Blood microbiome is associated with changes in portal hypertension after successful direct-acting antiviral therapy in patients with HCV-related cirrhosis.

BACKGROUND: Patients with a significant decrease in hepatic venous pressure gradient (HVPG) have a considerable reduction of liver complications and higher survival after HCV eradication. OBJECTIVES: To evaluate the association between the baseline blood microbiome and the changes in HVPG after successful direct-acting antiviral (DAA) therapy in patients with HCV-related cirrhosis. METHODS: We performed a prospective study in 32 cirrhotic patients (21 HIV positive) with clinically significant portal hypertension (HVPG ≥10 mmHg). Patients were assessed at baseline and 48 weeks after HCV treatment completion. The clinical endpoint was a decrease in HVPG of ≥20% or HVPG <12 mmHg at the end of follow-up. Bacterial 16S ribosomal DNA was sequenced using MiSeq Illumina technology, inflammatory plasma biomarkers were investigated using ProcartaPlex immunoassays and the metabolome was investigated using GC-MS. RESULTS: During the follow-up, 47% of patients reached the clinical endpoint. At baseline, those patients had a higher relative abundance of Corynebacteriales and Diplorickettsiales order, Diplorickettsiaceae family, Corynebacterium and Aquicella genus and Undibacterium parvum species organisms and a lower relative abundance of Oceanospirillales and Rhodospirillales order, Halomonadaceae family and Massilia genus organisms compared with those who did not achieve the clinical endpoint according to the LEfSe algorithm. Corynebacteriales and Massilia were consistently found within the 10 bacterial taxa with the highest differential abundance between groups. Additionally, the relative abundance of the Corynebacteriales order was inversely correlated with IFN-γ, IL-17A and TNF-α levels and the Massilia genus with glycerol and lauric acid. CONCLUSIONS: Baseline-specific bacterial taxa are related to an HVPG decrease in patients with HCV-related cirrhosis after successful DAA therapy.

Plasma IP-10 and IL-6 are linked to Child-Pugh B cirrhosis in patients with advanced HCV-related cirrhosis: a cross-sectional study.

We aimed to evaluate the association of plasma biomarkers linked to inflammation (bacterial translocation, inflammatory response, and endothelial dysfunction), coagulopathy, and angiogenesis with the severity of liver cirrhosis (assessed by the Child-Pugh-Turcotte score, CTP) and Child-Pugh B cirrhosis (CTP 7-9) in patients with advanced hepatitis C virus (HCV)-related cirrhosis. We carried out a cross-sectional study in 97 patients with advanced HCV-related cirrhosis (32 HCV-monoinfected and 65 HIV/HCV-coinfected). Plasma biomarkers were measured by ProcartaPlex multiplex immunoassays. The outcome variable was the CTP score and the Child-Pugh B cirrhosis (CTP 7-9). HIV/HCV-coinfected patients and HCV-monoinfected patients with advanced HCV-related cirrhosis had near-equivalent values of plasma biomarkers. Higher values of plasma biomarkers linked to an inflammatory response (IP-10, IL-8, IL-6, and OPG), endothelial dysfunction (sVCAM-1 and sICAM-1), and coagulopathy (D-dimer) were related to higher CTP values. The most significant biomarkers to detect the presence of Child-Pugh B cirrhosis (CTP 7-9) were IP-10 (p-value= 0.008) and IL-6 (p-value=0.002). The AUC-ROC values of IP-10, IL-6, and both biomarkers combined (IP-10+IL-6) were 0.78, 0.88, and 0.96, respectively. In conclusion, HIV infection does not appear to have a significant impact on the analyzed plasma biomarkers in patients with advanced HCV-related cirrhosis. However, plasma biomarkers linked to inflammation (inflammatory response and endothelial dysfunction) were related to the severity of liver cirrhosis (CTP score), mainly IP-10 and IL-6, which discriminated patients with Child-Pugh B concerning Child-Pugh A.

Plasma metabolomic fingerprint of advanced cirrhosis stages among HIV/HCV-coinfected and HCV-monoinfected patients.

BACKGROUND & AIMS: Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and cirrhosis induce metabolic disorders. Here, we aimed to evaluate the association of plasma metabolites with Child-Turcotte-Pugh (CTP) score and hepatic decompensation in HIV/HCV-coinfected and HCV-monoinfected patients with advanced cirrhosis. METHODS: A cross-sectional study was carried out in 62 HIV/HCV-coinfected and 28 HCV-monoinfected patients. Metabolomics analysis was performed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The statistical association analysis was performed by partial least squares discriminant analysis (PLS-DA) and generalized linear model (GLM) with binomial distribution (to analyse HIV coinfection, high alcohol intake, treatment with statins, previous HCV therapy failure and decompensation) and ordinal logistic regression (OLR) models to analyse different stages of cirrhosis (CTP score). RESULTS: The statistical analysis identified plasma metabolites associated with HIV coinfection, high alcohol intake, CTP score and hepatic decompensation. Overall, fatty acids, bile acids, aromatic and sulphur amino acids, butyrate derivatives, oxidized phospholipids, energy-related metabolites and bacterial fermentation-related metabolites were increased in more advanced cirrhosis stages; while lysophosphatidylcholines and lysophosphatidylethanolamines, branched-chain amino acids (BCAA) and metabolites of tricarboxylic acid cycle, among others, were decreased in more advanced cirrhosis. Most of the significant metabolites displayed a similar trend after stratifying for HIV/HCV- and HCV-infected patients. Glycolic acid, LPC (16:0) and taurocholic acid had high accuracy for discriminating patients according to decompensated cirrhosis (CTP ≥ 7). CONCLUSION: Altered plasma metabolomic profile was associated with advanced stages of cirrhosis in HIV/HCV-coinfected and HCV-monoinfected patients.

Enfermedades vasculares del hígado. Guías Clínicas de la Sociedad Catalana de Digestología y de la Asociación Española para el Estudio del Hígado / Vascular diseases of the liver. Clinical Guidelines from the Catalan Society of Digestology and the Spanish Association for the Study of the Liver

Las enfermedades vasculares hepáticas, a pesar de su relativamente baja prevalencia, representan un problema de salud importante en el campo de las enfermedades hepáticas. Una característica común a muchas de estas enfermedades es que pueden causar hipertensión portal, con la elevada morbimortalidad que ello conlleva. Con frecuencia estas enfermedades se diagnostican en pacientes jóvenes y el retraso en su diagnóstico y/o un tratamiento inadecuado pueden reducir de forma importante la esperanza de vida. El presente artículo revisa la evidencia actual en el síndrome de Budd-Chiari, la trombosis venosa portal en pacientes no cirróticos, la hipertensión portal idiopática, el síndrome de obstrucción sinusoidal, las malformaciones vasculares hepáticas en la telangiectasia hemorrágica hereditaria, la trombosis portal en la cirrosis, otras patologías vasculares menos frecuentes como las fístulas arterioportales, así como un apartado sobre el diagnóstico por imagen de las enfermedades vasculares hepáticas y su tratamiento desde el punto de vista hematológico (estudio de la diátesis trombótica y tratamiento anticoagulante). Las recomendaciones se han realizado de acuerdo a los estudios publicados extraídos de Pubmed. La calidad de la evidencia y la intensidad de las recomendaciones fueron graduadas de acuerdo al sistema Grading of Recommendations Assessment Development and Evaluation (GRADE). Cuando no existían evidencias suficientes, las recomendaciones se basaron en la opinión del comité que redactó la guía (AU)

Despite their relatively low prevalence, vascular diseases of the liver represent a significant health problem in the field of liver disease. A common characteristic shared by many such diseases is their propensity to cause portal hypertension together with increased morbidity and mortality. These diseases are often diagnosed in young patients and their delayed diagnosis and/or inappropriate treatment can greatly reduce life expectancy. This article reviews the current body of evidence concerning Budd-Chiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension, sinusoidal obstruction syndrome, hepatic vascular malformations in hereditary haemorrhagic telangiectasia, cirrhotic portal vein thrombosis and other rarer vascular diseases including arterioportal fistulas. It also includes a section on the diagnostic imaging of vascular diseases of the liver and their treatment from a haematological standpoint (study of thrombotic diathesis and anticoagulation therapy). All recommendations are based on published studies extracted from PubMed. The quality of evidence and strength of recommendations were rated in accordance with the GRADE system (Grading of Recommendations, Assessment Development and Evaluation). In the absence of sufficient evidence, recommendations were based on the opinion of the committee that produced the guide (AU)

Vascular diseases of the liver. Clinical Guidelines from the Catalan Society of Digestology and the Spanish Association for the Study of the Liver. / Enfermedades vasculares del hígado. Guías Clínicas de la Sociedad Catalana de Digestología y de la Asociación Española para el Estudio del Hígado.

Despite their relatively low prevalence, vascular diseases of the liver represent a significant health problem in the field of liver disease. A common characteristic shared by many such diseases is their propensity to cause portal hypertension together with increased morbidity and mortality. These diseases are often diagnosed in young patients and their delayed diagnosis and/or inappropriate treatment can greatly reduce life expectancy. This article reviews the current body of evidence concerning Budd-Chiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension, sinusoidal obstruction syndrome, hepatic vascular malformations in hereditary haemorrhagic telangiectasia, cirrhotic portal vein thrombosis and other rarer vascular diseases including arterioportal fistulas. It also includes a section on the diagnostic imaging of vascular diseases of the liver and their treatment from a haematological standpoint (study of thrombotic diathesis and anticoagulation therapy). All recommendations are based on published studies extracted from PubMed. The quality of evidence and strength of recommendations were rated in accordance with the GRADE system (Grading of Recommendations, Assessment Development and Evaluation). In the absence of sufficient evidence, recommendations were based on the opinion of the committee that produced the guide.

Prevalence and outcome of portal thrombosis in a cohort of cirrhotic patients undergoing liver transplantation.

INTRODUCTION: The prevalence of portal vein thrombosis (PVT) in patients that have undergone liver transplantation (LT) is 9.7% (SD 4.5). The aim of our study was to determine the prevalence, assess the factors that are associated with PVT and clarify their association with prognosis in patients with liver cirrhosis (LC) and LT. AIMS AND METHODS: From 2005 to 2014, laboratory, radiological and surgical data were collected from patients with LC in our center who had undergone LT for the first time. RESULTS: One hundred and ninety-one patients were included. The mean age was 55 (SD 9), 75.4% of patients were male and 48.7% had HCV. The Child-Pugh scores were A/B/C 41.9%/35.9%/25.5% and the MELD score was 15 (SD 6). Previous decompensations were: ascites (61.4%), hepatic encephalopathy (34.4%), variceal bleeding (25.4%), hepatocellular carcinoma (48.9%) and spontaneous bacterial peritonitis (SPB) (14.3%). The mean post-transplant follow-up was 42 months (0-113). PVT was diagnosed at LT in 18 patients (9.4%). Six patients were previously diagnosed using imaging tests (33.3%): 2 patients (11.1%) by DU and 4 patients (22.2%) by CT scan. All patients with PVT had DU in a mean time of 6 months before LT (0-44) and 90 patients (47.1%) had a CT scan in a median time of 6 months before LT (0-45). PVT was significantly related to the presence of SBP (33.3% vs 12.6%; p = 0.02) and lower levels of albumin (3.1g/dl vs 3.4g/dl; p = 0.05). MELD was higher in patients with PVT (16.6 vs 14.9; p = 0.3). There were no significant differences with regard to the need for transfusion of blood components. Moreover, the surgery time was similar in both groups. PVT correlated with a higher mortality in the first 30 days (8.8% vs 16.7%; p = 0.2). CONCLUSION: Prior history of SBP and lower levels of albumin were identified as factors associated with PVT. The pre-transplant diagnosis rate is very low and the presence of PVT may have implications for short-term mortality.

Idiopathic portal hypertension regarding thiopurine treatment in patients with inflammatory bowel disease.

INTRODUCTION: The possibility of developing idiopathic portal hypertension has been described with thiopurine treatment despite compromises the prognosis of these patients, the fact its true prevalence is unknown. MATERIAL AND METHODS: A cross-sectional study was conducted in a cohort of inflammatory bowel disease (IBD) patients followed at our unit, to determine the prevalence of diagnosis of idiopathic portal hypertension (IPH) and its relationship with thiopurine treatment. RESULTS: At the time of the analysis, 927/1,419 patients were under treatment with thiopurine drugs (65%). A total of 4 patients with IBD type Crohn's disease with idiopathic portal hypertension probably related to the thiopurine treatment were identified (incidence of 4.3 cases per 1,000). Seventy-five percent of patients started with signs or symptoms of portal hypertension. Only one patient was asymptomatic but the diagnosis of IPH because of isolated thrombocytopenia is suspected. However, note that all patients had thrombocytopenia previously. Abdominal ultrasound with fibroscan, hepatic vein catheterization and liver biopsy were performed on all of them as part of the etiology of portal hypertension. In the abdominal ultrasound, indirect portal hypertension data were observed in all patients (as splenomegaly) cirrhosis was also ruled out. The fibroscan data showed significant liver fibrosis (F2-F3). CONCLUSION: Idiopathic portal hypertension following thiopurine treatment in IBD patients is a rare occurrence, but it must be borne in mind in the differential diagnosis for early diagnosis, especially in patients undergoing thiopurine treatment over a long period. The presence of thrombocytopenia is often the only predictor of its development in the preclinical stage.

Hipertensión portal idiopática secundaria a tratamiento tiopurínico en pacientes con enfermedad inflamatoria intestinal / Idiopathic portal hypertension regarding thiopurine treatment in patients with inflammatory bowel disease

Introducción: entre los efectos adversos hepáticos secundarios al tratamiento tiopurínico en pacientes con enfermedad inflamatoria intestinal (EII), se ha descrito la posibilidad de desarrollar hipertensión portal idiopática. Esta patología de etiología y prevalencia real inciertas puede comprometer el pronóstico de estos pacientes, por lo que se debe tener un alto grado de sospecha para su diagnóstico precoz. Material y métodos: se ha llevado a cabo un estudio transversal en una cohorte de pacientes con EII en seguimiento en nuestra unidad para determinar la prevalencia del diagnóstico de HTP idiopática (HTPI) y su relación con el tratamiento tiopurínico. Resultados: en nuestro centro, en el momento del análisis había 1.419 pacientes en seguimiento por enfermedad inflamatoria intestinal. De estos, 927 pacientes se encuentran bajo tratamiento con fármacos tiopurínicos (o lo han estado durante la evolución de su enfermedad), lo que supone el 65,3% de la población: 689 pacientes con azatioprina (74,3%) y 238 con 6-mercaptopurina (25,7%). En total, se identificaron 4 pacientes con EII tipo enfermedad de Crohn con hipertensión portal idiopática en probable relación con el tratamiento tiopurínico, lo que supuso un 4,3% del total, es decir, una incidencia de 4,3 casos por cada 1.000 pacientes con EII tratados con tiopurínicos. Las características basales de los pacientes se describen en la tabla I. El 75% de los pacientes debutó con signos o síntomas de hipertensión portal: 1 paciente con encefalopatía hepática y 2 pacientes con hemorragia digestiva por varices esofágicas. Solo un paciente se encontraba asintomático, pero se sospechó el diagnóstico de HTP por trombopenia aislada. No obstante, cabe destacar que todos los pacientes presentaban trombopenia previamente aunque no se había sospechado el diagnóstico de HTP a pesar de un exhaustivo estudio. A todos los se realizó ecografía abdominal con fibroscan, cateterismo de venas suprahepáticas, así como biopsia hepática como parte del estudio etiológico de hipertensión portal. En la ecografía abdominal se objetivaron datos indirectos de HTP en todos los pacientes (como esplenomegalia), descartándose asimismo cirrosis hepática. El fibroscan mostraba datos de fibrosis hepática significativa (F2-F3). Además, a todos los pacientes se les realizó una angiorresonancia en la que se descartó trombosis del eje esplenoportal como causa de HTP. Por último, la anatomía patológica de la biopsia hepática descartó la presencia de cirrosis hepática, apoyando el diagnóstico de HTP idiopática (Tabla II). Conclusiones: la hipertensión portal idiopática secundaria a tratamiento tiopurínico en pacientes con enfermedad inflamatoria intestinal es un fenómeno poco frecuente, pero ha de ser tenido en cuenta en el diagnóstico diferencial para un diagnóstico precoz, principalmente en pacientes con tratamiento tiopurínico de larga evolución. La presencia de trombopenia es a menudo el único factor predictor de su desarrollo en fases preclínicas (AU)

Introduction: The possibility of developing idiopathic portal hypertension has been described with thiopurine treatment despite compromises the prognosis of these patients, the fact its true prevalence is unknown. Material and methods: A cross-sectional study was conducted in a cohort of inflammatory bowel disease (IBD) patients followed at our unit, to determine the prevalence of diagnosis of idiopathic portal hypertension (IPH) and its relationship with thiopurine treatment. Results: At the time of the analysis, 927/1,419 patients were under treatment with thiopurine drugs (65%). A total of 4 patients with IBD type Crohn’s disease with idiopathic portal hypertension probably related to the thiopurine treatment were identified (incidence of 4.3 cases per 1,000). Seventy-five percent of patients started with signs or symptoms of portal hypertension. Only one patient was asymptomatic but the diagnosis of IPH because of isolated thrombocytopenia is suspected. However, note that all patients had thrombocytopenia previously. Abdominal ultrasound with fibroscan, hepatic vein catheterization and liver biopsy were performed on all of them as part of the etiology of portal hypertension. In the abdominal ultrasound, indirect portal hypertension data were observed in all patients (as splenomegaly) cirrhosis was also ruled out. The fibroscan data showed significant liver fibrosis (F2-F3). Conclusion: Idiopathic portal hypertension following thiopurine treatment in IBD patients is a rare occurrence, but it must be borne in mind in the differential diagnosis for early diagnosis, especially in patients undergoing thiopurine treatment over a long period. The presence of thrombocytopenia is often the only predictor of its development in the preclinical stage (AU)

Shunt extrahepático. Causa rara de encefalopatía hepática / Extrahepatic shunt. Unusual cause of hepatic encephalopathy

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Prevalence of viral hepatitis (B and C) serological markers in healthy working population.

INTRODUCTION AND OBJECTIVES: prevalence of viral hepatitis (B and C) changes geographically. Our aim was to determinate the prevalence of hepatitis B (HBV) and hepatitis C virus (HCV) serological markers in healthy working population and to describe the epidemiological characteristics associated to its presence. METHODS: blood samples and epidemiological data of 5,017 healthy workers from Murcia and Madrid were recorded prospectively. RESULTS: a total of 5,017 healthy volunteers participated. Mean age 39 ± 11 years, men predominance (73 %). Prevalence of serological markers of HCV and HBV was 0.6 % and 0.7 %. Age of patients with HCV antibody was significantly higher (43 + or - 9 years vs. 39 + or - 11 years; p = 0.03). We observed significant differences in liver test values (alanine aminotransferase [ALT] 64 ± 56 IU/L vs. 28 ± 20 IU/L; p < 0.001; aspartate aminotransferase [AST] (51 + or - 45 IU/L vs. 23 + or - 12 IU/L; p < 0.001) and in gamma-glutamyltransferase(GGT) value (104 + or - 122 IU/L vs. 37 + or - 46 IU/L; p < 0.001. The presence of HCV antibody was related significantly to previous transfusion (13 % vs. 5 %; p = 0.03), tattoos (29 % vs. 13 %; p < 0.01), intravenous drug addiction (13 % vs. 0.2 %; p < 0.001) and coexistence with people with positive HCV antibody (16 % vs. 4 %; p < 0.001). In HBV no differences in basal characteristics were observed with exception in AST values (29 + or - 15 IU/L vs. 23 + or - 12 IU/L; p < 0.01). Hepatitis B surface antigen (HBsAg) was related significantly to previous transfusion (15 % vs. 5 %; p < 0.01), tattoos (26 % vs. 14 %; p = 0.04) and coexistence with people with positive HBsAg (17 % vs. 4 %; p < 0.001). CONCLUSIONS: Prevalence of serological markers in healthy working population is low. Risk factors for infection were previous transfusion and tattoos. Intravenous drug addiction was only a risk factor in HCV.

Prevalencia de marcadores serológicos de virus hepatotropos (B y C) en población trabajadora sana / Prevalence of viral hepatitis (B and C) serological markers in healthy working population

Introducción y objetivos: la prevalencia de las hepatitis víricas (B y C) varía geográficamente. Nuestro objetivo fue determinar la prevalencia de los marcadores serológicos de los virus de la hepatitis B (VHB) y de la hepatitis C (VHC) en población trabajadora sana describiendo las características epidemiológicas asociadas. Métodos: se recogieron prospectivamente muestras de sangre y datos epidemiológicos de 5.017 trabajadores sanos de Murcia y Madrid. Resultados: se incluyeron en el estudio 5.017 voluntarios sanos. Edad media 39 ± 11, 73 % varones. La prevalencia de los marcadores serológicos del VHC y el VHB fue de 0,6 % y 0,7 %, respectivamente. La edad de los pacientes con presencia de anti-VHC fue significativamente mayor (43 ± 9 años frente a 39 ± 11 años; p = 0,03). Se objetivaron diferencias significativas en los valores de transaminasas (alanina-aminotransferasa [ALT] 64 ± 56 UI/l frente a 28 ± 20 UI/l; p < 0,001; aspartato-aminotransferasa [AST] 51 ± 45 UI/l frente a 23 ± 12 UI/l; p < 0,001) y en los valores de gamma-glutamiltransferasa (GGT) (104 ± 122 UI/l frente a 37 ± 46 UI/l; p < 0,001). La presencia de anti-VHC se relacionó significativamente con transfusión previa (13 % frente a 5 %; p = 0,03), tatuajes (29 % frente a 13 %; p < 0,01), adicción a drogas por vía parenteral (ADPV) (13 % frente a 0,2 %; p < 0,001) y convivencia con personas con anti-VHC positivo (16 % frente a 4 %; p < 0,001). Respecto al VHB, no se evidenciaron diferencias en las características basales, a excepción de los valores de AST (29 ± 15 UI/l frente a 23 ± 12 UI/l; p < 0,01) El antígeno de superficie del VHB (AgHBs) se relacionó significativamente con transfusión previa (15 % frente a 5 %; p < 0,01), tatuajes (26 % frente a 14 %; p = 0,04) y convivencia con personas con AgHBs + (17 % frente a 4 %; p < 0,001). Conclusiones: la prevalencia de los marcadores serológicos del VHC y del VHB en población trabajadora sana es baja. Los factores de riesgo asociados a su presencia fueron la transfusión previa y la presencia de tatuajes. La ADVP se demostró como factor de riesgo solo en el caso del VHC (AU)

Introduction and objectives: prevalence of viral hepatitis (B and C) changes geographically. Our aim was to determinate the prevalence of hepatitis B (HBV) and hepatitis C virus (HCV) serological markers in healthy working population and to describe the epidemiological characteristics associated to its presence. Methods: blood samples and epidemiological data of 5,017 healthy workers from Murcia and Madrid were recorded prospectively. Results: a total of 5,017 healthy volunteers participated. Mean age 39 ± 11 years, men predominance (73 %). Prevalence of serological markers of HCV and HBV was 0.6 % and 0.7 %. Age of patients with HCV antibody was significantly higher (43 ± 9 years vs. 39 ± 11 years; p = 0.03). We observed significant differences in liver test values (alanine aminotransferase [ALT] 64 ± 56 IU/L vs. 28 ± 20 IU/L; p < 0.001; aspartate aminotransferase [AST] (51 ± 45 IU/L vs. 23 ± 12 IU/L; p < 0.001) and in gamma-glutamyltransferase (GGT) value (104 ± 122 IU/L vs. 37 ± 46 IU/L; p < 0.001. The presence of HCV antibody was related significantly to previous transfusion (13 % vs. 5 %; p = 0.03), tattoos (29 % vs. 13 %; p < 0.01), intravenous drug addiction (13 % vs. 0.2 %; p < 0.001) and coexistence with people with positive HCV antibody (16 % vs. 4 %; p < 0.001). In HBV no differences in basal characteristics were observed with exception in AST values (29 ± 15 IU/L vs. 23 ± 12 IU/L; p < 0.01). Hepatitis B surface antigen (HBsAg) was related significantly to previous transfusion (15 % vs. 5 %; p < 0.01), tattoos (26 % vs. 14 %; p = 0.04) and coexistence with people with positive HBsAg (17 % vs. 4 %; p < 0.001). Conclusions: prevalence of serological markers in healthy working population is low. Risk factors for infection were previous transfusion and tattoos. Intravenous drug addiction was only a risk factor in HCV (AU)