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SummaryBackground It is unclear whether the efficacy and long-term outcome of treating patients with hepatitis C virus (HCV)-positive cirrhosis with the new protease inhibitors will extend to those with Child C cirrhosis. Aim To assess the effectiveness of the interferon-free regimens in Child C cirrhotic patients with HCV infection. Methods A systematic Medline search was conducted to retrieve studies describing the treatment of Child C patients with direct-acting agents. Citations from identified studies were cross-referenced and abstracts from European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) meetings were checked. Extracted data were evaluated using a meta-analysis to calculate a weighted response rate. Results Seven full-text records and two conference abstracts were retained for analysis from the 649 records identified. Data from an Italian real-life trial were also interrogated. Information on treatment outcome was available for 228 of the 240 Child C patients evaluated in the 10 trials. Overall, the weighted mean sustained virological response (SVR12) was 74.9% (95% CI: 65.6–82.4%). Neither duration of treatment (24 or 12 weeks), nor addition of ribavirin influenced these rates. The weighted SVR12 was 65.4% (95% CI: 46.8–80.2) after sofosbuvir/simeprevir, 76.0% (95% CI: 54.4–89.3%) after sofosbuvir/daclatasvir and 83.0% (95% CI: 73.4–89.6) after sofosbuvir/ledipasvir. Some studies did not provide information on the rate of post-treatment relapse or functional improvement. However, in those studies that did provide such data, a relapse was documented in 12.1% of patients and an improvement of ≥2 points on the model for end-stage liver disease (MELD) score in 61.1% of patients. Conclusion The improvement in MELD scores strongly suggests HCV-positive patients with Child C cirrhosis should be treated with these agents.

Aliment Pharmacol Ther 31, 1346–1353 Summary Background The optimal dose of ribavirin to be used in combination with Peg-IFN in patients with HCV genotypes 2 and 3 undergoing short treatment has not been established. Aim To explore the relationship between starting ribavirin doses, expressed as mg/kg body weight and both rapid viral response at treatment week 4 (RVR) and sustained virological response (SVR) in patients treated for 12–14 weeks with peg-interferon α-2b and ribavirin. Methods A post hoc analysis of data collected from two multicenter clinical trials was performed. Multiple regression analyses were employed to identify independent baseline and on-treatment predictors of RVR and SVR. For each dose of ribavirin, the empirical estimated probability of response was computed and the continuous exposure index was dichotomized by using a recursive partitioning and amalgamation method. Results A nonlinear relationship was ascertained between ribavirin dose and RVR, but not SVR. A dose of 15.2 mg/kg was selected as the best splitting value for discriminating RVR vs. non-RVR. Regression analysis identified low baseline viraemia, genotype 2 and high ribavirin dose as independent prognostic factors for RVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, but was independently predicted by adherence to the full dose throughout treatment and normal platelet counts. Conclusions Starting high ribavirin doses appears capable of increasing the rate of RVR in patients with HCV genotypes 2 and 3 undergoing short treatment. Maintenance of the full planned dose throughout treatment is essential for achieving optimal SVR rates.

Summary Background Little data is available about predictors of sustained virological response (SVR) during anti-viral therapy of patients with decompensated HCV cirrhosis. Aims To determine whether rapid and early virological responses (RVR and EVR) could predict SVR and help optimize treatment in these patients. Methods A total of 94 cirrhotics underwent treatment with peg-interferon alfa-2b (1.5 μg/kg weekly) and ribavirin (800/1200 mg daily) for 48 or 24 weeks for genotypes 1/4 or genotypes 2/3, respectively. Results Overall, SVR was achieved in 33 patients (35.1%), 16% with genotype 1/4 and 56.8% with genotype 2/3 (P

Summary Background Anti-viral therapy seems more successful in HCV genotype 2 than genotype 3-infected patients. Aim To report sustained virological response (SVR) rates for HCV-2 and HCV-3 infection. Methods Meta-analyses were carried out on SVR data on 2275 patients treated for 24 weeks in eight individual trials and on 968 patients with rapid virological response (RVR) treated for 12–16 weeks or 24 weeks in four studies. Results After 24 weeks of therapy, SVR rates were 74% and 68%, respectively, for HCV-2 and HCV-3 genotype patients. Among high viraemics, SVR rate in HCV-2 infection (75%) differed from the 58% value in HCV-3 infection. Among low viraemic patients, respective rates were 79% and 75%. In RVR patients treated for 12–16 or 24 weeks, SVR rates in HCV-2 infection were 83% and 84%, respectively, and in HCV-3 infection 84% and 86%. In patients without RVR treated for 24 weeks, SVR was higher in HCV-2, with a 17.8% weighted difference. Conclusions Twenty-four weeks of therapy should remain standard duration for HCV-2 and low viraemic HCV-3 patients. In RVR patients, HCV-3 patients respond to short-treatment as well as HCV-2 patients, irrespective of basal viraemia. Patients without RVR may need longer treatment than the recommended 24 weeks.

Summary Background Variants of myosin IXB (MYO9B) gene, encoding for a motor protein implicated in epithelial permeability, have been recently associated with inflammatory bowel disease. Aims To investigate the contribution of three polymorphisms of MYO9B gene for predisposition to Crohn’s disease and ulcerative colitis, their association with clinical phenotypes, particularly intestinal permeability, and possible interaction with the CARD15 gene. Methods 549 Crohn’s disease patients, 658 ulcerative colitis patients and 674 controls were genotyped for the rs962917, rs1545620 and rs2305764 single nucleotide polymorphisms. Results Highly significant genotypic association with Crohn’s disease and ulcerative colitis was shown for all three single nucleotide polymorphisms, with odds ratio ranging from 1.5 to 1.7 (P-value

Summary Aim To evaluate the polymorphisms of several genes involved in the azathioprine and mercaptopurine metabolism, in an attempt to explain their toxicity and efficacy in Crohn’s disease and ulcerative colitis. Methods In 422 consecutive patients (250 with Crohn’s disease and 172 with ulcerative colitis) and 245 healthy controls, single nucleotide polymorphisms of thiopurine methyltransferase, inosine triphosphate pyrophosphatase and hypoxanthine phosphoribosyl transferase (HPRT1) genes were related to the occurrence of adverse drug reactions (ADRs) and efficacy of therapy. Results Seventy-three patients reported 81 episodes of ADRs; 45 patients did not respond to therapy. Frequency of thiopurine methyltransferase risk haplotypes was significantly increased in patients with leucopenia (26% vs. 5.7% in patients without ADRs, and 4% of controls) (P

Summary Background : Although administration of gastroprotective drugs may reduce the risk of peptic ulcers associated with the chronic use of non-steroidal anti-inflammatory drugs or aspirin, no consensus exists as to whether this co-therapy is effective for short-term prevention, particularly in old age. Aim : To evaluate the risk of peptic ulcer associated with acute and chronic non-steroidal anti-inflammatory drugs or aspirin therapy in elderly subjects, and the influence of antisecretory treatment on this risk. Methods : The study included 676 elderly non-steroidal anti-inflammatory drugs or aspirin users and 2435 non-users who consecutively underwent upper gastrointestinal endoscopy. The use of non-steroidal anti-inflammatory drugs and/or aspirin as well as antisecretory drugs (H2-blockers and proton-pump inhibitors) was evaluated by a structured interview. Diagnosis of gastric and duodenal ulcer as well as Helicobacter pylori infection were carried out by endoscopy and histological examination of the gastric mucosa. Results : About 47.3% of patients were acute and 52.7% chronic users of non-steroidal anti-inflammatory drugs or aspirin. The risk of peptic ulcer, adjusted for age, gender, H. pylori infection and antisecretory drug use was higher in acute (gastric ulcer: odds ratio, OR =4.47, 95% CI: 3.19–6.26 and duodenal ulcer: OR =2.39, 95% CI: 1.73–3.31) than chronic users (gastric ulcer: OR = 2.80, 95% CI: 1.97–3.99 and duodenal ulcer: OR = 1.68, 95% CI: 1.22–2.33). Proton-pump inhibitor treatment was associated with a reduced risk of peptic ulcer in both acute (OR = 0.70, 95% CI: 0.24–2.04) and chronic (OR = 0.32, 95% CI: 0.15–0.67) non-steroidal anti-inflammatory drugs/aspirin users. Conversely, concomitant treatment with H2-blockers was associated with a significantly higher risk of peptic ulcer both in acute (OR = 10.9, 95% CI: 3.87–30.9) and chronic (OR = 6.26, 95% CI: 2.56–15.3) non-steroidal anti-inflammatory drugs/aspirin users than non-users. Proton-pump inhibitor treatment resulted in an absolute risk reduction of peptic ulcer by 36.6% in acute and 34.6% in chronic non-steroidal anti-inflammatory drugs/aspirin users; indeed, the number needed to treat to avoid one peptic ulcer in elderly non-steroidal anti-inflammatory drugs/aspirin users was three both in acute and chronic users. Conclusions : These findings suggest that proton-pump inhibitor co-treatment is advisable in symptomatic elderly patients who need to be treated with non-steroidal anti-inflammatory drugs and/or aspirin for a short period of time.

Summary Background : Anti-Saccharomyces cerevisiae mannan antibodies have been proposed as a new serological marker associated with Crohn's disease. However, their clinical value is still unclear; furthermore, a standardization of anti-S. cerevisiae mannan measurements is lacking. Aim : In this study, we aimed to assess the correlation between anti-S. cerevisiae mannan detection and specific clinical features in Crohn's disease and ulcerative colitis. Moreover, we tested the concordance of four different anti-S. cerevisiae mannan assays. Materials and methods : Serum samples from 196 patients with Crohn's disease, 197 patients with ulcerative colitis and 100 unrelated healthy controls were tested for anti-S. cerevisiae mannan with a standard enzyme-linked immunosorbent assay method (Lille) by one of the authors (VP). Subsequently, 60 randomly selected serum samples (27 Crohn's disease, 28 ulcerative colitis and five healthy controls) were tested for anti-S. cerevisiae mannan with three different commercial kits. Results : With the Lille assay, anti-S. cerevisiae mannan were detected in 100 of 196 patients with Crohn's disease (51%; P

Summary Background : In patients with chronic hepatitis C virus infection and persistently normal alanine aminotransferase levels, liver fibrosis has been reported in 0–22% of cases and advanced liver disease in 5–10% of cases. Aim : To determine whether patients with persistently normal alanine aminotransferase levels clear infection after anti-viral therapy at equal or different rates from infected patients with raised alanine aminotransferase levels. Methods : Thirty-five hepatitis C virus RNA-positive patients with fibrosis at liver histology (Group 1) were matched for genotype, sex, age and histology with patients with raised alanine aminotransferase levels (Group 2). Both groups were treated with 3 MU interferon-α2b plus ribavirin (1000–1200 mg) for 12 months. Results : End-of-therapy response was achieved in 71.4%[95% confidence interval (CI), 56.4–86.3] of patients in Group 1 and in 52.3% (95% CI, 42.8–61.9) of those in Group 2 (P = 0.04). At week 72, 22 patients (62.8%; 95% CI, 46.8–78.1) in Group 1 and 50 patients (47.5%; 95% CI, 38.0–57.1) in Group 2 showed a sustained virological response (P = 0.11). Non-1 genotype was the only independent predictor of sustained response (P = 0.002), with an odds ratio of 3.45 (95% CI, 1.58–7.50). At month 3 of therapy, the positive predictive values for non-response were 100% and 96% in Groups 1 and 2, respectively. Conclusions : Interferon and ribavirin induce comparable sustained virological response in patients with persistently normal or raised alanine aminotransferase levels. Stage 1 fibrosis, rather than alanine aminotransferase levels, may be the criterion on which to decide whether or not to treat patients with persistently normal alanine aminotransferase levels.

Summary Aim : To evaluate the efficacy of a long-term course of lamivudine monotherapy in patients with anti-HBe-positive chronic hepatitis B who relapsed after the first course of either lamivudine/interferon (n = 16; Group 1) or lamivudine (n = 20; Group 2). Methods : Biochemical and virological tests were performed every 3 months. At baseline and breakthrough, the region coding for the YMDD amino acid motif was sequenced. Results : The length of re-treatment averaged 24 months. The virological response peaked at 6 months (94.4%), and declined to 66.7% and 50% at 12 and 24 months, respectively. The rates of breakthrough were 2.9%, 31.4% and 48.6% at 6, 12 and 24 months, respectively. By the second year, responders amounted to 62.5% and 40% in Groups 1 and 2, respectively (P = 0.10). The 18 responders at month 24 are still on therapy after 25–51 months of treatment: 14 still maintain a response, nine from Group 1 and five from Group 2. Conclusions : Re-treatment with lamivudine can control viral replication. This effect is maintained for the initial 12 months in two-thirds of patients, but afterwards the duration of response lessens due to the development of viral resistance.

Summary Background : Triple therapy with proton pump inhibitor, clarithromycin and amoxicillin and, in the event of eradication failure, quadruple therapy with proton pump inhibitor, bismuth, tetracycline and metronidazole have been proposed in Maastricht as the optimal sequential treatment of Helicobacter pylori infection. Aim : To compare two second-line regimens with quadruple therapy. Methods : One hundred and eighty patients with a previous failed course of standard therapy were randomly given one of the following 7-day treatments: ranitidine bismuth citrate 400 mg b.d. plus amoxicillin 1 g b.d. and tinidazole 500 mg b.d. (RBCAT), pantoprazole 40 mg b.d. plus amoxicillin 1 g b.d. and levofloxacin 500 mg/day (PAL) and pantoprazole 40 mg b.d., bismuth citrate 240 mg b.d., tetracycline 500 mg q.d.s. and metronidazole 500 mg b.d. (PBTM). The eradication rate was assessed by 13C-urea breath test. Side-effects and compliance were evaluated by a standardized questionnaire and by counting returned medication. Results : The RBCAT, PAL and PBTM groups achieved mean intention-to-treat eradication rates of 85%, 63% and 83%, respectively (P

Summary Background : The urea breath test is routinely used for diagnosing or confirming the eradication of Helicobacter pylori. Aim : To evaluate the appropriateness of urea breath test referrals. Methods : The age, sex, symptoms, endoscopic findings, use of non-steroidal anti-inflammatory drugs, family history of gastric cancer or H. pylori infection and concomitant diseases of patients referred for urea breath testing in a 1-year period were recorded. The appropriateness of urea breath test referrals was judged according to Maastricht guidelines. Results : One thousand, three hundred and twenty subjects (47 ± 16 years) were referred in 2001: 578 (43.8%) for the diagnosis and 742 (56.2%) for confirmation of the eradication of H. pylori. The urea breath test was considered to be appropriate in 836 (63.3%) patients, inappropriate in 192 (14.5%) and appropriate but avoidable in 292 (22.1%). The appropriateness ratios of urea breath test referrals were 4.6 and 9.0 (P

Background: Triple therapy with proton pump inhibitor, clarithromycin and amoxicillin has recently been proposed in Maastricht as first-line treatment for H. pylori infection. Aim: To determine predictors of unsuccessful eradication. Methods: Two hundred and forty-eight patients underwent endoscopy with biopsies for rapid urease test, histology and culture with antibiotic susceptibility tests, and 13C-UBT. All infected patients were given pantoprazole (40 mg b.d.), clarithromycin (500 mg b.d.) and amoxicillin (1 g b.d.) for 1 week. Eradication was assessed by UBT at 4–6 weeks after therapy. Results: One hundred and sixty-two of 248 patients (65%) were infected. Culture was positive in 144 (89%). Prevalence rates of metronidazole, clarithromycin and amoxicillin resistance were 14, 8 and 3%, respectively. Eradication rates (95% CI) were 63% (54.7–70.6) by intention-to-treat analysis and 67% (59.4–75.4) by per protocol analysis. Drug compliance was excellent and side-effects were mild. Age ≥ 45 years (OR: 2.35, CI: 1.30–4.25), smoking (OR: 1.37, CI 1.01–1.87) and high pre-treatment UBT results (OR: 1.36, CI: 1.08–1.72) were independent predictors of eradication failure. Gender, endoscopic findings, alcohol intake, and clarithromycin and amoxicillin resistance did not predict treatment failure. Conclusion: Despite the low prevalence of primary antibiotic resistance in our geographical area, triple therapy with pantoprazole, amoxicillin and clarithromycin achieves low eradication rates. Smoking, age and pre-treatment UBT results are predictors of potential eradication failure.

Background: Pharmacological prophylaxis of post-ERCP pancreatitis is costly and not useful in most non-selected patients, in whom the incidence of pancreatitis is 5% or less. However, it could be useful and probably cost-effective, in patients at high risk for this complication, where the post-procedure pancreatitis rate is 10% and more. Aim: To assess the efficacy of octreotide in reducing the incidence and severity of post-ERCP pancreatitis and procedure-related hospital stay, in subjects with known patient-related risk factors. Methods: A total of 120 patients were randomly allocated to receive octreotide or not, in a multicentre, randomized, controlled trial. The drug was given subcutaneously, 200 μg t.d.s., starting 24 h before the ERCP procedure, in patients with either sphincter of Oddi dysfunction, or a history of relapsing pancreatitis or post-ERCP pancreatitis, or who were aged under 35 years, or who had a small common bile duct diameter (

Background: Triple therapy with proton pump inhibitor, clarythromycin, and amoxicillin has been proposed in Maastricht as the first-line treatment of H. pylori infection. Aim: To determine whether ranitidine bismuth citrate (RBC) based regimens may be used as second-line treatments after ‘Maastricht therapy’ failure. Methods: A total of 285 patients with H. pylori infection were given a 7-day treatment with pantoprazole 40 mg b.d., clarythromycin 500 mg b.d., and amoxicillin 1 g b.d. Patients who were still infected were randomly given one of the following 14-day treatments: RBC 400 mg b.d. plus amoxicillin 1 g b.d. and tinidazole 500 mg b.d. (RAT group), RBC 400 mg b.d. plus amoxicillin 1 g b.d. and clarythromycin 500 mg b.d. (RAC group), and RBC 400 mg b.d. plus clarythromycin 500 mg b.d. and tinidazole 500 mg b.d. (RCT group). Results: The ‘Maastricht therapy’ achieved an eradication rate of 59% (95% CI: 54–65) on intention-to-treat analysis. The RAT, RAC, and RCT regimens achieved eradication rates of 81% (95% CI: 67–94), 43% (95% CI: 26–60), and 62% (95% CI: 44–80), respectively, on intention-to-treat analysis. Patient compliance was optimal in RAT and RAC groups. Conclusion: RBC plus tinidazole and either amoxicillin or clarythromycin can be used as second-line therapies after failure of the Maastricht triple therapy.

Background: The ideal treatment for patients who have failed eradication of Helicobacter pylori infection after standard proton pump inhibitor-based triple therapies has still to be determined. Although either a second course of triple therapy or a quadruple therapy (proton pump inhibitor plus bismuth-based triple therapy) has been proposed, the efficacy of these second-line therapies is relatively unknown. Therefore, alternative strategies are needed. Aim: To assess the efficacy and tolerability of rifabutin, a derivative of rifamycin-S, in patients who were still H. pylori infected after two or more courses of 1-week triple therapies. Methods: Patients were given a 1-week regimen of pantoprazole 40 mg b.d. + amoxycillin 1 g b.d. + rifabutin 300 mg daily. Side-effects and compliance were determined at the end of therapy. Eradication rate was assessed with a 13C-urea breath test performed at 4 and 12 weeks after treatment. Results: Forty-one patients (mean age 47 ± 15 years) were studied. All patients took medications according to the proposed schedule. Side-effects were infrequent and mild. The eradication rates were 71% (95% CI: 57–85%) on intention-to-treat analysis and 74% (95% CI: 61–88%) on per protocol analysis. Conclusions: Rifabutin, in combination with pantoprazole and amoxycillin, is an effective and well tolerated regimen in patients who failed standard eradication treatments.

Background : Intrasphincteric injection of botulinum toxin has been reported as a safe and effective alternative treatment in oesophageal achalasia, especially in high-risk and elderly patients. Aim : To compare two formulations of botulinum toxin in the management of achalasia. Patients and methods : We randomly compared the efficacy and safety of 100 U of Botox (Allergan, Irvine, USA) and 250 U of Dysport (Ipsen, Milan, Italy), injected through a sclerotherapy needle at the level of the lower oesophageal sphincter, in 78 consecutive patients with achalasia. Symptom score, oesophageal manometry and 24 h pH-metry were recorded (before and 1 month after therapy). Symptom score was also obtained 6 months after treatment. Results : One month after treatment, the effects of the toxin on symptoms and oesophageal tests were similar for both formulations. Lower oesophageal sphincter pressure decreased from 31 ± 12 to 18 ± 5 mmHg after Botox, and from 35 ± 9 to 18 ± 10 after Dysport. At the end of the follow-up period (6 months), symptom score decreased from 5 ± 1.2 to 1.2 ± 0.8 after Botox and from 5.2 ± 1.5 to 1.5 ± 1 after Dysport. Moreover, the percentages of patients who failed to respond to treatment (10% and 17.5%) and who relapsed during follow-up (12% and 24%) did not differ significantly. No patient complained of reflux symptoms after treatment, although abnormal acid exposure was documented in two subjects. Conclusions : Both formulations of botulinum toxin have comparable efficacy in the treatment of oesophageal achalasia, for up to 6 months of follow-up.

Background: Autodigestion of the pancreas, secondary to the activation of digestive enzymes, is the pathogenetic mechanism of acute pancreatitis (AP). Aim: Clinical trials in which somatostatin (SS), octreotide (OCT) and gabexate mesilate (FOY) were used to treat patients with AP, were submitted to a meta-analytical evaluation. Five end-points were evaluated: early and overall mortality, patients with complications, complication rate, and patients who needed surgery. Results: In mild AP, no agent proved of value. In severe AP, both SS and OCT were beneficial in improving the overall mortality: the odds ratios (OR) were, respectively, 0.36 (95% CI: 0.20–0.64, P = 0.001) and 0.57 (95% CI: 0.35–0.88, P = 0.006). FOY had no effect on either early or overall mortality, but was effective in improving complication rate (OR = 0.70, 95% CI: 0.56–0.88, P = 0.02), number of patients with complications (OR = 0.61, 95% CI: 0.41–0.91, P = 0.01), and number of cases submitted to surgery (OR = 0.60, 95% CI: 0.39–0.92, P = 0.01). SS and OCT had no effect on these latter outcomes. Conclusions: Antisecretory agents, such as SS and OCT, are able to reduce mortality without affecting complications, whereas antiproteases, such as FOY, have no effect on mortality but do reduce complications. A trial exploring the efficacy of combining antisecretory agents with antiproteases would be of great benefit in patients with severe AP.