Papers by Holger Hinrichsen
Gut, 2018
Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, where... more Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirr...
Gastroenterology, Mar 13, 2017
Little is known about substitutions that mediate resistance of HCV to direct-acting antivirals (D... more Little is known about substitutions that mediate resistance of HCV to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (NS3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1-4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than 2-fold changed in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks antiviral treatment were included in the analysis. RA...
The Lancet. Infectious diseases, Oct 14, 2017
The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coform... more The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis. We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained v...
Journal of hepatology, Jan 12, 2017
Little is known about the epidemiology and frequency of recombinant HCV genotype 2/1 strains whic... more Little is known about the epidemiology and frequency of recombinant HCV genotype 2/1 strains which may represent a challenge for direct antiviral therapy (DAA). Consecutive samples from HCV genotype 2 infected patients from Germany, Italy and Israel according to commercial genotyping were re-genotyped by Sanger-based sequencing. Virologic, epidemiological, and phylogenetic analyses including other published chimeras were performed. Sequence analysis of 442 supposed HCV genotype 2 isolates revealed 61 (genotype 2k/1b (n=59), 2a/1b (n=1) or 2b/1a (n=1)) chimeras. No chimeras were observed in Italy but the frequency was 14% and 25% in Germany and Israel. Treatment of viral chimera with sofosbuvir/ribavirin led to virologic relapse in 25/27 patients (93%) while nearly all patients treated initially (n=4/5) or after relapse (n=9/9) with genotype 1-based DAA-regimens achieved a sustained virologic response. The vast majority of patients with 2k/1b chimeras (88%) were originally from eight...
BMC infectious diseases, Jun 2, 2017
This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of si... more This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients. Patients who had failed PegIFNα/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNα/RBV. Eight patients in the Phase 1 group received short-term (≤14 days) simeprevir. Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNα-2a/RBV for 12 weeks followed by PegIFNα-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determin...
Transplant international : official journal of the European Society for Organ Transplantation, Jan 24, 2016
Optimizing therapy of post-transplant HCV recurrence remains important, especially in advanced li... more Optimizing therapy of post-transplant HCV recurrence remains important, especially in advanced liver disease. We evaluated daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in patients with post-liver transplant recurrence in a real-world European cohort at high risk of decompensation or death within 12 months. Recommended treatment was DCV 60mg plus SOF 400mg once-daily for 24 weeks; RBV use/shorter treatment duration was at physicians' discretion. Patients (N=87) were 70% male, 93% white, and mostly infected with HCV genotypes 1b (48%), 1a (32%), or 3 (9%); 37 (43%) had cirrhosis (16 decompensated), five had fibrosing cholestatic hepatitis. Sustained virologic response at post-treatment week 12 (SVR12) was 94% (80/85) in a modified intention-to-treat analysis: 95% (58/61) without RBV, 92% (22/24) with RBV, with no virologic failures. SVR12 was 100% (80/80) in an as-observed analysis excluding five non-virologic failures. Four patients (5%) discontinued ...
J Hepatol, 2002
In patients with chronic hepatitis C virus (HCV) infection scheduled for a 48-week treatment peri... more In patients with chronic hepatitis C virus (HCV) infection scheduled for a 48-week treatment period, premature discontinuation of treatment was previously recommended if HCV-RNA levels remained detectable at week 24 of therapy. Considering the number of side effects and treatment costs, measurement of initial viral decline during therapy may identify virologic nonresponse earlier than 24 weeks. We retrospectively analyzed 260 European patients treated with standard or pegylated interferon alfa (IFN-alpha) and ribavirin for 24 to 48 weeks. Early prediction of virologic response by HCV-RNA decline at weeks 4 and 12 (Versant Quantitative [branched DNA (bDNA) 3.0]; Bayer Diagnostics, Emeryville, CA; and Qualitative [transcription-mediated amplification (TMA)] HCV RNA assay; Bayer Diagnostics) as well as clinical, biochemical, virologic, and histologic baseline parameters were analyzed by logistic regression and receiver operating characteristic (ROC) curves. A viral load at treatment week 4 above 450,000 IU/mL and at week 12 above 30,000 IU/mL was 100% predictive for virologic nonresponse in all patients. From multivariate logistic regression analysis of all patients, independent predictors for sustained virologic response were: genotypes 2 and 3 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.0001), a low baseline gamma-glutamyltransferase (GGT) level (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.0001), a high baseline alanine aminotransferase level (P =.002), and a low baseline viral load (P =.04). None of the latter 3 factors were predictive for sustained virologic response when analysis was restricted to the subgroup of genotypes 2- and 3-infected patients. In conclusion, virologic nonresponse can be predicted early at week 12 of treatment independent from the applied therapeutic regimen based on a cutoff level for HCV RNA of 30,000 IU/mL. This algorithm recognizes 53.7% of nonresponders previously identified at week 24 of treatment.
Endocrine, 1997
Interferon-(~ (2a or 2b)is increasingly used for treatment of chronic hepatitis C virus (HCV) inf... more Interferon-(~ (2a or 2b)is increasingly used for treatment of chronic hepatitis C virus (HCV) infection. Recent reports suggested a correlation between increases in thyroid autoantibodies and the development of thyroid dysfunction during interferon-(~ therapy. In this study, we analyzed thyroid hormones and antithyroid antibodies at monthly intervals in 53 patients who received interferon c~ for chronic active hepatitis C infection. Of five patients with initially elevated levels of antithyroid peroxydase antibodies (anti-TPO), the antibodies increased further in two of them. Ten patients, who started interferon therapy with normal antibody levels, developed elevated anti-TPO antibodies for limited times during treatment. Levels of anti-TPO antibodies showed a marked fluctuation, and only three patients had increased anti-TPO antibodies persisting for longer than 3 mo. Antithyroglobulin antibodies appeared in four patients, all of whom were also positive for anti-TPO antibodies. No changes in TRAB levels were observed. All of these patients with elevated antithyroid antibodies remained in an euthyroid state. One patient with normal antithyroid antibodies developed thyroiditis with severe thyrotoxicosis after 9 wk of interferon therapy. These findings suggest that the induction of antithyroid antibodies during treatment with interferon-~ does not indicate clinical relevant thyroid dysfunction. Routine measurement of antithyroid antibodies during interferon-c~ therapy does not seem to be mandatory.
Medizinische Klinik, Aug 1, 2002
Erythema gyratum repens is a rare, clinically specific, and distinctive paraneoplastic syndrome. ... more Erythema gyratum repens is a rare, clinically specific, and distinctive paraneoplastic syndrome. A case of erythema gyratum repens in a 76-year-old woman with autoimmune hepatitis type I treated with glucocorticoids is reported. Within 3 weeks of supplementary azathioprine treatment, the patient reported gastrointestinal discomfort and developed an erythema gyratum repens confined to the abdomen, thighs and knees. Azathioprine medication was stopped and the dermatologic features resolved completely after a period of 1 week. Absence of any demonstrable underlying malignancy was confirmed by different tests. Molecular diagnosis detected heterozygous G460A and A719G transitions in the thiopurine methyltransferase (TPMT) gene. 18 month later, complete remission on maintenance therapy (prednisone 7.5 mg) was observed with further absence of malignancy. This is the first report of an erythema gyratum repens in association with azathioprine treatment in an autoimmune hepatitis type I patient with proven common polymorphism in the TPMT gene.
Medizinische Klinik, 2007
... In the first part of this review, the physiological and pathophysiological molecular mechanis... more ... In the first part of this review, the physiological and pathophysiological molecular mechanisms of heme and bile metabolism are described in detail on a scientific basis. The knowledge of the main principles of heme degra-dation ...
Deut Med Wochenschr, 1994
Clinical Pharmacology in Drug Development, 2013
Fehldiagnosen und Patientensicherheit, 2005
European journal of gastroenterology & hepatology, 2014
Viral hepatitis is major a public health problem affecting millions of people worldwide. Estimate... more Viral hepatitis is major a public health problem affecting millions of people worldwide. Estimates assume 400 000-500 000 people chronically infected with hepatitis C virus (HCV) in Germany. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The aim of the study was to assess the costs for treating patients with chronic HCV in Germany. We conducted a retrospective multicenter observational study. The design was approved by an ethics committee, and patients were asked for their informed consent. Patients were grouped in four different health states. Healthcare utilization data were extracted from doctor files of six medical centers in Germany. Data of 315 patients with chronic HCV were analyzed. The mean age was 49.4 years, 57.5% were male and 67.9% had a genotype 1 infection. The most common routes of transmission were injection drug use (39.0%) and infection through blood products (15.9%). The average total cost was €19 147 including ambulat...
Zeitschrift für Gastroenterologie, 2014
RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren, 2007
Journal of Hepatology, 2004
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Papers by Holger Hinrichsen