Effectiveness of first-wave protease inhibitors in hepatitis C virus genotype 1 infection: a multicenter study in Brazil.

INTRODUCTION: In 2013, combination therapy using peginterferon, ribavirin, and boceprevir or telaprevir was introduced to treat hepatitis C virus genotype 1 infection in Brazil. The effectiveness of this therapy in four Brazilian regions was evaluated. METHODS: Clinical and virological data were obtained from patients of public health institutions in five cities, including sustained virological response (SVR) and side effects. Patients with advanced fibrosis (F3/4), moderate fibrosis (F2) for > 3 years, or extra-hepatic manifestations were treated according to Ministry of Health protocol. Treatment effectiveness was verified by using bivariate and multivariate analysis; p-values of < 0.05 were considered significant. RESULTS: Of 275 patients (64.7% men; average age, 57 years old), most (61.8%) were treatment-experienced; 53.9% had subgenotype 1a infection, 85.1% had advanced fibrosis, and 85.5% were treated with telaprevir. SVR was observed in 54.2%. Rapid virological response (RVR) was observed in 54.6% of patients (data available for 251 patients). Overall, 87.5% reported side effects and 42.5% did not complete treatment. Skin rash, severe infection, and death occurred in 17.8%, 2.5%, and death in 1.4% of cases, respectively. SVR was associated with treatment completion, RVR, and anemia. CONCLUSIONS: The effectiveness of hepatitis C virus triple therapy was lower than that reported in phase III clinical trials, possibly owing to the prioritized treatment of patients with advanced liver fibrosis. The high frequency of side effects and treatment interruptions observed supported the decision of the Brazilian authorities to suspend its use when safer and more effective drugs became available in 2015.

Effectiveness of first-wave protease inhibitors in hepatitis C virus genotype 1 infection: a multicenter study in Brazil

Abstract INTRODUCTION: In 2013, combination therapy using peginterferon, ribavirin, and boceprevir or telaprevir was introduced to treat hepatitis C virus genotype 1 infection in Brazil. The effectiveness of this therapy in four Brazilian regions was evaluated. METHODS: Clinical and virological data were obtained from patients of public health institutions in five cities, including sustained virological response (SVR) and side effects. Patients with advanced fibrosis (F3/4), moderate fibrosis (F2) for > 3 years, or extra-hepatic manifestations were treated according to Ministry of Health protocol. Treatment effectiveness was verified by using bivariate and multivariate analysis; p-values of < 0.05 were considered significant. RESULTS: Of 275 patients (64.7% men; average age, 57 years old), most (61.8%) were treatment-experienced; 53.9% had subgenotype 1a infection, 85.1% had advanced fibrosis, and 85.5% were treated with telaprevir. SVR was observed in 54.2%. Rapid virological response (RVR) was observed in 54.6% of patients (data available for 251 patients). Overall, 87.5% reported side effects and 42.5% did not complete treatment. Skin rash, severe infection, and death occurred in 17.8%, 2.5%, and death in 1.4% of cases, respectively. SVR was associated with treatment completion, RVR, and anemia. CONCLUSIONS: The effectiveness of hepatitis C virus triple therapy was lower than that reported in phase III clinical trials, possibly owing to the prioritized treatment of patients with advanced liver fibrosis. The high frequency of side effects and treatment interruptions observed supported the decision of the Brazilian authorities to suspend its use when safer and more effective drugs became available in 2015.

Socioeconomic disparities in access to a hepatocellular carcinoma screening program in Brazil.

OBJECTIVES: Cirrhotic patients must receive an abdominal ultrasound every 6 months as part of hepatocellular carcinoma (HCC) screening. The aim of this study was to assess if HCC screening was performed as recommended by the literature and to observe the differences between the private and public services in Brazil. METHODS: We analyzed data from the HCC screenings of 253 cirrhotic patients from the University Hospital (n=177) and private sector (n=76) in Vitória, ES, Brazil. RESULTS: Ultrasound screening was performed every 13.1 months on average (SD 9.02). In 37 out of 253 patients, the screenings were performed close to the recommended frequency; 16 were performed every 6 months, and 21 were mostly performed during the follow-up period every 6 months. In the remaining 216 cases, ultrasounds were not performed according to the guidelines; for 106 patients, less than 50% of all ultrasounds were performed every 6 months and 110 patients showed an interval greater than one year. Patients from the private sector received ultrasound screenings near the ideal in 28.9% of cases, while patients from the University Hospital received ultrasounds in only 8.4% of cases (p<0.0001). HCC was diagnosed in 30 patients (11.8%). For these 30 patients, 11 screenings were properly performed within 6 months (36.6%) and only 1 out of the 11 (9%) met the criteria for transplant. In the remaining 19 patients who did not receive the screening within 6 months, 6 (31.5%) did not meet the criteria for transplant. CONCLUSION: HCC screening in our environment was irregularly performed, mainly in the public service setting, which prevented early diagnosis in a large number of patients.

Socioeconomic disparities in access to a hepatocellular carcinoma screening program in Brazil

OBJECTIVES: Cirrhotic patients must receive an abdominal ultrasound every 6 months as part of hepatocellular carcinoma (HCC) screening. The aim of this study was to assess if HCC screening was performed as recommended by the literature and to observe the differences between the private and public services in Brazil. METHODS: We analyzed data from the HCC screenings of 253 cirrhotic patients from the University Hospital (n=177) and private sector (n=76) in Vitória, ES, Brazil. RESULTS: Ultrasound screening was performed every 13.1 months on average (SD 9.02). In 37 out of 253 patients, the screenings were performed close to the recommended frequency; 16 were performed every 6 months, and 21 were mostly performed during the follow-up period every 6 months. In the remaining 216 cases, ultrasounds were not performed according to the guidelines; for 106 patients, less than 50% of all ultrasounds were performed every 6 months and 110 patients showed an interval greater than one year. Patients from the private sector received ultrasound screenings near the ideal in 28.9% of cases, while patients from the University Hospital received ultrasounds in only 8.4% of cases (p<0.0001). HCC was diagnosed in 30 patients (11.8%). For these 30 patients, 11 screenings were properly performed within 6 months (36.6%) and only 1 out of the 11 (9%) met the criteria for transplant. In the remaining 19 patients who did not receive the screening within 6 months, 6 (31.5%) did not meet the criteria for transplant. CONCLUSION: HCC screening in our environment was irregularly performed, mainly in the public service setting, which prevented early diagnosis in a large number of patients.

Hepatitis virus and hepatocellular carcinoma in Brazil: a report from the State of Espírito Santo.

INTRODUCTION: Few studies have examined hepatocellular carcinoma (HCC) in Brazil, and the incidence and risk factors for this type of malignancy vary greatly geographically. In this paper, we report several risk factors associated with HCC diagnosed at the University Hospital in Vitória, ES, Brazil. METHODS: We reviewed 274 cases of HCC (January 1993 to December 2011) in which hepatitis B (HBV) and C (HCV) virus infection and chronic alcoholism were investigated. A diagnosis of hepatocellular carcinoma was confirmed by histology or by the presence of a characteristic pattern on imaging. RESULTS: HCC with associated liver cirrhosis was noted in 85.4% of cases. The mean ages of men and women were 56.6 years and 57.5 years, respectively. The male-to-female ratio was 5.8:1. Associated risk factors included the following: HBV, 37.6% (alone, 23.4%; associated with chronic alcoholism, 14.2%); HCV, 22.6% (alone, 13.5%; associated with chronic alcoholism, 9.1%), chronic alcoholism, 17.1%, non-alcoholic steatohepatitis, 2.6% and cryptogenic, 19.3%. The male-to-female ratio was higher in cases associated with HBV or chronic alcoholism compared with HCV-associated or cryptogenic cases. In 40 cases without associated cirrhosis, the male-to-female ratio and mean age were lower than those in cirrhosis-associated cases. CONCLUSIONS: These results demonstrate that the main risk factor associated with HCC in the State of Espírito Santo is HBV. Chronic alcoholism is an important etiological factor, alone or in association with HBV or HCV infection.

Hepatitis virus and hepatocellular carcinoma in Brazil: a report from the State of Espírito Santo

Introduction Few studies have examined hepatocellular carcinoma (HCC) in Brazil, and the incidence and risk factors for this type of malignancy vary greatly geographically. In this paper, we report several risk factors associated with HCC diagnosed at the University Hospital in Vitória, ES, Brazil. Methods We reviewed 274 cases of HCC (January 1993 to December 2011) in which hepatitis B (HBV) and C (HCV) virus infection and chronic alcoholism were investigated. A diagnosis of hepatocellular carcinoma was confirmed by histology or by the presence of a characteristic pattern on imaging. Results HCC with associated liver cirrhosis was noted in 85.4% of cases. The mean ages of men and women were 56.6 years and 57.5 years, respectively. The male-to-female ratio was 5.8:1. Associated risk factors included the following: HBV, 37.6% (alone, 23.4%; associated with chronic alcoholism, 14.2%); HCV, 22.6% (alone, 13.5%; associated with chronic alcoholism, 9.1%), chronic alcoholism, 17.1%, non-alcoholic steatohepatitis, 2.6% and cryptogenic, 19.3%. The male-to-female ratio was higher in cases associated with HBV or chronic alcoholism compared with HCV-associated or cryptogenic cases. In 40 cases without associated cirrhosis, the male-to-female ratio and mean age were lower than those in cirrhosis-associated cases. Conclusions These results demonstrate that the main risk factor associated with HCC in the State of Espírito Santo is HBV. Chronic alcoholism is an important etiological factor, alone or in association with HBV or HCV infection. .

Mortality from liver cirrhosis in Espírito Santo State, Brazil.

To study mortality from liver cirrhosis in Espírito Santo State, Brazil, we reviewed death certificates (DC) from 2000-2010 and medical records of deceased patients with investigation of alcoholism and hepatitis B or C. From a total of 218,410 DC, 3,554 deaths from liver cirrhosis were retrieved. The annual mortality rate was 19.8/100,000 for men and 4.31/100,000 for women, without significant changes after correction for ICD-R98 and R99 and without a significant increase in the annual percentage change. In 49% of death certificates, the aetiology of cirrhosis was defined: of these alcoholism in 81.5% of cases and viral hepatitis in 15.7%. Aetiology was confirmed in 262 reviewed records, including alcoholism (40.5%); hepatitis B or C (26.7%); other (3.8%); and cryptogenic (10.6%). The mean annual potential years of life lost were 5,946 years and 1,739 years for men and women respectively. The mortality rate from cirrhosis in Espírito Santo State is intermediate in relationship to worldwide data; alcoholism and hepatitis B or C were the main aetiologies; probably alcoholism is overestimated and hepatitis B and C viruses are underestimated as causes of cirrhosis registered on death certificates.

Mortality from liver cirrhosis in Espírito Santo State, Brazil / Mortalidade por cirrose hepática no Estado do Espírito Santo, Brasil / La mortalidad por cirrosis hepática en estado de Espírito Santo, Brasil

To study mortality from liver cirrhosis in Espírito Santo State, Brazil, we reviewed death certificates (DC) from 2000-2010 and medical records of deceased patients with investigation of alcoholism and hepatitis B or C. From a total of 218,410 DC, 3,554 deaths from liver cirrhosis were retrieved. The annual mortality rate was 19.8/100,000 for men and 4.31/100,000 for women, without significant changes after correction for ICD-R98 and R99 and without a significant increase in the annual percentage change. In 49% of death certificates, the aetiology of cirrhosis was defined: of these alcoholism in 81.5% of cases and viral hepatitis in 15.7%. Aetiology was confirmed in 262 reviewed records, including alcoholism (40.5%); hepatitis B or C (26.7%); other (3.8%); and cryptogenic (10.6%). The mean annual potential years of life lost were 5,946 years and 1,739 years for men and women respectively. The mortality rate from cirrhosis in Espírito Santo State is intermediate in relationship to worldwide data; alcoholism and hepatitis B or C were the main aetiologies; probably alcoholism is overestimated and hepatitis B and C viruses are underestimated as causes of cirrhosis registered on death certificates.

Para estudar a mortalidade e conferir a etiologia da cirrose lançada nas Declarações de Óbito (DO) no Espírito Santo, Brasil, foi feita a revisão das DO (2000 a 2011) e de prontuários dos falecidos com investigação de alcoolismo e hepatites B e C. Entre 218.410 DO foram identificados 3.554 mortes por cirrose. A mortalidade anual foi 19,8/100 mil homens e 4,31/100 mil mulheres, sem variação anual significativa e sem alteração significativa após correção por CID R98 e R99. Em 49% dos DO a causa da cirrose foi identificada: alcoolismo 85% e hepatite B ou C 15,7%. As etiologias nos 262 casos revisados foram: alcoolismo 40,5%; hepatite B ou C 26,7%; outras causas 3,8%; criptogênicas 10,6%. A média anual de anos potenciais de vida perdidos foi 5946 e 1739 anos, respectivamente, para homens e mulheres. A taxa de mortalidade por cirrose no Espírito Santo é intermediária em relação a outras regiões do mundo; alcoolismo e hepatites B e C são as principais etiologias. É provável que alcoolismo seja superestimado e hepatites B e C subestimadas como causa de cirrose nas DO.

Para el estudio de la mortalidad por cirrosis hepática en el estado de Espírito Santo, Brasil, se revisaron los certificados de defunción entre 2000-2010 y los registros de los pacientes fallecidos con un historial de alcoholismo y hepatitis B y C. De entre 218.410 certificados de defunción, se recuperaron 3.554 muertes por cirrosis hepática. La tasa anual de mortalidad fue de 19,8/100.000 para los hombres y 4,31/100.000 para las mujeres, sin variación anual significativa y sin cambios significativos, después de la corrección por CID-R98 y R99. En el 49% de los certificados de defunción se definió la etiología: alcoholismo 81,5 % y hepatitis viral 15,7%. La etiología se confirmó en 262 registros revisados: alcoholismo 40,5%; hepatitis B o C en un 26,7%; otras causas 3,8% y en un 10,6% la cirrosis era criptogénetica. La media de años potenciales de vida perdidos fue 5946 y 1739 años para hombres y mujeres. La tasa de mortalidad es intermedia en relación con el resto del mundo; alcoholismo y hepatitis B o C fueron las principales etiologías; el alcoholismo probablemente está sobrevalorado y la hepatitis B o C se subestiman como causa en los certificados de defunción.

Etiology of liver cirrhosis in Brazil: chronic alcoholism and hepatitis viruses in liver cirrhosis diagnosed in the state of Espírito Santo.

OBJECTIVES: To report the etiology of liver cirrhosis cases diagnosed at the University Hospital in Vitoria, Espirito Santo, Brazil. METHODS: The medical charts of patients with liver cirrhosis who presented to the University Hospital in Vitoria were reviewed. Chronic alcoholism and the presence of hepatitis B or C infections (HBV and HCV, respectively) were pursued in all cases. RESULTS: The sample consisted of 1,516 cases (male:female ratio 3.5:1, aged 53.2 ± 12.6 years). The following main etiological factors were observed: chronic alcoholism alone (39.7%), chronic alcoholism in association with HBV or HCV (16.1 %), HCV alone (14.5%) and in association with alcoholism (8.6%) (total, 23.1 %), and HBV alone (13.1%) and in association with alcoholism (7.5%, total 20.6%). The remaining etiologies included cryptogenic cases (9.8%) and other causes (6.0%). The mean patient age was lower and the male-to-female ratio was higher in the cirrhosis cases that were associated with alcoholism or HBV compared with other causes. Intravenous drug abuse and a history of surgery or blood transfusion were significantly associated with HCV infection. Hepatocellular carcinoma was present at the time of diagnosis in 15.4% of cases. Chronic alcoholism associated with HCV infection was significantly associated (p<0.001) with reduced age (at the time of cirrhosis diagnosis) and increased prevalence of hepatocellular carcinoma (p = 0.052). CONCLUSION: Alcoholism, HCV and HBV are the main factors associated with liver cirrhosis in the state of Espirito Santo. Chronic alcoholism associated with HCV infection reduced the age of patients at the time of liver cirrhosis diagnosis.

Hepatocellular carcinoma and liver cirrhosis TP53 mutation analysis reflects a moderate dietary exposure to aflatoxins in Espírito Santo State, Brazil.

The close relationship between aflatoxins and 249ser TP53 gene mutation (AGG to AGT, Arg to Ser) in hepatocellular carcinoma (HCC) makes this mutation an indirect indicator of dietary contamination with this toxin. We have examined the prevalence of codon 249 TP53 mutation in 41 HCC and 74 liver cirrhosis (without HCC) cases diagnosed at the HUCAM University Hospital in Vitoria, Espírito Santo State, Brazil. DNA was extracted from paraffin sections and from plasma. The mutation was detected by DNA amplification, followed by restriction endonuclease digestion and confirmed by direct sequencing. DNA restriction showed 249ser mutation in 16 HCC and 13 liver cirrhosis, but sequencing confirmed mutations in only 6 HCC and 1 liver cirrhosis. In addition, sequencing revealed 4 patients with mutations at codon 250 (250ser and 250leu) in HCC cases. The prevalence of TP53 mutation was 10/41 (24.3%) in HCC and 1/74 (1.4%) in liver cirrhosis. No relationship between the presence of mutations and the etiology of HCC was observed. TP53 exon 7 mutations, which are related to aflatoxins exposure, were found at 14.6% (249ser), 7.3% (250leu) and 2.4% (250ser) in 41 cases of HCC and 1.4% in 74 liver cirrhosis (without HCC) cases, suggesting a moderate dietary exposure to aflatoxins in the Espírito Santo State, Brazil.

Etiology of liver cirrhosis in Brazil: chronic alcoholism and hepatitis viruses in liver cirrhosis diagnosed in the state of Espfrito Santo

OBJECTIVES: To report the etiology of liver cirrhosis cases diagnosed at the University Hospital in Vitoria, Espirito Santo, Brazil. METHODS: The medical charts of patients with liver cirrhosis who presented to the University Hospital in Vitoria were reviewed. Chronic alcoholism and the presence of hepatitis B or C infections (HBV and HCV, respectively) were pursued in all cases. RESULTS: The sample consisted of 1,516 cases (male:female ratio 3.5:1, aged 53.2±12.6 years). The following main etiological factors were observed: chronic alcoholism alone (39.7%), chronic alcoholism in association with HBV or HCV (16.1 %), HCV alone (14.5%) and in association with alcoholism (8.6%) (total, 23.1 %), and HBV alone (13.1%) and in association with alcoholism (7.5%, total 20.6%). The remaining etiologies included cryptogenic cases (9.8%) and other causes (6.0%). The mean patient age was lower and the male-to-female ratio was higher in the cirrhosis cases that were associated with alcoholism or HBV compared with other causes. Intravenous drug abuse and a history of surgery or blood transfusion were significantly associated with HCV infection. Hepatocellular carcinoma was present at the time of diagnosis in 15.4% of cases. Chronic alcoholism associated with HCV infection was significantly associated (p<0.001) with reduced age (at the time of cirrhosis diagnosis) and increased prevalence of hepatocellular carcinoma (p = 0.052). CONCLUSION: Alcoholism, HCV and HBV are the main factors associated with liver cirrhosis in the state of Espirito Santo. Chronic alcoholism associated with HCV infection reduced the age of patients at the time of liver cirrhosis diagnosis.

Branch retinal vein thrombosis and visual loss probably associated with pegylated interferon therapy of chronic hepatitis C.

Ophthalmological complications with interferon therapy are usually mild and reversible, not requiring the withdrawal of the treatment. We report a case of a patient who had visual loss probably associated with interferon therapy. Chronic hepatitis C virus infection (genotype 1a) was diagnosed in a 33-year old asymptomatic man. His past medical history was unremarkable and previous routine ophthalmologic check-up was normal. Pegylated interferon alpha and ribavirin were started. Three weeks later he reported painless reduction of vision. Ophthalmologic examination showed extensive intraretinal hemorrhages and cotton-wool spots, associated with inferior branch retinal vein thrombosis. Antiviral therapy was immediately discontinued, but one year later he persists with severely decreased visual acuity. This case illustrates the possibility of unpredictable and severe complications during pegylated interferon therapy.

Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis.

BACKGROUND AND AIMS: Primary biliary cirrhosis (PBC) has been reported in up to 4-6% of first degree relatives of patients with the disease. In addition, immune abnormalities, including hypergammaglobulinemia, autoantibodies and increased frequency of autoimmune disorders, were reported in family members of PBC patients. The aim of the present study was to investigate the prevalence of PBC in relatives of patients with PBC, and to investigate the occurrence of chronic liver disease (CLD) and immune abnormalities in these subjects. METHODS: One-hundred first degree relatives of 26 patients with PBC were interviewed and submitted to physical examination and determination of liver enzymes, gamma-globulin, bilirubin and auto-antibodies, including antinuclear (ANA), antismooth muscle (SMA), antimitochondrial antibodies (AMA) by indirect immunofluorescence (IIF) and anti-M2 antibody by immunoblotting (IB). RESULTS: Immune disturbances were rarely observed in relatives of PBC patients. Higher gamma-globulin levels, SMA and ANA were detected in four, eight and two family members, respectively. In most subjects, these autoantibodies were either in low titers or associated with concurrent diseases. Only four relatives had extrahepatic autoimmune diseases and another eight exhibited other CLD. Primary biliary cirrhosis was detected in a sister of one patient. Additionally, two other relatives of PBC patients who tested negative for AMA by IIF showed reactivity for anti-M2 by IB. CONCLUSIONS: Immune disturbances, including ANA and SMA, are uncommon in family members of PBC patients. Conversely, anti-M2 antibodies and overt PBC do occur in relatives of PBC patients, even in Brazil where the disease is quite rare.