Assessment of efficacy and safety of daclatasvir, sofusbuvirand ribavirin regimen for 12 weeks as compared to daclatasvir and sofusbuvir combination regimen for 24 weeks in decompensated cirrhotic patients due to hepatitis C virus genotype 3 infection

Background: Assessment of efficacy and safety of daclatasvir+sofosbuvir+ribavirin (DCV+SOF+RBV) for 12 weeks as compare to daclatasvir and sofusbuvirfor 24 weeks in decompensated cirrhotic patients due to hepatitis C virus (HCV) genotype 3 infection. Methods: An observational, prospective, COHORTstudy over 1 year, in decompensated cirrhosis due to G3-HCV infected adult patients. Treatment was a combination of sofosbuvir 400 mg/day+daclatasvir 60 mg/day, with or without a weight-adjusted dosing of ribavirin for 12 or 24 weeks. The primary efficacyendpoint was sustained virologic response rates 12 weeks after therapy (SVR 12). The primary safety endpoint was treatment withdrawal rates secondary to severe adverse events. Results: The32 patients were screened and 2 were excluded, one patient due toassociated HBV+, one patient due to severe anemia. 30 patients were randomized. All 30 randomized patients were divided into two groups. Group 1 was given SOF+DCV+RBV for 12 weeks while group 2 patients were given SOF+DCV for 24 weeks. 81.8% of the participants in the group1 achieved SVR 12. The 90.9% of the participants in the group 2 achieved SVR12 (p=1). No other patient or treatment basal variables influenced the treatment effectiveness. No patient treatment withdrawal secondary to severe adverse events was observed. Conclusions: Both the regimen SOF+DCV with or without RBV are highly efficacious and safe. Addition of RBV can reduce the treatment duration to 12 weeks, and it will further improve compliance and more convenient for the patients.

Progress in the treatment of chronic hepatitis C virus genotype 3 infection / 中华临床感染病杂志

Hepatitis C virus genotype 3 (HCV G3) infection is the second most prevalent hepatitis C genotype globally, with higher rates of disease progression and mortality compared with other genotypes. After the advent of direct-acting antiviral drugs (DAAs), the efficacy of antiviral therapy for hepatitis C patients has been greatly improved, but the therapy for G3 type is less effective than that for other genotypes, so it is considered to be one of the most difficult subtypes to treat. This article reviews the available treatment options for HCV G3 patients and their sustained virological response rates to provide clinical reference.

Evolutionary study of potentially zoonotic hepatitis E virus genotype 3 from swine in Northeast Brazil

Hepatitis E virus (HEV), an emerging virus associated with acute hepatic disease, leads to thousands of deaths worldwide. HEV has already been reported in Brazil; however, there is a lack of epidemiological and molecular information on the genetic variability, taxonomy, and evolution of HEV. It is thus unclear whether hepatitis E is a neglected disease in Brazil or it has low relevance for public health in this country. Here, for the first time, we report the presence of HEV in Northeast Brazil. A total of 119 swine faecal samples were screened for the presence of HEV RNA using real-time polymerase chain reaction (RT-PCR) and further confirmed by conventional RT-PCR; among these, two samples were identified as positive. Molecular evolution analyses based on capsid sequences revealed that the samples had close proximities to HEV sequences belonging to genotype 3 and were genetically related to subtype 3f isolated in humans. Parsimony ancestral states analysis indicated gene flow events from HEV cross-species infection, suggesting an important role of pig hosts in viral spillover. HEV's ability for zoonotic transmission by inter-species host switching as well as its possible adaptation to new animal species remain important issues for human health.

Hallmarks of liver lesions in pigs naturally infected by hepatitis E virus genotype 3 / Perfil das lesões histopatológicas hepáticas em suínos infectados naturalmente pelo genótipo 3 do vírus da hepatite E

Histopathological evaluation of liver from 33 pigs slaughtered for human consumption in Amazon region, previously tested by serology and molecular techniques for hepatitis E virus infection (HEV), was analysed in three groups: Group 1, negative for both HEV-RNA and anti-HEV IgG (n=10); Group 2, positive for HEV-RNA (n=13); Group 3, positive for anti-HEV IgG (n=10). Group 2 showed a significant difference among the groups for liver lesions such as lobular activity (P=0.007), periportal interface hepatitis (P=0.004), portal inflammation (P=0.028) hepatitis with lobular, portal and periportal interface activity (P=0.001). HEV detection by immunohistochemistry was performed and 3 of 6 samples of group 2 were positive. Pigs naturally infected by HEV genotype 3 present microscopic necroinflammatory liver lesions similar to HEV in humans. Liver histopathology showed be important in the diagnosis of active asymptomatic HEV infection in pigs slaughtered for human consumption because hepatic liver lesions may present distinct profiles according to molecular and serological diagnosis and in this sense, histopathology and immunohistochemistry may be an important complementary diagnostic tool.(AU)

A avaliação histopatológica hepática de 33 suínos abatidos para consumo humano na região amazônica, previamente testados para infecção pelo vírus da hepatite E (HEV) por sorologia e técnicas moleculares, foi realizada em três grupos: Grupo 1, animais negativos para HEV-RNA e anti-HEV IgG (n=10); Grupo 2, positivos para HEV-RNA (n=13); e Grupo 3, positivos para anti-HEV IgG (n=10). O grupo 2 apresentou diferenças estatísticas significantes entre os grupos em relação à presença de atividade lobular (P=0,007), hepatite periportal de interface (P=0,004), inflamação portal (P= 0.028) e atividade lobular acompanhada por inflamação portal e periportal de interface (P=0,001). A detecção imunohistoquímica do HEV foi realizada e três de seis amostras do Grupo 2 foram positivas. Suínos naturalmente infectados pelo genótipo 3 do HEV apresentam lesões necroinflamatórias no fígado similares a lesão em humanos. A histopatologia hepática demonstrou ser importante no diagnóstico de infecção ativa e assintomática por HEV em suínos abatidos para consumo humano, pois as lesões no fígado apresentaram perfis diferenciados de acordo com o diagnóstico sorológico e molecular da infecção e, neste sentido, a histopatologia e imunohistoquímica podem representar importantes ferramentas complementares de diagnóstico.(AU)

High frequency of hepatitis E virus infection in swine from South Brazil and close similarity to human HEV isolates

Abstract Hepatitis E virus is responsible for acute and chronic liver infections worldwide. Swine hepatitis E virus has been isolated in Brazil, and a probable zoonotic transmission has been described, although data are still scarce. The aim of this study was to investigate the frequency of hepatitis E virus infection in pigs from a small-scale farm in the rural area of Paraná State, South Brazil. Fecal samples were collected from 170 pigs and screened for hepatitis E virus RNA using a duplex real-time RT-PCR targeting a highly conserved 70 nt long sequence within overlapping parts of ORF2 and ORF3 as well as a 113 nt sequence of ORF2. Positive samples with high viral loads were subjected to direct sequencing and phylogenetic analysis. hepatitis E virus RNA was detected in 34 (20.0%) of the 170 pigs following positive results in at least one set of screening real-time RT-PCR primers and probes. The swine hepatitis E virus strains clustered with the genotype hepatitis E virus-3b reference sequences in the phylogenetic analysis and showed close similarity to human hepatitis E virus isolates previously reported in Brazil.

Treatment of hepatitis C virus genotype 3 infection with direct-acting antiviral agents

Hepatitis C virus (HCV) genotype 3 is responsible for 30.1% of chronic hepatitis C infection cases worldwide. In the era of direct-acting antivirals, these patients have become one of the most challenging to treat, due to fewer effective drug options, higher risk of developing cirrhosis and hepatocellular carcinoma and lower sustained virological response (SVR) rates. Currently there are 4 recommended drugs for the treatment of HCV genotype 3: pegylated interferon (PegIFN), sofosbuvir (SOF), daclatasvir (DCV) and ribavirin (RBV). Treatment with PegIFN, SOF and RBV for 12 weeks has an overall SVR rate of 83–100%, without significant differences among cirrhotic and non-cirrhotic patients. However, this therapeutic regimen has several contraindications and can cause significant adverse events, which can reduce adherence and impair SVR rates. SOF plus RBV for 24 weeks is another treatment option, with SVR rates of 82–96% among patients without cirrhosis and 62–92% among those with cirrhosis. Finally, SOF plus DCV provides 94–97% SVR rates in non-cirrhotic patients, but 59–69% in those with cirrhosis. The addition of RBV to the regimen of SOF plus DCV increases the SVR rates in cirrhotic patients above 80%, and extending treatment to 24 weeks raises SVR to 90%. The ideal duration of therapy is still under investigation. For cirrhotic patients, the optimal duration, or even the best regimen, is still uncertain. Further studies are necessary to clarify the best regimen to treat HCV genotype 3 infection.

HEPATOCELLULAR CARCINOMA IN A NON-CIRRHOTIC PATIENT WITH SUSTAINED VIROLOGICAL RESPONSE AFTER HEPATITIS C TREATMENT / Carcinoma hepatocelular em paciente não cirrótico com resposta virológica sustentada após tratamento para hepatite C

Chronic infection by hepatitis C virus (HCV) is one of the main risk factors for the development of liver cirrhosis and hepatocellular carcinoma. However, the emergence of hepatocellular carcinoma (HCC) in non-cirrhotic HCV patients, especially after sustained virological response (SVR) is an unusual event. Recently, it has been suggested that HCV genotype 3 may have a particular oncogenic mechanism, but the factors involved in these cases as well as the profile of these patients are still not fully understood. Thus, we present the case of a non-cirrhotic fifty-year-old male with HCV infection, genotype 3a, who developed HCC two years after treatment with pegylated-interferon and ribavirin, with SVR, in Brazil.

A infecção crônica pelo vírus da hepatite C é um dos principais fatores de risco para o desenvolvimento de cirrose hepática e carcinoma hepatocelular. Entretanto, o surgimento do carcinoma hepatocelular em pacientes portadores de hepatite C na ausência de cirrose, especialmente após o tratamento e a obtenção de resposta virológica sustentada, é um evento incomum. Recentemente tem sido sugerido que o genótipo 3 do vírus da hepatite C possa ter um mecanismo oncogênico particular, mas todos os fatores envolvidos nestes casos, assim como o perfil destes pacientes, ainda não estão totalmente esclarecidos. Deste modo, apresentamos o caso de um paciente masculino de 50 anos de idade, com infecção pelo vírus da hepatite C genótipo 3a, não cirrótico, que desenvolveu carcinoma hepatocelular dois anos após ter atingido resposta virológica sustentada com o tratamento com interferon peguilado e ribavirina.

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients

Objective:To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus (HCV) related metabolic disorder during early stages of disease. Methods:Patients of diverse age and sex, with positive HCV genotype 3 (HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), glucose-6-phosphatase catalytic subunit (G6PC) and associated forkhead box protein 01 (FOXO1).Results:Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression ofPCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression ofG6PC andFOXO1were found.Conclusions:PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.

Effect of interferon plus ribavirin therapy on hepatitis C virus genotype 3 patients from Pakistan: Treatment response, side effects and future prospective

More than 10 million people are suffering from hepatitis C virus (HCV) in Pakistan. The available treatment option is a combination of interferon and ribavirin. Treatment response is linked with several factors and also induces a number of side effects. We searched in Pubmed, Pak Medi Net and Google Scholar for the articles presenting the effect of interferon plus ribavirin therapy on HCV patients from Pakistan, their side effects and future prospects. The major prevalent HCV genotype in Pakistan is 3. Conventional interferon alpha plus ribavirin showed sustained virological response of 54%-64% while pegylated interferon alpha plus ribavirin showed sustained virological response of 58%-75%. IL-28B CC genotype is linked with better sustained virological response. Studies on patients with HCV genotype 3 infections showed no correlation between treatment response and interferon sensitivity determining region mutations. Interferon therapy is linked with a number of side effects like thyroid dysfuncton, haematological disorders, weight loss, gastrointestinal tract side effects and neuropsychiatric side effects. Unusual side effects of clubbing of fingers and seizures were also observed in a couple of patients. Interferon alpha plus ribavirin therapy showed better response rate in HCV genotype 3 patients from Pakistan with number of side effects. A couple of interferon free therapies are light of hope for the patients living with HCV.

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients

OBJECTIVE@#To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus (HCV) related metabolic disorder during early stages of disease.@*METHODS@#Patients of diverse age and sex, with positive HCV genotype 3 (HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), glucose-6-phosphatase catalytic subunit (G6PC) and associated forkhead box protein 01 (FOXO1).@*RESULTS@#Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression of PCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression of G6PC and FOXO1 were found.@*CONCLUSIONS@#PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.

doi:10.1016/S1995-7645(14)60193-0 Effect of interferon plus ribavirin therapy on hepatitis C virus genotype 3 patients from Pakistan：Treatment response, side effects and future prospective

More than10 million people are suffering from hepatitisC virus(HCV) inPakistan.The available treatment option is a combination of interferon and ribavirin.Treatment response is linked with several factors and also induces a number of side effects.We searched inPubmed,PakMedi Net andGoogleScholar for the articles presenting the effect of interferon plus ribavirin therapy onHCV patients fromPakistan, their side effects and future prospects.The major prevalent HCV genotype inPakistan is3.Conventional interferon alpha plus ribavirin showed sustained virological response of54%-64% while pegylated interferon alpha plus ribavirin showed sustained virological response of58%-75%.IL-28BCC genotype is linked with better sustained virological response.Studies on patients withHCV genotype3 infections showed no correlation between treatment response and interferon sensitivity determining region mutations.Interferon therapy is linked with a number of side effects like thyroid dysfuncton, haematological disorders, weight loss, gastrointestinal tractside effects and neuropsychiatric side effects.Unusual side effects of clubbing of fingers and seizures were also observedin a couple of patients.Interferon alpha plus ribavirin therapy showed better response rate inHCV genotype3 patients fromPakistan with number of side effects.A couple of interferon free therapies are light of hope for the patients living withHCV.

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients

Objective: To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus (HCV) related metabolic disorder during early stages of disease. Methods: Patients of diverse age and sex, with positive HCV genotype 3 (HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), glucose-6-phosphatase catalytic subunit (G6PC) and associated forkhead box protein 01 (FOXO1). Results: Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression of PCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression of G6PC and FOXO1 were found. Conclusions: PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.

Effect of interferon plus ribavirin therapy on hepatitis C virus genotype 3 patients from Pakistan: Treatment response, side effects and future prospective

More than 10 million people are suffering from hepatitis C virus (HCV) in Pakistan. The available treatment option is a combination of interferon and ribavirin. Treatment response is linked with several factors and also induces a number of side effects. We searched in Pubmed, Pak Medi Net and Google Scholar for the articles presenting the effect of interferon plus ribavirin therapy on HCV patients from Pakistan, their side effects and future prospects. The major prevalent HCV genotype in Pakistan is 3. Conventional interferon alpha plus ribavirin showed sustained virological response of 54%-64% while pegylated interferon alpha plus ribavirin showed sustained virological response of 58%-75%. IL-28B CC genotype is linked with better sustained virological response. Studies on patients with HCV genotype 3 infections showed no correlation between treatment response and interferon sensitivity determining region mutations. Interferon therapy is linked with a number of side effects like thyroid dysfuncton, haematological disorders, weight loss, gastrointestinal tract side effects and neuropsychiatric side effects. Unusual side effects of clubbing of fingers and seizures were also observed in a couple of patients. Interferon alpha plus ribavirin therapy showed better response rate in HCV genotype 3 patients from Pakistan with number of side effects. A couple of interferon free therapies are light of hope for the patients living with HCV.

Sustained virological response to pegylatedinterferon and ribavirin in patients with genotype3 HCV cirrhosis.

Background: Chronic hepatitis C (CHC) virus infection in patients with cirrhosis is difficult to treat. There is limited data on the outcome of treatment for genotype 3 HCV infection with cirrhosis. Aims: To determine sustained virological response (SVR) and its predictive factors in patients with cirrhosis due to genotype 3 HCV infection treated with pegylated interferon and ribavirin (RBV). Methods: Consecutive patients with compensated cirrhosis due to HCV genotype 3 with positive HCV RNA treated with peg-IFN and RBV in our Gastroenterology Clinics during November 2005 to December 2006 were included in this study. Cirrhosis was diagnosed on the basis of liver biopsy and/or biochemical testing and ultrasound of abdomen. Primary end point of treatment was SVR. Results: Of 66 patients, 32 (48.5%) were male. The mean age was 46.2±10.1 years; there were 61 (92.4%) patients with Child’s A cirrhosis followed by 5 (7.6%) with Child’s B type. 33 (50%) patients received pegylated interferon alfa-2a (180 μg/wk) with ribavirin and 33 (50%) received pegylated interferon alfa 2b (1 μg /kg/week) with ribavirin. EVR was achieved in 44 (66.7%), and ETR in 46 (69.7%); overall SVR was achieved in 38 (57.6%) patients. Factors predictive of SVR were age (p value = 0.03), treatment naïve status (p value = 0.04) and EVR (p value<0.001). Five patients were unable to complete the treatment due to side effects or cytopenias. Conclusions: Treatment of patients with HCV genotype 3, compensated cirrhosis, with pegylated interferon and ribavirin is effective and well tolerated.