D Hüppe

Long‐term efficacy of tenofovir monotherapy for hepatitis B virus‐monoinfected patients after failure of nucleoside/nucleotide analogues

Tenofovir disoproxil fumarate (TDF) has demonstrated high antiviral efficacy in treatment‐naive patients with chronic hepatitis B virus (HBV) infection but experience in nucleoside/nucleotide analogue (NA)‐experienced patients is limited. In this retrospective multicenter study we therefore assessed the long‐term efficacy of TDF monotherapy in patients with prior failure or resistance to different NA treatments. Criteria for inclusion were HBV DNA levels >4.0 log10 copies/mL at the start and a minimum period of TDF therapy for at least 6 months. In all, 131 patients (mean age 42 ± 12 years, 95 male, 65% hepatitis B e antigen [HBeAg]‐positive) were eligible. Pretreatment consisted of either monotherapy with lamivudine (LAM; n = 18), adefovir (ADV; n = 8), and sequential LAM‐ADV therapy (n = 73), or add‐on combination therapy with both drugs (n = 29). Three patients had failed entecavir therapy. Resistance analysis in 113 of the 131 patients revealed genotypic LAM and ADV resistance in 62% and 19% of patients, respectively. The mean HBV DNA level at TDF baseline was 7.6 ± 1.5 log10 copies/mL. The overall cumulative proportion of patients achieving HBV DNA levels <400 copies/mL was 79% after a mean treatment duration of 23 months (range, 6–60). Although LAM resistance did not influence the antiviral efficacy of TDF, the presence of ADV resistance impaired TDF efficacy (100% versus 52% probability of HBV DNA <400 copies/mL, respectively). However, virologic breakthrough was not observed in any of the patients during the entire observation period. Loss of HBeAg occurred in 24% of patients and HBsAg loss occurred in 3%. No significant adverse events were noticed during TDF monotherapy. Conclusion: TDF monotherapy induced a potent and long‐lasting antiviral response in NA‐experienced patients with previous treatment failure. Our data may have implications for current add‐on strategies. (HEPATOLOGY 2009.)

Screening colonoscopy for colorectal cancer prevention: results from a German online registry on 269 000 cases

Background The efficacy of screening colonoscopy in general use remains to be determined. Here we report data over a 39-month study period collected in a nationwide online registry. Study Data from consecutive screening colonoscopies performed on asymptomatic patients in the practices of 280 participating gastroenterologists (age 55–99 years) were collected in an online registry. The number and histology of colorectal polyps and carcinomas, complication rates of colonoscopy and polypectomy were registered. Advanced adenoma was defined as an adenoma of ≥10 mm in diameter, villous or tubulovillous in histology, or presence of high-grade dysplasia. Results A total of 269 144 colonoscopies (male 44%) were evaluated. Tubular, villous/tubulovillous adenomas and invasive cancers were found in 15.6, 3.7, and 0.8%, respectively. Advanced adenomas amounted to 7.1%. In 95% of polyps greater than 5 mm and less than 30 mm immediate polypectomy was performed. In 399 of the 575 carcinomas with complete tumor node metastasis stages, which were detected during colonoscopy, early stages dominated (UICC stages I and II in 43 and 27%, respectively). Complication rate was low and no fatalities were observed: cardiopulmonary complication in 0.10% of the colonoscopies, bleeding in 0.8% of polypectomies most of which were managed endoscopically (surgery in 0.03% of polypectomies). Perforation occurred in 0.02% of the colonoscopies and 0.09% of polypectomies. Conclusion Colonic neoplasias are detected in about 20% of patients most of which are immediately removed by polypectomy at a low risk. Polypectomy of adenomas and low UICC stages in cancer patients during screening colonoscopy may be tools for fighting colorectal cancer mortality.

Epidemiologie der chronischen Hepatitis C in Deutschland - Eine Analyse von 10 326 Hepatitis-C-Virus-Infizierten aus Schwerpunktpraxen und -ambulanzen

Little is known about the epidemiology of chronic hepatitis C (CHC) in Germany and especially about the importance of transmission, duration of infection, genotypes, symptoms and quality of life of the patients. The current study prospectively evaluates epidemiological and clinical data of patients infected with the hepatitis C virus (HCV). Using online data entry, various characteristics of 10,326 untreated patients with CHC were documented from March 2003 until May 2006 in 352 centres all over Germany. Mean age of patients was 43.4 years. Patients infected by i.v. drug abuse were considerably younger (36.5 years) than the remaining patients (49.2 years). As indicated by their native language, 64.4% of the patients came from Germany and 19.2% from Russia. 61.7% were infected with genotype 1 and 34.9% with genotype 2 or 3. 45.5% of the patients had been infected by i.v. drug abuse. In at least 5.4% of the patients liver cirrhosis had been proved by biopsy. 63.5% of the patients felt an impairment of quality of life caused by CHC. In many patients infected with hepatitis C socio-economic issues are existent. This is reflected, i.e., in very high rates of unemployment in special subpopulations. Coinfections with hepatitis B and HIV occurred in 1.5% and 4.7%, respectively. Nearly 80% of patients were managed near their homes. The data of the 10 326 patients represent about 2% of all German patients with CHC. This database is up to now the largest of its kind and gives a representative insight into the epidemiological situation of CHC in Germany.

Treatment results of chronic hepatitis C genotype 5 and 6 infections in Germany.

Chronic hepatitis C due to HCV genotype 5 and 6 infection is infrequently reported and patients are usually not included in trials. As boceprevir and telaprevir are not approved for these genotypes, pegylated interferon plus ribavirin will remain the treatment of choice for the coming years. Patients infected with HCV genotype 5 or 6 were identified by data base search from an ongoing observational cohort study in Germany. Of the total 23 893 patients, 39 patients (0.2 %) carried a HCV genotype 5 and 39 patients a HCV genotype 6 (0.2 %). Compared to other genotypes patients with genotype 5 were older and more often had a history of blood transfusion. Patients with genotype 6 were more often Asian and showed higher baseline alanine transaminase. Therapy with pegylated interferon alfa-2a and ribavirin was initiated in 24 patients with HCV genotype 5 and 27 patients with HCV genotype 6. After completion of 48 weeks of therapy an end of treatment response was achieved in 79 % and 81 % of treated patients, respectively. Sustained virological response was achieved in 58 % of patients with genotype 5 and in 59 % genotype 6 patients. HCV genotype 5 and 6 infections are rare in Germany. Our findings suggest that most HCV genotype 6 infections are seen in migrants from Asia, whereas HCV genotype 5 infections seem more due to spontaneous local infections. Sustained virological response seems to be better than for patients with genotype 1 or 4 with similar treatment duration.

Chronic hepatitis C: Treat or wait? Medical decision making in clinical practice

AIM To analyzes the decision whether patients with chronic hepatitis C virus (HCV) infection are treated or not. METHODS This prospective cohort study included 7658 untreated patients and 6341 patients receiving pegylated interferon α 2a/ribavirin, involving 434 physicians/institutions throughout Germany (377 in private practice and 57 in hospital settings). A structured questionnaire had to be answered prior to the treatment decision, which included demographic data, information about the personal life situation of the patients, anamnesis and symptomatology of hepatitis C, virological data, laboratory data and data on concomitant diseases. A second part of the study analyzes patients treated with pegylated interferon α2a. All questionnaires included reasons against treatment mentioned by the physician. RESULTS Overall treatment uptake was 45%. By multivariate analysis, genotype 1/4/5/6, HCV-RNA ≤ 520,000 IU/mL, normal alanine aminotransferase (ALT), platelets ≤ 142,500/μL, age > 56 years, female gender, infection length > 12.5 years, concomitant diseases, human immunodeficiency virus co-infection, liver biopsy not performed, care in private practice, asymptomatic disease, and unemployment were factors associated with reduced treatment rate. Treatment and sustained viral response rates in migrants (1/3 of cohort) were higher than in German natives although 1/3 of migrants had language problems. Treatment rate and liver biopsy were higher in clinical settings when compared to private practice and were low when ALT and HCV-RNA were low. CONCLUSION Some reasons against treatment were medically based whereas others were related to fears, socio-economical problems, and information deficits both on the side of physicians and patients.

Azathioprine-induced Acute Pancreatitis in Patients with Inflammatory Bowel Diseases--A Prospective Study on Incidence and Severity.

Background and Aims: Azathioprine [AZA] is recommended for maintenance of steroid-free remission in inflammatory bowel disease IBD. The aim of this study has been to establish the incidence and severity of AZA-induced pancreatitis, an idiosyncratic and major side effect, and to identify specific risk factors. Methods: We studied 510 IBD patients [338 Crohn’s disease, 157 ulcerative colitis, 15 indeterminate colitis] with initiation of AZA treatment in a prospective multicentre registry study. Acute pancreatitis was diagnosed in accordance with international guidelines. Results: AZA was continued by 324 [63.5%] and stopped by 186 [36.5%] patients. The most common cause of discontinuation was nausea [12.2%]. AZA-induced pancreatitis occurred in 37 patients [7.3%]. Of these: 43% were hospitalised with a median inpatient time period of 5 days; 10% had peripancreatic fluid collections; 24% had vomiting; and 14% had fever. No patient had to undergo nonsurgical or surgical interventions. Smoking was the strongest risk factor for AZA-induced acute pancreatitis [p < 0.0002] in univariate and multivariate analyses. Conclusions: AZA-induced acute pancreatitis is a common adverse event in IBD patients, but in this study had a mild course in all patients. Smoking is the most important risk factor.

Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry

Real‐world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real‐world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct‐acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post‐treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1‐ and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.

Predictive factors for sustained virological response after treatment with pegylated interferon α-2a and ribavirin in patients infected with HCV genotypes 2 and 3.

Background Previous trials have often defined genotype 2 and 3 patients as an “easy to treat” group and guidelines recommend similar management. Aims The present study looks for differences between the two genotypes and analyzes predictive factors for SVR. Methods Prospective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (n = 391) and 3 (n = 1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012. Results When compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL cholesterol and BMI, a higher frequency of drug use as infection mode and male gender (p<0.0001, respectively), and a higher APRI score (p<0.005). SVR was higher in genotype 2 when compared with genotype 3 (64.7% vs. 56.9%, p = 0.004). By multivariate analysis of genotype 2 patients, low baseline γ -GT and RVR predicted SVR. In genotype 3 age ≤45 years, cholesterol>130 mg/dl, a low APRI score, and a γ-GT ≥3-times ULN, RVR, and RBV starting dose were associated with SVR by multivariate analysis. Conclusions The present study corroborates that liver fibrosis is more pronounced in genotype 3 vs. 2. SVR is higher in genotype 2 versus genotype 3 partly because of follow-up problems in genotype 3 patients, in particular in those infected by drug use. Thus, subgroups of genotype 3 patients have adherence problems and need special attention also because they often have significant liver fibrosis. Trial Registration Verband Forschender Arzneimittelhersteller e.V., Berlin, Germany ML21645 ClinicalTrials.gov NCT02106156

Treatment of hepatitis C genotype 1 infection in Germany: effectiveness and safety of antiviral treatment in a real-world setting

Background In pivotal studies with direct-acting antivirals (DAAs), rates of sustained virological response in hepatitis C genotype 1 infection are >90%. Objective The objective of this article is to assess real-world safety and effectiveness of DAA treatment in a prospective multicenter registry study. Methods The German Hepatitis C-Registry includes 6606 patients with genotype 1 from 246 centers, treated between February 2014 and June 2016 at the discretion of the physician. Results A total of 4846 patients completed treatment and follow-up; 51% of these patients were treatment experienced and 28% had liver cirrhosis. Comorbidities were reported in 76% of patients, including HIV co-infection in 8%. SVR12 was 92% with 91% in GT1a and 93% in GT1b. HIV co-infected patients (n = 247) had an SVR12 of 92%. Treatment was discontinued prematurely in 2.5%. In multivariate analysis, SVR12 was dependent on the choice of antiviral regimen (OR 1.33 (1.24–1.43); p < 0.001), negatively associated with presence of liver cirrhosis (OR 0.71 (0.56–0.89); p < 0.003) and positively associated with female gender (OR 1.52 (1.21–1.91); p < 0.001). Conclusion Data from this real-world registry show SVR12 rates close to those obtained in clinical studies. Discontinuation rates are low, confirming good tolerance of the regimens and good adherence of patients (Trial registration number DRKS00009717, German Clinical Trials Register, DRKS).

537 TENOFOVIR DF FOR CHRONIC HEPATITIS B PATIENTS IN FIELD PRACTICE - RESULTS FROM THE GEMINIS GERMAN MULTICENTER OBSERVATIONAL STUDY

blood samples revealed that the percentage of viruses with at least one of these stop codons ranged from 3% to 79%. In two cases even additional stop codons in the HBsAg reading frame were detected in clonal experiments. Different stop codons were located either in the same HBV genome or in distinguished virus populations. Of note, the polymerase mutation A181T did not always lead to a stop codon in the HBsAg, which for one case was disclosed by clonal experiments. Furthermore, clonal experiments showed that in the vast majority of HBV clones the polymerase mutations M204V and A181T were not located in the same genome. Conclusions: The overlapping reading frames of viral HBsAg and polymerase lead to the occurrence of mutations with complex mutational patterns. The exact and sensitive detection of truncated HBsAgs in HBV resistant isolates is limited by using population sequencing methods in routine HBV drug resistance assays.