. A total of 259 chronic HBV-infected patients followed at the University Hospital, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil, and 202 healthy individuals were studied. Four Single Nucleotide Polymorphisms (SNPs) were amplified by Polymerase Chain Reaction (PCR). Liver biopsy was performed in 212 HBV-infected patients and classified according to severity of liver fibrosis (scores 0-4) and necroinflammatory activity (HAI scores 0-18). TNF-308*A allele (P < 0.001; OR = 2.16) and TNF -308 AA genotype (P = 0.026; OR = 5.43) were associated with susceptibility to HBV infection. An association was found between severe liver fibrosis when compared to mild fibrosis and the following polymorphisms: Alleles IL-18 -137*G (P = 0.004; OR = 3.45), TNF -308*A (P < 0.001; OR = 3.39), and IFNγ +874*T (P = 0.029; OR = 1.85) and IL-18 -137 GG genotype (P = 0.009; OR = 3.70). No significant association was found between IL-18 (-607 A/C) polymorphism and severity of liver fibrosis. Alleles IL-18 -137*G (P = 0.028; OR = 2.64) and TNF-308*A (P = 0.002; OR = 3.06) and IL-18 -137 GG genotype (P = 0.011; OR = 4.20) were associated with severe necroinflammatory activity (HAI>12) when compared to mild necroinflammatory activity (HAI 1-8). The results suggest that IL-18 -137C/G, TNF-308 G/A and IFNγ +874 A/T SNPs were associated to more severe liver injury in chronic HBV infection. TNF -308*A allele and TNF -308 AA genotype could play a role in the susceptibility to HBV infection.
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http://dx.doi.org/10.1002/jmv.24225DOI Listing
October 2015

Risk factors for hepatitis C virus transmission in the municipality of Catanduva, State of São Paulo: a case-control study.

Rev Soc Bras Med Trop 2014 May-Jun;47(3):295-301

Departamento de Medicina Social, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.

Introduction: Hepatitis C virus (HCV) is primarily transmitted via contact with the blood of infected patients, although the form of contact has not been identified for a significant percentage of carriers. The present study evaluated possible risk factors for HCV transmission in a medium-sized town located in the northwest region of the State of São Paulo.

Methods: This was a case-control study, with the case group consisting of 190 chronic HCV carriers older than 18 years residing in the municipality of Catanduva. The control group also consisted of 190 individuals with HCV-negative serology. The groups were paired (1:1) for gender, age range (± five years), and place of residence. The same structured questionnaire was applied to all subjects, who gave written informed consent to participate in the study. The data were statistically analyzed using crude and adjusted logistic regression, and the results were expressed as odds ratios with a 95% confidence interval.

Results: The demographic profiles of the groups indicated a predominance of males (68.9%) and mean ages of 47.1 years (case group) and 47.3 years (control group). After adjusting for conditional regression, the following factors were found to represent risks for HCV: history of sexually transmitted disease (STD) and blood transfusion; accidents with syringes and/or needles; tattoos; and the use of non-injectable drugs and injectable medications.

Conclusions: The transmission of HCV via the blood route has been well characterized. Other forms of contact with human blood and/or secretions are likely to transmit the virus, although with a lower frequency of occurrence.
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http://dx.doi.org/10.1590/0037-8682-0054-2014DOI Listing
October 2014

Methylenetetrahydrofolate reductase gene polymorphism and serum homocysteine levels in nonalcoholic fatty liver disease.

Ann Nutr Metab 2013 19;63(3):193-9. Epub 2013 Sep 19.

Nutrology Division, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

Background/aims: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by hepatic fat accumulation in the absence of alcohol consumption. Hyperhomocysteinemia is considered an independent risk factor for liver diseases, and the genetic polymorphisms C677T and A1298C in the MTHFR gene have been linked to hyperhomocysteinemia. The purpose of this study was to investigate serum homocysteine (Hcy) concentrations and the MTHFR C677T and A1298C polymorphisms as risk factors for the development of NAFLD.

Methods: One hundred and thirty-four Brazilian patients with biopsy-proven NAFLD and 134 healthy controls were recruited. The MTHFR C677T and A1298C polymorphisms were detected through polymerase chain reaction restriction fragment length polymorphism. Serum Hcy levels were determined by chemiluminescence.

Results: Serum Hcy levels were higher in NAFLD patients as compared to control subjects, but there were no differences between patients with steatosis and nonalcoholic steatohepatitis. The NAFLD and control groups did not differ in genotypic and allelic frequencies of the MTHFR C677T and A1298C polymorphisms, either. Elevated plasma Hcy levels were positively correlated with age in the NAFLD subjects.

Conclusion: The MTHFR C677T and A1298C polymorphisms are not genetic risk factors for the development of NAFLD. Higher Hcy levels exist in NAFLD subjects, but they are not associated with liver disease severity.
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http://dx.doi.org/10.1159/000353139DOI Listing
August 2014

Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: a study in Brazilian patients.

Gene 2013 Oct 24;529(2):326-31. Epub 2013 Jul 24.

Clinical Nutrition Division, Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; Department of Pathology and Legal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD.

Methods: One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).

Results: NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP.

Conclusions: We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the progression of NAFLD.
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http://dx.doi.org/10.1016/j.gene.2013.06.091DOI Listing
October 2013

Clinical Characteristics of 130 Patients With Hepatocellular Carcinoma Followed at a Tertiary Hospital From Brazil.

World J Oncol 2012 Aug 26;3(4):165-172. Epub 2012 Aug 26.

Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto-University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.

Background: Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver that represents a serious public health problem all over the world, corresponding to the third cause of cancer death worldwide. The object was to present the clinical characteristics and follow-up of patients with HCC attended at the University Hospital of the Faculty of Medicine of Ribeirao Preto-USP (HCFMRP-USP), Ribeirao Preto, Sao Paulo, Brazil.

Methods: Epidemiological and clinical data were revised from medical records.

Results: A total of 130 patients participated in the study, 81.5% of them being males. Mean (± SD) age at the time of HCC diagnosis was 55.6 ± 11.2 years. Cirrhosis was present in 89.2% of cases, with 53.4% of the patients being Child-Pugh A; chronic hepatitis B or C without cirrhosis was detected in 3.2%, non-alcoholic steatohepatitis (NASH) in 3.8%, and a normal liver in 3.8%. Orthotopic liver transplantation was performed in 26.2% of the subjects, 16.9% of the patients were submitted to surgical resection, and 6.2% to percutaneous ethanol infusion (PEI). Transarterial embolization and transarterial chemoembolization were performed in 9.2% of the patients. Systemic chemotherapy was applied to 4.6% of cases and 24.6% of the patients received symptomatic treatment.

Conclusion: Thus, in the present series cirrhosis was the main risk factor for HCC, with 53.4% of the patients being Child-Pugh A. Liver transplantation or surgical resection of the tumor, potentially curative techniques, were possible in only 43.1% of cases.
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http://dx.doi.org/10.4021/wjon549wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649839PMC
August 2012

Risk factors for hepatitis C virus infection in Inland Brazil: an analysis of pooled epidemiological sectional studies.

J Med Virol 2012 May;84(5):756-62

Faculdade de Medicina, Universidade Federal de Mato Grosso, Cuiabá, Mato Grosso, Brazil.

In order to assess the contribution of different parenteral routes as risk exposure to the hepatitis C virus (HCV), samples from nine surveys or cross-sectional studies conducted in two Brazilian inland regions were pooled, including a total of 3,910 subjects. Heterogeneity among the study results for different risk factors was tested and the results were shown to be homogeneous. Anti-HCV antibodies were observed in 241 individuals, of which 146 (3.7%, 95% CI = 3.2-4.4) had HCV exposure confirmed by immunoblot analysis or PCR test. After adjustment for relevant variables, a correlation between confirmed HCV exposure and injection drug use, tattooing, and advance age was observed. In a second logistic model that included exposures not searched in all nine studies, a smaller sample was analyzed, revealing an independent HCV association with past history of surgery and males who have sex with other males, in addition to repeated injection drug use. Overall, these analyses corroborate the finding that injection drug use is the main risk factor for HCV exposure and spread, in addition to other parenteral routes.
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http://dx.doi.org/10.1002/jmv.23256DOI Listing
May 2012

Upregulation of soluble and membrane-bound human leukocyte antigen G expression is primarily observed in the milder histopathological stages of chronic hepatitis C virus infection.

Hum Immunol 2012 Mar 8;73(3):258-62. Epub 2011 Dec 8.

Department of Clinical Analysis and Toxicology, Federal University of Rio Grande do Norte, Natal, CEP 59012-570, Brazil.

Chronic hepatitis C virus (HCV) infection is a worldwide health problem that may evolve to cirrhosis and hepatocellular carcinoma. Incompletely understood immune system mechanisms have been associated with impaired viral clearance. The nonclassical class I human leukocyte antigen G (HLA-G) molecule may downregulate immune system cell functions exhibiting well-recognized tolerogenic properties. HCV genotype was analyzed in chronic HCV-infected patients. Because HLA-G expression may be induced by certain viruses, we evaluated the presence of HLA-G in the liver microenvironment obtained from 89 biopsies of patients harboring chronic HCV infection and stratified according to clinical and histopathological features. Overall, data indicated that HCV genotype 1 was predominant, especially subgenotype 1a, with a prevalence of 87%. HLA-G expression was observed in 45 (51%) liver specimens, and it was more frequent in milder stages of chronic hepatitis (67.4%) than in moderate (27.8%; p = 0.009) and severe (36.0%; p = 0.021) stages of the disease. Altogether, these results suggest that the expression of HLA-G in the context of HCV is a complex process modulated by many factors, which may contribute to an immunologic environment favoring viral persistence. However, because the milder forms predominantly expressed HLA-G, a protective role of this molecule may not be excluded.
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http://dx.doi.org/10.1016/j.humimm.2011.12.004DOI Listing
March 2012

Clinical, demographic and epidemiological characteristics of patients with hepatitis B followed at a university hospital in southeastern Brazil: predominance of HBeAg negative cases.

Rev Soc Bras Med Trop 2011 Jan-Feb;44(1):13-7

Department of Medicine, Federal University of São Carlos, São Carlos, SP, Brazil.

Introduction: Hepatitis B is common in Brazil, although there are regional differences regarding the degree of endemicity, the most frequent forms of transmission and the presence of different evolutive stages of chronic disease. The present study aimed to determine the clinical, demographic and epidemiological characteristics of patients chronically infected with hepatitis B virus (HBV) residing in the Ribeirão Preto region, southeastern Brazil.

Methods: A total of 529 medical records of individuals with HBV monoinfection were reviewed.

Results: More than 60% of the subjects were males, with a mean age of 38 years-old. The HBeAg-negative serological pattern was verified in 84.4% of the patients, among whom the risk of vertical/intrafamily transmission was 43.2% (p = 0.02). The consumption of alcohol in amounts exceeding 20 g a day was observed in 21.3% of the subjects and was more frequent among men (33%) (p < 0.001). Among patients with cirrhosis, 54.1% were alcohol abusers (p = 0.04), all of them males. The presence of cirrhosis was more frequent in the HBeAg-positive group (24.4%) than in the HBeAg-negative group (10.2%) (p < 0.001).

Conclusions: High proportions of HBV-infected subjects with an HBeAg-negative pattern were observed, with a higher risk of vertical/intrafamily transmission. Alcohol abuse was associated with male subjects and with cirrhosis of the liver in this group. A tendency toward an increase in the number of HBeAg-negative cases was observed over time.
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http://dx.doi.org/10.1590/s0037-86822011000100004DOI Listing
September 2011

Long-term follow-up of patients with chronic hepatitis C with sustained virologic response to interferon.

Braz J Infect Dis 2010 Jul-Aug;14(4):330-4

Department of Medicine, Ribeirão Preto University Hospital, Universidade de São Paulo, SP, Brazil.

Background And Aim: The durability of the sustained virologic response (SVR) in patients with chronic hepatitis C after treatment and the ideal follow-up time for these patients remains undefined. The objective of the study was to evaluate the durability of the virologic response in patients with chronic hepatitis C followed up for at least 12 months after SVR at HCFMRP-USP.

Methods: The study was conducted on 174 patients with chronic hepatitis C treated with different antiviral regimens who had achieved SVR. Qualitative serum HCV-RNA was determined by the commercial kit (COBAS AMPLICOR HCV, v2.0).

Results: There was predominance of male (73%) with a mean age of 45.6 ± 10 years. Liver cirrhosis was present in 16.1% of the study subjects. Mean follow-up time after SVR was 47 months (12-156 months). Twenty-two patients received monotherapy with interferon; 94 received interferon plus ribavirin, and 58 received pegylated interferon plus ribavirin. A total of 134 patients (77.0%) received one treatment course, 29 (16.7%) received two courses, and 11 (6.3%) received three courses. The distribution of HCV genotypes was: genotype 1 (40.2%), genotype 3 (40.8%) and genotype 2 (10.3%). Genotype was undetermined in 8.7% of cases. None of the 174 patients had recurrence of HCV infection. Two cirrhotic patients developed hepatocellular carcinoma (HCC) during follow-up.

Conclusions: Among patients with SVR there was no recurrence of HCV infection or evidence of liver disease progression in any patient followed up for a mean of 47 months after SVR, except for patients with advanced hepatic disease before treatment, who may develop HCC despite SVR. Therefore, one can assume that SVR is associated with long term good prognosis.
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http://dx.doi.org/10.1590/s1413-86702010000400003DOI Listing
March 2011

Hepatitis B virus genotyping among chronic hepatitis B patients with resistance to treatment with lamivudine in the City of Ribeirão Preto, State of São Paulo.

Rev Soc Bras Med Trop 2010 May-Jun;43(3):224-8

Regional Blood Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil.

Introduction: Lamivudine is a nucleoside analogue that is used clinically for treating chronic hepatitis B infection. However, the main problem with prolonged use of lamivudine is the development of viral resistance to the treatment. Mutations in the YMDD motif of the hepatitis B virus DNA polymerase gene have been associated with resistance to drug therapy. So far, there have not been many studies in Brazil reporting on genotype-dependent development of resistance to lamivudine. Thus, the aim of the present study was to determine the possible correlation between a certain genotype and increased development of resistance to lamivudine among chronic hepatitis B patients.

Methods: HBV DNA in samples from 50 patients under lamivudine treatment was amplified by means of conventional PCR. Samples were collected at Hospital das Clínicas, FMRP-USP. The products were then sequenced and phylogenetic analysis was performed.

Results: Phylogenetic analysis revealed that 29 (58%) patients were infected with genotype D, 20 (40%) with genotype A and one (2%) with genotype F. Mutations in the YMDD motif occurred in 20% of the patients with genotype A and 27.6% of the patients with genotype D.

Conclusions: Despite the small number of samples, our results indicated that mutations in the YMDD motif were 1.38 times more frequent in genotype D than in genotype A.
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http://dx.doi.org/10.1590/s0037-86822010000300002DOI Listing
January 2011

Hepatitis C among former athletes: association with the use of injectable stimulants in the past.

Mem Inst Oswaldo Cruz 2008 Dec;103(8):809-12

Departamento de Medicina Social, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.

This study was performed with the purpose of testing the hypothesis that the high prevalence of hepatitis C among former athletes is associated with their past use of injectable stimulants. The study involved the participation of 208 former professional and amateur soccer and basketball players from the region of Ribeirão Preto, Brazil, who answered a questionnaire regarding their exposure to risk factors, including the use of injectable stimulants in the time they were engaged in sporting activities. ELISA tests were used to detect infection by the hepatitis C virus, and confirmed with PCR and genotyping for the positive cases. It was observed that the former use of injectable stimulants was a practice disseminated among the participants (24.5%), reaching 50.8% in the professionals. The overall prevalence for hepatitis C was 7.2%, with values of 11% among professionals and 5.5% among amateurs. In both categories, the presence of infection was markedly higher among those who admitted past use of injectable stimulants when compared to those who denied such practice (36% and 0.8% among amateurs; 21.9% and 0% among professionals, respectively). Multivariate analysis showed that the use of those substances was the only variable associated with the risk of hepatitis C. This confirms previous observations, performed with reduced sample sizes and without comparison groups, which indicated that the use of injectable vitamins was a risk factor of hepatitis C among former athletes.
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http://dx.doi.org/10.1590/s0074-02762008000800011DOI Listing
December 2008

HCV virological response during treatment of chronic hepatitis C is associated with liver histological improvement in patients with HCV/HIV co-infection.

Braz J Infect Dis 2008 Jun;12(3):180-5

Department of Internal Medicine, Division of Tropical and Infectious Diseases, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

Liver histological improvement after treatment for chronic hepatitis C in patients co-infected with human immunodeficiency virus-1 (HIV-1) has been described. Paired liver biopsies in twenty six HCV/HIV co-infected patients were compared to determine factors possibly associated with histological improvement. The patients were submitted to a liver biopsy before treatment for hepatitis C and 25 months after the end of treatment. Fragments of the liver biopsy obtained before and after treatment were compared regarding the following parameters: histological activity index (HAI) and degree of fibrosis (Knodell); intensity of collagen deposits (Sirius Red staining) and degree of stellate cell activation (alpha-smooth muscle actin labeling). The ratios of the post and pre-treatment variables were related through logistic regression to body mass index (BMI), alcohol ingestion, HCV genotype, HCV viremia, presence of hepatic iron and pre-treatment hepatic steatosis. A negative RNA test in the 24th week of treatment was associated with improvement in fibrosis, collagen deposits and stellate cell numbers. The other variables analyzed did not correlate to an improvement in hepatic histology after hepatitis C treatment. Reduction in HCV viremia during treatment may result in reduced hepatic fibrosis even in patients without a sustained virological response.
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http://dx.doi.org/10.1590/s1413-86702008000300004DOI Listing
June 2008