Impact of eradicating hepatitis C virus on the work productivity of chronic hepatitis C (CH-C) patients: an economic model from five European countries.

CH-C negatively affects work productivity (WP), creating a large economic burden. The aim of this study was to model the impact of sustained virologic response (SVR) on WP in CHC genotype 1 (GT1) patients in five European countries (EU5). Work Productivity and Activity Index-Specific Health Problem questionnaire was administered to patients across the ION clinical trials (n = 629 European patients). The analysis modelled a population of GT1 CHC patients over one year, who had been either not treated or treated with LDV/SOF. Sensitivity analyses assessed the possibility that CHC patients' labour costs were lower than the general population's and presented results by fibrosis stage. Before initiation of treatment, EU patients with CHC GT1 exhibited absenteeism and presenteeism impairments of 3.54% and 9.12%, respectively. About 91.8% of EU patients in the ION trials achieved SVR and improved absenteeism and presenteeism impairments by 16.3% and 19.5%, respectively. Monetizing these data, treatment with LDV/SOF resulted in an annual productivity gain of €435 million and a weighted average per-employed patient (PEP) gain of €900 in the EU5. PEP gains from treatment are projected to be higher in cirrhotic than in noncirrhotic patients. If CHC patients are assumed to earn 20% less than the general population, gains of €348 million (€720 PEP) annually are projected. CHC results in a significant economic burden to European society. Due to improvements in WP, SVR with treatment could provide substantial economic gains, partly offsetting the direct costs related to its widespread use.

Association between IL28B polymorphism, TNFα and biomarkers of insulin resistance in chronic hepatitis C-related insulin resistance.

TNFα has been shown to play a role in hepatitis C virus (HCV)-induced insulin resistance (IR). Polymorphism of the IL28B gene that encodes IFN-lambda 3 may be associated with IR through modulation of TNFα. The aim of this study was to investigate the relationship between IL28B rs12979860 genotype, the level of TNFα activation and the degree of IR in patients with chronic hepatitis C. One hundred and thirty-three nondiabetic genotype 1 HCV-infected patients with biopsy proven noncirrhotic hepatitis C were investigated for IR (using HOMA index), IL28B rs12979860 genotype and fasting circulating levels of soluble receptor 1 of TNFα (sTNFR1) and adipokines: leptin, adiponectin and IL-6. The HOMA-IR was positively correlated with serum levels of leptin (r = 0.35, P < 0.0001) and sTNFR1 (r = 0.35, P < 0.0001) but not with IL-6 or adiponectin. IL28B rs12979860 CC genotype was observed in 35% patients. Genotype CC and nongenotype CC patients were similar in terms of HOMA-IR (means 1.6 ± 0.9 vs 1.7 ± 1.4) and had similar circulating levels of sTNFR1 and adipokines. Independent factors associated with IR were ferritin (OR = 1.002, P = 0.02), leptin (OR = 1.06, P = 0.02) and sTNFR1 (OR = 7.9, P = 0.04). This study suggests that in nondiabetic, noncirrhotic, HCV genotype 1-infected patients, there is no relationship between IL28B rs12979860 genotype and HOMA-IR or sTNFR1 level. HCV-related IR may be mediated through TNFα independent of IL28B genotype.

The effect of ursodesoxycholic acid on duodenal adenomas in familial adenomatous polyposis: a prospective randomized placebo-control trial.

AIM: Duodenal adenomas occur in about 90% of patients with familial adenomatous polyposis (FAP) and are the second cause of death of patients who have had a prophylactic proctocolectomy. Studies suggest that biliary acids have a role in the development of duodenal adenomas. The aim of this study was to evaluate the impact of ursodesoxycholic acid (UDCA) on duodenal adenoma formation in patients with FAP. METHOD: A randomized, double-blinded, placebo-controlled study was carried out of 71 patients (20-65 years) who already had a restorative proctocolectomy. Subjects received either 10 mg/kg of UDCA orally per day or a placebo tablet for 24 months. The Spigelman severity score was determined after duodenal axial and lateral view endoscopy at 12 and 24 months. RESULTS: At 2 years 55 patients had completed the entire period of treatment. At the end of the follow-up period, nine (25%) patients in the UDCA group and seven (20%) in the placebo group had a decrease in the Spigelman score (P = 0.6142). Patients receiving UDCA had no side-effects (0%) compared with four (14%) in the placebo group (P = 0.0392). CONCLUSION: UDCA had no effect on the development of duodenal adenomas in FAP patients (NCT: 00134758).

Impact of HAART exposure and associated lipodystrophy on advanced liver fibrosis in HIV/HCV-coinfected patients.

The impact of antiretroviral drug exposure and associated lipodystrophy and/or insulin resistance (IR) on advanced liver fibrosis in HIV/HCV-coinfected patients is not fully documented. We determined the prevalence of advanced liver fibrosis (defined by hepatic stiffness ≥9.5 kPa) and associated factors, focusing on the impact of highly active antiretroviral therapy and its major adverse effects (lipodystrophy and IR), in 671 HIV/HCV-coinfected patients included in the ANRS CO13 HEPAVIH cohort. One hundred ninety patients (28.3%) had advanced liver fibrosis. In univariate analysis, advanced liver fibrosis was significantly associated with male sex, higher body mass index, HCV infection through intravenous drug use, a lower absolute CD4 cell count, a longer history of antiretroviral treatment, longer durations of protease inhibitors, non-nucleoside reverse transcriptase inhibitors and NRTI exposure, lipodystrophy, diabetes, and a high homeostasis model assessment method (HOMA) value. The only antiretroviral drugs associated with advanced liver fibrosis were efavirenz, stavudine and didanosine. In multivariate analysis, male sex (OR 2.0, 95% CI 1.1-3.5; P = 0.018), HCV infection through intravenous drug use (OR 2.0, 95% CI 1.1-3.6; P = 0.018), lipodystrophy (OR 2.0, 95% CI 1.2-3.3; P = 0.01), median didanosine exposure longer than 5 months (OR 1.7, 95% CI 1.0-2.8; P = 0.04) and a high HOMA value (OR 1.1, 95% CI 1.0-1.2; P = 0.005) remained significantly associated with advanced liver fibrosis. Mitochondrial toxicity and IR thus appear to play a key role in liver damage associated with HIV/HCV-coinfection, and this should be taken into account when selecting and optimizing antiretroviral therapy. Antiretroviral drugs with strong mitochondrial toxicity (e.g. didanosine) or a major effect on glucose metabolism should be avoided.

Longitudinal evaluation of viral interactions in treated HIV-hepatitis B co-infected patients with additional hepatitis C and D virus.

Virological interactions of hepatitis B (HBV), hepatitis C (HCV) and hepatitis D (HDV) viruses in HIV-infected patients have been poorly characterized especially under treatment influences. Undetection rates of hepatitis viruses were longitudinally analyzed in a 3-year cohort of 308 HIV-HBV co-infected patients and compared using Generalized Estimating Equation models adjusted for age, HIV-RNA, CD4 cell-count and antiviral treatment. Chronic hepatitis co-infection in HIV-infected patients (age years, SD) was: 265 HBV (40.7, 8.2); 19 HBV-HCV (39.7, 4.1); 12 HBV-HDV (35.2, 9.9); 12 HBV-HCV-HDV (39.2, 5.2). At inclusion, treatment with lamivudine/tenofovir was not significantly different between co-infection groups. HBV suppression was significantly associated with HDV (aOR = 3.85, 95%CI 1.13-13.10, P = 0.03) and HCV tri-infection (aOR = 2.65, 95%CI 1.03-6.81, P = 0.04), but marginally associated with HIV-HBV-HCV-HDV (aOR = 2.32, 95%CI 0.94-5.74, P = 0.07). In quad-infection, lower HDV-undetectability (vs HIV-HBV-HDV, P = 0.2) and higher HCV-undetectability (vs HIV-HBV-HCV, P = 0.1) were demonstrated. The degree of HBV suppression varied between visits and co-infection groups [range of aOR during follow-up (vs HIV-HBV co-infection): HIV-HBV-HCV = 2.23-5.67, HIV-HBV-HDV = 1.53-15.17]. In treated co-infected patients, HDV expressed continuous suppression over HCV- and HBV-replications. Peaks and rebounds from undetectable hepatitis B, C and/or D viremia warrant closer follow-up in this patient population. HDV-replication was uncontrolled even with antiviral treatment.

Ursodeoxycholic acid and chemoprevention of colorectal cancer.

Colorectal cancer is respectively the third and second most common cancer among men and women in France. Interest in chemoprevention for colorectal cancer has increased over the last two decades. Beside non-steroidal anti-inflammatory drugs, ursodeoxycholic acid (UDCA) may have chemopreventive action in colorectal cancer with a likely better tolerance. In high-risk populations such as patients with inflammatory bowel disease or prior colorectal adenoma or carcinoma, retrospective and prospective studies have suggested a beneficial effect of UDCA. In azoxymethane model, UDCA inhibits tumor development by countering the tumor-promoting effects of secondary bile acids, such as deoxycholic acid (DCA). The opposing effects of UDCA and DCA on lipid raft composition may be central to their effects on colonic tumorigenesis. Differential effects of DCA and UDCA on growth factor and inflammatory signals involved in colorectal carcinogenesis, such as epidermal growth factor receptors (EGFR) signaling and Cox-2 expression, likely mediate their opposing effects on colonic tumor promotion and tumor inhibition, respectively.

Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone.

BACKGROUND/AIMS: To assess the benefit of the UDCA-budesonide combination in association with mycophenolate mofetil (MMF) in patients with primary biliary cirrhosis (PBC) at high risk of developing cirrhosis or liver failure. METHODS: Inclusion criteria for this three-year open study were: 1) suboptimal biochemical response to one-year UDCA therapy at 13-15 mg/kg/d; 2) significant interface hepatitis without cirrhosis at liver biopsy. Treatment regimen included UDCA (13-15 mg/kg/d), budesonide (6 mg/d) and MMF (1.5 g/d). All patients underwent a control biopsy at three years. RESULTS: Fifteen patients fulfilled the inclusion criteria. Six patients (41%) normalized biochemistries and seven (47%) had a partial but significant biochemical response, as defined by a serum bilirubin less than 17 micromol/L, alanine aminotransferase less than 70 UI/L and alkaline phosphatase less than 250 UI/L. Histological activity and fibrosis were markedly improved. Side effects were minimal or absent. CONCLUSIONS: Triple therapy with UDCA, budesonide and MMF may provide benefit in non-cirrhotic PBC patients with features of severe disease not responding to UDCA.

Metabolic disorders and chronic viral disease: the case of HIV and HCV.

The importance of metabolic disorders in the pathophysiology of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections is becoming increasingly apparent. Metabolic anomalies, with their potential for multiple-organ involvement, are to be expected, given the chronic nature of these diseases, and the intracellular dysregulation associated with them. Not only have the endocrine and cytokine metabolic anomalies seen in HIV and HCV infections been linked with the metabolic syndrome, but they also appear to have some pathways in common. Studying the differences and similarities between these metabolic anomalies may add to our understanding of HIV and HCV infection, and provide guidance on how to treat these chronic diseases. This review highlights the principal underlying factors for metabolic disorders in these chronic viral diseases-namely insulin resistance and liver damage. Both the chronic viral state itself and the host immune response give rise to glucose and lipid metabolic disorders that, in turn, are risk factors for hepatic damage. The various interactions between HIV and/or HCV with insulin resistance, type 2 diabetes, steatosis and fibrogenesis should be considered when determining the treatment and long-term follow-up of patients. Recent data indicate that HCV clearance improves insulin resistance and hepatic function in HCV-infected patients treated with interferon with or without ribavirin.

Definition and natural history of metabolic steatosis: clinical aspects of NAFLD, NASH and cirrhosis.

Metabolic steatosis or non-alcoholic fatty liver (NAFLD) is the most common cause of chronic liver injury in Western countries. Histological signs of necroinflammation, indicating the presence of non-alcoholic steatohepatitis (NASH), are present in 20-30% of cases. While steatosis on its own has a benign course, NASH may be associated with fibrosis and may progress to cirrhosis, terminal liver failure and hepatocellular carcinoma. NAFLD is closely associated with the metabolic syndrome, its prevalence reaching 50-90% in obese patients. The clinical impact of NAFLD has been demonstrated in large cohort studies by the overprevalence of cirrhosis and hepatocellular carcinoma in obese and diabetic patients. In terms of survival, liver disease is the third most common cause of mortality in patients with NAFLD. When associated with other causes of liver disease such as alcohol consumption or hepatitis C infection, metabolic steatosis may be a major risk factor for disease progression.

[Alcohol, steatohepatitis, insulin resistance and hepatitis C]. / Alcool, stéatohépatite métabolique, insulinorésistance et hépatite C.

Patients with chronic hepatitis C have frequently other morbidities, either because they are frequent in the general population (metabolic syndrome) and/or because the route of contamination (chronic alcohol consumption succeeding to drug abuse). These co-morbidities have a harmfull impact on fibrosis progression during the natural history of HCV infection and reduce the efficacy of antiviral treatments. Thus, it is crucial to diagnose early and treat these different diseases which may be combined. They are the metabolic syndrome and/or chronic alcohol consumption resulting in insuline resistance, infection by the human immune deficiency virus or by the hepatitis B virus as well as chronic tobacco use or excessive consumption of cannabis. An optimal is based on a multidisciplinary approach to reduce fibrosis progression and improve the efficiency of antiviral therapies. However, the hepatologist has to come back to a global care, which is mandatory at the individual level as well as for the public health.

A Model-Based Illustrative Exploratory Approach to Optimize the Dosing of Peg-IFN/RBV in Cirrhotic Hepatitis C Patients Treated With Triple Therapy.

Hézode et al. recently reported the frequent occurrence of anemia and thrombocytopenia in the ANRS-CO20-CUPIC cohort of hepatitis C virus (HCV) cirrhotic experienced patients treated with pegylated-interferon (Peg-IFN), ribavirin (RBV), and telaprevir or boceprevir.1,2 Using frequent measurements of serum drug concentrations, hemoglobin, and platelet concentrations obtained in 15 patients of this cohort, we show how an on-treatment model-based approach could be used to individualize dose regimen and avoid the occurrence of RBV-induced anemia and Peg-IFN-induced thrombocytopenia.

Impact of early-untreated HIV infection on chronic hepatitis C in intravenous drug users: a case-control study.

OBJECTIVE: The impact of early-untreated HIV infection on chronic hepatitis C was determined in a case-control study, aimed at limiting factors associated with the progression of immunodeficiency. METHODS: HIV-infected patients attending for a medical examination during 1995-1996 were systematically screened for: previous intravenous drug use without other HIV or Hepatitis C virus (HCV) risk factor, CD4 cell count > 200/microl, no AIDS, no antiretroviral treatment, positive anti-HCV antibody, negative hepatitis B surface antigen, abnormal aminotransferase activity. Thirty-eight consecutive eligible HIV-infected patients (cases) were included. Thirty-eight HCV-infected patients without HIV infection whose unique risk factor was intravenous drug use (controls) were paired to cases according to age, sex, and duration of HCV infection. RESULTS: Cases and controls had similar ages, sex ratios, duration of HCV infection, and alcohol intake. They were infected predominantly by genotypes 1 and 3. Viraemia was higher in cases than in controls. METAVIR histological scores of activity and fibrosis in cases versus controls were 2.2 +/- 0.8 versus 1.6 +/- 0.7 (P = 0.0008) and 1.8 +/- 1 versus 1.5 +/- 0.8 (P = 0.06), respectively. The percentage of cirrhosis was higher in cases, without reaching statistical difference. The progression rate of fibrosis was higher in cases. Age at contamination and METAVIR activity score were significantly associated with the progression of fibrosis in cases. CONCLUSION: Early-untreated HIV infection is associated with higher HCV viraemia and more severe liver injury in intravenous drug users with chronic hepatitis C.

[Hemorrhagic ascites disclosing massive Fasciola hepatica infection]. / Ascite hémorragique révélant une infection massive à Fasciola hepatica.

Multi-organ infection with Fasciola hepatica is uncommon. We report a case of severe infection with Fasciola hepatica as a cause of liver and peritoneum injuries with hemorrhagic ascites as well as pulmonary, pericardial, splenic and portal system injuries in a 37-year old man who was a native of Green Cape. The patient was in poor general health, had a major inflammatory syndrome, and polyclonal hypergammaglobulinemia (90 g/L). The diagnosis was confirmed by positive distomatosis serology and the presence of eggs of Fasciola hepatica in the histological samples of the liver and peritoneum. After treatment with praziquantel then triclabendazole, the global outcome was favorable.

[Chronic viral hepatitis C. Anatomoclinical and biological correlations]. / Hépatite chronique virale C. Corrélations anatomo-cliniques et biologiques.

OBJECTIVES: The relations between the severity of histopathological lesions and epidemiological, clinical and biological data were studied in 86 patients with chronic viral hepatitis C. PATIENTS AND METHODS: None of the patients had any clinical signs of decompensated liver disease. Three groups of patients were individualized according to histopathological findings: 17 (20%) had chronic persistent hepatitis, 48 (56%) had chronic active hepatitis without cirrhosis, and 21 (24%) had cirrhosis. RESULTS: Patients with cirrhosis differed significantly from patients in the two other groups for all biological parameters. With multivariate analysis, alkaline phosphatase activity and serum hyaluronic acid were two independent parameters significantly associated with cirrhosis. A serum hyaluronic acid level above 150 micrograms/L or alkaline phosphatase activity above normal were predictive of cirrhosis with a sensitivity of 87% and a specificity of 93%. None of the parameters in this study provided a clear distinction between patients with chronic persistent and chronic active hepatitis. CONCLUSION: Determination of serum hyaluronic acid and alkaline phosphatase activity as a non invasive index of cirrhosis could be useful for diagnosis and follow-up in patients with chronic viral hepatitis C.

[Hepatitis C]. / L'hépatite C.

Hepatitis C virus (HCV), identified in 1989, is the main agent of Non-A, Non-B hepatitis. The number of HCV carriers in France is estimated between 500,000 and 2 millions. The main risk factors for HCV infection are blood products transfusion and i.v. drug abuse. Cirrhosis occurs in 30% of cases with a delay ranging from 10 to 30 years, and hepatocellular carcinoma in 2.5% of cases. Interferon is, for instance, the only effective therapy in patients with chronic hepatitis C; however, prolonged response (in terms of transaminase normalization) after stopping treatment occurs only in 20% of patients.

[Non-transfusional and non-intravenous drug addiction related transmission of hepatitis C virus]. / Modes de transmission non transfusionnelle et non par toxicomanie intra-veineuse du VHC.

PARENTERAL TRANSMISSION: Among subjects infected by the hepatitis C virus (HCV), about 40% have no history of blood transfusion or intravenous drug abuse. The highly variable presence of HCV in biological fluids other than blood would suggest that HVC transmission basically follows the parenteral route. Transmission of HCV via medical material contaminated by blood of an infected subject is a clinical reality: accidental needle prick, medical material (endoscope, physician-patient), tattooing, acupuncture, ear piercing, certain traditional practices, sharing toilet instruments (tooth brush, razor, fingernail shears). RARE SEXUAL TRANSMISSION: The prevalence of HCV infection is higher in people living with infected subjects, particularly spouses, than in the general population. However, transmission of HCV in this population probably follows a parenteral route (common risk factors, sharing toilet instruments) rather than by sexual transmission which plays a minor role except in sexually transmitted diseases with genital lesions. MOTHER-INFANT TRANSMISSION: Per- or post-partum transmission is possible though the risk is low, less than 5% of all infants are infected at the age of 1 year. The data are contradictory, but breast feeding would appear to play a role. Co-infection by the HIV virus, via high HCV viremia, clearly increases the risk of mother-infant transmission and perhaps also sexual transmission. NOSOCOMIAL TRANSMISSION: Nosocomial transmission is probably the most important factor in HCV transmission, but the risk remains to be quantified.

[Cholestatic icterus induced by the administration of fusidic acid in a cirrhotic patient]. / Ictère cholestatique induit par la prise d'acide fucidique chez un patient cirrhotique.

INTRODUCTION: Fucidic acid is an antibiotic essentially used to treat staphylococcal infections. Its chemical structure is very similar to that of bilary acids and hence implies competitive mechanisms between their elimination and metabolization. OBSERVATION: A patient with a past history of alcohol-induced cirrhosis was treated with fucidic acid for a Staphylococci aureus urinary infection. On day 2 of treatment a conjugate bilirubine icterus appeared. There was no argument to suggest a decompensation of the icterus. The icterus disappeared on suspension of fucidic acid. COMMENTS: The occurrence of an icterus in a cirrhotic patient may evoke decompensation of the hepatopathy and an extensive exploration must be made. A thorough survey of all drug administration must be made. Notably, the possibility of the occurrence of a connective bilirubin icterus during treatment with fucidic acid must be known. The icterus always regresses on withdrawal of treatment and this etiology must be evoked before conducting invasive examinations.

[Prevention and treatment of hepatitis C]. / Prophylaxle et traitement de l'hépatite C.

Interferon is the only treatment shown to be effective on hepatitis C in controlled trials. The response to treatment is generally assessed in terms of a return to normal transaminase activity, but also negative PCR testing for viral RNA and histopathological examination of the liver. At a dose of 3 MU three times a week for 6 months, 25% of patients have a persistent return to normal transaminase activity, 25% relapse when interferon is withdrawn, and the remaining 50% have persistently high levels at the end of treatment and are considered resistant. The rate of persistent responses increases to 40% when treatment is extended to one year. Viral RNA becomes undetectable in the serum of 80% of these responders. Most also have a histological improvement, but so do a number of patients who relapse or who are resistant. In the longer term, interferon could prevent the onset of liver cancer in patients with viral C cirrhosis. Interferon is generally well tolerated at the doses currently used, most side effects (hematologic, neuropsychiatric and thyroid disorders) resolving when treatment is stopped. The following factors are clearly predictive of the response to interferon : young age, short time since onset, absence of cirrhosis, lower-level viremia, and infection by HCV genotypes other than 1b. Interferon is markedly less effective in immunodeficient patients (transplant, HIV infection, etc.). Several add-on treatments have been tried, but ribavirin appears to be the most promising, both during initial interferon therapy and for patients who relapse or are resistant to a first course. Interferon therapy of the acute phase of hepatitis C significantly reduces the risk of chronic liver disease. There is no vaccine against HCV infection.

Toxic hepatitis induced by a herbal medicine: Tinospora crispa.

Herbal remedies are becoming increasingly popular in many countries. Tinospora species (Menispermaceae) is commonly used as a herbal medicine in South Asia, but very few toxic effects have been described. We report a case of acute hepatitis associated with chronic use of high doses of Tinospora crispa. A 49-year-old male with chronic low back pain bought a herbal medicine at a market in Vietnam that was supposed to be Tinospora crispa, and started to take 10 pellets per day. He had no medical history and did not take any other drugs or toxins. Four weeks later; he developed dark urine and pale stools, associated with asthenia and right hypochondrial pain. Two months after starting treatment, he was referred to the hepatology department with jaundice. Blood tests showed aspartate aminotransferase: 1.169 IU/l, alanine aminotransferase: 2.029 IU/l, total bilirubin: 20.47 mg/dl, direct bilirubin: 13.29 mg/dl, and γ-glutamyltransferase: 243 IU/l. Viral and autoimmune hepatitis were eliminated. Upper abdominal ultrasound was normal. Histopathological findings were consistent with a toxic reaction. The herbal medicine was stopped on admission and the patient fully recovered without treatment, with normal liver function 2 months after the acute episode. Tinospora crispa was clearly identified in the pellets by microscopic analysis of the botanical characters combined with chromatographic fingerprints. The use of herbal medicines containing Tinospora crispa can induce toxic hepatitis. Recovery can be complete after discontinuation. This case highlights the risk associated with traditional herbal remedies.