Renal dysfunction associated with telaprevir-containing triple therapy for chronic hepatitis C: is early prediction possible?

INTRODUCTION: Renal dysfunction has recently been described as a potential complication of tritherapy with telaprevir (TVR) in patients with chronic hepatitis C. This study aimed to identify predictive factors for and consequences of TVR-associated renal dysfunction. PATIENTS AND METHODS: A retrospective-prospective study was carried out in 96 patients with chronic hepatitis C, genotype 1, treated with TVR-based tritherapy in 2012-2013, in whom regular serum creatinine measurements were performed during the first 12 weeks of treatment. The patients received standard doses of peginterferon, ribavirin and TVR (2250 mg/day). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula. RESULTS: eGFR decreased significantly from baseline at weeks 4, 8 and 12, the mean maximum decrease being 22.0±23.6 ml/min, with a significant correlation between baseline and minimum eGFR (r=0.58, P<10), stronger between week 2 and minimum eGFR in the subgroup of 62 patients in whom creatinine measurement was performed at week 2. Thirteen patients had an eGFR below 60 ml/min during treatment. Age and baseline eGFR were independent predictors of eGFR below 60 ml/min in the entire population, and only week 2 eGFR when available. The decrease in haemoglobin was significantly correlated with the decrease in eGFR. Age, baseline haemoglobin and the maximum variation in eGFR were independent predictors for minimum haemoglobin. The patients with decreased eGFR had more severe anaemia, and received more blood transfusions and erythropoietin. Renal dysfunction regressed in all patients after stopping TVR. CONCLUSION: The reversible decrease in eGFR in patients receiving TVR-containing tritherapy can be predicted early, possibly allowing measures aimed at preventing anaemia.

Epidemiology and adherence to guidelines on the management of bleeding peptic ulcer: a prospective multicenter observational study in 1140 patients.

BACKGROUND AND OBJECTIVE: Mortality of upper gastrointestinal bleeding seems declining. Whether practice guidelines for the management of peptic ulcer bleeding are followed is unknown. We aimed to update epidemiology of peptic ulcer bleeding and to assess the adherence to guidelines in the French community. METHODS: Between March, 2005 and February, 2006, a prospective multicenter study was conducted including all patients with communautary upper gastrointestinal bleeding. Data from patients with peptic ulcer bleeding were extracted and analyzed. RESULTS: Out of 3203 analyzable patients included, 1140 (35.6%) had a peptic ulcer bleeding and 965 of them a duodenal and/or gastric ulcer. Seven hundred and thirty-five were male (64.5%) and mean age was 66.4 years (±18.8). Overall, 699 patients (61.3%) were taking medication inducing upper gastrointestinal bleeding. Two-hundred and sixty-eight (23.5%) patients had endoscopic therapy, 190 (70.9%) of whom had epinephrine injection alone. Among the 349 patients with high risk stigmata on endoscopy (Forrest IA, IB, IIA), 209 (59.9%) underwent endoscopic therapy. One thousand one hundred and seven patients (97.1%) were given proton-pump inhibitors. One hundred and thirty-four patients (11.8%) experienced haemorrhagic recurrence. Forty-eight patients (4.2%) underwent surgery and 61 (5.4%) died. CONCLUSIONS: Consistently with previous studies, mortality of upper gastrointestinal bleeding seems declining. Further progress lies above all in prevention but also probably in better adherence to therapeutic guidelines and management of comorbidities.

Treatment of chronic hepatitis C with pegylated interferon and ribavirin in treatment-naive patients in 'true life': a plea in favor of independent postmarketing evaluations.

BACKGROUND: Results of treatments for chronic hepatitis C virus are only estimated and disclosed from pivotal trials. AIM: To report the 'true life' results of pegylated interferon and ribavirin in treatment-naive patients. METHODS: A prospective, multicenter observatory in 22 general hospitals. RESULTS: Five-hundred and one patients were included, with 309 men (62%), aged 46 ± 11 years, weighting 70 ± 13 kg, infected with the following hepatitis C virus genotypes: 1 (50%), 2 (12%), 3 (28%), 4 (7.5%), 5 (0.6%). Liver biopsy, available in 436 patients showed stage F3 fibrosis in 24% and F4 in 13%. Two-hundred and seven patients had a comorbid condition. Treatment consisted of interferon alpha 2b in 340 patients and interferon alpha 2a in 161 patients. Dose reductions were necessary in 145 patients (29%). Treatment was prematurely interrupted in 145 patients (29%) owing to lack of efficacy (n =72) or side-effects (n =73). Sustained virological response (SVR) rates were 50% for all patients, and 37.1, 70.5, and 71% for patients with genotype 1, 2 and 3, respectively. At multivariate analysis, age, genotype, and fibrosis severity were the only independent factors of SVR. CONCLUSION: In true life, patients are older and more severe, and SVR is about 10% lower than in pivotal trials.

Analysis of candidate genes in occurrence and growth of colorectal adenomas.

Predisposition to sporadic colorectal tumours is influenced by genes with minor phenotypic effects. A case-control study was set up on 295 patients treated for a large adenoma matched with polyp-free individuals on gender, age, and geographic origin in a 1 : 2 proportion. A second group of 302 patients treated for a small adenoma was also characterized to distinguish effects on adenoma occurrence and growth. We focussed the study on 38 single nucleotide polymorphisms (SNPs) encompassing 14 genes involved in colorectal carcinogenesis. Effect of SNPs was tested using unconditional logistic regression. Comparisons were made for haplotypes within a given gene and for biologically relevant genes combinations using the combination test. The APC p.Glu1317Gly variant appeared to influence the adenoma growth (P = .04, exact test) but not its occurrence. This result needs to be replicated and genome-wide association studies may be necessary to fully identify low-penetrance alleles involved in early stages of colorectal tumorigenesis.

Prevalence of hepatitis C infection and risk factors in hospitalized diabetic patients: results of a cross-sectional study.

OBJECTIVES: Although there may exist a nosocomial risk of hepatitis C virus (HCV) infection in patients with type 1 or type 2 diabetes, this risk has not been fully investigated thus far and its magnitude is unknown. The aim of this multicenter cross-sectional study was to evaluate the prevalence of, and risk factors for, hepatitis C infection in consecutive hospitalized patients with diabetes and to assess the nosocomial risk and magnitude of HCV infection in these patients. PATIENTS AND METHODS: Consecutive hospitalized patients with diabetes seen in 11 French hepatogastroenterology and diabetology departments were studied. The prevalence of anti-HCV antibodies was compared with that observed in healthy blood donors and individuals seen during routine medical checkup. Diabetic patients with anti-HCV antibodies were compared with patients without anti-HCV antibodies for assessment of risk factors. RESULTS: In total 1561 patients were studied. Independent risk factors for HCV infection were assessed through multivariate analysis. Thirty-three patients (2.11%) had anti-HCV antibodies and 21 (63.70%) had HCV identified risk factors. The prevalence of HCV infection was higher in patients with diabetes than in blood donors (0.08%) or healthy controls (0.20%) (P<0.001). Multivariate analysis identified four independent risk factors for HCV infection: blood transfusion before 1991 [odds ratio (OR)=2.88, P=0.033], intravenous drug use (OR=21.37, P=0.012), treatment in a hepatogastroenterology center (OR=4.17, P=0.002) and a high number (>2) of previous admissions since the onset of diabetes (OR=2.52, P=0.039). CONCLUSION: A nosocomial source of HCV infection in hospitalized diabetic patients is suggested by the increased risk of HCV infection associated with the number of hospitalizations. This may account for at least 36% of cases of HCV infection.

Mitochondrial D310 mutations in colorectal adenomas: an early but not causative genetic event during colorectal carcinogenesis.

Somatic mutations of the D310 sequence of the mitochondrial DNA are reported in human cancers, including colorectal cancers (CRC). The presence of these mutations at early or late steps of colorectal carcinogenesis is unknown. Their prevalence increased significantly with the number of cytosines in the D310 sequence of the matched normal tissue (D310 polymorphism), suggesting that this polymorphism could be a risk factor for CRC. The aim of this study was (i) to investigate the prevalence of D310 mutations in 64 colorectal adenomas and 36 liver metastases from 15 CRC patients, (ii) to assess the relation between D310 polymorphism and the risk of colorectal adenoma in a case-control study including 613 cases with colorectal adenoma and 572 polyp-free (PF) controls. D310 mutations were found in colorectal adenomas and liver metastases from CRC patients in 27 and 33%, respectively and so are an early genetic event in colorectal carcinogenesis. The frequency of the mutations increased significantly with the number of cytosines in the matched normal tissue D310 sequence (p < 0.001) but the distribution of D310 polymorphisms was not significantly different between adenoma cases (large (>9 mm) and small (<5 mm) adenomas) and PF controls (C(4)-C(7)TC(6): 47, 52 and 49%; C(8)TC(6): 44, 39 and 41%; C(9)-C(10)TC(6): 9, 9 and 10%, respectively; p > 0.05), suggesting that germline D310 polymorphism is not a risk factor for colorectal adenomas. Considering their high frequency in colorectal adenomas, mitochondrial D310 mutations could represent a biomarker for early detection of CRC although their causative role in colorectal carcinogenesis remains uncertain.

Colonoscopic screening of first-degree relatives of patients with large adenomas: increased risk of colorectal tumors.

BACKGROUND & AIMS: The risk of developing colorectal neoplasia is not well established among family members of individuals with large adenomas, and screening strategies remain under debate in this population. This study aimed at quantifying the risk of colorectal adenomas and cancers using colonoscopic screening in first-degree relatives of patients with large adenomas. METHODS: This case-control study was performed in 18 endoscopic units of French nonuniversity hospitals. A colonoscopy was offered to first-degree relatives of 306 index cases with adenomas > or =10 mm if they were alive, aged 40-75 years, and could be contacted by the index case. Among them, 168 were examined and matched for age, sex, and geographical area with 2 controls (n = 307). Controls were randomly selected from 1362 consecutive patients aged 40-75 years having undergone a colonoscopy for minor symptoms. RESULTS: The prevalence of large adenomas and cancers was 8.4% and 4.2%, in relatives and controls, respectively. Odds ratios (ORs) associated with a history of large adenomas in relatives were 2.27 (95% confidence interval [CI], 1.01-5.09) for cancers or large adenomas, 1.21 (95% CI, 0.68-2.15) for small adenomas, and 1.56 (95% CI, 0.96-2.53) for all colorectal neoplasia. The risk of large adenomas and cancers was higher in relatives of index cases younger than 60 years (OR, 3.82; 95% CI, 0.92-15.87) and when the index case had large distal adenomas (OR, 3.14; 95% CI, 1.27-7.73). CONCLUSIONS: First-degree relatives of patients with large adenomas are at increased risk of developing colorectal cancers or large adenomas. This result has implications for screening in this high-risk population.

Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma.

BACKGROUND: Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. METHODS: Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. RESULTS: No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95% CI: 1.20-2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95% CI: 1.08-3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. CONCLUSION: These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis.

High dose daily interferon-alpha induction and secondary adjunction of ribavirin in treatment-naive patients with chronic hepatitis C. A multicentric, randomised, controlled trial.

OBJECTIVES: To evaluate in naive patients with chronic hepatitis C 1- the efficacy and safety of one month interferon alpha (IFN-alpha) induction regimen; 2- the potential virological benefit of a secondary adjunction of ribavirin among HCV RNA negative patients after 20 weeks of IFN therapy, with or without an initial 4-week IFN induction. MATERIAL AND METHODS: 151 naive HCV-RNA positive patients presenting with biopsy- proven chronic hepatitis C and elevated ALT were randomised in a 2: 1 ratio in two arms: IFN-alpha 3 MU thrice a week (tiw) for 24 weeks (non-induced patients); IFN-alpha 6 MU daily for two weeks, then 3 MU daily for two weeks then 3 MU tiw for 20 weeks (induced patients). At week 24, HCV-RNA negative patients were randomised to receive in addition or not ribavirin 1-1.2 g daily for 24 additional weeks. Induction efficacy was assessed on the early viral response (EVR) defined as undetectable HCV RNA at week 4 then week 20. Ribavirin efficacy was assessed on the proportion of maintained complete response until the end of follow-up, 24 weeks after discontinuation of treatment. Data were analysed on an intent-to-treat basis. RESULTS: Efficacy of IFN-alpha induction: 104 patients were randomised to the non-induction group, 47 to the induction group. Gender, age, genotype distribution and HCV viral load at baseline did not differ significantly between the two groups. There was one treatment discontinuation because of adverse events in induced patients versus four in non-induced patients (P > 0.05). The 4 week EVR was significantly greater in induced patients in patients with HCV genotype 1, 4 or 5 (47% vs 12%, P=0.0002) only. There was no impact of induction in patients with HCV genotype 2 or 3. Efficacy of ribavirin: at week 24, 28 and 26 HCV-RNA negative patients were randomised to addition of ribavirin or not, respectively. Patients randomised to secondary additive ribavirin were more often HCV-RNA negative at the end of follow-up than patients treated with IFN-alpha alone: 18/28 (64%) vs 10/26 (39%); P=0.06. Among patients randomised to bitherapy, the relapse rate was significantly lower in patients with genotype 2 or 3 (0/12 vs 6/13, P=0.01) and not in those with genotype 1, 4 or 5 (5/11 vs 3/6, P=0.99). CONCLUSION: A 4 week IFN-alpha induction significantly increases the EVR rate in patients with HCV genotype 1, 4 or 5. Late secondary adjunction of ribavirin to IFN-alpha for 6 months in HCV-RNA negative patients after 6 months of IFN-alpha significantly decreases the relapse rate in patients with HCV genotype 2 or 3, but not in patients with genotypes 1, 4 or 5.

Validation of the short-form REFLUX-QUAL (RQS), a gastro-esophageal reflux disease (GERD) specific quality of life questionnaire.

INTRODUCTION: Being an easy-to-use (eight items) quality of life questionnaire specific to GERD, the Reflux-Qual Short form (RQS) was developed for use in everyday practice. The purpose of this study was to assess the psychometric properties of the RQS. METHODS AND MATERIALS: The reliability of the RQS was measured by the Cronbach's alpha coefficient and its clinical validity by comparing the RQS score for increasing clinical severity groups. The RQS discriminative power was compared with that of the SF12. Sensitivity to change over time was measured by calculating effect-sizes. RESULTS: The reliability and validity of the questionnaire were assessed on a sample of 1195 patients. Its psychometric properties were very satisfactory: Cronbach alpha = 0.84; RQS score significantly reduced for the worst-affected patients; the discriminative power was up to 5 times higher when compared with the SF-12. Sensitivity to change over time, evaluated with 362 patients, showed highly significant differences between groups with different levels of clinical progression (P = 0.0001). CONCLUSION: The RQS is a quality of life measurement instrument specific to GERD which is short, reliable, valid, and sensitive to within and between-subject differences.