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Berkan-Kawińska A, Piekarska A, Janczewska E, Lorenc B, Tudrujek-Zdunek M, Tomasiewicz K, Berak H, Horban A, Zarębska-Michaluk D, Pabjan P, Buczyńska I, Pazgan-Simon M, Dybowska D, Halota W, Pawłowska M, Klapaczyński J, Mazur W, Czauż-Andrzejuk A, Socha Ł, Laurans Ł, Garlicki A, Sitko M, Jaroszewicz J, Citko J, Dobracka B, Krygier R, Białkowska-Warzecha J, Tronina O, Belica-Wdowik T, Baka-Ćwierz B, Flisiak R. Real-world effectiveness and safety of direct-acting antivirals in patients with cirrhosis and history of hepatic decompensation: Epi-Ter2 Study. Liver Int 2021; 41:1789-1801. [PMID: 33655628 DOI: 10.1111/liv.14858] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 01/30/2021] [Accepted: 02/18/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS The aim of this study was to assess the real-life effectiveness and safety of direct acting antivirals (DAAs) in patients with cirrhosis and history of hepatic decompensation compared to those with compensated cirrhosis. METHOD Data of patients treated with DAAs and included in the EpiTer-2 database (N = 10 152) were collected retrospectively. The primary endpoint was sustained viral response (SVR) at 12 weeks posttreatment. Patients were also evaluated in terms of liver-related adverse events and treatment modification/discontinuation. RESULTS The overall SVR rate was 91.4% in the intent to treat (ITT) analysis and 95.2% in the per-protocol (PP) analysis (P < .001). Patients with decompensated cirrhosis had lower SVR rates compared to those with compensated cirrhosis in ITT analysis (86.4% vs 92.0%, P < .001), while not in PP analysis (92.9% vs 95.5%, P > .05). Adverse events (AE) occurred 45.6% and 29.3% of patients with decompensated and compensated cirrhosis (P < .001). Patients with decompensated cirrhosis were at higher risk of death (5.4% vs 0.9%; P < .0001) or liver decompensation (21.5% vs 1.3%; P < .0001). Treatment with protease inhibitors was not associated with hepatic decompensation (P = .3). Only 82.6% of patients with decompensated cirrhosis completed DAA treatment (vs 92.8% in compensated cirrhotics; P < .0001). CONCLUSION Despite higher frequency of AE and treatment modifications, once completed, DAAs yield comparable results for patients with decompensated and compensated cirrhosis. High rate of serious adverse events in patients with advanced liver disease treated with PI may not be related to the detrimental effect of the medications, but rather to the disease itself.
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Affiliation(s)
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Lodz, Łódź, Poland
| | - Ewa Janczewska
- Medical University of Silesia, School of Public Health in Bytom, Department of Basic Medical Sciences, Bytom, Poland.,ID Clinic, Hepatology Outpatient Department, Mysłowice, Poland
| | - Beata Lorenc
- Department of Infectious Diseases, Pomeranian Center of Infectious Diseases, Medical University of Gdansk, Gdansk, Poland
| | | | | | - Hanna Berak
- Hospital for Infectious Diseases, Warsaw Medical University, Warszawa, Poland
| | - Andrzej Horban
- Hospital for Infectious Diseases, Warsaw Medical University, Warszawa, Poland
| | - Dorota Zarębska-Michaluk
- Department of Infectious Disease, Voivodeship Hospital, Jan Kochanowski University, Kielce, Poland
| | - Paweł Pabjan
- Department of Infectious Disease, Voivodeship Hospital, Jan Kochanowski University, Kielce, Poland
| | - Iwona Buczyńska
- Department of Infectious Diseases and Hepatology, Wroclaw Medical University, Wrocław, Poland
| | - Monika Pazgan-Simon
- Department of Infectious Diseases and Hepatology, Wroclaw Medical University, Wrocław, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Waldemar Halota
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Małgorzata Pawłowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, Central Clinical Hospital of Internal Affairs and Administration, Warszawa, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases, Medical University of Silesia, Chorzów, Poland
| | - Agnieszka Czauż-Andrzejuk
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Łukasz Socha
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Łukasz Laurans
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland.,Multidisciplinary Regional Hospital, Gorzów Wielkopolski, Poland
| | - Aleksander Garlicki
- Department of Infectious and Tropical Diseases, Collegium Medicum, Jagiellonian University, Kraków, Poland
| | - Marek Sitko
- Department of Infectious and Tropical Diseases, Collegium Medicum, Jagiellonian University, Kraków, Poland
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia in Katowice, Bytom, Poland
| | | | | | - Rafał Krygier
- NZOZ Gemini, Infectious Diseases and Hepatology Outpatient Clinic, Zychlin, Poland
| | | | - Olga Tronina
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warszawa, Poland
| | - Teresa Belica-Wdowik
- Regional Center for Diagnosis and Treatment of Viral Hepatitis and Hepatology, John Paul II Hospital, Kraków, Poland
| | - Barbara Baka-Ćwierz
- Regional Center for Diagnosis and Treatment of Viral Hepatitis and Hepatology, John Paul II Hospital, Kraków, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
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Song X, Cai C, Jin Q, Chen X, Yu C. The efficacy of Helicobacter pylori eradication in diabetics and its effect on glycemic control: A systematic review and meta-analysis. Helicobacter 2021; 26:e12781. [PMID: 33465265 DOI: 10.1111/hel.12781] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND AIMS Previous studies have revealed the association between Helicobacter pylori (H. pylori) and diabetes mellitus, but conflicts still exist. The present study tried to investigate the underlying link between these two diseases by making comprehensive analyses of the impact of diabetes on H. pylori eradication and the influence of H. pylori eradication on diabetes. METHODS We systematically searched relevant studies from PubMed, Cochrane Library, Web of Science, and Embase updated to April 23, 2020. Studies examining the association between H. pylori eradication and diabetes were included. Pooled odds ratio (OR) and weighted mean differences (WMD) were calculated for different results. RESULTS Among the 2125 retrieved studies, 36 studies were included. Patients with type 2 diabetes mellitus (T2DM) have higher risk of H. pylori eradication failure than the non-diabetic one (OR = 2.59, 95% CI 1.82-3.70). Body mass index (BMI) was identified as a major factor affecting the efficacy of H. pylori eradication in diabetics, and better glycemic control was also found in eradication succeed patients (WMD: 0.51, 95% CI 0.20-0.81). Moreover, after eradication of H. pylori, improvement of HbA1c was proved (WMD = -0.33, 95% CI -0.65 to -0.02) in T2DM. CONCLUSION A higher risk of H. pylori eradication failure in T2DM was confirmed, and it was associated with BMI and glycemic control. Moreover, we also provided evidence that H. pylori eradication could improve glycemic control in patients with T2DM, which indirectly reflect the interaction between H. pylori and the diabetes.
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Affiliation(s)
- Xin Song
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Changzhou Cai
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Qi Jin
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xueyang Chen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Huppke B, Ellenberger D, Hummel H, Stark W, Röbl M, Gärtner J, Huppke P. Association of Obesity With Multiple Sclerosis Risk and Response to First-line Disease Modifying Drugs in Children. JAMA Neurol 2019; 76:1157-1165. [PMID: 31305922 PMCID: PMC6632118 DOI: 10.1001/jamaneurol.2019.1997] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 05/03/2019] [Indexed: 12/12/2022]
Abstract
Importance Obesity reportedly increases the risk of pediatric multiple sclerosis (MS), but little is known about its association with disease course. Objective To investigate the association of obesity with pediatric MS risk and with first-line therapy response among children with MS. Design, Setting, and Participants This single-center retrospective study used the medical records and database at the Center for MS in Childhood and Adolescence, Göttingen, Germany. The study included 453 patients with relapsing-remitting pediatric MS and body mass index (BMI) measurement taken within 6 months of diagnosis. Onset of the disease occurred between April 28, 1990, and June 26, 2016, and the mean disease duration was 38.4 months. Data were collected from July 14, 2016, to December 18, 2017. Main Outcomes and Measures Data on BMIs were stratified by sex and age using German BMI references and compared with the BMI data of 14 747 controls from a nationwide child health survey for odds ratio (OR) estimates. Baseline magnetic resonance imaging findings, intervals between first and second MS attacks, annualized relapse rates before and during treatment with interferon beta-1a or -1b and glatiramer acetate, frequency of second-line treatment, and Expanded Disability Status Scale (EDSS) scores were compared between nonoverweight (BMI≤90th percentile), overweight (BMI>90th-97th percentile), and obese (BMI>97th percentile) patients. Results In total, 453 patients with pediatric MS were included, of whom 306 (67.5%) were female, and the mean (SD) age at diagnosis was 13.7 (2.7) years. At diagnosis, 126 patients (27.8%) were overweight or obese, with obesity associated with statistically significant twofold odds of MS in both sexes (girls OR, 2.19; 95% CI, 1.5-3.1; P < .001 vs boys OR, 2.14; 95% CI, 1.3-3.5; P = .003). Obese patients, compared with nonoverweight patients, had statistically significantly more relapses on first-line treatment with interferon beta and glatiramer acetate (ARR, 1.29 vs 0.72; P < .001) and a higher rate of second-line treatment (21 [56.8%] of 37 vs 48 [38.7%] of 124; P = .06). Baseline neuroimaging, interval between first and second MS attacks, pretreatment relapses, and EDSS progression scores were not correlated with BMI. Conclusions and Relevance In this study, increased pediatric MS risk appeared to be associated with obesity, and obese patients did not respond well to first-line medications; altered pharmacokinetics appeared to be most likely factors in treatment response, suggesting that achieving healthy weight or adjusting the dose according to BMI could improve therapy response.
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Affiliation(s)
- Brenda Huppke
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany
| | - David Ellenberger
- Department of Medical Statistics, University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany
| | - Hannah Hummel
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany
| | - Wiebke Stark
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany
| | - Markus Röbl
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany
| | - Jutta Gärtner
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany
| | - Peter Huppke
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany
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Fabrizi F, Lunghi G, Martin P. Treatment of HCV-related Liver Disease in the Dialysis Population: A Novel Challenge for Clinical Nephrologists. Int J Artif Organs 2018. [DOI: 10.1177/039139880102400602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- F. Fabrizi
- Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milan - Italy
| | - G. Lunghi
- Institute of Hygiene and Preventive Medicine, Maggiore Hospital, IRCCS, Milan - Italy
| | - P. Martin
- Liver Transplant Program, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA - USA
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Cortés KC, Zagordi O, Perlejewski K, Laskus T, Maroszek K, Bukowska-Ośko I, Pawełczyk A, Płoski R, Berak H, Horban A, Radkowski M. Deep sequencing of hepatitis C virus hypervariable region 1 reveals no correlation between genetic heterogeneity and antiviral treatment outcome. BMC Infect Dis 2014; 14:389. [PMID: 25016390 PMCID: PMC4226954 DOI: 10.1186/1471-2334-14-389] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 07/07/2014] [Indexed: 01/26/2023] Open
Abstract
Background Hypervariable region 1 (HVR1) contained within envelope protein 2 (E2) gene is the most variable part of HCV genome and its translation product is a major target for the host immune response. Variability within HVR1 may facilitate evasion of the immune response and could affect treatment outcome. The aim of the study was to analyze the impact of HVR1 heterogeneity employing sensitive ultra-deep sequencing, on the outcome of PEG-IFN-α (pegylated interferon α) and ribavirin treatment. Methods HVR1 sequences were amplified from pretreatment serum samples of 25 patients infected with genotype 1b HCV (12 responders and 13 non-responders) and were subjected to pyrosequencing (GS Junior, 454/Roche). Reads were corrected for sequencing error using ShoRAH software, while population reconstruction was done using three different minimal variant frequency cut-offs of 1%, 2% and 5%. Statistical analysis was done using Mann–Whitney and Fisher’s exact tests. Results Complexity, Shannon entropy, nucleotide diversity per site, genetic distance and the number of genetic substitutions were not significantly different between responders and non-responders, when analyzing viral populations at any of the three frequencies (≥1%, ≥2% and ≥5%). When clonal sample was used to determine pyrosequencing error, 4% of reads were found to be incorrect and the most abundant variant was present at a frequency of 1.48%. Use of ShoRAH reduced the sequencing error to 1%, with the most abundant erroneous variant present at frequency of 0.5%. Conclusions While deep sequencing revealed complex genetic heterogeneity of HVR1 in chronic hepatitis C patients, there was no correlation between treatment outcome and any of the analyzed quasispecies parameters.
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Affiliation(s)
- Kamila Caraballo Cortés
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3c Pawińskiego Street, 02-106 Warsaw, Poland.
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Gupta S, Singh R. Analysis of the virus dynamics model reveals that early treatment of HCV infection may lead to the sustained virological response. PLoS One 2012; 7:e41209. [PMID: 22911761 PMCID: PMC3404063 DOI: 10.1371/journal.pone.0041209] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Accepted: 06/18/2012] [Indexed: 01/24/2023] Open
Abstract
Considerable progress has been made towards understanding hepatitis C virus, its pathogenesis and the effect of the drug therapy on the viral load, yet around 50% of patients do not achieve the sustained virological response (SVR) by the standard treatment. Although several personalized factors such as patients’ age and weight may be important, by mathematical modeling we show that the time of the start of the therapy is a significant factor in determining the outcome. Toward this end, we first performed sensitivity analysis on the standard virus dynamics model. The analysis revealed four phases when the sensitivity of the infection to drug treatment differs. Further, we added a perturbation term in the model to simulate the drug treatment period and predict the outcome when the therapy is carried out during each of the four phases. The study shows that while the infection may be difficult to treat in the late phases, the therapy is likely to result in SVR if it is carried out in the first or second phase. Thus, development of newer and more sensitive screening methods is needed for the early detection of the infection. Moreover, the analysis predicts that the drug that blocks new infections is more effective than the drug that blocks the virus production.
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Affiliation(s)
- Saurabh Gupta
- Department of Chemical Engineering, Indian Institute of Technology Kanpur, Kanpur, India
| | - Raghvendra Singh
- Department of Chemical Engineering, Indian Institute of Technology Kanpur, Kanpur, India
- * E-mail:
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Alsiö Å, Rembeck K, Askarieh G, Christensen PB, Färkkilä M, Langeland N, Rauning Buhl M, Pedersen C, Mørch K, Haagmans BL, Nasic S, Westin J, Hellstrand K, Norkrans G, Lagging M. Impact of obesity on the bioavailability of peginterferon-α2a and ribavirin and treatment outcome for chronic hepatitis C genotype 2 or 3. PLoS One 2012; 7:e37521. [PMID: 22655053 PMCID: PMC3360051 DOI: 10.1371/journal.pone.0037521] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Accepted: 04/20/2012] [Indexed: 12/18/2022] Open
Abstract
Background and Aims Having a body mass index above or equal to 30 kg/m2 in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear. Methods This study evaluated impact of obesity on outcome as well as interferon and ribavirin concentrations following standard-of-care fixed dosing with peginterferon-α2a 180 µg once weekly and ribavirin 800 mg daily among 303 HCV genotype 2/3-infected patients enrolled in the per-protocol analysis of a recently completed phase III trial (NORDynamIC). Results Patients with BMI ≥30 kg/m2 showed poorer outcome following 24 weeks of therapy (SVR 62% vs. 89% for BMI ≥30 vs. <30; P = 0.006) along with significantly higher steatosis grade (P = 0.002), HOMA-IR (P<0.0001), triglyceride levels (P = 0.0002), and baseline viral load (P = 0.028). Obesity was also significantly associated with lower plasma interferon concentrations on days 3, 7, and 29 (P = 0.02, P = 0.0017, and P<0.0001, respectively) and lower plasma ribavirin concentrations day 29 (P = 0.025), and lower concentration of interferon in turn was associated with a poorer first phase reduction in HCV RNA (P<0.0001). In multivariate analysis, ribavirin concentrations week 12, interferon concentrations day 29, and baseline HCV RNA levels were independent predictors of achieving SVR among patients treated for 24 weeks (n = 140). Conclusions Reduced bioavailability of interferon and ribavirin along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic hepatitis C.
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Affiliation(s)
- Åsa Alsiö
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Karolina Rembeck
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Galia Askarieh
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | | | - Martti Färkkilä
- Department of Gastroenterology, Helsinki University, Helsinki, Finland
| | - Nina Langeland
- Department of Medicine, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway
| | - Mads Rauning Buhl
- Department of Infectious Diseases, Aarhus University, Aarhus, Denmark
| | - Court Pedersen
- Department of Infectious Diseases, University of Southern Denmark, Odense, Denmark
| | - Kristine Mørch
- Department of Medicine, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway
| | | | - Salmir Nasic
- Department of Research and Development/Statistics, Skaraborg Hospital, Skövde, Sweden
| | - Johan Westin
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Kristoffer Hellstrand
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar Norkrans
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- * E-mail:
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Bressler B, Wang K, Grippo JF, Heathcote EJ. Pharmacokinetics and response of obese patients with chronic hepatitis C treated with different doses of PEG-IFN alpha-2a (40KD) (PEGASYS). Br J Clin Pharmacol 2009; 67:280-7. [PMID: 19523011 DOI: 10.1111/j.1365-2125.2008.03349.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
AIMS To evaluate whether higher doses of peginterferon alpha-2a (40KD) [PEG-IFN alpha-2a (40KD)] can compensate for lower exposure observed among obese patients with chronic hepatitis C (CHC) treated with the standard dose of PEG-IFN alpha-2a (40KD). METHODS Noncirrhotic, obese (body mass index > or =30 kg m(-2)) patients with CHC participated in a single-centre, open-label study. Patients were randomized to 180 or 270 microg week(-1) PEG-IFN alpha-2a (40KD) + ribavirin (1000/1200 mg day(-1)) for 48 weeks. Blood samples were collected predose and up to 168 h after the first dose and at week 12 for pharmacokinetic analysis. Trough serum concentrations (C(trough)) were determined up to week 24. RESULTS In the 180 microg week(-1) group mean +/- SD steady-state (week 12) estimates of AUC(0-168) (ng h(-1) ml(-1)), C(max) (ng ml(-1)) and CL/F (l h(-1)) were 2154 +/- 919, 13.8 +/- 6.7 and 0.102 +/- 0.051, respectively. In the 270 microg week(-1) group, estimates were 3374 +/- 1844, 23.4 +/- 10.7 and 0.090 +/- 0.042, respectively. The mean (range) C(trough) (ng ml(-1)) was 11.2 (4.4-18.5) in the 180 microg week(-1) group and 16.1 (0.4-44.2) in the 270 microg week(-1) group. Overall, 14 of 20 (70%) and 16 of 20 (80%) patients in the 180 microg week(-1) and 270 microg week(-1) groups were infected with hepatitis C virus genotype 1 or 4. In the 180 microg week(-1) and 270 microg week(-1) groups 14 of 20 (70%) and 15 of 19 (79%) patients, respectively, achieved a sustained viral response. Safety was similar between groups. CONCLUSIONS Mean PEG-IFN alpha-2a (40KD) exposure was dose proportional from 180 to 270 microg week(-1). Increasing PEG-IFN alpha-2a (40KD) from 180 to 270 microg week(-1) achieves higher serum drug exposure in obese patients.
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Affiliation(s)
- Brian Bressler
- St Paul's Hospital, University of British Columbia, Vancouver, Canada
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Abdullahi M, Annibale B, Capoccia D, Tari R, Lahner E, Osborn J, Leonetti F, Severi C. The eradication of Helicobacter pylori is affected by body mass index (BMI). Obes Surg 2008; 18:1450-4. [PMID: 18443890 DOI: 10.1007/s11695-008-9477-z] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2008] [Accepted: 02/25/2008] [Indexed: 02/05/2023]
Abstract
BACKGROUND Bariatric surgeons often advocate preoperative Helicobacter pylori (H. pylori) testing and eradication because of the increased risk of postoperative ulcers and foregut symptoms in H. pylori-positive patients. The aim of this pilot study was to evaluate whether body mass index (BMI) might influence the success rate of eradication. METHODS Eighty one nondiabetic naïve H. pylori-positive patients were divided into two groups according to their BMI, with 41 in the control group (normal BMI) and 40 in the overweight/obese group (BMI > or = 25). Gastroscopy was performed and multiple biopsies were obtained from the antrum and corpus. Both groups were given a triple therapy consisting of pantoprazole 40 mg for 2 weeks plus amoxicillin 1 g tris in die (t.i.d), and clarithromycin 250 mg t.i.d, for the first week of treatment. Eradication was confirmed by the (13)C-urea breath test at 3 months. RESULTS Successful eradication was observed in 55.0% of the overweight/obese group compared with 85.4% [p < 0.005; odds ratio (OR): 4.77; 95% confidence interval (CI): 1.64-13.87]. The distribution of age, gender, and smoking, as well as the proportion with corpus predominant gastritis (41.4% and 35.0% in control and overweight/obese groups, respectively), did not differ significantly between the two groups. Regression analysis showed that risk factors for treatment failure were BMI (p < 0.02) with an OR of 1.06 (95% CI: 1.01-1.11) and corpus-predominant gastritis (p < 0.001) with an OR of 8.74 (95% CI: 2.48-30.8). CONCLUSION Overweight/obese nondiabetic patients showed a significantly lower rate of eradication rate of H. pylori infection than controls. BMI and corpus-predominant gastritis appear to be independent risk factors for eradication failure.
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Affiliation(s)
- Mohamed Abdullahi
- Gastrointestinal Unit, Department of Clinical Sciences, University La Sapienza, Viale del Policlinico, 00161, Rome, Italy
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Abstract
CONTEXT In the last few years, several data have accumulated suggesting that obesity may be associated with liver disease and disease progression. Accordingly, the worldwide epidemic of obesity is likely to become a relevant source of morbidity and mortality in the general population. EVIDENCE ACQUISITION We reviewed the literature on two main issues: 1) the evidence that obesity carries out an increased risk of liver disease, both in the general population and in selected cohorts; and 2) the evidence that obesity is a risk factor for nonalcoholic fatty liver disease and its progression in a series observed in liver units. EVIDENCE SYNTHESIS The presence of obesity increases the risk of elevated liver enzymes by a factor of two to three, whereas the risk of steatosis at ultrasonography is increased by a factor of 3 in the presence of overweight and peaks at a factor of approximately 15 in the presence of obesity. Both cirrhosis (cryptogenic cirrhosis) and hepatocellular carcinoma are also associated with obesity in the general population. In patients with nonalcoholic fatty liver disease observed in liver units, obesity and weight gain are systematically associated with advanced fibrosis and fibrosis progression. CONCLUSION Liver disease of metabolic origin, associated with obesity, is now recognized as the most prevalent liver disease in Western countries. Strategies are needed to approach obesity-associated liver disease by behavior programs, motivating people to adopt a healthier lifestyle. Such programs should be coupled with public policies at a societal level to obtain the maximum effects in lifestyle changes.
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Impact of obesity, hepatic steatosis, and insulin resistance on hepatitis C treatment outcomes. ACTA ACUST UNITED AC 2008. [DOI: 10.1007/s11901-008-0026-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Dahari H, Layden-Almer JE, Perelson AS, Layden TJ. Hepatitis C Viral Kinetics in Special Populations. ACTA ACUST UNITED AC 2008; 7:97-105. [PMID: 19148305 DOI: 10.1007/s11901-008-0022-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Mathematical models of hepatitis C viral (HCV) kinetics provide a means of estimating the antiviral effectiveness of therapy, the rate of virion clearance and the rate of loss of HCV-infected cells. They have also proved useful in evaluating the extrahepatic contribution to HCV plasma viremia and they have suggested mechanisms of action for both interferon-α and ribavirin. Viral kinetic models can explain the observed HCV RNA profiles under treatment, e.g., flat partial response, biphasic and triphasic viral decay and viral rebound. Current therapy with (pegylated) interferon-α and ribavirin has a poorer success in patients having insulin resistance, hepatic fibrosis, African American ethnicity, HCV/HIV-coinfection, HCV genotype-1 and high baseline viral load. The use of mathematical modeling and statistical analysis of experimental data have been useful in understanding some of these treatment obstacles.
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Affiliation(s)
- Harel Dahari
- Department of Medicine, Section of Hepatology, The University of Illinois at Chicago 840 S. Wood Street MC787, Chicago, IL 60612
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13
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Neuman MG, Sha K, Esguerra R, Zakhari S, Winkler RE, Hilzenrat N, Wyse J, Cooper CL, Seth D, Gorrell MD, Haber PS, McCaughan GW, Leo MA, Lieber CS, Voiculescu M, Buzatu E, Ionescu C, Dudas J, Saile B, Ramadori G. Inflammation and repair in viral hepatitis C. Dig Dis Sci 2008; 53:1468-1487. [PMID: 17994278 DOI: 10.1007/s10620-007-0047-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2007] [Accepted: 09/26/2007] [Indexed: 02/07/2023]
Abstract
Hepatitis C viral infection (HCV) results in liver damage leading to inflammation and fibrosis of the liver and increasing rates of hepatic decompensation and hepatocellular carcinoma (HCC). However, the host's immune response and viral determinants of liver disease progression are poorly understood. This review will address the determinants of liver injury in chronic HCV infection and the risk factors leading to rapid disease progression. We aim to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. We will accomplish this task by discussion of three topics: (1) the role of cytokines in the adaptive immune response against the HCV infection; (2) the progression of fibrosis; and (3) the risk factors of co-morbidity with alcohol and human immunodeficiency virus (HIV) in HCV-infected individuals. Despite recent improvements in treating HCV infection using pegylated interferon alpha (PEGIFN-alpha) and ribavirin, about half of individuals infected with some genotypes, for example genotypes 1 and 4, will not respond to treatment or cannot be treated because of contraindications. This review will also aim to describe the importance of IFN-alpha-based therapies in HCV infection, ways of monitoring them, and associated complications.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology, Biophysics and Global Health, Institute of Drug Research, University of Toronto, Toronto, ON, Canada.
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14
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Howell CD, Dowling TC, Paul M, Wahed AS, Terrault NA, Taylor M, Jeffers L, Hoofnagle JH. Peginterferon pharmacokinetics in African American and Caucasian American patients with hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 2008; 6:575-83. [PMID: 18407798 PMCID: PMC2704736 DOI: 10.1016/j.cgh.2008.02.035] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The relationship between serum peginterferon pharmacokinetics and pharmacodynamics and the early virologic response (EVR) to peginterferon and ribavirin therapy was assessed in patients with chronic hepatitis C virus (HCV) genotype 1 infection. METHODS A total of 333 patients (160 African Americans [AA] and 173 Caucasian Americans [CA]) who received peginterferon alpha-2a (180 microg/wk) without a dose modification during the initial 4 weeks of therapy were analyzed. Peginterferon and 2,5-oligoadenylate synthetase (2,5-OAS) serum levels were measured on days 0, 1, 2, 3, 7, 14, 28, 56, 84, and 168 of treatment. The EVR (>or=2-log(10) decline in HCV RNA levels by week 12 of therapy) was the primary virologic end point. RESULTS Peginterferon pharmacokinetics after the first dose were similar in AA and CA, but AA had greater peginterferon concentrations at days 1, 3, 14, and 28 (P < .05). AA had higher absolute serum 2,5-OAS levels on days 0, 1, 2, 3, 7, 14, 28, and 56 (P < .05), but the magnitude of 2,5-OAS induction during treatment were similar. AA patients showed a smaller decline in serum HCV RNA during the first 28 days of treatment (P < .001) and a lower EVR (65% vs 83%). AA and CA with EVR had significantly higher serum peginterferon concentrations and serum 2,5-OAS induction during the first 12 weeks than patients without an EVR. CONCLUSIONS Peginterferon alpha-2a pharmacokinetic and pharmacodynamic variability is associated with EVR in both AA and CA with HCV infection, but do not explain the racial disparity in combination treatment efficacy.
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15
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Economou M, Milionis H, Filis S, Baltayiannis G, Christou L, Elisaf M, Tsianos E. Baseline cholesterol is associated with the response to antiviral therapy in chronic hepatitis C. J Gastroenterol Hepatol 2008; 23:586-91. [PMID: 17498221 DOI: 10.1111/j.1440-1746.2007.04911.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) partially interacts with low-density lipoprotein (LDL) receptors, suggesting a role for lipids in regulating HCV clearance. Our aim was to study if baseline lipids can discriminate responders from non-responders among patients with HCV infection. METHODS A total of 109 HCV patients were studied. Laboratory measurements included serum lipids, aminotransferases and viral load, as well as HCV genotype determinations. RESULTS Responders (n = 53) had significantly higher serum baseline levels of total cholesterol, LDL cholesterol and apolipoprotein B compared to non-responders (n = 56). Multivariate logistic regression analysis showed that a 10 mg/dL increase in total cholesterol was associated with 3.02 higher odds of responding to treatment (95% CI 1.74-5.32, P < 0.001), while a 10 mg/dL increase in apolipoprotein B levels was associated with 1.81 higher odds of responding to treatment (95% CI 1.37-2.54, P < 0.001), after adjustment for age, sex, body mass index (BMI), smoking habits, baseline viral load, liver histology and administration of pegylated interferon. An inverse association between BMI and response to treatment was also evident (adjusted odds ratio 0.73, 95% CI 0.55-0.96; P = 0.03). CONCLUSION Baseline serum total cholesterol levels and BMI could be helpful in discriminating responders to antiviral therapy among patients with HCV infection.
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Affiliation(s)
- Michael Economou
- First Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece.
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16
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Poustchi H, Negro F, Hui J, Cua IHY, Brandt LR, Kench JG, George J. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. J Hepatol 2008; 48:28-34. [PMID: 17977612 DOI: 10.1016/j.jhep.2007.07.026] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Revised: 07/04/2007] [Accepted: 07/05/2007] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS Obesity is associated with impaired treatment responses in chronic hepatitis C. The aim of this study was to determine the relationship between the insulin resistance frequently seen in obese subjects and sustained virological response to anti-viral therapy (SVR) in patients with genotype 2 or 3 infection. METHODS Eighty-two patients were studied; 59 received interferon/ribavirin while 23 received peg-interferon/ribavirin. RESULTS The overall SVR was (77%). Patients with a SVR had lower mean serum insulin (10.7+/-0.8 microU/ml vs. 22.2+/-4.9; P = 0.03), fibrosis stage (1.9+/-0.1 vs. 2.7+/-0.3; P = 0.007) and insulin resistance measured by the homeostasis model (HOMA-IR) (2.5+/-0.2 vs. 6.1+/-1.5; P = 0.03). Age, gender, ethnicity, alcohol consumption, treatment regimen, viral load, portal activity and steatosis did not influence the SVR. By linear regression, body mass index (P < 0.001) and fibrosis stage (P < 0.001) were independently associated with HOMA-IR. After adjusting for fibrosis stage, patients with HOMA-IR of < 2 were 6.5 times more likely to achieve SVR than those with HOMA-IR > or = 2. CONCLUSIONS Even in treatment-responsive genotypes 2 and 3, high HOMA-IR is associated with a reduced response. Improving insulin sensitivity may be a useful adjunct to anti-viral therapy in these individuals.
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Affiliation(s)
- Hossein Poustchi
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, NSW, Australia
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17
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Pegylated Interferons: Clinical Applications in the Management of Hepatitis C Infection. HEPATITIS C VIRUS DISEASE 2008. [PMCID: PMC7122148 DOI: 10.1007/978-0-387-71376-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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18
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Abstract
Hepatitis C infection and non-alcohol-related hepatic steatosis are the most common liver diseases worldwide, and both conditions often co-exist in the same patient. Hepatitis C virus (HCV) genotype 3 directly induces development of steatosis, whereas in patients with non-genotype 3 chronic hepatitis C infection, insulin resistance plays a key role in the pathophysiology of steatosis. Insulin resistance and its clinical components including obesity, hyperglycemia, hypertriglyceridemia, increased blood pressure, and low HDL-cholesterol levels are often seen in patients with chronic hepatitis C infection. Both increased adipocity and presence of steatosis may increase the risk of fibrosis progression, and both have been associated with a decreased rate of response to antiviral treatment. Hence, liver steatosis in the setting of HCV infection is a distinct condition with specific clinical and prognostic implications. Accumulating evidence suggests that weight management may lead not only to a decrease in steatosis but also improvement in fibrosis severity. However, further studies are necessary to determine whether weight reduction improves response to antiviral therapy.
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Affiliation(s)
- Einar Björnsson
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
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19
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Cicinnati VR, Iacob S, Klein CG, Baba HA, Sotiropoulos GC, Hilgard P, Erim Y, Broelsch CE, Gerken G, Beckebaum S. Ribavirin with either standard or pegylated interferon to treat recurrent hepatitis C after liver transplantation. Aliment Pharmacol Ther 2007; 26:291-303. [PMID: 17593075 DOI: 10.1111/j.1365-2036.2007.03363.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM To investigate the efficacy of two anti-viral protocols in hepatitis C virus-reinfected liver transplant recipients. METHODS In this prospective study, 26 liver transplant patients were treated with standard interferon-alpha2b for 12 months or standard interferon-alpha2b for 3 months followed by pegylated interferon-alpha2b for 9 months. Interferon was combined with ribavirin in all patients. The histological course of the study population was compared with an untreated historic control group (n = 38) with similar baseline characteristics. RESULTS The sustained virological response rates in the standard interferon group and in the pegylated interferon group were 27.3% and 26.7%, respectively. Only 29% of patients with sustained virological response had end of treatment histological response, whereas 47% of viral non-responders showed end of treatment histological response. The percentage of patients with histological improvement was significantly higher in the study population when compared to the controls. Univariate analysis indicated that hepatitis C virus genotype non-1, high baseline alanine aminotransferase, the time interval between liver transplant and interferon therapy and the body mass index predicted sustained virological response. In the multivariate model, baseline alanine aminotransferase and the body mass index remained a significant predictor of sustained virological response. CONCLUSIONS Both treatment regimens offer similar efficacy profiles. Failure to eradicate hepatitis C virus should not lead to treatment discontinuation if serial liver biopsies demonstrate histological response.
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Affiliation(s)
- V R Cicinnati
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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20
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Clouston AD, Jonsson JR, Powell EE. Steatosis as a cofactor in other liver diseases: hepatitis C virus, alcohol, hemochromatosis, and others. Clin Liver Dis 2007; 11:173-89, x. [PMID: 17544978 DOI: 10.1016/j.cld.2007.02.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
As obesity prevalence rises, there is evidence that fatty liver disease can act synergistically with other chronic liver diseases to aggravate parenchymal injury. This is characterized best in chronic hepatitis C, where steatosis is caused by viral and metabolic effects. There is evidence that steatosis and its metabolic abnormalities also exacerbate other diseases, such as alcoholic liver disease, hemochromatosis, and, possibly, drug-induced liver disease. The pathogenesis seems related to increased susceptibility of steatotic hepatocytes to apoptosis, enhanced oxidative injury, and altered hepatocytic regeneration. Data suggest that active management of obesity may improve liver injury and decrease the progression of fibrosis in patients who have other chronic liver diseases.
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Affiliation(s)
- Andrew D Clouston
- School of Medicine, Southern Division, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia
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21
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Abstract
Obesity and the metabolic syndrome have hepatic manifestations, including steatosis and progression of fibrosis. In individuals with chronic hepatitis C, obesity is associated with inflammation, insulin resistance, steatosis, progression of fibrosis, and nonresponse to treatment with interferon or peginterferon alpha and ribavirin. Patients with both hepatitis C and obesity-related nonalcoholic fatty liver disease are at greater risk for more advanced liver disease. We review the mechanisms by which obesity may be associated with decreased efficacy of interferon-based therapies in individuals with chronic hepatitis C and the therapeutic strategies that may increase the effectiveness of these therapies in obese individuals.
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Affiliation(s)
- Michael R Charlton
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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22
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Eguchi Y, Mizuta T, Yasutake T, Hisatomi A, Iwakiri R, Ozaki I, Fujimoto K. High serum leptin is an independent risk factor for non-response patients with low viremia to antiviral treatment in chronic hepatitis C. World J Gastroenterol 2006; 12:556-60. [PMID: 16489668 PMCID: PMC4066087 DOI: 10.3748/wjg.v12.i4.556] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether body weight and/or serum leptin were independent predictors of response to antiviral treatment in patients with chronic hepatitis C.
METHODS: A retrospective evaluation was performed in 139 patients with chronic hepatitis C treated with interferon (IFN) from 1996 to 2000. Sustained response was defined as negative by hepatitis C virus (HCV) RNA analysis using PCR and normal transaminase at 24 wk after cessation of IFN therapy. Patients who remained positive for HCV RNA at the end of IFN treatment were defined as resistant to IFN therapy. Sex, age, body mass index (BMI) (≥ 25 vs < 25), complication of diabetes mellitus, serum leptin level (≥ 8.0 μg/L vs < 8.0 μg/L), and the stage of liver fibrosis by needle biopsy (F1/F2 vs F3/F4) were examined.
RESULTS: Sustained response was achieved in 33 patients (23.7%), while others failed to show a response to IFN therapy. Overall, the factors associated with sustained antiviral effects were HCV-RNA load, HCV genotype, serum leptin level, and stage of liver fibrosis evaluated by univariate analysis. BMI was not associated with any therapeutic effect of IFN. Multivariate analysis indicated that HCV-RNA load was a significant risk factor, but among the patients with low viremia (HCV-RNA < 100 MU/L), leptin level was an independent risk factor for IFN resistance. Namely, a high level of serum leptin attenuated the effect of IFN on both male and female patients with low viremia.
CONCLUSION: High serum leptin level is a negative predictor of response to antiviral treatment in chronic hepatitis C with low viremia.
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Affiliation(s)
- Yuichiro Eguchi
- Department of Internal Medicine, Saga Medical School, Saga, 5-1-1 Nabeshima, Saga 849-8501, Japan
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23
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Abstract
The prevalence of fatty liver is rising in association with the global increase in obesity and type 2 diabetes. In the past, simple steatosis was regarded as benign, but the presence of another liver disease may provide a synergistic combination of steatosis, cellular adaptation, and oxidative damage that aggravates liver injury. In this review, a major focus is on the role of steatosis as a co-factor in chronic hepatitis C (HCV), where the mechanisms promoting fibrosis and the effect of weight reduction in minimizing liver injury have been most widely studied. Steatosis, obesity, and associated metabolic factors may also modulate the response to alcohol- and drug-induced liver disease and may be risk factors for the development of hepatocellular cancer. The pathogenesis of injury in obesity-related fatty liver disease involves a number of pathways, which are currently under investigation. Enhanced oxidative stress, increased susceptibility to apoptosis, and a dysregulated response to cellular injury have been implicated, and other components of the metabolic syndrome such as hyperinsulinemia and hyperglycemia are likely to have a role. Fibrosis also may be increased as a by-product of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells. In conclusion, active management of obesity and a reduction in steatosis may improve liver injury and decrease the progression of fibrosis.
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Affiliation(s)
- Elizabeth E Powell
- School of Medicine, Southern Division, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
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24
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Abstract
The association of metabolic disorders with liver disease is receiving increasing attention in the gastroenterological community. Cohort studies have shown that advanced liver disease may stem from metabolic disorders, via fatty liver, non-alcoholic steatohepatitis, cryptogenic cirrhosis, and eventually hepatocellular carcinoma. In both obesity and diabetes, deaths from cirrhosis are higher than expected, mainly in subjects with no or moderate alcohol consumption, but high rates of fatty liver disease have been associated with all features of the metabolic syndrome. Also the risk of hepatocellular carcinoma is higher than normal, being dependent on body mass index (BMI) in obesity, and independent of age, BMI, gender and race in diabetes. Finally, metabolic liver disease may interact with hepatitis C virus infection, increasing the risk of steatosis and liver disease progression, as well as reducing the chances of an effective antiviral treatment. There is evidence that treatments aimed at reducing insulin resistance are also effective in improving liver histology. Although cardiovascular disease remains the major cause of increased morbidity and excess mortality in metabolic disorders, the risk of progressive liver disease should no longer be underestimated, being a threat to millions of people at risk in the present epidemics of obesity and diabetes, and therapeutic strategies need to be tested.
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Affiliation(s)
- Giulio Marchesini
- Unit of Metabolic Diseases, Alma Mater Studiorum University, Bologna, and San Giovanni Battista Hospital, Turin, Italy.
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25
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Abstract
The results of interferon and ribavirin combination therapy for chronic hepatitis C infection have substantially improved in recent years, such that the majority of patients in randomized-controlled trials now achieve a sustained virological response. However, adverse effects are commonplace, often disabling and may lead to interruption or cessation of therapy with subsequent loss of efficacy. Constitutional, neuropsychiatric and haematological reactions have proved particularly troublesome. In this review, we discuss these adverse effects in more detail and highlight recent advances in their management.
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Affiliation(s)
- R J Aspinall
- Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA 92037, USA
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26
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Pijak MR, Gazdik F, Hrusovsky S. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 2004; 40:760-1; author reply 761. [PMID: 15349918 DOI: 10.1002/hep.20397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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27
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Aigner ES. Treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004; 351:831-2; author reply 831-2. [PMID: 15317901 DOI: 10.1056/nejm200408193510822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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28
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Barry J, Bourke M, Buckley M, Coughlan B, Crowley D, Cullen W, Dooley S, Keating S, Kelleher D, Moloney J, Murray F, McCormick PA, MacMathuna P, O'Connor J, O'Grady J, O'Sullivan C, O'Sullivan P, Quinn C, Smyth B, Sweeney B. Hepatitis C among drug users: consensus guidelines on management in general practice. Ir J Med Sci 2004; 173:145-50. [PMID: 15693384 DOI: 10.1007/bf03167929] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Hepatitis C (HCV) is a common cause of morbidity among patients who attend general practitioners (GPs) in Ireland for methadone maintenance treatment. AIMS To describe the development and content of guidelines for the management of HCV among current or former opiate users in the Eastern Regional Health Authority area attending GPs for methadone treatment. METHODS The guidelines were produced in five stages: identification of key stakeholders; development of evidence-based draft guidelines; discussion of content; determination of 'Delphi'-facilitated consensus and review by a sample of GPs for whom the guidelines would be intended. RESULTS The guidelines contain advice for GPs on all aspects of care of patients at risk of HCV, including general and preventative care, care of other bloodborne and hepatotoxic viruses, and the factors to be considered and appropriate evaluation prior to referring a patient for assessment at a hepatology unit. CONCLUSIONS GPs have an important role to play in the care of patients at risk of, or infected with, HCV.
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Affiliation(s)
- J Barry
- Eastern Regional Health Authority
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29
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Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003; 38:639-44. [PMID: 12939590 DOI: 10.1053/jhep.2003.50350] [Citation(s) in RCA: 266] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The aim of this study was to determine if body mass index (BMI) was an independent predictor of response to antiviral treatment in patients with chronic hepatitis C. A retrospective review was performed of all patients at a single center with chronic hepatitis C treated with antiviral medication from 1989 to 2000. A sustained response was defined as either negative hepatitis C virus (HCV) RNA by polymerase chain reaction and/or normal alanine aminotransferase (ALT) level (only in those treated before availability of HCV RNA testing) 6 months following completion of therapy. All patients were classified into one of 3 groups according to BMI (normal, <25 kg/m(2); overweight, 25-30 kg/m(2); obese, >30 kg/m(2)). A total of 253 patients were treated with either interferon (IFN) monotherapy or IFN in combination with ribavirin. Patients were excluded if predetermined clinical characteristics were unavailable. Using logistic regression, and after adjusting for the examined variables (age, sex, history of alcohol consumption >50 g/d, cirrhosis on pretreatment biopsy, and BMI), likelihood ratio tests showed significant differences in response to treatment according to BMI group (P =.01), genotype (P <.01), and cirrhosis (P <.01). Those with genotypes 2 or 3 had an odds ratio (OR) for success of 11.7 compared with those with genotype 1, cirrhotic patients had an OR of 0.15 compared with noncirrhotic patients, and obese patients had an OR of 0.23 compared with normal and overweight patients. Hepatic steatosis was not an independent risk factor for response to antiviral treatment. In conclusion, obesity, only when defined as a BMI greater than 30 kg/m(2), is an independent (of genotype and cirrhosis) negative predictor of response to hepatitis C treatment.
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Affiliation(s)
- Brian L Bressler
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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30
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Layden-Almer JE, Ribeiro RM, Wiley T, Perelson AS, Layden TJ. Viral dynamics and response differences in HCV-infected African American and white patients treated with IFN and ribavirin. Hepatology 2003; 37:1343-50. [PMID: 12774013 DOI: 10.1053/jhep.2003.50217] [Citation(s) in RCA: 154] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Studies have suggested that African American patients infected with hepatitis C virus (HCV) do not respond as well to treatment with interferon (IFN) as white patients. Here we analyzed the difference in the viral kinetic response between genotype 1 HCV-infected African American patients (n = 19) and white patients (n = 16). Patients were treated with 10 mIU IFN-alpha2b daily with or without ribavirin for 1 month followed by 3 mIU IFN-alpha2b 3 times a week with ribavirin. The kinetic parameters (epsilon, treatment effectiveness at inhibiting virion production; delta, loss rate of virus-producing cells; c, clearance rate of free virions; tau, delay until viral decline starts) were estimated from the viral load decay profiles using a previously described mathematical model. Differences in early kinetic parameters and viral negativity frequencies at weeks 4, 12, and 48 were compared. Ribavirin did not appear to enhance any of the viral kinetic parameters, although this may have been due to the high dose of IFN used. African American patients exhibited significantly (P =.005) lower drug effectiveness (88.6% vs. 98.2%) compared with white patients, accounting for a 0.8 log lower HCV RNA decrease in the first 24 hours of treatment. Significant differences (P =.006) were also noted for delta. There was no correlation between any of the viral kinetic parameters and either age, body mass index (BMI), or genotype 1 subtype. No patient achieved viral negativity at weeks 4, 12, or 48 without an epsilon greater than 90%. The mean viral decline and viral negativity rates were statistically different between the two races; however, when controlling for treatment effectiveness, these differences were no longer apparent. In conclusion, the failure of IFN response in African American patients infected with genotype 1 HCV is in part due to an impaired ability to inhibit viral production.
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Akuta N, Suzuki F, Tsubota A, Suzuki Y, Someya T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Efficacy of interferon monotherapy to 394 consecutive naive cases infected with hepatitis C virus genotype 2a in Japan: therapy efficacy as consequence of tripartite interaction of viral, host and interferon treatment-related factors. J Hepatol 2002; 37:831-6. [PMID: 12445425 DOI: 10.1016/s0168-8278(02)00301-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS The mechanism of variable response to interferon (IFN) monotherapy in patients infected with HCV genotype 2a is still unclear. Here we investigated the response in a large group of patients infected with genotype 2a. METHODS We evaluated 394 consecutive non-cirrhotic naive patients infected with genotype 2a who received IFN monotherapy for 24 weeks, including initial aggressive induction therapy. Of these, 97 were also evaluated for early viral kinetics in serum and treatment efficacy. RESULTS The overall sustained response (SR) rate was 68.3% (viral load <1.0 Meq/ml (82.4%); >/=1.0 (52.4%)). Multivariate analysis identified five independent factors associated with SR; viral load <1.0 Meq/ml, total IFN dose > or =700 million units, hepatocyte steatosis none or mild, albumin > or =3.9 g/dl, and alanine aminotransferase > or =75 IU/l. The kinetic study showed that serum viral clearance at < or =1 week was the best predictor of SR, and persistence at > or = 4 weeks was a predictor of non-SR. CONCLUSIONS Our study suggests that viral, host and IFN treatment-related factors determine the response to IFN monotherapy in patients infected with HCV genotype 2a. Further, we report that IFN monotherapy is very effective for patients with genotype 2a, especially for those with low viral load; and that early viral kinetics is useful as a predictor of the response.
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Affiliation(s)
- Norio Akuta
- Division of Gastroenterology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-0001, Japan.
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Lamb MW, Martin NE. Weight-based versus fixed dosing of peginterferon (40kDa) alfa-2a. Ann Pharmacother 2002; 36:933-5. [PMID: 12014351 DOI: 10.1177/106002800203600501] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Affiliation(s)
- Matthew W Lamb
- Department of Clinical Science, Hoffmann-LaRoche Inc., 340 Kingsland Street, Nutley, NJ 07110-1199, USA.
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Affiliation(s)
- J M Pawlotsky
- Department of Bacteriology and Virology and INSERM U99, Hôpital Henri Mondor, Université Paris XII, Créteil, France.
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Abstract
Obesity is a worldwide problem, with major health, social and economic implications. The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow and the affinity of the drug for plasma proteins and/or tissue components. Obese people have larger absolute lean body masses as well as fat masses than non-obese individuals of the same age, gender and height. However, the percentage of fat per kg of total bodyweight (TBW) is markedly increased, whereas that chrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available. Pharmacokinetic studies provide differing data on renal function in obese patients. This review analyses recent publications on several classes of drugs: antibacterials, anticancer drugs, psychotropic drugs, anticonvulsants, general anaesthetics, opioid analgesics, neuromuscular blockers, beta-blockers and drugs commonly used in the management of obesity. Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity (e.g. lithium and vecuronium) is generally rather predictable, as these drugs are distributed mainly in lean tissues. The dosage of these drugs should be based on the ideal bodyweight (IBW). However, some of these drugs (e.g. antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient's excess bodyweight. There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g. remifentanil and some beta-blockers) and their distribution in obese individuals. The distribution of a drug between fat and lean tissues may influence its pharmacokinetics in obese patients. Thus, the loading dose should be adjusted to the TBW or IBW, according to data from studies carried out in obese individuals. Adjustment of the maintenance dosage depends on the observed modifications in clearance. Our present knowledge of the influence of obesity on drug pharmacokinetics is limited. Drugs with a small therapeutic index should be used prudently and the dosage adjusted with the help of drug plasma concentrations.
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Affiliation(s)
- G Cheymol
- Department of Pharmacology, Faculty of Medicine Saint-Antoine, Paris, France
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Causse X, Payen JL, Izopet J, Babany G, Girardin MF. Does HIV-infection influence the response of chronic hepatitis C to interferon treatment? A French multicenter prospective study. French Multicenter Study Group. J Hepatol 2000; 32:1003-10. [PMID: 10898321 DOI: 10.1016/s0168-8278(00)80105-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIM The aim of this prospective study was to compare the response to alfa-interferon treatment of chronic hepatitis C in two groups of patients: coinfected with human immunodeficiency virus (HIV) (G I) or not (G II). METHODS One hundred and fifty-three patients with chronic hepatitis C had been enrolled in 30 French liver units or infectious diseases units between May 1992 and January 1995 (G I: 76, G II: 77) to receive alfa-2a interferon: 3 MU thrice weekly for 6 months. RESULTS One hundred and twenty-seven patients (G I: 63, G II: 64) fulfilled all criteria for analysis. The two groups were comparable for all demographic data, while significantly more severe biological and histological (p=0.001) parameters attested to more serious hepatitis among HIV-HCV coinfected patients. HCV viremia was higher among HIV-coinfected patients (p=0.0169), while genotype repartition was identical among the two groups (more than 52% of genotype 1, more than 31% of genotype 3). ALT normalization was, respectively, (G I/G II) obtained in 17.46%/26.56% (not significant) of patients at the end of treatment and in 11.11%/12.5% (not significant) of patients after 6 months of follow-up. In a multivariate analysis, GGT level before therapy (relative risk 2.1, confidence interval 1.1-5.8) and body surface area (relative risk 1.9, confidence interval 1.1-3.7) were the variables independently associated with the response to alfa-interferon treatment (higher GGT and more elevated body surface area were associated with a risk of non-response). CONCLUSION In our study HIV infection did not affect the alfa-interferon treatment response of chronic hepatitis C, and response could be achieved among HIV-coinfected patients. Present therapeutic anti-HCV schedules need to be proposed to HIV-HCV coinfected patients before severe immunosuppression occurs. On the other hand, more severe biological and histological parameters were observed among HIV-HCV coinfected patients, which suggests a need to study whether HIV infection is associated with a worsening course of chronic hepatitis C.
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Affiliation(s)
- X Causse
- Hepatogastroenterology Unit, CHR Orléans La Source, France
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Chatelut E, Rostaing L, Grégoire N, Payen JL, Pujol A, Izopet J, Houin G, Canal P. A pharmacokinetic model for alpha interferon administered subcutaneously. Br J Clin Pharmacol 1999; 47:365-71. [PMID: 10233199 PMCID: PMC2014240 DOI: 10.1046/j.1365-2125.1999.00912.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/1998] [Accepted: 11/18/1998] [Indexed: 11/20/2022] Open
Abstract
AIMS To model the pharmacokinetic profiles of alpha interferon (alphaIFN) after a single subcutaneous (s.c.) injection of 3 million units of alpha 2b interferon, to correlate the pharmacokinetic parameters with patient demographic covariates, and to develop a limiting sampling strategy for determining the alphaIFN plasma area under the curve of concentration vs time (AUC). METHODS The plasma alphaIFN pharmacokinetics were determined in 27 patients with chronic hepatitis C virus infection after the first s.c. injection of the drug. Ten patients had normal renal function and 17 were chronic haemodialysis patients. Plasma samples were assayed by an Elisa method. Concentration-time data was analysed by a population approach using NONMEM. RESULTS The pharmacokinetic model which better described the concentration vs time data was a one-compartment model with two processes of absorption: a zero-order followed by a first-order process. The mean clearance of dialysis patients represented 37% (with 95% confidence interval: 30% -44%) of the mean value of the patients with normal renal function. The volume of distribution was significantly correlated to the body surface area. Bayesian analysis using NONMEM allowed determination of the individual plasma AUC from three samples within the 24 h period post s.c. injection. CONCLUSIONS The present pharmacokinetic model will allow one to obtain individual parameters such as, the area under the curve of concentration vs time from a limited-sampling strategy, and to perform pharmacokinetic-pharmacodynamic analysis of combined alphaIFN plasma concentrations and viraemic data.
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Affiliation(s)
- E Chatelut
- Institut Claudius-Regaud, Centre Hospitalier Universitaire, Toulouse, France
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