[Show abstract][Hide abstract] ABSTRACT: There is no established therapy for hepatitis E virus (HEV) infection. The aim of this retrospective, multicenter case series was to assess the effects of ribavirin as monotherapy for solid-organ transplant recipients with prolonged HEV viremia.
We examined the records of 59 patients who had received a solid-organ transplant (37 kidney-transplant recipients, 10 liver-transplant recipients, 5 heart-transplant recipients, 5 kidney and pancreas-transplant recipients, and 2 lung-transplant recipients). Ribavirin therapy was initiated a median of 9 months (range, 1 to 82) after the diagnosis of HEV infection at a median dose of 600 mg per day (range, 29 to 1200), which was equivalent to 8.1 mg per kilogram of body weight per day (range, 0.6 to 16.3). Patients received ribavirin for a median of 3 months (range, 1 to 18); 66% of the patients received ribavirin for 3 months or less.
All the patients had HEV viremia when ribavirin was initiated (all 54 in whom genotyping was performed had HEV genotype 3). At the end of therapy, HEV clearance was observed in 95% of the patients. A recurrence of HEV replication occurred in 10 patients after ribavirin was stopped. A sustained virologic response, defined as an undetectable serum HEV RNA level at least 6 months after cessation of ribavirin therapy, occurred in 46 of the 59 patients (78%). A sustained virologic response was also observed in 4 patients who had a recurrence and were re-treated for a longer period. A higher lymphocyte count when ribavirin therapy was initiated was associated with a greater likelihood of a sustained virologic response. Anemia was the main identified side effect and required a reduction in ribavirin dose in 29% of the patients, the use of erythropoietin in 54%, and blood transfusions in 12%.
This retrospective, multicenter study showed that ribavirin as monotherapy may be effective in the treatment of chronic HEV infection; a 3-month course seemed to be an appropriate duration of therapy for most patients.
New England Journal of Medicine 03/2014; 370(12):1111-20. DOI:10.1056/NEJMoa1215246 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With the growing role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension complications, a number of women of childbearing age are now being treated with TIPS. However, if pregnancy is unusual in patients with cirrhosis, it can occur in the case of noncirrhotic portal hypertension. To our knowledge, there are no data on pregnancy safety after TIPS insertion. We report the first case of a patient with noncirrhotic portal hypertension treated by TIPS who had two successful pregnancies. She presented with HIV-associated obliterative portopathy with recurrent variceal bleeding treated by TIPS. Pregnancies occurred later and progressed normally without maternal or fetal morbidity. There was no effect on TIPS patency, but only a moderate increase in the flow velocity in the portal vein, the stent, and the hepatic artery. Thus, TIPS does not seem to impair progression of pregnancy.
European journal of gastroenterology & hepatology 02/2014; 26(4). DOI:10.1097/MEG.0000000000000048 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C remains a challenging public health problem worldwide. The identification of viral variants establishing de novo infections and definition of the phenotypic requirements for transmission would facilitate the design of preventive strategies. We explored the transmission of HCV variants in three cases of acute hepatitis following needlestick accidents. We used single-genome amplification of glycoprotein E1E2 gene sequences to map the genetic bottleneck upon transmission accurately. We found that infection was likely established by a single variant in two cases and six variants in the third case. Studies of donor samples showed that the transmitted variant E1E2 amino-acid sequences were identical or closely related to those of variants from the donor virus populations. The transmitted variants harbored a common signature site at position 394, within hyper variable region 1 of E2, together with additional signature amino acids specific to each transmission pair. Surprisingly, these E1E2 variants conferred no greater capacity for entry than the E1E2 derived from non transmitted variants, in lentiviral pseudoparticle assays. Mutants escaping the antibodies of donor sera did not predominate among the transmitted variants either. The fitness parameters affecting the selective outgrowth of HCV variants after transmission in an immunocompetant host may thus be more complex than suggested by mouse models. Human antibodies directed against HCV envelope effectively cross-neutralized the lentiviral particles bearing E1E2 derived from transmitted variants. These findings provide insight into the molecular mechanisms underlying HCV transmission and suggest that viral entry is a potential target for the prevention of HCV infection.
Journal of Virology 10/2013; 87(24). DOI:10.1128/JVI.02119-13 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most clinical studies suggest that the prevalence and severity of liver steatosis are higher in patients infected with hepatitis C virus (HCV) genotype 3 than in patients infected with other genotypes. This may reflect the diversity and specific intrinsic properties of genotype 3 virus proteins. We analyzed the possible association of particular residues of the HCV core and NS5A proteins known to dysregulate lipid metabolism with steatosis severity in the livers of patients chronically infected with HCV. We used transmission electron microscopy to quantify liver steatosis precisely in a group of 27 patients, 12 of whom were infected with a genotype 3 virus, the other 15 being infected with viruses of other genotypes. We determined the area covered by lipid droplets in liver tissues and analyzed the diversity of the core and NS5A regions encoded by the viral variants circulating in these patients. The area covered by lipid droplets did not differ significantly between patients infected with genotype 3 viruses and those infected with other genotypes. The core and NS5A protein sequences of the viral variants circulating in patients with mild or severe steatosis were evenly distributed throughout the phylogenic trees established from all the collected sequences. Thus, individual host factors seem to play a much greater role than viral factors in the development of severe steatosis in patients chronically infected with HCV, including those infected with genotype 3 viruses.
PLoS ONE 03/2012; 7(3):e33749. DOI:10.1371/journal.pone.0033749 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis E virus (HEV) is an emerging problem amongst transplant recipients. We report a patient with chronic HEV hepatitis after a heart transplant. The patient received a 3-month course of oral ribavirin (17 mg/kg/day). HEV RNA became undetectable in the serum after 1 month of treatment and remained undetectable in serum and stool samples until the last follow-up, 2 months after completion of ribavirin therapy. The values of liver function indicators returned to normal reference ranges. The main ribavirin-induced side effect was a significant but well-tolerated anemia. We confirmed that ribavirin may induce a sustained virologic response (4 months after ribavirin cessation) in heart transplant patients with chronic HEV infection. Liver cytolysis is rather common in patients after heart transplantation. Rapid evolution to liver fibrosis lesions and available anti-viral therapy highlight the need to look for HEV infection in heart transplant recipients with unexplained hepatitis.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 07/2011; 30(7):841-3. DOI:10.1016/j.healun.2011.03.013 · 6.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The epidemic history of HCV genotype 5a is poorly documented in France, where its prevalence is very low, except in a small central area, where it accounts for 14.2% of chronic hepatitis C cases. A Bayesian coalescent phylogenetic investigation based on the E1 envelope gene and a non-structural genomic segment (NS3/4) was carried out to trace the origin of this epidemic using a large sample of genotype 5a isolates collected throughout France. The dates of documented transmissions by blood transfusion were used to calibrate five nodes in the phylogeny. The results of the E1 gene analysis showed that the best-fitting population dynamic model was the expansion growth model under a relaxed molecular clock. The rate of nucleotide substitutions and time to the most recent common ancestors (tMRCA) of genotype 5a isolates were estimated. The divergence of all the French HCV genotype 5a strains included in this study was dated to 1939 [95% HPD: 1921-1956], and the tMRCA of isolates from central France was dated to 1954 [1942-1967], which is in agreement with epidemiological data. NS3/4 analysis provided similar estimates with strongly overlapping HPD values. Phylodynamic analyses give a plausible reconstruction of the evolutionary history of HCV genotype 5a in France, suggesting the concomitant roles of transfusion, iatrogenic route and intra-familial transmission in viral diffusion.
Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 03/2011; 11(2):496-503. DOI:10.1016/j.meegid.2010.12.015 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Portal vein thromboses are frequent in cirrhotic patients and may be favoured by hypercoagulability in the splanchnic venous system. The coagulation balance and thrombin generation (TG) were evaluated in platelet-free plasma obtained from portal and systemic blood samples in 28 cirrhotic patients while undergoing transjugular intrahepatic porto-systemic shunt. TG assay (TGA) was performed with all samples from cirrhotic patients and with plasma samples from 14 healthy controls, with varying concentrations of tissue factor and phospholipids, with or without thrombomodulin. Screening tests and specific assays were also performed and activated partial thromboplastin time was shorter in portal plasma samples with higher FVIII and lower protein C levels, well correlated with Child-Pugh scores, and higher D-dimers and F1+2 levels However, all TGA parameters were similar in portal and jugular samples, possibly due in part to similar concentrations of factor II and antithrombin in these two sites of plasma sampling. TGA showed lower thrombin peaks and endogenous thrombin potential values in cirrhotic plasma compared to those of healthy controls. Importantly, a resistance to thrombomodulin that well correlated with factor VIII and PC levels, was evidenced in all samples from patients with cirrhosis, and was more significant in those from severely affected cases. This study therefore supports the existence of a relative hypercoagulability in the portal vein of cirrhotic patients that is likely due to protein C/S deficiency and to high FVIII levels.
Thrombosis and Haemostasis 10/2010; 104(4):741-9. DOI:10.1160/TH10-01-0040 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection.
Four hundred and sixty-seven patients were included into derivation (n=183) or validation (n=284) populations. Within these populations, the diagnostic target, significant fibrosis (Metavir F > or = 2), was found in 66% and 72% of the patients, respectively. Two new fibrosis tests, FibroMeter HICV and HICV test, were constructed in the derivation population.
Unadjusted AUROCs in the derivation population were: APRI: 0.716, Fib-4: 0.722, Fibrotest: 0.778, Hepascore: 0.779, FibroMeter: 0.783, HICV test: 0.822, FibroMeter HICV: 0.828. AUROCs adjusted on classification and distribution of fibrosis stages in a reference population showed similar values in both populations. FibroMeter, FibroMeter HICV and HICV test had the highest correct classification rates in F0/1 and F3/4 (which account for high predictive values): 77-79% vs. 70-72% in the other tests (p=0.002). Reliable individual diagnosis based on predictive values > or = 90% distinguished three test categories: poorly reliable: Fib-4 (2.4% of patients), APRI (8.9%); moderately reliable: Fibrotest (25.4%), FibroMeter (26.6%), Hepascore (30.2%); acceptably reliable: HICV test (40.2%), FibroMeter HICV (45.6%) (p<10(-3) between tests). FibroMeter HICV classified all patients into four reliable diagnosis intervals (< or =F1, F1+/-1, > or =F1, > or =F2) with an overall accuracy of 93% vs. 79% (p<10(-3)) for a binary diagnosis of significant fibrosis.
Tests designed for HCV infections are less effective in HIV/HCV infections. A specific test, like FibroMeter HICV, was the most interesting test for diagnostic accuracy, correct classification profile, and a reliable diagnosis. With reliable diagnosis intervals, liver biopsy can therefore be avoided in all patients.
Journal of Hepatology 08/2010; 53(2):238-44. DOI:10.1016/j.jhep.2010.03.007 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many researchers consider portal thrombosis (PT) as a contraindication to transjugular intrahepatic portosystemic shunt (TIPS). The aim of this retrospective study was to compare the feasibility and long-term prognosis of TIPS in cirrhotic patients, with and without, complete PT.
Four hundred and thirty-six consecutive cirrhotic patients with portal hypertension were referred for TIPS, between 1990 and 2004. These patients were divided into two groups according to their portal patency. PT+: 34 patients with complete PT with cavernoma (19) or without (15) cavernoma versus PT-: 402 patients with normal portal patency (308) and partial PT (94). Epidemiological data were compared using the chi and Student's t-tests, and comparative evolution was made from actuarial data using the log-rank test.
PT+ patients were more frequently women with viral hepatitis, and TIPS was performed more often for bleeding indications. The TIPS success rate was significantly lower in the PT+ group (79%) than in the PT- group (99.5%) (P<10). Presence of a cavernoma decreased the success rate to 63%. TIPS was always feasible in cases of recent PT and portal cavernoma with an accessible intrahepatic patent portal branch. Early and late outcome and complications were not significantly different between the two groups.
Complete PT does not modify TIPS' long-term outcome. Rather than a contraindication, PT should be considered as an indication for TIPS in cirrhotic patients with accessible intrahepatic portal vein. Further randomized studies should be planned in cirrhotic patients with recent PT to better qualify TIPS and anticoagulation indications, respectively.
European journal of gastroenterology & hepatology 03/2010; 22(9):1093-8. DOI:10.1097/MEG.0b013e328338d995 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Injection drug users are often excluded from hepatitis C virus (HCV) treatment. This study compares sustained virological response, adherence, and quality of life in patients with or without a history of illicit drug use in routine clinical practice.
This is a post-hoc analysis of a prospective, observational study conducted in 1860 patients who received peginterferon alpha-2b/ribavirin combination therapy. Nondrug users (NDUs) were defined as patients without a history of drug addiction; former drug users (FDUs) as patients who had stopped using illicit drugs or opioid maintenance therapy and active drug users (ADUs) as patients using illicit drugs or on opioid maintenance therapy. Virological response, adherence, and the health-related quality of life were assessed by the measure of HCV RNA in the serum, self-report and 36-item short-form health survey Questionnaire, respectively.
The analyzed population included 1038 (56%) NDUs, 578 (31%) FDUs, and 244 (13%) ADUs. About 85% of ADUs were on opioid maintenance therapy and 25% used illicit drugs. Although ADUs had a more chaotic lifestyle and more psychiatric disorders, sustained virological response of ADUs (58%) did not differ from that of NDUs (49%) and FDUs (51%) (P=0.133). Adherence rates were 39% in NDUs and FDUs, and 37% in ADUs (P=0.883). Health-related quality of life was improved in the three groups after the end of treatment.
Our study suggests that HCV therapy in ADUs on opioid maintenance therapy is as effective as in other HCV patients. The effectiveness of HCV therapy in illicit drug users needs to be evaluated in further studies.
European journal of gastroenterology & hepatology 03/2010; 22(9):1050-7. DOI:10.1097/MEG.0b013e328338d9aa · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The hepatitis C virus genotype is considered to be the most important baseline predictor of a sustained virological response in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. The influence of the subtype on the sustained virological response was investigated in patients infected with genotypes 1, 4, 5, or 6. This study was done on 597 patients with chronic hepatitis C who were given pegylated interferon and ribavirin for 48 weeks. The overall rate of sustained virological response in the 597 patients was 37.8%. Univariate analysis indicated that the sustained virological response of patients infected with subtype 1b (39%) tended to be higher than that of patients infected with subtype 1a (30.6%; P = 0.06) and it was similar to those patients infected with subtypes 4a (51.3%; P = 0.12) or 4d (51.7%; P = 0.16). Multivariate analysis indicated that five factors were independently associated with sustained virological response: the age (OR 0.97; 95% CI = 0.95-0.99), absence of cirrhosis (OR: 2.92; 95% CI = 1.7-5.0; P < 0.01), absence of HIV co-infection (OR: 2.08; 95% CI = 1.2-3.5; P < 0.01), low baseline plasma HCV RNA concentration (OR: 1.74; 95% CI = 1.2-2.6; P < 0.01), and the subtype 1b (OR: 1.61; 95% CI = 1.0-2.5; P = 0.04) or subtypes 4a and 4d (OR: 2.03; 95% CI = 1.1-3.8; P = 0.03). In conclusion, among difficult-to-treat genotypes, the subtype 1a is associated with a lower response to anti-HCV therapy than subtypes 1b, 4a, and 4d.
Journal of Medical Virology 12/2009; 81(12):2029-35. DOI:10.1002/jmv.21583 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis.
European Radiology 07/2009; 19(8). DOI:10.1007/s00330-009-1468-5 · 4.01 Impact Factor