المؤلفون: Loomba, Rohit, Sanyal, Arun J, Kowdley, Kris V, Terrault, Norah, Chalasani, Naga P, Abdelmalek, Manal F, McCullough, Arthur J, Shringarpure, Reshma, Ferguson, Beatrice, Lee, Lois, Chen, Jianfen, Liberman, Alexander, Shapiro, David, Neuschwander-Tetri, Brent A

المصدر: Gastroenterology. 156(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Liver Disease, Clinical Trials and Supportive Activities, Chronic Liver Disease and Cirrhosis, Hepatitis, Digestive Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Oral and gastrointestinal, Adult, Biomarkers, Biopsy, Chenodeoxycholic Acid, Clinical Enzyme Tests, Decision Support Techniques, Female, Gastrointestinal Agents, Humans, Ligands, Liver, Liver Cirrhosis, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Predictive Value of Tests, Receptors, Cytoplasmic and Nuclear, Time Factors, Treatment Outcome, United States, FLINT Trial, OCA, FXR Agonist, NAFLD, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics

الوصف: Background & aimsNonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation, and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in the NASH treatment trial evaluated the effects of obeticholic acid vs placebo on histologic response (defined as decrease in nonalcoholic fatty liver disease activity score [NAS] by ≥2, with no worsening of fibrosis); 45% of patients had a histologic response to obeticholic acid (25 mg), and 21% had a response to placebo (P < .01). We performed a secondary analysis of data from this trial to identify clinical parameters associated with a histologic response.MethodsWe used a logistic regression model with a stepwise selection procedure to identify baseline and early on-treatment factors associated with a histologic response at 72 weeks. Baseline demographics, liver histology, medical history, concomitant medications, cardiometabolic parameters, and serum biochemistry, as well as the changes over the course of the trial (at weeks 12 and 24), were evaluated as potential predictors of a histologic response. The model was cross-validated by a jackknife method, and performance was evaluated with the area under the receiver operating characteristic curve.ResultsThe logistic regression model found that obeticholic acid treatment, baseline NAS > 5, baseline triglyceride level ≤ 154 mg/dL, baseline international normalized ratio ≤ 1, baseline aspartate aminotransferase level ≤ 49 U/L, and a decrease in alanine aminotransferase level at week 24 by 17 U/L or more, to be significantly associated with histologic response (area under the receiver operating characteristic curve, 0.83; 95% confidence interval, 0.77-0.89; P < .0001).ConclusionsIn a secondary analysis of data from a clinical trial of obeticholic acid in patients with NASH, we identified routine clinical and laboratory parameters during the first 24 weeks of treatment (such as baseline NAS, triglyceride levels, and a decrease in alanine aminotransferase level) to significantly associate with histologic markers of response.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/91b0661cTest

المؤلفون: Lim, Joseph K, Liapakis, Ann Marie, Shiffman, Mitchell L, Lok, Anna S, Zeuzem, Stefan, Terrault, Norah A, Park, James S, Landis, Charles S, Hassan, Mohamed, Gallant, Joel, Kuo, Alexander, Pockros, Paul J, Vainorius, Monika, Akushevich, Lucy, Michael, Larry, Fried, Michael W, Nelson, David R, Ben-Ari, Ziv, Group, HCV-TARGET Study

المصدر: Clinical Gastroenterology and Hepatology. 16(11)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Chronic Liver Disease and Cirrhosis, Hepatitis, Emerging Infectious Diseases, Hepatitis - C, Digestive Diseases, Clinical Research, Infectious Diseases, Liver Disease, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Adolescent, Adult, Aged, Aged, 80 and over, Antiviral Agents, Benzimidazoles, Drug Therapy, Combination, Drug-Related Side Effects and Adverse Reactions, Europe, Female, Fluorenes, Genotype, Hepacivirus, Hepatitis C, Chronic, Humans, Liver Cirrhosis, Longitudinal Studies, Male, Middle Aged, North America, Prospective Studies, Ribavirin, Sofosbuvir, Sustained Virologic Response, Treatment Outcome, Young Adult, Real World, Viral Hepatitis, Therapy, HCV-TARGET, HCV-TARGET Study Group, Gastroenterology & Hepatology, Clinical sciences

الوصف: BACKGROUND & AIMS:We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET). METHODS:We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow-up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per-protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS:The per-protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16-5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46-6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59-7.00) were associated with SVR12. CONCLUSIONS:In an analysis of safety and effectiveness data from the HCV-TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment-experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

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الوصول الحر: https://escholarship.org/uc/item/0sg8z5mvTest

المؤلفون: Flemming, Jennifer A, Kim, W Ray, Brosgart, Carol L, Terrault, Norah A

المصدر: Hepatology. 65(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Chronic Liver Disease and Cirrhosis, Organ Transplantation, Liver Cancer, Emerging Infectious Diseases, Infectious Diseases, Cancer, Digestive Diseases, Rare Diseases, Hepatitis - C, Liver Disease, Hepatitis - B, Hepatitis, Transplantation, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Adult, Antiviral Agents, Cohort Studies, Dideoxyadenosine, End Stage Liver Disease, Female, Hepatitis B, Hepatitis C, Chronic, Humans, Liver Transplantation, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Preoperative Care, Quality Improvement, Registries, Retrospective Studies, Time Factors, Treatment Outcome, United States, Waiting Lists, Medical Biochemistry and Metabolomics, Immunology, Gastroenterology & Hepatology, Clinical sciences

الوصف: Direct-acting antiviral (DAA) therapy, recently approved for patients with decompensated cirrhosis (DC) secondary to hepatitis C virus (HCV), is associated with improved hepatic function. We analyzed trends in liver transplant (LT) wait-listing (WL) to explore potential impact of effective medical therapy on WL registration. This is a cohort study using the Scientific Registry of Transplant Recipients database from 2003 to 2015. A total of 47,591 adults wait-listed for LT from HCV, hepatitis B virus (HBV), and nonalcoholic steatohepatitis (NASH) were identified. LT indication was defined as DC if the Model for End-Stage Liver Disease (MELD) at WL was ≥15 or hepatocellular carcinoma (HCC). Era of listing was divided into interferon (IFN; 2003-2010), protease inhibitor (PI; 2011-2013), and direct-acting antiviral (DAA; 2014-2015). Annual standardized incidence rates of WL were analyzed using Poisson regression. Adjusted incidences of LT WL for DC in HCV patients decreased by 5% in the PI era (P = 0.004) and 32% in the DAA era (P < 0.001) compared to the IFN era. Listing for DC in HBV also decreased in the PI (-17%; P = 0.002) and DAA eras (-24%; P < 0.001). Conversely, WL for DC in NASH increased by 41% in the PI era (P < 0.001) and 81% in the DAA era (P < 0.001). WL for HCC in both the HCV and NASH populations increased in both the PI and DAA eras (P < 0.001 for all) whereas HCC WL in HBV remained stable (P > 0.05 for all).ConclusionThe rate of LT WL for HCV complicated by DC has decreased by over 30% in the era of DAA therapy. Further reductions in WL are anticipated with increased testing, linkage to care, and access to DAA therapy. (Hepatology 2017;65:804-812).

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الوصول الحر: https://escholarship.org/uc/item/0sx1s1cqTest

المؤلفون: Zoulim, Fabien, Liang, T Jake, Gerbes, Alexander L, Aghemo, Alessio, Deuffic-Burban, Sylvie, Dusheiko, Geoffrey, Fried, Michael W, Pol, Stanislas, Rockstroh, Jürgen Kurt, Terrault, Norah A, Wiktor, Stefan

المصدر: Gut. 64(11)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Liver Disease, Chronic Liver Disease and Cirrhosis, Emerging Infectious Diseases, Digestive Diseases, Orphan Drug, Infectious Diseases, Hepatitis - C, Rare Diseases, Hepatitis, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Antiviral Agents, Health Services Accessibility, Hepatitis C, Chronic, Humans, Treatment Outcome, HEPATITIS C, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics

الوصف: Chronic HCV infections represent a major worldwide public health problem and are responsible for a large proportion of liver related deaths, mostly because of HCV-associated hepatocellular carcinoma and cirrhosis. The treatment of HCV has undergone a rapid and spectacular revolution. In the past 5 years, the launch of direct acting antiviral drugs has seen sustained virological response rates reach 90% and above for many patient groups. The new treatments are effective, well tolerated, allow for shorter treatment regimens and offer new opportunities for previously excluded groups. This therapeutic revolution has changed the rules for treatment of HCV, moving the field towards an interferon-free era and raising the prospect of HCV eradication. This manuscript addresses the new challenges regarding treatment optimisation in the real world, improvement of antiviral efficacy in 'hard-to-treat' groups, the management of patients whose direct acting antiviral drug treatment was unsuccessful, and access to diagnosis and treatment in different parts of the world.

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الوصول الحر: https://escholarship.org/uc/item/46g9w77vTest

المؤلفون: Saxena, Varun, Nyberg, Lisa, Pauly, Marypat, Dasgupta, Aditi, Nyberg, Anders, Piasecki, Barbara, Winston, Bradley, Redd, Jacquelyn, Ready, Joanna, Terrault, Norah A

المصدر: Hepatology. 62(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Liver Disease, Hepatitis, Clinical Research, Digestive Diseases, Chronic Liver Disease and Cirrhosis, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Aged, Analysis of Variance, Antiviral Agents, Case-Control Studies, Drug Therapy, Combination, Female, Follow-Up Studies, Hepacivirus, Hepatitis C, Humans, Liver Cirrhosis, Logistic Models, Male, Middle Aged, Multivariate Analysis, Patient Safety, Reference Values, Retrospective Studies, Ribavirin, Risk Assessment, Severity of Illness Index, Simeprevir, Sofosbuvir, Treatment Outcome, Medical Biochemistry and Metabolomics, Immunology, Gastroenterology & Hepatology, Clinical sciences

الوصف: UnlabelledRisks and benefits of simeprevir plus sofosbuvir (SIM+SOF) in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virological responses (SVR) of SIM+SOF with and without ribavirin (RBV) in patients with Child-Pugh (CP)-B/C versus CP-A cirrhosis and compared to matched untreated controls. This study was of a multicenter cohort of adults with hepatitis C virus genotype 1 and cirrhosis treated with SIM+SOF with/without RBV for 12 weeks. Controls were matched on treatment center, age, CP class, and Model for End-Stage Liver Disease (MELD) score. Of 160 patients treated with SIM+SOF with/without RBV, 35% had CP-B/C and 64% had CP-A, with median baseline MELD 9 (interquartile range, 8-11). Sustained virological response at week 12 (SVR12) was achieved by 73% of CP-B/C versus 91% of CP-A (P

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الوصول الحر: https://escholarship.org/uc/item/4zm8p3m6Test

المؤلفون: Verna, Elizabeth C, Saxena, Varun, Burton, James R, O’Leary, Jacqueline G, Dodge, Jennifer L, Stravitz, Richard T, Levitsky, Josh, Trotter, James F, Everson, Gregory T, Brown, Robert S, Terrault, Norah A

المصدر: Transplantation. 99(8)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Hepatitis, Organ Transplantation, Liver Disease, Emerging Infectious Diseases, Chronic Liver Disease and Cirrhosis, Hepatitis - C, Digestive Diseases, Infectious Diseases, Clinical Research, Transplantation, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Antiviral Agents, Biomarkers, Cholestasis, Drug Therapy, Combination, Female, Genotype, Hepacivirus, Hepatitis C, Humans, Liver Cirrhosis, Liver Transplantation, Logistic Models, Male, Middle Aged, Multivariate Analysis, Odds Ratio, Oligopeptides, Proline, RNA, Viral, Recurrence, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome, United States, Viral Load, CRUSH-C Consortium, Medical and Health Sciences, Surgery, Clinical sciences, Immunology

الوصف: BackgroundAntiviral treatment with sustained virologic response (SVR) improves survival in liver transplant (LT) recipients, and is especially relevant to patients with advanced recurrent hepatitis C virus (HCV). We assessed the safety and efficacy of protease inhibitor-based triple therapy in patients with recurrent advanced fibrosis and cholestatic hepatitis.MethodsThe LT recipients with genotype 1 HCV and advanced fibrosis (F3-4/4) or cholestatic hepatitis treated with telaprevir- or boceprevir-based triple therapy at 6 centers (CRUSH-C consortium) were retrospectively assessed. The primary endpoints were SVR at 12 weeks (SVR12) and safety.ResultsForty-five patients with advanced fibrosis and 9 with cholestatic hepatitis (74% men, 57% genotype 1a, 63% previous nonresponders) were included. SVR12 occurred in 51% with advanced fibrosis and 44% with cholestatic hepatitis. Extended rapid virologic response was highly predictive of SVR12. Hispanic ethnicity (odds ratio, 0.16; P = 0.03), previous null/partial response (0.24; P = 0.02), IL28B genotype CC (7.0; P = 0.02), albumin (3.87; P = 0.03), platelet count (1.01; P = 0.02), and steroid use (0.21; P = 0.03) were associated with SVR12. Six (11%) patients died, and hepatic decompensation occurred in 22% with advanced fibrosis and 33% with cholestatic hepatitis. Albumin (0.02; P = 0.001), encephalopathy (12.0; P = 0.04) and Hispanic ethnicity (odds ratio, 6.17; P = 0.01) were associated with death or decompensation.ConclusionsFor LT recipients with recurrent advanced HCV and at greatest need of cure, protease inhibitor-based triple therapy achieved approximately 50% SVR12. However, there is significant risk of serious adverse events, arguing for earlier intervention. The availability of treatments with better efficacy and safety is of particular importance for posttransplant patients with advanced disease.

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الوصول الحر: https://escholarship.org/uc/item/8gp2m329Test

المؤلفون: Neuschwander-Tetri, Brent A, Loomba, Rohit, Sanyal, Arun J, Lavine, Joel E, Van Natta, Mark L, Abdelmalek, Manal F, Chalasani, Naga, Dasarathy, Srinivasan, Diehl, Anna Mae, Hameed, Bilal, Kowdley, Kris V, McCullough, Arthur, Terrault, Norah, Clark, Jeanne M, Tonascia, James, Brunt, Elizabeth M, Kleiner, David E, Doo, Edward, Network, for the NASH Clinical Research

المصدر: The Lancet. 385(9972)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Diabetes, Liver Disease, Chronic Liver Disease and Cirrhosis, Clinical Trials and Supportive Activities, Digestive Diseases, Hepatitis, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Oral and gastrointestinal, Administration, Oral, Chenodeoxycholic Acid, Cholesterol, HDL, Cholesterol, LDL, Double-Blind Method, Female, Humans, Liver, Liver Cirrhosis, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Receptors, Cytoplasmic and Nuclear, Treatment Outcome, Weight Loss, NASH Clinical Research Network, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences

الوصف: BackgroundThe bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.MethodsWe did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase -24%, 95% CI -45 to -3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498.FindingsBetween March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1·9, 95% CI 1·3 to 2·8; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group.InterpretationObeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.FundingNational Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

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الوصول الحر: https://escholarship.org/uc/item/8m8374t5Test

المؤلفون: Burton, James R, O’Leary, Jacqueline G, Verna, Elizabeth C, Saxena, Varun, Dodge, Jennifer L, Stravitz, Richard T, Levitsky, Joshua, Trotter, James F, Everson, Gregory T, Brown, Robert S, Terrault, Norah A

المصدر: Journal of Hepatology. 61(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Digestive Diseases, Organ Transplantation, Hepatitis - C, Liver Disease, Transplantation, Chronic Liver Disease and Cirrhosis, Emerging Infectious Diseases, Infectious Diseases, Hepatitis, Clinical Research, Genetics, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Adult, Aged, Cohort Studies, Drug Therapy, Combination, Female, Genotype, Hepacivirus, Hepatitis C, Humans, Interferon-alpha, Male, Middle Aged, Oligopeptides, Polyethylene Glycols, Proline, Protease Inhibitors, RNA, Viral, Recombinant Proteins, Retrospective Studies, Ribavirin, Treatment Outcome, United States, Telaprevir, Boceprevir, Antiviral therapy, Interferon, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences

الوصف: Background & aimsNS3/4A protease inhibitors, boceprevir or telaprevir, combined with peginterferon and ribavirin was the standard treatment for HCV genotype 1 and remains the only available direct antiviral drug based therapy in some countries. Efficacy and safety data in liver transplant recipients are limited.MethodsThis was a retrospective cohort study of 81 patients with genotype 1 HCV treated with boceprevir (10%) or telaprevir (90%) plus peginterferon and ribavirin at 6 US transplant centers (53% stage 3-4/4 fibrosis, 57% treatment experienced). The primary end point was undetectable HCV RNA 12 weeks after treatment completion (SVR12).ResultsThe intent-to-treat SVR12 rate was 63% (51/81). Patients with an extended rapid virologic response, (undetectable HCV RNA at 4 and 12 weeks after starting boceprevir or telaprevir), had a higher rate of SVR12 than all other patients (85% vs. 15%, p

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الوصول الحر: https://escholarship.org/uc/item/74g8r7b9Test

المؤلفون: Everson, Gregory T, Terrault, Norah A, Lok, Anna S, Rodrigo, Del R, Brown, Robert S, Saab, Sammy, Shiffman, Mitchell L, Al‐Osaimi, Abdullah MS, Kulik, Laura M, Gillespie, Brenda W, Everhart, James E, Study, and the Adult‐to‐Adult Living Donor Liver Transplantation Cohort

المصدر: Hepatology. 57(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Sexually Transmitted Infections, Clinical Research, HIV/AIDS, Digestive Diseases, Emerging Infectious Diseases, Organ Transplantation, Clinical Trials and Supportive Activities, Patient Safety, Hepatitis, Transplantation, Liver Disease, Infectious Diseases, Hepatitis - C, Chronic Liver Disease and Cirrhosis, Prevention, Comparative Effectiveness Research, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Antiviral Agents, Dose-Response Relationship, Drug, Drug Therapy, Combination, End Stage Liver Disease, Female, Genotype, Hepacivirus, Hepatitis C, Chronic, Humans, Interferon alpha-2, Interferon-alpha, Liver Transplantation, Male, Middle Aged, Polyethylene Glycols, Preoperative Care, Recombinant Proteins, Recurrence, Ribavirin, Treatment Outcome, Adult-to-Adult Living Donor Liver Transplantation Cohort Study, Medical Biochemistry and Metabolomics, Immunology, Gastroenterology & Hepatology, Clinical sciences

الوصف: UnlabelledHepatitis C virus (HCV) infection recurs in liver recipients who are viremic at transplantation. We conducted a randomized, controlled trial to test the efficacy and safety of pretransplant pegylated interferon alpha-2b plus ribavirin (Peg-IFN-α2b/RBV) for prevention of post-transplant HCV recurrence. Enrollees had HCV and were listed for liver transplantation, with either potential living donors or Model for End-Stage Liver Disease upgrade for hepatocellular carcinoma. Patients with HCV genotypes (G) 1/4/6 (n = 44/2/1) were randomized 2:1 to treatment (n = 31) or untreated control (n = 16); HCV G2/3 (n=32) were assigned to treatment. Overall, 59 were treated and 20 were not. Peg-IFN-α2b, starting at 0.75 μg/kg/week, and RBV, starting at 600 mg/day, were escalated as tolerated. Patients assigned to treatment versus control had similar baseline characteristics. Combined virologic response (CVR) included pretransplant sustained virologic response and post-transplant virologic response (pTVR), defined as undetectable HCV RNA 12 weeks after end of treatment or transplant, respectively. In intent-to-treat analyses, 12 (19%) assigned to treatment and 1 (6%) assigned to control achieved CVR (P = 0.29); per-protocol values were 13 (22%) and 0 (0%) (P = 0.03). Among treated G1/4/6 patients, 23 of 30 received transplant, of whom 22% had pTVR; among treated G2/3 patients 21 of 29 received transplant, of whom 29% had pTVR. pTVR was 0%, 18%, and 50% in patients treated for 16 weeks, respectively (P = 0.01). Serious adverse events (SAEs) occurred with similar frequency in treated versus untreated patients (68% versus 55%; P = 0.30), but the number of SAEs per patient was higher in the treated group (2.7 versus 1.3; P = 0.003).ConclusionPretransplant treatment with Peg-IFN-α2b/RBV prevents post-transplant recurrence of HCV in selected patients. Efficacy is higher with >16 weeks of treatment, but treatment is associated with increased risk of potentially serious complications.

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الوصول الحر: https://escholarship.org/uc/item/9d64q2whTest
https://escholarship.org/content/qt9d64q2wh/qt9d64q2wh.pdfTest

المؤلفون: Terrault, Norah A, Roland, Michelle E, Schiano, Thomas, Dove, Lorna, Wong, Michael T, Poordad, Fred, Ragni, Margaret V, Barin, Burc, Simon, David, Olthoff, Kim M, Johnson, Lynt, Stosor, Valentina, Jayaweera, Dushyantha, Fung, John, Sherman, Kenneth E, Subramanian, Aruna, Millis, J Michael, Slakey, Douglas, Berg, Carl L, Carlson, Laurie, Ferrell, Linda, Stablein, Donald M, Odim, Jonah, Fox, Lawrence, Stock, Peter G, Solid Organ Transplantation in HIV: Multi-Site Study Investigators

المصدر: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 18(6)

مصطلحات موضوعية: Solid Organ Transplantation in HIV: Multi-Site Study Investigators, Humans, Hepatitis C, Chronic, HIV Infections, Postoperative Complications, Abdomen, Acute, Treatment Outcome, Kidney Transplantation, Liver Transplantation, Incidence, Risk Factors, Survival Analysis, Follow-Up Studies, Prospective Studies, Graft Rejection, Graft Survival, Adult, Middle Aged, United States, Female, Male, Coinfection, Liver Disease, Organ Transplantation, Infectious Diseases, Hepatitis, Hepatitis - C, HIV/AIDS, Digestive Diseases, Emerging Infectious Diseases, Clinical Research, Chronic Liver Disease and Cirrhosis, Transplantation, 6.4 Surgery, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Clinical Sciences, Surgery

الوصف: Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV-coinfected patients and 2 control groups: 235 HCV-monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3-year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%-71%] and 53% (95% CI = 40%-64%) for the HCV/HIV patients and 79% (95% CI = 72%-84%) and 74% (95% CI = 66%-79%) for the HCV-infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney-liver transplantation (HR = 3.8), an anti-HCV-positive donor (HR = 2.5), and a body mass index < 21 kg/m(2) (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV-coinfected LT patients versus HCV-monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV-coinfected recipients versus HCV-infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes.

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الوصول الحر: https://escholarship.org/uc/item/33k8r0psTest