Efficacy and safety of treatment of chronic hepatitis C with sofosbuvir and ribavirin with or without peginterferon: a French prospective real-life cohort study of unselected 211 patients.

INTRODUCTION: Sofosbuvir is the first directly-acting antiviral for the treatment of hepatitis C virus. First, the regimens were combinations with sofosbuvir+ribavirin (SR) or with sofosbuvir+ribavirin and pegylated-interferon α-2a (SPR) with cure rates around 90%. The aim of this study was to report the results of these combinations in 'real-life' in France. MATERIALS AND METHODS: Main features of patients treated with SR or SPR in 24 hospitals were collected. Undetectable hepatitis C virus week 12 viral load after treatment defined sustained virological response (SVR12). Statistics were performed using StatView software for descriptive analysis and χ for the sub-groups comparisons. RESULTS: Two hundred and eleven patients were analyzed. The average age was 56.1. One hundred and seventy-one (89%) patients had a fibrosis score of at least 3. Seventy-nine patients were infected by a genotype 1 (G1). One hundred and thirteen patients were treated with SR and 95 with SPR. In naive patients: with SPR for 12 weeks, SVR12 was 93% in G1, 100% in G3 and 83% in G4. With SR for 12 weeks, SVR12 was 100% in G2 patients (6/6). The safety of these regimens was satisfactory with only two patients who had to stop P due to severe side effects. Multivariate analysis shows a higher SVR in SPR versus SR (odds ratio = 1.28; P = 0.05) and in G2 or G3 versus others (odds ratio = 1.56; P = 0.04). Moreover, Child-Pugh score B or C (P = 0.02), platelets count under 100G/l (P = 0.05) or a past event of ascites (P = 0.04) was independently associated with less SVR. CONCLUSION: This multicenter large study confirms the good results of SR for 12 weeks in G2 naive patients. Finally, a decompensated cirrhosis, a past event of ascites and a baseline low platelet count were strongly associated with poor response.

Chronic Hepatitis C Treatment in Patients with Drug Injection History: Findings of the INTEGRATE Prospective, Observational Study.

INTRODUCTION: People who inject drugs represent an under-treated chronic hepatitis C virus (HCV)-infected patient population. METHODS: INTEGRATE was a prospective, observational study investigating the effectiveness, safety, and adherence in routine clinical practice to telaprevir in combination with peg-interferon and ribavirin (Peg-IFN/RBV) in patients with history of injecting drug use chronically infected with genotype 1 HCV. RESULTS: A total of 46 patients were enrolled and included in the intent-to-treat (ITT) population. Among heroin and/or cocaine users (n = 37; 80%), 22% reported use in the past month; 74% (34/46) of patients were on opioid substitution therapy in the pre-treatment phase, and 43% (20/46) discontinued HCV treatment prematurely. Sustained virologic response rate was 54% (25/46) in the ITT population and 74% (25/34) in the per protocol (evaluable-for-effectiveness) population. The main reason for failure in the ITT analysis was loss to follow-up (n = 8; 17%). Adverse events occurred in 91% (42/46) of patients. Mean patient-reported adherence to study drugs was >89% at Week 4, Week 12 and end of treatment. CONCLUSION: Despite a high rate of treatment discontinuation (including loss to follow-up), self-reported adherence to treatment was good and virologic cure rates were similar to those reported in large real-world cohorts. Our findings suggest that people with a history of injecting drug use should be considered for treatment of chronic HCV infection, and highlight the need for improvements in patient support to boost retention in care and, in turn, help to prevent reinfection and transmission. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01980290. FUNDING: Janssen Pharmaceuticals.

Endoscopic ultrasound-guided needle-based confocal laser endomicroscopy in solid pancreatic masses.

BACKGROUND AND STUDY AIMS: The differential diagnosis of solid pancreatic masses by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is currently suboptimal in centers that are not equipped with rapid on-site evaluation. Needle-based confocal laser endomicroscopy (nCLE) enables real-time in vivo microscopic imaging during endoscopy. This study aimed to describe nCLE interpretation criteria for the characterization of pancreatic masses, with histopathological correlation, and to perform the first validation of these criteria. PATIENTS AND METHODS: A total of 40 patients were evaluated by EUS-FNA combined with nCLE for the diagnosis of pancreatic masses. Final diagnosis was based on EUS-FNA histology and follow-up at 1 year. Five unblinded examiners defined nCLE criteria for adenocarcinoma, chronic pancreatitis, and neuroendocrine tumor (NET) using a set of video sequences from 14 patients with confirmed pathology (Step 1). These criteria were retrospectively validated by four independent, blinded examiners using sequences from 32 patients (Step 2). RESULTS: nCLE criteria were described for adenocarcinoma (dark cell aggregates, irregular vessels with leakages of fluorescein), chronic pancreatitis (residual regular glandular pancreatic structures), and NET (black cell aggregates surrounded by vessels and fibrotic areas). These criteria correlated with the histological features of the corresponding lesions. In the validation review, a conclusive nCLE result was obtained in 75 % of cases (96 % correct). Statistical evaluation provided promising results, with high specificity, and negative and positive predictive values for all types of pancreatic masses. CONCLUSION: Considering the low negative predictive value of EUS-FNA, nCLE could help to rule out malignancy after a previous inconclusive EUS-FNA. Larger studies are required to confirm these findings and to establish the role of nCLE in the diagnosis of pancreatic masses. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01563133).

In vivo characterization of pancreatic cystic lesions by needle-based confocal laser endomicroscopy (nCLE): proposition of a comprehensive nCLE classification confirmed by an external retrospective evaluation.

BACKGROUND AND AIMS: The differential diagnosis of solitary pancreatic cystic lesions is sometimes difficult. Needle-based confocal laser endomicroscopy (nCLE) performed during endoscopic ultrasound-fine-needle aspiration (EUS-FNA) enables real-time imaging of the internal structure of such cysts. Criteria have already been described for serous cystadenoma and intraductal papillary mucinous neoplasm (IPMN). The aims of the study were to determine new nCLE criteria for the diagnosis of pancreatic cystic lesions, to propose a comprehensive nCLE classification for the characterization of those lesions, and to carry out a first external retrospective validation . METHODS: Thirty-three patients with a lone pancreatic cystic lesion were included (CONTACT 1 study). EUS-FNA was combined with nCLE. Diagnosis was based on either pathology result (Group 1, n = 20) or an adjudication committee consensus (Group 2, n = 13). Six investigators, unblinded, studied cases from Group 1 and identified nCLE criteria for mucinous cystic neoplasm (MCN), pseudocyst (PC), and cystic neuroendocrine neoplasm (NEN). Four external reviewers assessed, blinded, the yield and interobserver agreement for the newly identified (MCN, PC) and previously described (IPMN, SC) criteria in a subset of 31 cases. RESULTS: New nCLE criteria were described for MCN (thick gray line), PC (field of bright particles), and cystic NEN (black neoplastic cells clusters with white fibrous areas). These criteria correlated with the histological features of the corresponding lesions. In the retrospective validation, a conclusive nCLE result was obtained for 74 % of the cases (87 % "true" and 13 % "false" with respect to the final diagnosis). On this limited case series, the nCLE criteria showed a trend for high diagnostic specificity (>90 % for mucinous cysts, 100 % for non-mucinous cysts). CONCLUSIONS: Based on this newly completed atlas of interpretation criteria, nCLE could facilitate the diagnosis of pancreatic cystic lesion types.

A novel approach to the diagnosis of pancreatic serous cystadenoma: needle-based confocal laser endomicroscopy.

BACKGROUND AND STUDY AIMS: The differential diagnosis of solitary pancreatic cystic lesions is frequently difficult. Needle-based confocal laser endomicroscopy (nCLE) performed during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a new technology enabling real-time imaging of the internal structure of such cysts. The aim of this pilot study was to identify and validate new diagnostic criteria on nCLE for pancreatic cystic lesions. PATIENTS AND METHODS: A total of 31 patients with a solitary pancreatic cystic lesion of unknown diagnosis were prospectively included at three centers. EUS-FNA was combined with nCLE. The final diagnosis was based on either a stringent gold standard (surgical specimen and/or positive cytopathology) or a committee consensus. Six nonblinded investigators reviewed nCLE sequences from patients with the most stringent final diagnosis, and identified a single feature that was only present in serous cystadenoma (SCA). The findings were correlated with the pathology of archived specimens. After a training session, four blinded independent observers reviewed a separate independent video set, and the yield and interobserver agreement for the criterion were assessed. RESULTS: A superficial vascular network pattern visualized on nCLE was identified as the criterion. It corresponded on pathological specimen to a dense and subepithelial capillary vascularization only seen in SCA. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of this sign for the diagnosis of SCA were 87 %, 69 %, 100 %, 100 %, and 82 %, respectively. Interobserver agreement was substantial (κ = 0.77). CONCLUSION: This new nCLE criterion seems highly specific for the diagnosis of SCA. The visualization of this criterion could have a direct impact on the management of patients by avoiding unnecessary surgery or follow-up.Clinicaltrials.gov NCT01563133.

Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis.

BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.

Endoscopic treatment of iatrogenic gastrointestinal perforations: an overview.

In the past, the treatment of iatrogenic gastrointestinal perforations was limited to surgical management or to medical observation. Natural Orifice Transluminal Endoscopic Surgery (NOTES) has paved the way towards the development of reliable endoscopic closure techniques, which can be applicable in accidental perforations of the gastrointestinal tract. When endoscopic treatment is feasible, hemoclips are preferred in smaller perforations, while over-the-scope-clips or a combination of hemoclips, endoloops, and glue are used in larger ones. Endoscopic stitching is rarely utilized, and endoscopic stapling has been practically abandoned. The use of self-expandable covered stents can be considered in the esophagus and duodenum. Broad spectrum antibiotics are recommended in most cases. Clinical follow-up in a medico-surgical unit is mandatory and surgical intervention should not be delayed more than 24h if clinical or biological worsening occurs. Imaging with oral contrast medium is advisable before resumption of oral feeding in the case of large perforations.

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890.

BACKGROUND & AIMS: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS: 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS: The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Longitudinal liver stiffness assessment in patients with chronic hepatitis C undergoing antiviral therapy.

BACKGROUND/AIMS: Liver stiffness (LS) measurement by means of transient elastography (TE) is accurate to predict fibrosis stage. The effect of antiviral treatment and virologic response on LS was assessed and compared with untreated patients with chronic hepatitis C (CHC). METHODS: TE was performed at baseline, and at weeks 24, 48, and 72 in 515 patients with CHC. RESULTS: 323 treated (62.7%) and 192 untreated patients (37.3%) were assessed. LS experienced a significant decline in treated patients and remained stable in untreated patients at the end of study (P<0.0001). The decline was significant for patients with baseline LS ≥ 7.1 kPa (P<0.0001 and P 0.03, for LS ≥ 9.5 and ≥ 7.1 kPa vs lower values, respectively). Sustained virological responders and relapsers had a significant LS improvement whereas a trend was observed in nonresponders (mean percent change -16%, -10% and -2%, for SVR, RR and NR, respectively, P 0.03 for SVR vs NR). In multivariate analysis, high baseline LS (P<0.0001) and ALT levels, antiviral therapy and non-1 genotype were independent predictors of LS improvement. CONCLUSIONS: LS decreases during and after antiviral treatment in patients with CHC. The decrease is significant in sustained responders and relapsers (particularly in those with high baseline LS) and suggests an improvement in liver damage.

Factors of accuracy of transient elastography (fibroscan) for the diagnosis of liver fibrosis in chronic hepatitis C.

UNLABELLED: The purpose of this study was to assess the influence of success rate and interquartile range on the accuracy of transient elastography for the diagnostic of fibrosis in hepatitis C virus infection. Two-hundred fifty-four consecutive patients had liver stiffness measurements and liver biopsy of at least 15 mm. Discordances of at least two stages between transient elastography and histological assessment were observed in 28 cases (11%). Factors of discordance were assessed by comparing the 28 misclassified cases with the 226 others. In multivariate analysis, fibrosis stage (F0-F2 versus F3-F4) and the ratio interquartile range/median value of liver stiffness measurement (IQR/M) were associated with discordances (P or= 0.21, discordances of at least two stages of fibrosis were respectively observed in 10 of 135 cases (7.4%) versus 18 of 119 cases (15.1%) (P or= 0.21 versus IQR/M < 0.21, for the diagnosis of liver fibrosis F >or= 2, F >or= 3, F = 4, areas under the receiver operating characteristic curve (AUROCs) were 0.80 (95% confidence interval [CI], 0.73-0.89) versus 0.81 (95% CI, 0.70-0.90), (P = NS); 0.80 (95% CI, 0.72-0.88) versus 0.89 (95% CI, 0.83-0.95) (P = 0.04); and 0.86 (95% CI, 0.77-0.94) versus 0.95 (95% CI, 0.92-0.99) (P = NS). No association was found between success rate and discordance. CONCLUSION: IQR/M is a factor of overestimation of liver fibrosis, and the most discriminant cutoff value is 0.21. Success rate is not a factor of accuracy for the diagnosis of hepatic fibrosis.

Non-invasive assessment of liver fibrosis by transient elastography in post transfusional iron overload.

BACKGROUND: Liver fibrosis, assessed by biopsy, is the main complication of post transfusional liver iron overload. Transient elastography (TE) is a new, non invasive method able to measure liver stiffness (LS) caused by fibrosis. METHOD: We prospectively evaluated the predictive value of LS measurement for liver fibrosis evaluation in 15 chronically transfused patients and compared these results with the METAVIR histological fibrosis stage from liver biopsies. RESULTS: Mean TE values significantly differed in patients with severe fibrosis (METAVIR F3, F4): 9.1 (+/-3.7 SD) kPa from those with mild or no fibrosis (METAVIR F0, F1, F2): 5.9 (+/-1.8 SD) kPa (P = 0.046). TE value above 6.25 kPa (Se = 80%; Sp = 70%; AUROC = 0.820) identified patients at risk for severe fibrosis (Negative Predictive Value 88%; Positive Predictive Value 57%). CONCLUSION: Transient elastography appears to be a reliable tool to evaluate liver fibrosis in post-transfusional iron overload.

Routine practice HCV infection screening with saliva samples: multicentric study in an intravenous drug user population.

OBJECTIVE: The purpose of this randomized multicentric study was to evaluate the diagnostic contribution of screening for HCV infection on saliva samples in day-to-day practice in the intravenous drug-user (IVDU) population. METHODS: Between January and May 2004, 274 presumably HCV-negative IVDU were screened for HCV infection in 15 centers in France (median age 29 years). After centralized randomization, screening tests were performed on blood samples (arm A) or saliva samples (arm B). Screening tests were performed in 78 subjects (28%) had never been screened before and in 196 subjects (72%) who had had a negative HCV screening test on average 12 months prior to the beginning of the study. In the event of a positive saliva test for anti-HCV Ab, a serum test for anti-HCV Ab was performed. In the event of a positive serum test for anti-HCV Ab, PCR was performed on serum to measure HCV-RNA. RESULTS: Fourteen individuals were positive for HCV RNA (7 in each arm). Six of these cases had not been detected before. In eight cases, the median time between the last negative screening test and study inclusion was 11 months (range 6-94 months). CONCLUSIONS: Viremia tests were positive in 5% percent of the target population, although one-third of the individuals in arm A (blood samples) were not tested. The saliva test may be a useful alternative in the event of refusal of a blood test or when poor venous conditions compromise venous puncture. A confirmatory blood test still remains difficult to obtain in nearly half of patients.

Acute hepatitis C during the third trimester of pregnancy.

A pregnant woman presented at 32 weeks of amenorrhea with jaundice secondary to acute hepatitis C. Spontaneous delivery took place 3 days later. The infant's serum tested negative for C viral RNA 6 months after delivery. Treatment with high doses of interferon-alpha for a period of 4 weeks was begun 4 days after delivery. Although a virological response was noted at the end of the treatment, the hepatitis relapsed and progressed toward chronicity. Case reports of acute hepatitis C during pregnancy are very rare, as the methods used for the follow-up of pregnant women render the diagnosis of asymptomatic forms difficult. In one case, the acute hepatitis C was severe. The occurrence of acute hepatitis C during pregnancy seems to increase the risk of premature delivery, but not that of vertical transmission. Given the frequency of side effects, it seems preferable not to begin interferon treatment until after delivery.

[Crohn's disease associated with interferon and ribavirin treatment for chronic hepatitis C]. / Maladie de Crohn au cours du traitement de l'hépatite chronique C par interféron et ribavirine.

Digestive side effects associated with interferon and ribavirin in the treatment of chronic hepatitis C seem to be non specific. So far, inflammatory bowel diseases have only been rarely described in this context. We report two cases of Crohn's disease which occurred a few months after interferon and ribavirin treatment for chronic hepatitis C. The first case was a 43 year old man treated for 7 months with a interferon and ribavirin combination for chronic hepatitis C who experienced colitis related to Crohn's disease, with the occurrence of articular and cutaneous manifestations. The second case was a 43 year old women treated for 8 months with a pegylated interferon and ribavirin combination for chronic hepatitis C who developed Crohn's disease with right ileo-colic topography and severe evolution requiring an ileo-coecal resection because of the failure of medical treatment. The alpha interferon used for its antiviral action against hepatitis C virus, has complex immuno-modulation effects which could reveal latent Crohn's disease.

[An inter-laboratory study of anti-HCV antibody detection in saliva samples]. / Etude inter-laboratoires de la détection des anticorps anti-VHC sur prélèvements salivaires.

AIM: The purpose of this study was to evaluate the efficacy of anti-hepatitis C virus (HCV) antibody detection in the saliva samples of 108 drug users in an inter-laboratory study. METHODS: Between January and June 2001, 108 subjects in Lille, Metz and Lens received a test to detect anti-HCV antibodies in their saliva. Two consecutive saliva samples were taken in each subject (Salivette system, Sarstedt). An HCV serology (Axsym HCV 3.0, Abbott) was also performed and serum HCV RNA detection by Amplicor HCV 2.0 (Roche) was performed when HCV serology was positive. Sixty three patients had a negative HCV serology, 45 had a positive HCV serology, and 31 of these had positive HCV RNA as well. Tests for the detection of the anti HCV antibody in saliva samples were performed as a blind study in both the Lille and the Thionville laboratories. RESULTS: The sensitivity of saliva anti-HCV antibody tests was respectively 71% (32/45) and 78% (35/45) in Lille and Thionville. In the event of positive HCV viremia, the sensitivity was respectively 90% (28/31) and 93% (29/31). The specificity was respectively 97% (61/63) and 98.5% (62/63). Results from the two laboratories agreed for 101 saliva tests while discrepancies were found in 7 (Kappa Concordance Coefficient: 0.85). CONCLUSIONS: This study confirms, in a large, unselected population sample, that anti-HCV antibody detection tests in saliva allow the detection of 90% of viremic HCV-antibody-positive patients with excellent specificity. The simplicity and reproductibility of this technique makes it a precious tool for epidemiological studies.