Clinical and histological impact of occult hepatitis B infection in hepatitis C virus chronic carriers

Introdução: Define-se como infecção oculta pelo vírus da hepatite B (HBV) a detecção de HBV-DNA no soro ou tecido hepático de pacientes com HBsAg negativo. Estudos sugerem que portadores do vírus da hepatite C (HCV) com esta infecção exibem fibrose hepática mais extensa, pior resposta ao tratamento com interferon alfa e maior risco de desenvolvimento de hepatocarcinoma. Achados similares foram descritos em portadores de HCV com marcadores de infecção prévia pelo HBV (anti-HBc positivo, com ou sem anti-HBs), independentemente da detecção de HBV-DNA. Entretanto, tais estudos não exerceram controle adequado para variáveis associadas à progressão da fibrose na hepatite C, como tempo de infecção, etilismo e idade no momento da infecção. Objetivos: Determinar a prevalência e o impacto da infecção oculta e da infecção prévia pelo HBV nas características clínicas, bioquímicas, virológicas e histológicas de portadores de infecção crônica pelo HCV. Material e Métodos: Estudo caso-controle que avaliou pacientes não-etilistas com HBsAg e anti-HIV negativos e HCV-RNA positivo. Todos os casos possuíam exposição parenteral como provável modo de contaminação pelo HCV (antecedentes transfusionais ou drogadição). Amostras séricas coletadas em intervalo de até 6 meses da biópsia hepática foram submetidas à pesquisa de HBV-DNA por ensaio comercial baseado em PCR, com limite de detecção de 103 cópias/mL (Amplicor HBV MONITOR® Test, Roche). A classificação de METAVIR foi usada para análise histológica. Resultados: Cento e onze pacientes foram incluídos, sendo 46% do gênero masculino e 82% com transfusão prévia. As médias da idade na infecção e do tempo de infecção pelo HCV foram de 25,5+12,4 e 21,9+6,5 anos, respectivamente. O anti-HBc foi positivo em 31 indivíduos (28%) e nenhuma amostra foi positiva para o HBV-DNA. Pacientes com antiHBc positivo foram comparáveis aos com anti-HBc negativo com relação ao gênero, idade na infecção pelo HCV, tempo de infecção, raça, modo de aquisição do HCV e prevalência de descompensação hepática. A distribuição de genótipos do HCV foi semelhante entre os dois grupos. Entretanto, indivíduos com anti-HBc positivo mostraram níveis mais baixos de albumina (P = 0,001) e menor atividade de protrombina (P = 0,046) e maiores níveis de ALT (P = 0,052), AST (P = 0,004) e GGT (P = 0,010). Estes pacientes também demonstraram maior atividade histológica (P < 0,001), maior escore de fibrose hepática (P = 0,001) e taxa de progressão de fibrose (TPF) mais rápida (P = 0.002) do que aqueles com anti-HBc negativo. Na análise multivariada, ALT > 2 vezes o limite superior do normal (xLSN) (OR = 4,460; P = 0,002), GGT > 1,5 xLSN (OR = 7,582; P < 0,001) e anti-HBc positivo (OR = 4,009; P = 0,019) foram preditivos de atividade necroinflamatória moderada ou acentuada (A2/A3). A positividade do anti-HBc (OR = 3,364; P = 0,017) e a aquisição do HCV após 30 anos de idade (OR = 4,252; P = 0,002) foram independentemente associados à fibrose significativa (F2/F3/F4). Os fatores associados à rápida progressão da fibrose, definida como TPF > 0,133 unidade de fibrose/ano, foram idade na infecção > 30 anos (OR = 2,913; P = 0,033) e anti-HBc positivo (OR = 3,241; P = 0,015). O tempo esperado até o surgimento de cirrose hepática foi de 26 anos (20 a 44 anos) para indivíduos anti-HBcpositivo que se infectaram com o HCV com idade > 30 anos. Aqueles com anti-HBc negativo contaminados com menos de 30 anos de idade desenvolveriam cirrose após 80 anos de infecção (60 a 93 anos) (P < 0,001). Conclusões: A infecção prévia pelo HBV é encontrada em cerca de um terço dos portadores do HCV e pode exercer impacto negativo sobre a história natural da infecção crônica pelo HCV. Este efeito parece independer da presença da infecção oculta pelo HBV.Background: Occult hepatitis B virus (HBV) infection is defined by the presence of HBV-DNA by PCR in serum or liver tissue samples from HBsAg-negative individuals. Recent reports suggest that hepatitis C virus (HCV) carriers who also harbor this silent infection have more advanced liver fibrosis, reduced response to interferon, and increased risk of developing hepatocellular carcinoma. Similar findings have been described among chronic hepatitis C patients with serological markers of prior HBV infection (anti-HBc positive, with or without anti-HBs), irrespective of HBV-DNA detection. However, these studies have failed to appropriately control for factors known to impact HCV-related fibrogenesis including duration of infection, alcohol abuse, and age at infection. Aims: To assess the prevalence and impact of occult and previous HBV infection on clinical, biochemical, virological and histological features in patients with chronic hepatitis C from a liver clinic cohort. Methods: This case-control study included non-alcoholic subjects whose sera tested negative for HBsAg and anti-HIV, and positive for HCV-RNA. All patients had prior parenteral exposure as the probable source of HCV infection (blood transfusions or IV drug use). Serum samples were collected within 6 months of liver biopsy and were tested for HBV-DNA using a commercial PCR assay with sensitivity of 103 copies/mL (Amplicor HBV MONITOR® Test, Roche). METAVIR scoring system was applied for grading necroinflammatory activity and staging fibrosis. Results: One hundred and eleven patients were evaluated. Forty six percent were male and 82% reported past transfusion of blood derivates. The mean age at infection and the estimated duration of infection were 25.5 + 12.4 and 21.9 + 6.5 years, respectively. Thirty-one out of 111 patients (28%) tested positive for antiHBc. HBV-DNA was not detected in any sample. There were no differences between anti-HBc-positive and -negative patients concerning gender, age at infection, estimated duration of infection, ethnicity, source of HCV infection, and prevalence of hepatic decompensation. In addition, HCV genotyping distribution were not influenced by antiHBc status. However, anti-HBc-positive patients showed lower albumin levels (P = 0.001), lower prothrombin activity (P = 0.046) and higher levels of ALT (P = 0.052), AST (P = 0.004), and GGT (P = 0.010). These patients also showed higher histological grading (P < 0.001) and staging scores (P = 0.001), and higher rate of fibrosis progression (RFP) (P = 0.002) as compared to those who tested negative for anti-HBc. By multivariate analysis, ALT > 2x upper limit of normal (ULN) (OR = 4.460; P = 0.002), GGT > 1.5x ULN (OR = 7.582; P < 0.001) and anti-HBc-positivity (OR = 4.009; P = 0.019) were predictive of moderate to severe necroinflammatory activity (A2/A3). AntiHBc-positivity (OR = 3.364; P = 0.017) and age at infection > 30 years (OR = 4.252; P = 0.002) were independently associated with significantly hepatic fibrosis (F2/F3/F4). Likewise, independent predictors of rapid fibrosis progression, defined as a RFP > 0,133 fibrosis unit/year, were age at infection > 30 years (OR = 2.913; P = 0.033) and anti-HBc-positivity (OR = 3.241; P = 0.015). The median duration from HCV infection to cirrhosis was 26 years (20 to 44) in anti-HBc-positive patients who were infected with HCV when older than 30 years. On the other hand, among anti-HBc-negative subjects who acquired HCV before the age of 30, the expected time to cirrhosis was 80 years (60 to 93) (P < 0,001). Conclusions: Previous HBV infection is common among HCVinfected individuals and may exert a negative impact on the natural history of hepatitis C virus infection. This effect seems to be independent of the presence of occult HBV infection.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP: 2002/05260-6BV UNIFESP: Teses e dissertaçõe

Clinical and histological impact of occult hepatitis B infection in hepatitis C virus chronic carriers

Introdução: Define-se como infecção oculta pelo vírus da hepatite B (HBV) a detecção de HBV-DNA no soro ou tecido hepático de pacientes com HBsAg negativo. Estudos sugerem que portadores do vírus da hepatite C (HCV) com esta infecção exibem fibrose hepática mais extensa, pior resposta ao tratamento com interferon alfa e maior risco de desenvolvimento de hepatocarcinoma. Achados similares foram descritos em portadores de HCV com marcadores de infecção prévia pelo HBV (anti-HBc positivo, com ou sem anti-HBs), independentemente da detecção de HBV-DNA. Entretanto, tais estudos não exerceram controle adequado para variáveis associadas à progressão da fibrose na hepatite C, como tempo de infecção, etilismo e idade no momento da infecção. Objetivos: Determinar a prevalência e o impacto da infecção oculta e da infecção prévia pelo HBV nas características clínicas, bioquímicas, virológicas e histológicas de portadores de infecção crônica pelo HCV. Material e Métodos: Estudo caso-controle que avaliou pacientes não-etilistas com HBsAg e anti-HIV negativos e HCV-RNA positivo. Todos os casos possuíam exposição parenteral como provável modo de contaminação pelo HCV (antecedentes transfusionais ou drogadição). Amostras séricas coletadas em intervalo de até 6 meses da biópsia hepática foram submetidas à pesquisa de HBV-DNA por ensaio comercial baseado em PCR, com limite de detecção de 103 cópias/mL (Amplicor HBV MONITOR® Test, Roche). A classificação de METAVIR foi usada para análise histológica. Resultados: Cento e onze pacientes foram incluídos, sendo 46% do gênero masculino e 82% com transfusão prévia. As médias da idade na infecção e do tempo de infecção pelo HCV foram de 25,5+12,4 e 21,9+6,5 anos, respectivamente. O anti-HBc foi positivo em 31 indivíduos (28%) e nenhuma amostra foi positiva para o HBV-DNA. Pacientes com antiHBc positivo foram comparáveis aos com anti-HBc negativo com relação ao gênero, idade na infecção pelo HCV, tempo de infecção, raça, modo de aquisição do HCV e prevalência de descompensação hepática. A distribuição de genótipos do HCV foi semelhante entre os dois grupos. Entretanto, indivíduos com anti-HBc positivo mostraram níveis mais baixos de albumina (P = 0,001) e menor atividade de protrombina (P = 0,046) e maiores níveis de ALT (P = 0,052), AST (P = 0,004) e GGT (P = 0,010). Estes pacientes também demonstraram maior atividade histológica (P < 0,001), maior escore de fibrose hepática (P = 0,001) e taxa de progressão de fibrose (TPF) mais rápida (P = 0.002) do que aqueles com anti-HBc negativo. Na análise multivariada, ALT > 2 vezes o limite superior do normal (xLSN) (OR = 4,460; P = 0,002), GGT > 1,5 xLSN (OR = 7,582; P < 0,001) e anti-HBc positivo (OR = 4,009; P = 0,019) foram preditivos de atividade necroinflamatória moderada ou acentuada (A2/A3). A positividade do anti-HBc (OR = 3,364; P = 0,017) e a aquisição do HCV após 30 anos de idade (OR = 4,252; P = 0,002) foram independentemente associados à fibrose significativa (F2/F3/F4). Os fatores associados à rápida progressão da fibrose, definida como TPF > 0,133 unidade de fibrose/ano, foram idade na infecção > 30 anos (OR = 2,913; P = 0,033) e anti-HBc positivo (OR = 3,241; P = 0,015). O tempo esperado até o surgimento de cirrose hepática foi de 26 anos (20 a 44 anos) para indivíduos anti-HBcpositivo que se infectaram com o HCV com idade > 30 anos. Aqueles com anti-HBc negativo contaminados com menos de 30 anos de idade desenvolveriam cirrose após 80 anos de infecção (60 a 93 anos) (P < 0,001). Conclusões: A infecção prévia pelo HBV é encontrada em cerca de um terço dos portadores do HCV e pode exercer impacto negativo sobre a história natural da infecção crônica pelo HCV. Este efeito parece independer da presença da infecção oculta pelo HBV.Background: Occult hepatitis B virus (HBV) infection is defined by the presence of HBV-DNA by PCR in serum or liver tissue samples from HBsAg-negative individuals. Recent reports suggest that hepatitis C virus (HCV) carriers who also harbor this silent infection have more advanced liver fibrosis, reduced response to interferon, and increased risk of developing hepatocellular carcinoma. Similar findings have been described among chronic hepatitis C patients with serological markers of prior HBV infection (anti-HBc positive, with or without anti-HBs), irrespective of HBV-DNA detection. However, these studies have failed to appropriately control for factors known to impact HCV-related fibrogenesis including duration of infection, alcohol abuse, and age at infection. Aims: To assess the prevalence and impact of occult and previous HBV infection on clinical, biochemical, virological and histological features in patients with chronic hepatitis C from a liver clinic cohort. Methods: This case-control study included non-alcoholic subjects whose sera tested negative for HBsAg and anti-HIV, and positive for HCV-RNA. All patients had prior parenteral exposure as the probable source of HCV infection (blood transfusions or IV drug use). Serum samples were collected within 6 months of liver biopsy and were tested for HBV-DNA using a commercial PCR assay with sensitivity of 103 copies/mL (Amplicor HBV MONITOR® Test, Roche). METAVIR scoring system was applied for grading necroinflammatory activity and staging fibrosis. Results: One hundred and eleven patients were evaluated. Forty six percent were male and 82% reported past transfusion of blood derivates. The mean age at infection and the estimated duration of infection were 25.5 + 12.4 and 21.9 + 6.5 years, respectively. Thirty-one out of 111 patients (28%) tested positive for antiHBc. HBV-DNA was not detected in any sample. There were no differences between anti-HBc-positive and -negative patients concerning gender, age at infection, estimated duration of infection, ethnicity, source of HCV infection, and prevalence of hepatic decompensation. In addition, HCV genotyping distribution were not influenced by antiHBc status. However, anti-HBc-positive patients showed lower albumin levels (P = 0.001), lower prothrombin activity (P = 0.046) and higher levels of ALT (P = 0.052), AST (P = 0.004), and GGT (P = 0.010). These patients also showed higher histological grading (P < 0.001) and staging scores (P = 0.001), and higher rate of fibrosis progression (RFP) (P = 0.002) as compared to those who tested negative for anti-HBc. By multivariate analysis, ALT > 2x upper limit of normal (ULN) (OR = 4.460; P = 0.002), GGT > 1.5x ULN (OR = 7.582; P < 0.001) and anti-HBc-positivity (OR = 4.009; P = 0.019) were predictive of moderate to severe necroinflammatory activity (A2/A3). AntiHBc-positivity (OR = 3.364; P = 0.017) and age at infection > 30 years (OR = 4.252; P = 0.002) were independently associated with significantly hepatic fibrosis (F2/F3/F4). Likewise, independent predictors of rapid fibrosis progression, defined as a RFP > 0,133 fibrosis unit/year, were age at infection > 30 years (OR = 2.913; P = 0.033) and anti-HBc-positivity (OR = 3.241; P = 0.015). The median duration from HCV infection to cirrhosis was 26 years (20 to 44) in anti-HBc-positive patients who were infected with HCV when older than 30 years. On the other hand, among anti-HBc-negative subjects who acquired HCV before the age of 30, the expected time to cirrhosis was 80 years (60 to 93) (P < 0,001). Conclusions: Previous HBV infection is common among HCVinfected individuals and may exert a negative impact on the natural history of hepatitis C virus infection. This effect seems to be independent of the presence of occult HBV infection

Management of hepatitis C in patients with chronic kidney disease

Hepatitis C virus (HCV) infection is highly prevalent among chronic kidney disease (CKD) subjects under hemodialysis and in kidney transplantation (KT) recipients, being an important cause of morbidity and mortality in these patients. the vast majority of HCV chronic infections in the hemodialysis setting are currently attributable to nosocomial transmission. Acute and chronic hepatitis C exhibits distinct clinical and laboratorial features, which can impact on management and treatment decisions. in hemodialysis subjects, acute infections are usually asymptomatic and anicteric; since spontaneous viral clearance is very uncommon in this context, acute infections should be treated as soon as possible. in KT recipients, the occurrence of acute hepatitis C can have a more severe course, with a rapid progression of liver fibrosis. in these patients, it is recommended to use pegylated interferon (PEG-IFN) in combination with ribavirin, with doses adjusted according to estimated glomerular filtration rate. There is no evidence suggesting that chronic hepatitis C exhibits a more aggressive course in CKD subjects under conservative management. in these subjects, indication of treatment with PEG-IFN plus ribavirin relies on the CKD stage, rate of progression of renal dysfunction and the possibility of a preemptive transplant. HCV infection has been associated with both liver disease-related deaths and cardiovascular mortality in hemodialysis patients. Among those individuals, low HCV viral loads and the phenomenon of intermittent HCV viremia are often observed, and sequential HCV RNA monitoring is needed. Despite the poor tolerability and suboptimal efficacy of antiviral therapy in CKD patients, many patients can achieve sustained virological response, which improve patient and graft outcomes. Hepatitis C eradication before KT theoretically improves survival and reduces the occurrence of chronic graft nephropathy, de novo glomerulonephritis and post-transplant diabetes mellitus.Universidade Federal de São Paulo, Div Gastroenterol, Hepatol Sect, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Div Gastroenterol, Hepatol Sect, BR-04023900 São Paulo, BrazilWeb of Scienc

Acute pancreatitis associated with boceprevir: a case report

Approximately 170 million people are infected with hepatitis C, and the sustained virological response rate to treatment with pegylated interferon and ribavirin is 30-50%. In an attempt to improve the chances of cure, boceprevir is being added to therapy, but it is associated with an increased incidence of adverse events. We herein report a case of acute pancreatitis developed during treatment with pegylated interferon, ribavirin and boceprevir. Boceprevir was the most likely cause of drug-associated pancreatitis after the most common causes were ruled out, since this adverse event had not occurred when the patient had previously been exposed to pegylated interferon and ribavirin and there was no recurrence of the episode of pancreatitis when these two drugs were reintroduced. Acute pancreatitis is a rare adverse event associated with boceprevir therapy, but a potentially fatal event. Sequential determination of pancreatic enzymes should be considered during hepatitis C treatment with boceprevir

Expanding the applicability of noninvasive fibrosis markers in HIV/HCV co-infected patients

Universidade Federal de São Paulo, Div Gastroenterol, Hepatitis Sect, São Paulo, BrazilUniversidade Federal de São Paulo, Div Gastroenterol, Hepatitis Sect, São Paulo, BrazilWeb of Scienc

Influência do gênero no tratamento da hepatite C crônica genótipo 1

INTRODUCTION: Although various studies have been published regarding the treatment of chronic hepatitis C (CHC) with peginterferon (Peg-IFN) and ribavirin, little is known regarding the real impact of gender on the characteristics that influence the effectiveness and safety of antiviral treatment for CHC patients. The objective of this study was to evaluate the influence of gender on HCV treatment outcomes. METHODS: A retrospective analytical study was conducted among selected carriers of CHC genotype 1, who were treated with Peg-IFN α-2b at a dose of 1.5 μg/kg or Peg-IFN α-2a at a dose of 180 μg/week plus a ribavirin dose of 1,000-1,250 mg/day, according to weight, between 2001 and 2007. RESULTS: Among 181 patients undergoing treatment, the mean age was 46.4 ± 11.0 years and 46% were women. At baseline, 32% of the patients had advanced fibrosis (F3-F4 Scheuer), and 83% of the subjects had viral load > 400,000 IU/ml, without significant difference between the genders (p = 0.428 and p = 0.452, respectively). When compared with men, women had higher incidence of many adverse events such as anemia (p < 0.001) and higher need for dose reduction, for both Peg-IFN (p = 0.004) and ribavirin (p = 0.006). However, the rate of sustained virological response (SVR) did not differ between the genders: 45% (female) vs 41% (male); p=0.464. CONCLUSIONS: This study suggests that women and men react differently to combined therapy, especially in relation to the incidence of adverse events and the need for dose modification. Nevertheless, these differences do not influence the SVR rate.INTRODUÇÃO: Apesar dos vários estudos publicados a respeito do tratamento da hepatite C crônica (CHC) com Peg-Interferon (Peg-IFN) e ribavirina, se desconhece o real impacto do gênero sobre as características que influenciam a eficácia e a segurança da terapia antiviral em portadores de CHC. O objetivo deste estudo foi avaliar a influência do gênero no tratamento da CHC. MÉTODOS: Foi realizado um estudo analítico retrospectivo de portadores de CHC genótipo 1 tratados com Peg-IFN α-2b na dose de 1,5μg/kg ou Peg-IFN α-2a na dose de180μg/sem associado à ribavirina 1.000-1.250 mg/dia, de acordo com o peso, entre 2001 e 2007. RESULTADOS: Entre 181 pacientes submetidos ao tratamento, a média de idade foi de 46,4±11,0 anos e 46% eram mulheres. No pré-tratamento, 32% dos pacientes apresentavam fibrose avançada (F3-F4 Scheuer), e 83% dos indivíduos apresentavam carga viral >400.000IU/mL, sem diferença significativa entre os gêneros (p=0,428 e p=0,452, respectivamente). Quando comparadas aos homens, as mulheres exibiram maior incidência de eventos adversos como anemia (p<0,001) e maior necessidade de redução de dose tanto do Peg-IFN (p=0,004) quanto da ribavirina (p=0,006). Entretanto, as taxas de resposta virológica sustentada (RVS) não diferiram entre os gêneros (45% (mulheres) . vs 41% (homens); p=0,464). CONCLUSÕES: Este estudo sugere que homens e mulheres reagem à terapia combinada de forma diferente, especialmente com relação aos eventos adversos e à necessidade de modificação de dose. No entanto, essas diferenças não influenciam as taxas de RVS