|
1
|
Samuel S, Abulawi A, Malik R. Hepatitis C and Nonalcoholic Steatohepatitis in the 21st Century: Impact on Liver Disease and Liver Transplantation. GASTROENTEROLOGY INSIGHTS 2023; 14:249-270. [DOI: 10.3390/gastroent14030018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Hepatitis C infection is a leading etiology of hepatic dysfunction and a major indication for liver transplantation due to the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Nonalcoholic fatty liver disease (NAFLD) and, specifically, its subtype nonalcoholic steatohepatitis (NASH) is a rising cause of liver disease. It is predicted to surpass hepatitis C as a leading indication for transplant. The introduction of direct-acting antivirals (DAAs) decreased the prevalence of chronic hepatitis C infections, but the obesity epidemic and metabolic syndrome have increased the prevalence of NASH. Weight loss and dietary modifications are recommended NASH therapies, but unlike for hepatitis C, federally approved agents are lacking and currently under investigation. Clinical trials face many barriers in NASH treatment because of the difficulty of diagnosis and a lack of standardized and accurate clinical and histologic responses. Mortality and morbidity in NASH are heightened because of the presence of multiple comorbidities including cardiovascular disease, diabetes, and renal dysfunction. A liver transplant may be indicated, but a thorough screening of candidates, including a comprehensive cardiovascular assessment, is essential to ensuring successful outcomes pre- and post-transplant. Therapeutic agents for NASH are warranted before it becomes a significant and leading cause of morbidity and mortality worldwide.
Collapse
Affiliation(s)
- Sonia Samuel
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
| | - Ahmad Abulawi
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
| | - Raza Malik
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
| |
Collapse
|
|
2
|
Viral proteases as therapeutic targets. Mol Aspects Med 2022; 88:101159. [PMID: 36459838 PMCID: PMC9706241 DOI: 10.1016/j.mam.2022.101159] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022]
Abstract
Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation and pathogenesis. Viral protease inhibitors have become an important class of antiviral drugs. Development of the first-in-class viral protease inhibitor saquinavir, which targets HIV protease, started a new era in the treatment of chronic viral diseases. Combining several drugs that target different steps of the viral life cycle enables use of lower doses of individual drugs (and thereby reduction of potential side effects, which frequently occur during long term therapy) and reduces drug-resistance development. Currently, several HIV and HCV protease inhibitors are routinely used in clinical practice. In addition, a drug including an inhibitor of SARS-CoV-2 main protease, nirmatrelvir (co-administered with a pharmacokinetic booster ritonavir as Paxlovid®), was recently authorized for emergency use. This review summarizes the basic features of the proteases of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and SARS-CoV-2 and discusses the properties of their inhibitors in clinical use, as well as development of compounds in the pipeline.
Collapse
|
|
3
|
Legaz I, Muro M. Analysis of hepatitis C virus-positive organs in liver transplantation. World J Hepatol 2022; 14:1840-1843. [PMID: 36185718 PMCID: PMC9521459 DOI: 10.4254/wjh.v14.i9.1840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/07/2022] [Accepted: 08/30/2022] [Indexed: 02/06/2023] Open
Abstract
The authors of this study note that in liver transplantation (LT), the survival rates of hepatitis C virus (HCV)-positive donors and HCV-negative receivers are comparable to those of HCV-negative donors and recipients. Direct-acting antiviral (DAA) therapies have nearly 100% effectiveness in treating HCV. Between 2006 and 2016, the percentages of HCV-positive patients on the waiting list and HCV-positive LT recipients fell by 8.2 percent and 7.6 percent, respectively. Records from April 1, 2014, in which the donor and receiver were both at least 18 years old and had a positive HCV status, were the only ones eligible for the study. The analysis for this study was restricted to the first transplant recorded for each patient using a data element that documented the number of prior transplants for each recipient, although some recipients appeared multiple times in the data set. HCV-positive recipients or people with fulminant hepatic failure were the main beneficiaries of primary biliary cirrhosis among HCV-positive donors. However, there is still a reticence to use HCV-positive donor organs in HCV recipients due to clinical and ethical considerations. Similar survival rates between HCV-positive donors and recipients and HCV-negative donors and receivers illustrate the efficacy of these DAA regimens.
Collapse
Affiliation(s)
- Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute, Regional Campus of International Excellence "Campus Mare Nostrum", Faculty of Medicine, University of Murcia, Murcia 30100, Spain
| | - Manuel Muro
- Department of Immunology Service, Instituto Murciano de Investigación Biosanitaria, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia 30120, Spain
| |
Collapse
|
|
4
|
Evon DM, Dong M, Reeve BB, Peter J, Michael L, Lok AS, Nelson DR, Stewart PW. Sustainable and equivalent improvements in symptoms and functional well-being following viral cure from ledipasvir/sofosbuvir versus elbasvir/grazoprevir for chronic hepatitis C infection: Findings from the randomized PRIORITIZE trial. J Viral Hepat 2022; 29:795-806. [PMID: 35657133 DOI: 10.1111/jvh.13716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/25/2022] [Indexed: 12/09/2022]
Abstract
The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.
Collapse
Affiliation(s)
- Donna M Evon
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Meichen Dong
- Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Bryce B Reeve
- Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA
| | - Joy Peter
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Larry Michael
- Center for Gastroenterology Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - David R Nelson
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Paul W Stewart
- Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA
| |
Collapse
|
|
5
|
Impact of utilization of hepatitis C positive organs in liver transplant: Analysis of united network for organ sharing database. World J Hepatol 2022. [DOI: 10.4254/wjh.v14.i5.985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
6
|
Dhaliwal A, Dhindsa B, Ramai D, Sayles H, Chandan S, Rangray R. Impact of utilization of hepatitis C positive organs in liver transplant: Analysis of united network for organ sharing database. World J Hepatol 2022; 14:984-991. [PMID: 35721288 PMCID: PMC9157704 DOI: 10.4254/wjh.v14.i5.984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 08/06/2021] [Accepted: 04/09/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The utility of hepatitis C virus (HCV) organs has increased after the Food and Drug Administration approval of direct acting anti-viral (DAA) medications for the HCV treatment. The efficacy of DAA in treating HCV is nearly 100%. AIM To analyze the United Network for Organ Sharing (UNOS) database to compare the survival rates between the hepatitis C positive donors and negative recipients and hepatitis C negative donors and recipients. METHODS We analyzed the adult patients in UNOS database who underwent deceased donor liver transplant from January 2014 to December 2017. The primary endpoint was to compare the survival rates among the four groups with different hepatitis C donor and recipient status: (Group 1) Both donor and recipient negative for HCV (Group 2) Negative donor and positive recipient for HCV (Group 3) Positive donor and negative recipient for HCV (Group 4) Both positive donor and recipient for HCV. SAS 9.4 software was used for the data analysis. Kaplan Meier log rank test was used to analyze the estimated survival rates among the four groups. RESULTS A total of 24512 patients were included: Group 1: 16436, Group 2: 6174, Group 3: 253 and Group 4: 1649. The 1-year (Group 1: 91.8%, Group 2: 92.12%, Group 3: 87%, Group 4: 92.8%), 2-year (Group 1: 88.4%, Group 2: 88.1%, Group 3: 84.3%, Group 4: 87.5%), 3-year (Group 1: 84.9%, Group 2: 84.3%, Group 3: 75.9%, Group 4: 83.2%) survival rates showed no statistical significance among the four groups. Kaplan Meier log rank test did not show any statistical significance difference in the estimated survival rates between Group 3 vs all the other groups. CONCLUSION The survival rates in hepatitis C positive donors and negative recipients are similar as compared to both hepatitis C negative donors and recipients. This could be due to the use of DAA therapy with cure rates of nearly 100%. This study supports the use of hepatitis C positive organs in the selected group of recipients with and without HCV infection. Further long-term studies are needed to further validate these findings.
Collapse
Affiliation(s)
- Amaninder Dhaliwal
- Department of Gastroenterology and Hepatology, Moffitt Cancer Center, Tampa, FL 33612, United States.
| | - Banreet Dhindsa
- Department of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Daryl Ramai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, United States
| | - Harlan Sayles
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Saurabh Chandan
- Department of Gastroenterology and Hepatology, Creighton University Medical Center, Omaha, NE 68124, United States
| | - Rajani Rangray
- Department of Gastroenterology and Hepatology, Creighton University Medical Center, Omaha, NE 68124, United States
| |
Collapse
|
|
7
|
Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
Collapse
Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
8
|
Peng P, Xu Y, Fried MW, Di Bisceglie AM, Fan X. Genome-wide capture sequencing to detect hepatitis C virus at the end of antiviral therapy. BMC Infect Dis 2020; 20:632. [PMID: 32847527 PMCID: PMC7448998 DOI: 10.1186/s12879-020-05355-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 08/17/2020] [Indexed: 11/10/2022] Open
Abstract
Background Viral relapse is a major concern in hepatitis C virus (HCV) antiviral therapy. Currently, there are no satisfactory methods to predict viral relapse, especially in the era of direct acting antivirals in which the virus often quickly becomes undetectable using PCR-based approaches that focus on a small viral region. Next-generation sequencing (NGS) provides an alternative option for viral detection in a genome-wide manner. However, owing to the overwhelming dominance of human genetic content in clinical specimens, direct detection of HCV by NGS has a low sensitivity and hence viral enrichment is required. Methods Based on template-dependent multiple displacement amplification (tdMDA), an improved method for whole genome amplification (Wang et al., 2017. Biotechniques 63, 21–27), we evaluated two strategies to enhance the sensitivity of NGS-based HCV detection: duplex-specific nuclease (DSN)-mediated depletion of human sequences and HCV probe-based capture sequencing. Results In DSN-mediated depletion, human sequences were significantly reduced in the two HCV serum samples tested, 65.3% → 55.6% → 33.7% (#4727) and 68.6% → 56% → 21% (#4970), respectively for no normalization, self- and driver-applied normalization. However, this approach was associated with a loss of HCV sequences perhaps due to its micro-homology with the human genome. In capture sequencing, HCV-mapped sequencing reads occupied 96.8% (#4727) and 22.14% (#4970) in NGS data, equivalent to 1936x and 7380x enrichment, respectively. Capture sequencing was then applied to ten serum samples collected at the end of HCV antiviral therapy. Interestingly, the number of HCV-mapped reads was significantly higher in relapsed patients (n = 5) than those from patients with sustained virological response (SVR) (n = 5), 102.4 ± 72.3 vs. 2.6 ± 0.55, p = 0.014. Conclusions Our data provides concept evidence for a highly sensitive HCV detection by capture sequencing. The abundance difference of HCV sequencing reads at the end of HCV antiviral therapy could be applied to predict treatment outcomes.
Collapse
Affiliation(s)
- Peng Peng
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.,Wuhan Pulmonary Hospital, Wuhan, 430030, Hubei, China
| | - Yanjuan Xu
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Michael W Fried
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC, 27516, USA
| | - Adrian M Di Bisceglie
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.,Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Xiaofeng Fan
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA. .,Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
| |
Collapse
|
|
9
|
Hong CM, Liu CH, Su TH, Yang HC, Chen PJ, Chen YW, Kao JH, Liu CJ. Real-world effectiveness of direct-acting antiviral agents for chronic hepatitis C in Taiwan: Real-world data. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2020; 53:569-577. [PMID: 30316726 DOI: 10.1016/j.jmii.2018.09.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 09/12/2018] [Accepted: 09/18/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND/PURPOSE Treatment of chronic hepatitis C (CHC) has entered a new era since the introduction of direct-acting antiviral agents (DAAs). Numerous clinical trials have shown that treatment response as well as tolerability of DAAs are superior to those of conventional therapy with pegylated interferon and ribavirin. However, the results of clinical trials may not be directly applied to real-world practice. Therefore our study tried to investigate the effectiveness of various DAA regimens in Taiwanese patients with chronic hepatitis C. METHODS We performed a retrospective study on 400 CHC patients. The primary endpoint was undetectable HCV RNA (an HCV RNA level of <25 IU/mL) at 12 weeks posttreatment (SVR12). The results were stratified by different DAAs and HCV genotypes. RESULTS Genotype 1b was the major genotype (297, 74.3%), followed by genotype 2 (65, 16.3%). The patients were treated according to HCV genotype, clinical practice and reimbursement guidelines. The SVR12 rates of 57 patients treated with sofosbuvir and ribavirin, 107 treated with ledipasvir/sofosbuvir with or without ribavirin, 60 treated with daclatasvir/asunaprevir with or without ribavirin, 129 treated with ombitasvir/paritaprevir/ritonavir/dasabuvir with or without ribavirin, 12 treated with sofosbuvir/daclatasvir with or without ribavirin, and 35 treated with elbasvir/grazoprevir were 98.2%, 97.2%, 85.0%, 97.7%, 100.0%, and 100.0%, respectively. CONCLUSIONS The overall SVR12 rates in our study were comparable with those in previous pivotal trials. DAAs are generally safe. The interaction of HBV and HCV during DAA therapy and the observation of de novo HCC development and HCC recurrence during or after DAAs warrants additional studies.
Collapse
Affiliation(s)
- Chun-Ming Hong
- Division of Hospital Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Wen Chen
- Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
| | - Chun-Jen Liu
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
|
10
|
Islam M, Nicholas S, Oakley R, Healy B. Successful treatment of resistant HCV in a patient with Child-Pugh B cirrhosis using sofosbuvir and glecaprevir/pibrentasvir. BMJ Case Rep 2020; 13:e232931. [PMID: 32624483 PMCID: PMC7337621 DOI: 10.1136/bcr-2019-232931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2020] [Indexed: 11/04/2022] Open
Abstract
Treatments for hepatitis C are now well tolerated with very high rates of sustained virological response and almost all patients have a suitable and effective treatment option. However, treatment options remain limited for a minority of patients and are limited for patients with Child-Pugh B or C cirrhosis due to the risk of decompensation with protease inhibitors. We present a case of successful treatment with glecaprevir/pibrentasvir (Maviret) and sofosbuvir in a patient with Child-Pugh B cirrhosis and resistant virus who had failed three previous attempts of treatment including two courses of direct acting antiviral agents and in whom liver transplantation was deemed unsuitable. We propose that the balance of risks favours a trial of treatment with protease inhibitors in some circumstances in patients with Child-Pugh B cirrhosis where no other suitable alternatives including treatment post liver transplantation are available/appropriate.
Collapse
Affiliation(s)
- Munim Islam
- Microbiology/Infectious Diseases, University Hospital of Wales Healthcare NHS Trust, Cardiff, UK
| | - Sarah Nicholas
- Infectious Diseases, University Hospital of Wales Healthcare NHS Trust, Cardiff, UK
| | - Rhys Oakley
- Pharmacy, University Hospital of Wales Healthcare NHS Trust, Cardiff, UK
| | - Brendan Healy
- Microbiology/Infectious Diseases, Public Health Wales NHS Trust, Cardiff, UK
| |
Collapse
|
|
11
|
Kiser JJ. Safety of Hepatitis C Viral Protease Inhibitors in Compensated Cirrhotics: Lingering Concerns Put to Rest? Clin Infect Dis 2020; 69:1665-1666. [PMID: 30923805 DOI: 10.1093/cid/ciz025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/02/2019] [Accepted: 01/11/2019] [Indexed: 02/06/2023] Open
Affiliation(s)
- Jennifer J Kiser
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora
| |
Collapse
|
|
12
|
Daniel KE, Saeian K, Rizvi S. Real-world experiences with direct-acting antiviral agents for chronic hepatitis C treatment. J Viral Hepat 2020; 27:195-204. [PMID: 31602715 DOI: 10.1111/jvh.13218] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 08/12/2019] [Accepted: 09/03/2019] [Indexed: 12/16/2022]
Abstract
As direct-acting antiviral (DAA) agents become more readily available for the treatment of chronic hepatitis C, it is important to understand real-world treatment experiences. In order to assess the effectiveness of DAA regimens and factors that influence sustained virologic response (SVR) rates in the Veterans Affairs healthcare system, we retrospectively identified veterans with chronic hepatitis C who were treated with DAAs from January 2014 to June 2015. We determined SVR rates and collected data on demographics, genotype (GT), previous interferon-based treatment, antiviral regimens, and co-morbidities (HIV, prior solid organ transplant, haemodialysis) for analysis. Of 15 720 veterans, the majority were infected with genotype 1a (GT1a, 60.5%). Excluding the special populations, the overall cohort SVR rate was 92%. Compared to treatment-experienced patients, treatment-naïve patients had significantly higher SVR rates (90% vs 92%, P = .006). Subgroups associated with lower likelihood of achieving SVR-included African Americans (OR 0.79, 95% CI 0.69-0.91), GT3 (OR 0.65, CI 0.50-0.86), and cirrhosis (OR 0.91, CI 0.84-0.99) or decompensated cirrhosis (ascites: OR 0.78, CI 0.67-0.91, variceal bleed: OR 0.75, CI 0.57-0.99). The only treatment regimen independently associated with lower SVR rates was SOF+RBV+IFN (OR 0.65, CI 0.50-0.84). Special populations achieved high SVR rates: HIV 92%, haemodialysis 93%, liver transplant 96% and renal transplant 94%. In conclusion, overall SVR rates were comparable to those reported in clinical trials and carried over to historically more difficult-to-treat patients. Several patient- and treatment-related factors were identified as independent predictors of treatment failure and suggest subgroups to target for efforts to improve therapeutic strategies.
Collapse
Affiliation(s)
- Kimberly E Daniel
- Division of Gastroenterology & Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA.,Division of Gastroenterology and Hepatology, University of Wisconsin, Madison, WI, USA
| | - Kia Saeian
- Division of Gastroenterology & Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Syed Rizvi
- Division of Gastroenterology & Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| |
Collapse
|
|
13
|
The Evaluation of Medication Adherence in Patients Infected With HCV Receiving Protease Inhibitors: A Pilot Study. Gastroenterol Nurs 2019; 42:259-268. [PMID: 31145250 DOI: 10.1097/sga.0000000000000386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Adherence to treatment is essential for hepatitis C cure. Studies show the complexity of the treatment due to side effects, many pills, and rigor in the schedules. The aim of this study was to evaluate the adherence to treatment with protease inhibitor in patients with hepatitis C. It is a longitudinal, observational, prospective pilot study with patients with hepatitis C genotype 1. Bimonthly consultations and biweekly calls for 20 weeks were performed. Evaluation methods for adherence were Measure of Adherence to Treatment score, patient report, count pills, and sustained virological response. Twenty-two patients were enrolled. Mean age was 54.0 ± 8.72 years; 50% were men, educational level was 7.9 ± 3.89 years for the study, and intake of pills was 2.2 ± 1.60 per day. Adverse events reported were fatigue (90.9%), muscular pain (72.7%), and nausea (68.2%). In total, 71.4% of patients took 100% of medications and were classified as having a high degree of adherence to treatment. The sustained virological response was not significant in relation to the high or low adherence degree. Measure of Adherence to Treatment score is a good instrument to measure adherence to protease inhibitor treatment. The adherence of patients undergoing long-term and complex treatments improves when the multidisciplinary team follows up every 7-15 days. The patient's access to the team through additional phone calls or medical/nursing appointment is essential to improve adherence.
Collapse
|
|
14
|
Radhakrishnan K, Di Bisceglie AM, Reddy KR, Lim JK, Levitsky J, Hassan MA, Darling JM, Feld JJ, Akushevich L, Vainorius M, Nelson DR, Fried MW, Brown RS, Terrault NA. Treatment Status of Hepatocellular Carcinoma Does Not Influence Rates of Sustained Virologic Response: An HCV-TARGET Analysis. Hepatol Commun 2019; 3:1388-1399. [PMID: 31592494 PMCID: PMC6771159 DOI: 10.1002/hep4.1412] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 06/24/2019] [Indexed: 12/12/2022] Open
Abstract
Recent studies have suggested a negative impact of hepatocellular carcinoma (HCC) on sustained virologic response (SVR) to hepatitis C virus (HCV) direct acting antivirals (DAAs). We compared the effectiveness of DAAs in patients with cirrhosis, with and without HCC, and in those with HCC partially treated or untreated (PT/UT-HCC) versus completely treated (CT-HCC). HCC status was based on imaging 6 months before or 2 months after start of DAA therapy. Absence and presence of enhancing lesions after HCC treatment defined CT-HCC and PT/UT-HCC, respectively. Using minimally adjusted logistic regression, the association between the presence of HCC and SVR rates was estimated. Among the 1,457 patients with cirrhosis from HCV-TARGET with complete virologic data (per-protocol population) who did not undergo liver transplantation during treatment and followup, 1,300 were without HCC, 91 with CT-HCC, and 66 with PT/UT-HCC. Most patients were genotype 1 (81%) and treatment-experienced (56%), 41% had history of prior decompensation, and the median pretreatment Model for End-Stage Liver Disease was 9 (range 6-39). The SVR rates were 91% for patients without HCC, 84% for CT-HCC, and 80% for PT/UT-HCC. The presence of HCC (versus not having HCC) was associated with significantly lower odds of achieving SVR (odds ratio [OR] = 0.51, 95% confidence interval [CI]: 0.33-0.81; P = 0.003). However, among those with HCC, HCC treatment status (PT/UT-HCC versus CT-HCC) did not show association with SVR (OR = 0.79, 95% CI: 0.35-1.79, P = 0.569). Conclusions: The presence of HCC reduces the likelihood of SVR by 50%, but with no evident difference in those with completely treated HCC versus partially treated/untreated HCC.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Norah A. Terrault
- Keck School of Medicine of the University of Southern CaliforniaLos AngelesCA
| |
Collapse
|
|
15
|
Kwo PY, Puenpatom A, Zhang Z, Hui SL, Kelley AA, Muschi D. Initial uptake, time to treatment, and real-world effectiveness of all-oral direct-acting antivirals for hepatitis C virus infection in the United States: A retrospective cohort analysis. PLoS One 2019; 14:e0218759. [PMID: 31437170 PMCID: PMC6705774 DOI: 10.1371/journal.pone.0218759] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 06/08/2019] [Indexed: 12/12/2022] Open
Abstract
Background Data on initiation and utilization of direct-acting antiviral therapies for hepatitis C virus infection in the United States are limited. This study evaluated treatment initiation, time to treatment, and real-world effectiveness of direct-acting antiviral therapy in individuals with hepatitis C virus infection treated during the first 2 years of availability of all-oral direct-acting antiviral therapies. Methods A retrospective cohort analysis was undertaken using electronic medical records and chart review abstraction of hepatitis C virus-infected individuals aged >18 years diagnosed with chronic hepatitis C virus infection between January 1, 2014, and December 31, 2015 from the Indiana University Health database. Results Eight hundred thirty people initiated direct-acting antiviral therapy during the 2-year observation window. The estimated incidence of treatment initiation was 8.8%±0.34% at the end of year 1 and 15.0%±0.5% at the end of year 2. Median time to initiating therapy was 300 days. Using a Cox regression analysis, positive predictors of treatment initiation included age (hazard ratio, 1.008), prior hepatitis C virus treatment (1.74), cirrhosis (2.64), and history of liver transplant (1.5). History of drug abuse (0.43), high baseline alanine aminotransferase levels (0.79), hepatitis B virus infection (0.41), and self-pay (0.39) were negatively associated with treatment initiation. In the evaluable population (n = 423), 83.9% (95% confidence interval, 80.1–87.3%) of people achieved sustained virologic response. Conclusion In the early years of the direct-acting antiviral era, <10% of people diagnosed with chronic hepatitis C virus infection received direct-acting antiviral treatment; median time to treatment initiation was 300 days. Future analyses should evaluate time to treatment initiation among those with less advanced fibrosis.
Collapse
Affiliation(s)
- Paul Y. Kwo
- Department of Medicine – Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, United States of America
- * E-mail:
| | - Amy Puenpatom
- Center for Observational and Real-World Evidence (CORE), Merck & Co., Inc., Kenilworth, New Jersey, United States of America
| | - Zuoyi Zhang
- Department of Medicine, Regenstrief Institute, Indianapolis, Indiana, United States of America
| | - Siu L. Hui
- Department of Biostatistics, Regenstrief Institute, Indianapolis, Indiana, United States of America
| | - Andrea A. Kelley
- Data Core Services, Regenstrief Institute, Indianapolis, Indiana, United States of America
| | - David Muschi
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, United States of America
| |
Collapse
|
|
16
|
Cotter TG, Jensen DM. Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C: design, development, and place in therapy. Drug Des Devel Ther 2019; 13:2565-2577. [PMID: 31534310 PMCID: PMC6681154 DOI: 10.2147/dddt.s172512] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 06/27/2019] [Indexed: 12/13/2022] Open
Abstract
Direct-acting antiviral (DAA) therapy has changed the landscape of hepatitis C virus (HCV) management and has changed the focus to the possibility of HCV elimination in the near future. Glecaprevir, an NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor, have addressed many of the existing shortcomings in the DAA therapy spectrum. This combination has proven to be a highly efficacious pan-genotypic DAA with a high barrier to resistance as a once-daily, all-oral medication. This review explores the design and development of glecaprevir and pibrentasvir, its place in current HCV management in the midst of a myriad of DAA therapy options, and also remaining challenges.
Collapse
Affiliation(s)
- Thomas G Cotter
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL, USA
| | - Donald M Jensen
- Section of Hepatology, RUSH University Medical Center, Chicago, IL, USA
| |
Collapse
|
|
17
|
Cotter TG, Paul S, Sandıkçı B, Couri T, Bodzin AS, Little EC, Sundaram V, Charlton M. Increasing Utilization and Excellent Initial Outcomes Following Liver Transplant of Hepatitis C Virus (HCV)-Viremic Donors Into HCV-Negative Recipients: Outcomes Following Liver Transplant of HCV-Viremic Donors. Hepatology 2019; 69:2381-2395. [PMID: 30706517 DOI: 10.1002/hep.30540] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 01/23/2019] [Indexed: 12/11/2022]
Abstract
Direct-acting antiviral (DAA) therapy has altered the frequency and outcome of liver transplantation (LT) for hepatitis C virus (HCV). The high efficacy and tolerability of DAA therapy has also created a rationale for utilizing HCV-viremic (HCV-RNA-positive) donors, including into HCV-negative recipients. We examined trends in frequency of organ utilization and graft survival in recipients of HCV-viremic donors (HCV-RNA positive as measured by nucleic acid testing [NAT]). Data were collected from the Scientific Registry of Transplant Recipients (SRTR) on adult patients who underwent a primary, single-organ, deceased donor LT from January 1, 2008 to January 31, 2018. Outcomes of HCV-negative transplant recipients (R- ) who received an allograft from donors who were HCV-RNA positive (DNAT+ ) were compared to outcomes for R- patients who received organs from donors who were HCV-RNA negative (DNAT- ). There were 11,270 DNAT- /R- ; 4,748 DNAT- /R+ ; 87 DNAT+ /R- ; and 753 DNAT+ /R+ patients, with 2-year graft survival similar across all groups: DNAT- /R- 88%; DNAT- /R+ 88%; DNAT+ /R- 86%; and DNAT+ /R+ 90%. Additionally, there were 2,635 LTs using HCV antibody-positive donors (DAb+ ): 2,378 DAb+ /R+ and 257 DAb+ /R- . The annual number of DAb+ /R- transplants increased from seven in 2008 to 107 in 2017. In the post-DAA era, graft survival improved for all recipients, with 3-year survival of DAb+ /R- patients and DAb+ /R+ patients increasing to 88% from 79% and to 85% from 78%, respectively. Conclusion: The post-DAA era has seen increased utilization of HCV-viremic donor livers, including HCV-viremic livers into HCV-negative recipients. Early graft outcomes are similar to those of HCV-negative recipients. These results support utilization of HCV-viremic organs in selected recipients both with and without HCV infection.
Collapse
Affiliation(s)
- Thomas G Cotter
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL
| | - Sonali Paul
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL
| | | | - Thomas Couri
- Department of Medicine, The University of Chicago Medicine, Chicago, IL
| | - Adam S Bodzin
- Department of Surgery, Section of Abdominal Organ Transplantation, The University of Chicago Medicine, Chicago, IL
| | | | - Vinay Sundaram
- Division of Gastroenterology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Michael Charlton
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL
| |
Collapse
|
|
18
|
Bach TA, Zaiken K. Outcomes of treatment with direct-acting antivirals for infection with hepatitis C virus genotypes 1-4 in an ambulatory care setting. Am J Health Syst Pharm 2019; 74:S1-S9. [PMID: 28213381 DOI: 10.2146/ajhp160567] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Outcomes with direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) genotypes 1-4 were determined. METHODS A total of 360 patients at 36 clinical sites in Massachusetts with HCV genotypes 1-4 and a prescription for at least one DAA medication between May 2011 and October 2015 were included. The primary investigator completed a retrospective and concurrent chart review, and data were collected through April 2016. RESULTS A total of 446 patients were assessed for eligibility into the study, with 86 patients excluded. The majority of patients were white males with genotype 1 infection. About half of the patients were treatment naive (TN), and 40% of patients had documented cirrhosis. TN patients without cirrhosis had the highest overall sustained virologic response (SVR) rate at 107 of 109 (98.2%), followed by treatment-experienced (TE) patients without cirrhosis at 59 of 63 (93.7%), TN patients with cirrhosis at 40 of 46 (87.0%), and TE patients with cirrhosis at 64 of 79 (81.0%) when boceprevir- and telaprevir-containing regimens were excluded. A total of 7 of 360 (1.9%) patients reported missing at least one dose of medication. Adverse drug reactions reported in the electronic medical record (EMR) were collected for analysis and included patients who received at least one dose of medication and had adequate EMR documentation. CONCLUSION In patients treated with DAAs for infection with HCV genotypes 1-4, variables favoring achievement of SVR included an age of <45 years, a body mass index of <25 kg/m2, absence of cirrhosis, a fibrosis score of 0-2, and being TN.
Collapse
|
|
19
|
Cotter TG, Paul S, Sandıkçı B, Couri T, Bodzin AS, Little EC, Sundaram V, Charlton M. Improved Graft Survival After Liver Transplantation for Recipients With Hepatitis C Virus in the Direct-Acting Antiviral Era. Liver Transpl 2019; 25:598-609. [PMID: 30716208 DOI: 10.1002/lt.25424] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 01/27/2019] [Indexed: 12/12/2022]
Abstract
Highly effective direct-acting antiviral (DAA) therapy has transformed outcomes of liver transplantation in hepatitis C virus (HCV) patients. We examined longer-term outcomes in HCV-positive recipients in the DAA era and analyzed the Scientific Registry of Transplant Recipients for primary adult, single-organ, nonfulminant liver transplant recipients in the United States from January 1, 2008 to June 30, 2018. Graft loss was compared among HCV-positive liver transplant recipients who received either an HCV-negative or HCV-positive donor (donor [D]-/recipient [R]+; D+/R+) and HCV-negative liver transplant recipients who received a HCV-negative donor (D-/R-). The groups were further divided between the pre-DAA and DAA eras. There were 52,526 patients included: 31,193 were D-/R- patients; 18,746 were D-/R+ patients; and 2587 were D+/R+ patients. The number of D-/R+ transplants decreased from 2010 in 2008 to 1334 in 2017, with this decline particularly noticeable since 2015. D-/R+ patients in the DAA era (n = 7107) were older, had higher rates of hepatocellular carcinoma, and lower Model for End-Stage Liver Disease scores than those in the pre-DAA era. Graft survival improved for all recipients in the DAA era but improved most dramatically in HCV-positive recipients: D-/R+ 1-year survival was 92.4% versus 88.7% and 3-year survival was 83.7% versus 77.7% (DAA versus pre-DAA era, respectively) compared with D-/R- 1-year survival of 92.7% versus 91.0% and 3-year survival of 85.7% versus 84.0% (DAA versus pre-DAA era, respectively). The magnitude of improvement in 3-year graft survival was almost 4-fold greater for D-/R+ patients. The 3-year survival for D+/R+ patients was similar to HCV-negative patients. In conclusion, the number of liver transplants for HCV has decreased by more than one-third over the past decade. Graft survival among HCV-positive recipients has increased disproportionately in the DAA era with HCV-positive recipients now achieving similar outcomes to non-HCV recipients.
Collapse
Affiliation(s)
- Thomas G Cotter
- Center for Liver Diseases, University of Chicago Medicine, Chicago, IL
| | - Sonali Paul
- Center for Liver Diseases, University of Chicago Medicine, Chicago, IL
| | | | - Thomas Couri
- Department of Medicine, University of Chicago Medicine, Chicago, IL
| | - Adam S Bodzin
- Section of Abdominal Organ Transplantation, Department of Surgery, University of Chicago Medicine, Chicago, IL
| | | | - Vinay Sundaram
- Division of Gastroenterology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Michael Charlton
- Center for Liver Diseases, University of Chicago Medicine, Chicago, IL
| |
Collapse
|
|
20
|
Lim JK, Liapakis AM, Shiffman ML, Lok AS, Zeuzem S, Terrault NA, Park JS, Landis CS, Hassan M, Gallant J, Kuo A, Pockros PJ, Vainorius M, Akushevich L, Michael L, Fried MW, Nelson DR, Ben-Ari Z. Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients With Genotype 1 Hepatitis C Virus Infection and Cirrhosis. Clin Gastroenterol Hepatol 2018; 16:1811-1819.e4. [PMID: 29306043 PMCID: PMC6034985 DOI: 10.1016/j.cgh.2017.12.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 11/30/2017] [Accepted: 12/22/2017] [Indexed: 02/07/2023]
Abstract
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.
Collapse
Affiliation(s)
- Joseph K Lim
- Yale University School of Medicine, New Haven, Connecticut.
| | | | | | - Anna S Lok
- University of Michigan, Ann Arbor, Michigan
| | - Stefan Zeuzem
- J. W. Goethe University Hospital, Frankfurt, Germany
| | - Norah A Terrault
- University of California-San Francisco, San Francisco, California
| | | | | | | | | | | | | | | | | | - Larry Michael
- University of North Carolina, Chapel Hill, North Carolina
| | | | | | | |
Collapse
|
|
21
|
Cunha-Silva M, Mazo D, Arrelaro R, Vaz N, Rabello M, Lopes T, Corrêa B, Torino AB, Cintra M, Lorena S, Sevá-Pereira T, Almeida J. Hand-foot syndrome due to hepatitis C therapy. ACTA ACUST UNITED AC 2018; 64:415-419. [PMID: 30304139 DOI: 10.1590/1806-9282.64.05.415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 08/05/2017] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Direct-acting antivirals are new drugs for chronic hepatitis C treatment. They are usually safe and well tolerated, but can sometimes cause serious adverse effects and there is no consensus on how to treat or prevent them. We described a case of hand-foot syndrome due to hepatitis C virus interferon-free therapy. METHODS We report the case of a 49-year-old man with compensated liver cirrhosis due to chronic hepatitis C genotype 1, treatment-naïve, who started viral treatment with sofosbuvir, simeprevir and ribavirin for 12 weeks. RESULTS At the sixth week of treatment he had anemia, requiring a lower dose of ribavirin. At the tenth week, he had erythematous, pruritic, scaly and flaky lesions on hands and feet, which showed a partial response to oral antihistamines and topical corticosteroids. It was not necessary to discontinue antiviral treatment, but in the first week after the end of treatment, there was worsening of injuries, including signs of secondary infection, that required hospitalization, antibiotics and oral corticosteroid, with progressive improvement. Biopsy of the lesions was consistent with pharmacodermia. The patient had sustained a virological response, despite the side effect. He had a history of pharmacodermia one year ago attributed to the use of topiramate, responsive to oral corticosteroid. CONCLUSION Interferon-free therapies can rarely lead to severe adverse reactions, such as skin lesions. Patients receiving ribavirin combinations and those who had a history of pharmacodermia or skin disease may be more susceptible. There is no consensus on how to prevent skin reactions in these patients.
Collapse
Affiliation(s)
- Marlone Cunha-Silva
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Daniel Mazo
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.,Department of Gastroenterology, University of Sao Paulo School of Medicine (FMUSP), São Paulo, SP, Brasil
| | - Raquel Arrelaro
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Nayana Vaz
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Marcello Rabello
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Tirzah Lopes
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Bárbara Corrêa
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Ana Beatriz Torino
- Department of Dermatology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Maria Cintra
- Department of Dermatology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Sonia Lorena
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Tiago Sevá-Pereira
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| | - Jazon Almeida
- Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil
| |
Collapse
|
|
22
|
Asselah T, Bourgeois S, Pianko S, Zeuzem S, Sulkowski M, Foster GR, Han L, McNally J, Osinusi A, Brainard DM, Subramanian GM, Gane EJ, Feld JJ, Mangia A. Sofosbuvir/velpatasvir in patients with hepatitis C virus genotypes 1-6 and compensated cirrhosis or advanced fibrosis. Liver Int 2018; 38:443-450. [PMID: 28756625 DOI: 10.1111/liv.13534] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 07/24/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis. METHODS This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir-velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined. RESULTS Forty-four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96-99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment-naïve patients and 97% (184/190) for treatment-experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs. CONCLUSIONS Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis.
Collapse
Affiliation(s)
- Tarik Asselah
- Department of Hepatology, Hôpital Beaujon, APHP, INSERM CRI, UMR1149, University Paris-Diderot, Clichy, France
| | | | - Stephen Pianko
- Monash Health and Monash University, Clayton, Vic., Australia
| | - Stefan Zeuzem
- Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany
| | | | | | | | | | | | | | | | - Edward J Gane
- Auckland Clinical Studies Ltd, Auckland, New Zealand
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto, ON, Canada
| | - Alessandra Mangia
- Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| |
Collapse
|
|
23
|
Kjellin M, Wesslén T, Löfblad E, Lennerstrand J, Lannergård A. The effect of the first-generation HCV-protease inhibitors boceprevir and telaprevir and the relation to baseline NS3 resistance mutations in genotype 1: experience from a small Swedish cohort. Ups J Med Sci 2018; 123. [PMID: 29536805 PMCID: PMC5901468 DOI: 10.1080/03009734.2018.1441928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The clinical experience with protease-inhibitor (PI) triple regimen appears disappointing regarding effect, side effects, high work load, and costs. This real-world study evaluates baseline and emerging resistance-associated substitutions (RASs) and their significance for treatment outcome. METHOD Thirty-six genotype 1a/b patients treated according to Swedish recommendations during 2011-2013 with triple therapy including pegylated interferon and ribavirin in combination with a protease-inhibitor, either boceprevir (BOC) or telaprevir (TVR), were retrospectively evaluated. Frozen serum samples from the patients were tested for resistance with pan-genotypic population sequencing. RESULTS Overall, 56% (20/36) of the patients achieved sustained viral response (SVR). The SVR was comparable between BOC (64%; 9/14) and TVR (50%; 11/22) (p = 0.07), and the IL28B type non-CC (48%; 12/25) and CC (46%; 6/13) (p = 0.77). The SVR was higher in patients without cirrhosis (89.5%; 17/19) (p < 0.0005), in treatment-naïve patients (70%; 14/20) (p = 0.02), and those with low viral load (<800,000 IU/mL) (66.7%; 8/12) (p < 0.0002), compared to those with cirrhosis (17.6%; 3/17), treatment-experienced (37.5%; 6/16), and high viral load (>800,000 IU/mL) (50%; 12/24). CONCLUSION PI triple regimes were highly effective in treatment-naïve patients without cirrhosis, but in this real-world cohort an inferior effect was evident in cirrhotic and treatment-experienced patients. Although tested on a limited sample, the baseline resistance testing seems to have no impact on prediction of therapy outcome. The reason could be that the baseline RASs T54S and V55A have relatively low resistance towards BOC and TVR. Emerging RASs, mainly R155K, with known high resistance to BOC and TVR were frequently found in non-responders.
Collapse
Affiliation(s)
- Midori Kjellin
- Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Terése Wesslén
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Erik Löfblad
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Johan Lennerstrand
- Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Anders Lannergård
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
- CONTACT Anders Lannergård Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, S 751 85 Uppsala, Sweden
| |
Collapse
|
|
24
|
Chamorro-de-Vega E, Gimenez-Manzorro A, Rodriguez-Gonzalez CG, Escudero-Vilaplana V, De Lorenzo-Pinto A, Iglesias-Peinado I, Herranz-Alonso A, Sanjurjo Saez M. Twelve weeks of ombitasvir/paritaprevir/r and dasabuvir without ribavirin is effective and safe in the treatment of patients with HCV genotype 1b infection and compensated cirrhosis: results from a real-world cohort study. Expert Opin Drug Saf 2018; 17:235-241. [PMID: 29325476 DOI: 10.1080/14740338.2018.1424829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To explore the effectiveness and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV) for 12 weeks without ribavirin in adults with chronic HCV genotype 1b infection and compensated cirrhosis. METHODS Observational study of a prospective cohort of adult patients with HCV genotype 1b infection and compensated cirrhosis who received 12 weeks of OBV/PTV/r and DSV without ribavirin. Effectiveness was assessed by recording the percentage of patients achieving sustained virological response at week 12 post-treatment (SVR12). Safety outcomes were based on the incidence of adverse events. RESULTS Seventy-eight patients were included. The SVR12 rate was 96.1% (95%CI 89.2-99.2). Adverse events were recorded in 78.0% of patients. Of these, 97.7% were grade 1/2. One patient discontinued treatment prematurely owing to adverse events. Eighty-six interactions were detected in 43 patients (55.1%). Overall, 81.4% of interactions required close monitoring, alteration of drug dosage, or timing of administration. In 7.0% of cases, the interactions arose from contraindications that required the suspension of the concomitant drug. In 11.6% of cases, medicinal plants or foods were withdrawn. CONCLUSIONS The simplified regimen of OBV/PTV/r+DSV administered for 12 weeks is effective and safe in patients with chronic HCV genotype 1b infection and compensated cirrhosis. No adverse reactions related to drug-drug interactions were recorded.
Collapse
Affiliation(s)
- Esther Chamorro-de-Vega
- a Pharmacy Department , Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón , Madrid , Spain
| | - Alvaro Gimenez-Manzorro
- a Pharmacy Department , Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón , Madrid , Spain
| | - Carmen-Guadalupe Rodriguez-Gonzalez
- a Pharmacy Department , Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón , Madrid , Spain
| | - Vicente Escudero-Vilaplana
- a Pharmacy Department , Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón , Madrid , Spain
| | - Ana De Lorenzo-Pinto
- a Pharmacy Department , Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón , Madrid , Spain
| | | | - Ana Herranz-Alonso
- a Pharmacy Department , Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón , Madrid , Spain
| | - Maria Sanjurjo Saez
- a Pharmacy Department , Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón , Madrid , Spain
| | | |
Collapse
|
|
25
|
Aspinall AI, Shaheen AA, Kochaksaraei GS, Haslam B, Lee SS, Macphail G, Kapler J, Larios OE, Burak KW, Swain MG, Borman MA, Coffin CS. Real-world treatment of hepatitis C with second-generation direct-acting antivirals: initial results from a multicentre Canadian retrospective cohort of diverse patients. CMAJ Open 2018; 6:E12-E18. [PMID: 29305405 PMCID: PMC5963434 DOI: 10.9778/cmajo.20170059] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND High hepatitis C cure rates have been observed in registration trials with second-generation direct-acting antivirals. Real-world data also indicate high sustained viral response (SVR) rates. Our objective was to determine real-world SVR rates for patients infected with hepatitis C virus (HCV) who were treated with second-generation direct-acting antivirals in the first 18 months of their availability in Canada. METHODS Four centres in Calgary contributed their treatment data for a diverse patient population including those who had or had not undergone liver transplantation, those coinfected with HIV and vulnerable populations. We included all patients documented to have started hepatitis C treatment with direct-acting antivirals between October 2014 and April 2016, with follow-up through October 2016. We used multivariate analysis to determine independent predictors of treatment failure. RESULTS Outcome data were available for 351 patients, of whom 326 (92.9%) achieved an SVR (193/206 [93.7%], 57/59 [96.6%] and 44/51 [86.3%] for genotypes 1a, 1b and 3, respectively, p = 0.2). Independent predictors of not achieving SVR were older age (adjusted odds ratio [OR] 0.95 [95% confidence interval (CI) 0.90-1.00]), male sex (adjusted OR 0.30 [95% CI 0.10-0.89]) and, in patients with genotype 1a infection, history of hepatocellular carcinoma (adjusted OR 0.13 [95% CI 0.03-0.53]). In the entire cohort, the presence of cirrhosis, genotype and hepatocellular carcinoma were not associated with a lower SVR rate. There were no differences in SVR rate according to treatment centre, HIV coinfection or liver transplantation. Among patients with genotype 3 infection, a significantly lower SVR rate was observed for those treated outside of standard of care than for those treated within standard of care (33.3% v. 89.6%, p = 0.04). De novo hepatocellular carcinoma developed in 12 patients (3.4%) despite successful direct-acting antiviral therapy. INTERPRETATION We report high SVR rates in a real-world diverse cohort of HCV-infected patients treated with second-generation direct-acting antivirals. The results highlight the importance of conducting real-world analyses to elucidate clinical factors associated with poorer outcomes that may not be identified in registration trials.
Collapse
Affiliation(s)
- Alex I Aspinall
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Abdel A Shaheen
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Golasa S Kochaksaraei
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Breean Haslam
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Samuel S Lee
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Gisela Macphail
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Jeff Kapler
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Oscar E Larios
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Kelly W Burak
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Mark G Swain
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Meredith A Borman
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| | - Carla S Coffin
- Affiliations: Calgary Liver Unit (Aspinall, Shaheen, Kochaksaraei, Haslam, Lee, Burak, Swain, Borman, Coffin), Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary; Calgary Urban Project Society (Macphail); Southern Alberta Clinic (Kapler, Larios, Coffin), Alberta Health Services, Calgary, Alta
| |
Collapse
|
|
26
|
Huang CF, Yu ML. Treating hepatitis C in the elderly: pharmacotherapeutic considerations and developments. Expert Opin Pharmacother 2017; 18:1867-1874. [PMID: 29086615 DOI: 10.1080/14656566.2017.1400010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 10/30/2017] [Indexed: 12/17/2022]
Abstract
The seroprevalence of hepatitis C virus (HCV) infection tends to be higher in the elderly than in younger populations. Meanwhile, age per sec is an unfavorable determinant that has an impact on liver-related outcomes. Geriatric chronic hepatitis C (CHC) patients would be viewed as a special population and have an urgent need for viral eradication. Areas covered: The antivirals for CHC have evolved from interferon (IFN)-based therapyto interferon-free DAAs. The treatment strategy, in terms of its clinical efficacy and drug safety, in the elderly is presented. Expert opinion: In the previous IFN era, the sustained virological response (SVR) rate of the elderly was lower. More unfavorable safety concerns attributing to the underlying liver disease severity and extra-hepatic presentations further compromised the treatment efficacy. In the IFN-free DAA era, data showing similar SVR rates and safety profiles between the elderly and their counterparts have been demonstrated. Notably, aging is an unfavorable factor for fibrosis regression and HCC development even after HCV eradication. The extent of the improvement of extra-hepatic manifestations in the elderly with SVR is also unclear. The long-term benefits of viral eradication by DAAs in the elderly await further explorations.
Collapse
Affiliation(s)
- Chung-Feng Huang
- a Hepatobiliary Division, Department of Internal Medicine , Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung , Taiwan
- b Faculty of Internal Medicine, School of Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan
- c Department of Occupational Medicine, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Ming-Lung Yu
- a Hepatobiliary Division, Department of Internal Medicine , Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung , Taiwan
- b Faculty of Internal Medicine, School of Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan
- d Institute of Biomedical Sciences , National Sun Yat-Sen University , Kaohsiung , Taiwan
- e Liver Center, Division of Gastroenterology , Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA
- f College of Biological Science and Technology , National Chiao Tung University , Hsin-Chu , Taiwan
| |
Collapse
|
|
27
|
El-Khayat HR, Fouad YM, Maher M, El-Amin H, Muhammed H. Efficacy and safety of sofosbuvir plus simeprevir therapy in Egyptian patients with chronic hepatitis C: a real-world experience. Gut 2017; 66:2008-2012. [PMID: 27511197 DOI: 10.1136/gutjnl-2016-312012] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 07/14/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Simeprevir plus sofosbuvir (SIM/SOF) regimen was recommended by professional guidelines for certain patients with HCV genotype 1 infection and there is lack of data about this regimen in patients with genotype 4 infection. AIM To evaluate the efficacy and safety of this regimen in Egyptian patients with chronic HCV genotype 4 infection in the real world. METHODS Multicentre observational study included 583 patients with HCV genotype 4 infection who began 12 weeks of treatment with SIM plus SOF. Demographic, clinical and virological data as well as adverse outcomes were collected. Treatment naïve patients were 342 (59%) of all included patients, 45% of patients had severe fibrosis (F3 and F4) while 55% had mild fibrosis (F1 and F2) and the primary outcome was sustained virological response (SVR). RESULTS The overall SVR rate was 95.7% (558 out of 583 patients). In total, SVR12 in naïve patients with mild fibrosis score (F1 and F2) was achieved in 98.9% (94/95) for F1 and 98.1% (105/107) for F2, while naïve patients with severe fibrosis (F3 and F4) achieved SVR of 97.7% (86/88) for F3 and (42/52) 80.8% for F4. SVR in patients with previous interferon treatment achieved in 100% (45/45) for patients with F1 and 98.7% (74/75) for F2. While 94.7% (72/76) in experienced patients with F3; and 88.9% (40/45) for F4 achieved SVR12. Notable side effects included rash in 21 patients, photosensitivity in 18 patients, pruritus in 44 patients and hyperbilirubinemia in 42 patients. CONCLUSIONS A 12-week regimen of simeprevir/sofosbuvir was efficacious and well tolerated by treatment-naïve and treatment-experienced patients with chronic HCV genotype 4.
Collapse
Affiliation(s)
- Hisham R El-Khayat
- Gastroenterology and Endemic Medicine Department, Theodore Research Institute, Cairo, Egypt
| | - Yasser M Fouad
- Gastroenterology and Endemic Medicine Department, Minia University, Minia, Egypt
| | - Mohsen Maher
- Gastroenterology and Endemic Medicine Department, Ain Shams University, Cairo, Egypt
| | - Hussain El-Amin
- Internal Medicine Department, Assuit University, Assuit, Egypt
| | - Hala Muhammed
- Gastroenterology and Endemic Medicine, Endemic Medicine Department, Minia University, Faculty of Medicine, Minia, Egypt
| |
Collapse
|
|
28
|
Saxena V, Khungar V, Verna EC, Levitsky J, Brown RS, Hassan MA, Sulkowski MS, O’Leary JG, Koraishy F, Galati JS, Kuo AA, Vainorius M, Akushevich L, Nelson DR, Fried MW, Terrault N, Reddy K. Safety and efficacy of current direct-acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: Results from the HCV-TARGET study. Hepatology 2017; 66:1090-1101. [PMID: 28504842 PMCID: PMC5756478 DOI: 10.1002/hep.29258] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 04/06/2017] [Accepted: 05/09/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Data outside of clinical trials with direct-acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct-acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≥3.5 g/dL, baseline total bilirubin ≤1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. CONCLUSION In a large prospective observational cohort study, direct-acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090-1101).
Collapse
Affiliation(s)
- Varun Saxena
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Norah Terrault
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco
| | | |
Collapse
|
|
29
|
Mishra P, Florian J, Peter J, Vainorius M, Fried MW, Nelson DR, Birnkrant D. Public-Private Partnership: Targeting Real-World Data for Hepatitis C Direct-Acting Antivirals. Gastroenterology 2017; 153:626-631. [PMID: 28757271 DOI: 10.1053/j.gastro.2017.07.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Poonam Mishra
- US Food and Drug Administration, Silver Spring, Maryland
| | - Jeffry Florian
- US Food and Drug Administration, Silver Spring, Maryland
| | - Joy Peter
- University of Florida, Gainesville, Florida
| | | | | | | | | |
Collapse
|
|
30
|
Abstract
Recent developments in our understanding of the pathogenesis of kidney disease in the setting of liver failure have highlighted that kidney injury, rather than occurring in isolation, is a marker of systemic disease and poor prognosis. The differential diagnosis of kidney disease associated with liver failure is broader than formerly described and new biopsy data, along with better acute kidney injury classification tools, have increased appreciation for distinct pathophysiological mechanisms. Evidence suggests that acute kidney injury contributes to worsening hepatic failure by directly injuring hepatic cells and by imposing restrictions on therapeutic strategies for portal hypertension. Furthermore, kidney injury limits the use of various therapeutic agents and increases their toxicity due to altered pharmacodynamics. A greater appreciation of CKD in this population is also overdue because management decisions are affected and increased vigilance may avoid further kidney injury. A multidisciplinary approach to kidney injury in the setting of liver failure will enable targeted therapeutic strategies that are safe and effective and serve to guide further research, while limiting clinical potential for harm. Finally, new hepatitis C antiviral therapies promise to change the landscape of liver failure, and a discussion of kidney risk factors and antiviral therapy of patients with kidney disease and hepatitis C is worthwhile.
Collapse
|
|
31
|
Maan R, Al Marzooqi SH, Klair JS, Karkada J, Cerocchi O, Kowgier M, Harrell SM, Rhodes KD, Janssen HLA, Feld JJ, Duarte-Rojo A. The frequency of acute kidney injury in patients with chronic hepatitis C virus infection treated with sofosbuvir-based regimens. Aliment Pharmacol Ther 2017; 46:46-55. [PMID: 28470850 DOI: 10.1111/apt.14117] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 01/12/2017] [Accepted: 04/04/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND Guidelines recommend withholding sofosbuvir (SOF) in patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min. AIM To assess the risk of acute kidney injury (AKI) in patients with no renal contraindications for SOF-based treatment. METHODS This multicenter retrospective observational study included all consecutive patients that were treated with SOF-based or telaprevir/boceprevir (TVR/BOC)-based regimens at two tertiary university centers in North America. AKI was defined as an increase of ≥0.3 mg/dL (≥26.5 μmol/L) in serum creatinine level. Multivariable logistic regression analysis was used to identify risk factors for the occurrence of AKI. RESULTS In total, 426 patients were included and treated with a SOF-based regimen (n=233, 54.7%) or TVR/BOC-based regimen (n=193, 45.3%). Among patients treated with a TVR/BOC-based regimen 34 (18%) of 193 patients experienced AKI compared to 26 (11%) of 233 patients treated with SOF-based regimens (P=.056). Multivariable logistic regression analysis showed that the presence of ascites (OR: 4.44, 95%CI: 1.46-13.54, P=.009) and the use of NSAIDs (OR: 4.47, 95%CI: 1.32-15.19, P=.016) were associated with a risk of AKI during SOF-based antiviral therapy. Creatinine levels returned to normal at end of follow-up in 23 (88%) of the 26 patients who experienced AKI with a SOF-based regimen and had a creatinine level available during follow-up. CONCLUSIONS Although the risk for AKI was lower than for patients treated with TVR/BOC-based regimens, AKI was seen during 11% of SOF-based regimens and was mostly reversible. Patients with ascites and patients using NSAIDs have an increased risk for AKI during SOF-based antiviral therapy.
Collapse
Affiliation(s)
- R Maan
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada.,Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - S H Al Marzooqi
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada
| | - J S Klair
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - J Karkada
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada
| | - O Cerocchi
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada
| | - M Kowgier
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - S M Harrell
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - K D Rhodes
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - H L A Janssen
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada.,Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - J J Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada
| | - A Duarte-Rojo
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| |
Collapse
|
|
32
|
Effects of microvirin monomers and oligomers on hepatitis C virus. Biosci Rep 2017; 37:BSR20170015. [PMID: 28507200 PMCID: PMC6434159 DOI: 10.1042/bsr20170015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 05/02/2017] [Accepted: 05/10/2017] [Indexed: 12/25/2022] Open
Abstract
Microvirin (MVN) is a carbohydrate-binding protein which shows high specificity for high-mannose type N-glycan structures. In the present study, we tried to identify whether MVN could bind to high-mannose containing hepatitis C virus (HCV) envelope glycoproteins, which are heavily decorated high-mannose glycans. In addition, recombinantly expressed MVN oligomers in di-, tri- and tetrameric form were evaluated for their viral inhibition. MVN oligomers bound more efficiently to HCV virions, and displayed in comparison with the MVN monomer a higher neutralization potency against HCV infection. The antiviral effect was furthermore affected by the peptide linker sequence connecting the MVN monomers. The results indicate that MVN oligomers such as trimers and tetramers may be used as future neutralization agents against HCV infections.
Collapse
|
|
33
|
Callefi LA, Villela-Nogueira CA, de Barros Tenore S, Carnaúba-Júnior D, Coelho HSM, Pinto PDTA, Nabuco LC, Pessoa MG, Ferraz MLCG, Ferreira PRA, de Lourdes Candolo Martinelli A, Chachá SGF, de Souza Paiva Ferreira A, de Macedo Bisio AP, Brandão-Mello CE, Álvares-Da-Silva MR, Reuter T, Ivantes CAP, de Mello Perez R, Mendes-Correa MCJ. Effectiveness and safety of first-generation protease inhibitors in real-world patients with hepatitis C virus genotype 1 infection in Brazil: a multicenter study. Clinics (Sao Paulo) 2017; 72:378-385. [PMID: 28658438 PMCID: PMC5463255 DOI: 10.6061/clinics/2017(06)08] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 03/15/2017] [Accepted: 04/17/2017] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE: To evaluate the effectiveness and safety of first-generation protease inhibitors for the treatment of genotype 1 hepatitis C virus-infected patients at Brazilian reference centers. METHODS: This multicenter cross-sectional study included hepatitis C virus genotype 1 monoinfected patients treated with Peg-interferon, ribavirin, and either boceprevir (n=158) or telaprevir (n=557) between July 2013 and April 2014 at 15 reference centers in Brazil. Demographic, clinical, virological, and adverse events data were collected during treatment and follow-up. RESULTS: Of the 715 patients, 59% had cirrhosis and 67.1% were treatment-experienced. Based on intention-to-treat analysis, the overall sustained viral response was 56.6%, with similar effectiveness in both groups (51.9% for boceprevir and 58% for telaprevir, p=0.190). Serious adverse events occurred in 44.2% of patients, and six deaths (0.8%) were recorded. Cirrhotic patients had lower sustained viral response rates than non-cirrhotic patients (46.9% vs. 70.6%, p<0.001) and a higher incidence of serious adverse events (50.7% vs. 34.8%, p<0.001). Multivariate analysis revealed that sustained viral response was associated with the absence of cirrhosis, viral recurrence after previous treatment, pretreatment platelet count greater than 100,000/mm3, and achievement of a rapid viral response. Female gender, age>65 years, diagnosis of cirrhosis, and abnormal hemoglobin levels/platelet counts prior to treatment were associated with serious adverse events. CONCLUSION: Although serious adverse events rates were higher in this infected population, sustained viral response rates were similar to those reported for other patient cohorts.
Collapse
Affiliation(s)
- Luciana Azevedo Callefi
- Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina, Universidade de Sao Paulo (USP), SP, BR
| | | | | | | | - Henrique Sérgio Moraes Coelho
- Servico de Hepatologia, Departamento de Clinica Medica, Universidade Federal do Rio de Janeiro (UFRJ), RJ, BR
- Centro de Doencas Hepaticas (CDH), RJ, BR
| | - Paulo de Tarso A. Pinto
- Setor de Gastro/Hepatologia, Hospital Federal dos Servidores do Estado do Rio de Janeiro (HFSE), RJ, BR
| | - Letícia Cancella Nabuco
- Setor de Gastro/Hepatologia, Hospital Federal dos Servidores do Estado do Rio de Janeiro (HFSE), RJ, BR
| | - Mário Guimarães Pessoa
- Departamento de Gastroenterologia e Hepatologia, Faculdade de Medicina, Universidade de Sao Paulo (USP), SP, BR
| | | | - Paulo Roberto Abrão Ferreira
- Disciplina de Infectologia, Escola Paulista de Medicina (EPM), Universidade Federal de Sao Paulo (UNIFESP), SP, BR
| | - Ana de Lourdes Candolo Martinelli
- Divisao de Gastroenterologia, Departamento de Clinica Medica, Faculdade de Medicina de Ribeirao Preto (FMRP), Universidade de Sao Paulo (USP), SP, BR
| | - Silvana Gama Florencio Chachá
- Divisao de Gastroenterologia, Departamento de Clinica Medica, Faculdade de Medicina de Ribeirao Preto (FMRP), Universidade de Sao Paulo (USP), SP, BR
| | | | | | - Carlos Eduardo Brandão-Mello
- Disciplina de Clinica Medica e Gastroenterologia, Universidade Federal do Estado do Rio de Janeiro (UNIRIO), RJ, BR
| | | | - Tânia Reuter
- Ambulatorio HIV/AIDS/ Hepatites Virais, Universidade Federal do Espirito Santo (UFES), ES, BR
| | | | - Renata de Mello Perez
- Servico de Gastroenterologia, Universidade do Estado do Rio de Janeiro (UERJ), RJ, BR
| | - Maria Cássia Jacintho Mendes-Correa
- Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina, Universidade de Sao Paulo (USP), SP, BR
- Laboratorio de Virologia-LIM 52, Instituto de Medicina Tropical (IMT), SP, BR
| |
Collapse
|
|
34
|
Evon DM, Golin CE, Stewart P, Fried MW, Alston S, Reeve B, Lok AS, Sterling RK, Lim JK, Reau N, Sarkar S, Nelson DR, Reddy KR, Di Bisceglie AM. Patient engagement and study design of PROP UP: A multi-site patient-centered prospective observational study of patients undergoing hepatitis C treatment. Contemp Clin Trials 2017; 57:58-68. [PMID: 28342989 PMCID: PMC5495187 DOI: 10.1016/j.cct.2017.03.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 03/16/2017] [Accepted: 03/21/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND New highly efficacious direct-acting antiviral (DAA) therapies are available to treat chronic hepatitis C viral (HCV) infection. Real-world, patient-centered data on harms and benefits associated with these therapies are needed. METHODS PROP UP is a multi-center prospective observational study that plans to enroll 1600 patients starting treatment with recently-approved DAA regimens. Informed by extensive input from a HCV patient engagement group who prioritized outcomes most important to them, patient-reported outcomes will be characterized using surveys at five time points: Baseline (T1), treatment week 4 (T2), end of treatment (T3), 12weeks post-treatment (T4), 12months post-treatment (T5). OUTCOMES (1) Changes in side effects, functioning, pre-existing conditions, and out-of-pocket costs during therapy (T1 vs T2/T3); (2) Medication adherence in relation to a history of mental health/substance abuse, treatment regimens, pill burden, reasons for missed doses, and cure rates; (3) Short term impact of cure on functioning and amelioration of symptoms (T1 vs T4); (4) Long-term treatment harms or benefits of cure on symptoms, side effects, pre-existing conditions, and functioning (T1 vs T5). Similarities between regimens will be examined where comparisons are appropriate and meaningful. CONCLUSION PROP UP complements previous clinical trials by focusing on patient-reported outcomes in a representative sample of patients treated in clinical practice, by collaborating with a patient engagement group, by characterizing the experiences of vulnerable subgroups, and by investigating long-term harms and benefits of treatments. PROP UP is designed to provide novel and detailed information to support informed decision-making for patients and providers contemplating HCV treatment (PCORI CER-1408-20,660; NCT02601820).
Collapse
Affiliation(s)
- Donna M Evon
- Division of Gastroenterology and Hepatology, University of North Carolina, United States.
| | - Carol E Golin
- Division of General Medicine and Clinical Epidemiology, University of North Carolina, United States; Department of Health Behavior, University of North Carolina, United States
| | - Paul Stewart
- Department of Biostatistics, University of North Carolina, United States
| | - Michael W Fried
- Division of Gastroenterology and Hepatology, University of North Carolina, United States
| | - Shani Alston
- Division of Gastroenterology and Hepatology, University of North Carolina, United States
| | - Bryce Reeve
- Department of Health Policy and Management, University of North Carolina, United States
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, United States
| | - Richard K Sterling
- Department of Internal Medicine, Virginia Commonwealth University, United States
| | - Joseph K Lim
- Department of Internal Medicine, Yale University, United States
| | - Nancy Reau
- Department of Internal Medicine, Rush Medical College, United States
| | - Souvik Sarkar
- Department of Internal Medicine, University of California, Davis, United States
| | - David R Nelson
- Department of Medicine, University of Florida, United States
| | - K R Reddy
- Department of Medicine, the University of Pennsylvania, United States
| | | |
Collapse
|
|
35
|
Calleja JL, Crespo J, Rincón D, Ruiz-Antorán B, Fernandez I, Perelló C, Gea F, Lens S, García-Samaniego J, Sacristán B, García-Eliz M, Llerena S, Pascasio JM, Turnes J, Torras X, Morillas RM, Llaneras J, Serra MA, Diago M, Rodriguez CF, Ampuero J, Jorquera F, Simon MA, Arenas J, Navascues CA, Bañares R, Muñoz R, Albillos A, Mariño Z. Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: Results from a Spanish real-world cohort. J Hepatol 2017; 66:1138-1148. [PMID: 28189751 DOI: 10.1016/j.jhep.2017.01.028] [Citation(s) in RCA: 142] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 01/25/2017] [Accepted: 01/29/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. METHODS Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. RESULTS The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. CONCLUSIONS In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. LAY SUMMARY In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.
Collapse
Affiliation(s)
- Jose Luis Calleja
- Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid and CIBERehd, Madrid, Spain.
| | - Javier Crespo
- Hospital Universitario Marques de Valdecilla, IDIVAL, Santander and Facultad de Medicina, Universidad de Cantabria, Spain
| | - Diego Rincón
- Hospital General Universitario Gregorio Marañón, Facultad de Medicina de la Universidad Complutense and CIBERehd, Madrid, Spain
| | | | | | | | | | - Sabela Lens
- Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | | | | | | | - Susana Llerena
- Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Cantabria, Spain
| | | | - Juan Turnes
- Complejo Hospitalario Universitario de Pontevedra and IISGS, Spain
| | - Xavier Torras
- Hospital Santa Creu i Sant Pau and CIBERehd, Barcelona, Spain
| | | | | | | | - Moises Diago
- Hospital Universitario General de Valencia, Valencia, Spain
| | | | - Javier Ampuero
- Hospital Universitario Virgen del Rocío, IBIS and CIBERehd, Spain
| | - Francisco Jorquera
- Complejo Asistencial Universitario León, León, IBIOMED and CIBERehd, Spain
| | - Miguel A Simon
- Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Juan Arenas
- Hospital Universitario Donostia, San Sebastian, Spain
| | | | - Rafael Bañares
- Hospital General Universitario Gregorio Marañón, Facultad de Medicina de la Universidad Complutense and CIBERehd, Madrid, Spain
| | - Raquel Muñoz
- Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | - Zoe Mariño
- Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| |
Collapse
|
|
36
|
Iketani R, Ide K, Yamada H, Kawasaki Y, Masaki N. The Safety Profile of Telaprevir-Based Triple Therapy in Clinical Practice: A Retrospective Cohort Study. Biol Pharm Bull 2017; 40:687-692. [PMID: 28179602 DOI: 10.1248/bpb.b16-00989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study was designed to evaluate the safety profile of adding telaprevir to therapy using pegylated interferon-alfa-2b and ribavirin (PR) using real world patient data obtained from a nationwide Japanese interferon database. This retrospective cohort study compared telaprevir-based triple therapy (T/PR) with PR therapy. The study population comprised patients with genotype 1 chronic hepatitis C represented in the database between December 2009 and August 2015. The primary endpoint was dropout from treatment due to adverse events during the relevant standard treatment duration based on guidelines from the Japan Society of Hepatology. The dropout odds ratio (OR) and 95% confidence interval (95% CI) were calculated using univariate logistic regression analysis. Covariates were detected using a stepwise logistic regression analysis, and the adjusted OR and 95% CI were calculated. A total of 25989 patients were registered, and 4619 patients (T/PR: 1334, PR: 3285) were appropriate for primary endpoint analysis. The dropout rate due to adverse events was lower in the T/PR group (13.4%) than in the PR group (22.6%) (OR: 0.530; 95% CI, 0.444-0.633). After adjustment for the covariates detected by stepwise selection, the OR was 0.529 (95% CI, 0.441-0.634). Our study showed that there was a difference in dropout rate between real world T/PR and PR therapy in Japan. Although the addition of telaprevir to PR therapy may improve treatment continuity under the care of hepatologists, this study could not fully determine which therapy was safer or the factors influencing this result. Therefore, additional research will be required to confirm this.
Collapse
Affiliation(s)
- Ryo Iketani
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Kazuki Ide
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
| | - Hiroshi Yamada
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Yohei Kawasaki
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
| | - Naohiko Masaki
- Laboratory Testing Department, National Center for Global Health and Medicine
| |
Collapse
|
|
37
|
Gray E, Pasta DJ, Norris S, O'Leary A. Effectiveness of triple therapy with direct-acting antivirals for hepatitis C genotype 1 infection: application of propensity score matching in a national HCV treatment registry. BMC Health Serv Res 2017; 17:288. [PMID: 28424064 PMCID: PMC5395881 DOI: 10.1186/s12913-017-2188-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 03/24/2017] [Indexed: 11/18/2022] Open
Abstract
Background Observational studies are used to measure the effectiveness of an intervention in non-experimental, real world scenarios at the population level and are recognised as an important component of the evidence pyramid. Such data can be accrued through prospective cohort studies and a patient registry is a proven method for this type of study. The national hepatitis C (HCV) registry was established in Ireland in 2012 with the aim of monitoring the clinical and economic outcomes from new, high cost regimens for the treatment of HCV infection. A sustained virological response (SVR) 24 weeks following completion of therapy with interferon-containing regimens is considered a cure. Non-randomisation in these studies can result in confounding or selection bias. Propensity score (PS) matching is one of a number of statistical tools that can be used to mitigate the effects of confounding in observational studies. Methods We analysed the data of 309 patients who underwent triple therapy treatment with telaprevir (TPV) in combination with pegylated-interferon and ribavirin (PR) or boceprevir (BOC)/PR between June 2012 and December 2014. The decision to initiate treatment and the selection of the treatment regimen was at the discretion of the physician. To adjust for confounding, three approaches to propensity score matching were assessed Adjusted sustained-virological response rates (SVR), odds ratios, p-values and 95% confidence intervals were calculated from the three PS matched dataset. Results Prior to matching, the unadjusted sustained virological response rates 24 weeks after treatment complete (SVR24) were 74% (n = 158/215) and 61% (n = 57/94) for telaprevir/PR and boceprevir/PR, respectively. After matching, adjusted SVR24 rates were between 73–74% and 60–61% for telaprevir/PR and boceprevir/PR, respectively. Conclusion Efficacy rates were comparable with those reported in pivotal clinical trials and real world studies. After adjusting for confounding, we conclude that there was no difference in treatment effect after PS matching. The small sample size limits the conclusions that can be made about the effect of PS matching. Propensity score adjustment remains a tool that can be applied to future analysis, however, we suggest, where possible, using a larger sample size in order to reduce the uncertainty around the outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s12913-017-2188-1) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Emma Gray
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
| | | | - Suzanne Norris
- School of Medicine, Trinity College Dublin, Dublin, Ireland.,Department of Hepatology, St James' Hospital, Dublin, Ireland
| | - Aisling O'Leary
- National Centre for Pharmacoeconomics, St. James' Hospital, Dublin, Ireland.,School of Pharmacy, Royal College of Surgeons of Ireland, Dublin, Ireland
| | | |
Collapse
|
|
38
|
Effectiveness of ledipasvir/sofosbuvir in real-world patients with chronic hepatitis C: a collaborative treatment approach. Int J Antimicrob Agents 2017; 49:778-781. [PMID: 28389353 DOI: 10.1016/j.ijantimicag.2017.01.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 01/10/2017] [Accepted: 01/14/2017] [Indexed: 02/07/2023]
Abstract
The effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in routine use in clinical practice for the management of chronic hepatitis C virus (HCV) has not been well described. Data with prior agents suggest that management of HCV using an interprofessional approach in clinical practice is associated with better outcomes. This single-centre, prospective, observational cohort study evaluated patients treated with LDV/SOF for 8, 12 or 24 weeks as part of the standardized interprofessional treatment protocol at Novant Health Infectious Diseases Specialists. Eighty-four patients treated with LDV/SOF were evaluated; of these, 97.5% and 91.7% of patients achieved a sustained virological response (SVR) in the per-protocol analysis and the intention-to-treat analysis, respectively. Two patients were not cured after relapse of HCV. No patients required LDV/SOF discontinuation and all patients completed the appropriate treatment duration. The majority (56%) of patients reported no adverse effects and all adverse effects that were reported were mild. The most commonly reported adverse effects were headache and fatigue. SVR and tolerability rates were similar to those seen in the clinical trials. LDV/SOF was associated with a successful translation from the clinical trial setting to clinical practice. A collaborative treatment approach should be considered in the management of HCV.
Collapse
|
|
39
|
Sbarigia U, Wirth D, Van Nuys K, Huber C, Brookmeyer R, Stahmeyer J, Krauth C. Economic study of the value of expanding HCV treatment capacity in Germany. BMJ Open Gastroenterol 2017; 4:e000130. [PMID: 28461903 PMCID: PMC5387957 DOI: 10.1136/bmjgast-2016-000130] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/07/2017] [Accepted: 02/14/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Today's highly efficacious, low-toxicity interferon-free treatment regimens for chronic hepatitis C virus (HCV) can cure most patients with HCV in 12-24 weeks. The aim of this study was to understand how the introduction of shorter duration treatment regimens for HCV will impact the capacity for treatment and value to society. METHODS A Markov model of HCV transmission and progression was constructed, incorporating nationally representative data on HCV prevalence, incidence and progression; mortality, treatment costs, medical expenditures, employment probabilities and disability payments in Germany. The model was stratified by HCV genotype and exposure route (1-time healthcare exposure, injection drug use and sexual activity). Treatment scenarios were based on German treatment guidelines and projected treatment capacity. The impact of different treatment scenarios on disease transmission and prevalence, quality-adjusted life years (QALYs), treatment costs, medical expenditures, employment and disability expenditures was calculated. RESULTS Depending on their adoption profile, new treatment regimens and protocols introduced over the next several years will increase HCV treatment capacity in Germany by 8-30%, reducing disease transmission and prevalence, increasing QALYs and adding €94-310 million in discounted social value (QALYs plus medical savings net of treatment costs) over a 30-year horizon. Additional social value in the form of higher employment and lower disability would also result. CONCLUSIONS The introduction of shorter HCV treatment regimens and the resulting increased treatment capacity in Germany would result in large gains to society by reducing disease transmission and prevalence, resulting in longer, healthier, more productive lives for current and future generations.
Collapse
|
|
40
|
Kowdley KV, Sundaram V, Jeon CY, Qureshi K, Latt NL, Sahota A, Lott S, Curry MP, Tsai N, Chaiyakunapruk N, Lee Y, Petersen J, Buggisch P. Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection. Hepatology 2017; 65:1094-1103. [PMID: 28027579 DOI: 10.1002/hep.29005] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 11/28/2016] [Accepted: 12/15/2016] [Indexed: 12/22/2022]
Abstract
UNLABELLED Eight weeks duration of ledipasvir/sofosbuvir (LDV/SOF) can be considered in genotype 1 hepatitis C virus-infected patients who are treatment-naive, do not have cirrhosis, and have a pretreatment viral load <6,000,000 IU/mL. The effectiveness of this regimen, however, has not been fully confirmed by real-world experience. Using data from real-world cohorts, we aimed to determine the effectiveness of 8 weeks of LDV/SOF treatment, examine variables associated with relapse after treatment with this regimen, and compare the effectiveness of 8 weeks and 12 weeks of LDV/SOF treatment. To evaluate the effectiveness of 8 weeks of therapy and characteristics associated with relapse, we used individual patient data from the IFI (Institut für Interdisziplinäre Medizin), Burman's Pharmacy, and Kaiser Permanente Southern California. All patients had fibrosis staging assessed with biopsy, transient elastography, or serum biomarkers. We also performed a systematic review and meta-analysis of six additional real-world cohorts, to compare effectiveness of 8 weeks to 12 weeks duration. In our pooled data analysis, 634 patients were treated for 8 weeks with LDV/SOF, of whom all had outcomes of cure or relapse without loss to follow-up. Per protocol rates of sustained virologic response at 12 weeks were 98.1% (622/634) in the full cohort and 97.9% (571/583) among treatment-eligible patients. Exact logistic regression revealed no specific patient characteristics associated with relapse. Our meta-analysis of six additional real-world cohorts, comprised of 5,637 patients, demonstrated similar risk for relapse between 8 weeks and 12 weeks of LDV/SOF (relative risk = 0.99, 95% confidence interval 0.98-1.00). CONCLUSION An 8-week duration of treatment with LDV/SOF is highly effective in properly selected patients; greater use of this regimen is recommended. (Hepatology 2017;65:1094-1103).
Collapse
Affiliation(s)
| | - Vinay Sundaram
- Department of Medicine and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Christie Y Jeon
- Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Kamran Qureshi
- Department of Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA
| | - Nyan L Latt
- Department of Medicine, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA
| | - Amandeep Sahota
- Department of Medicine, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA
| | | | - Michael P Curry
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA
| | - Naoky Tsai
- Department of Medicine, University of Hawaii, Honolulu, HI
| | - Nathorn Chaiyakunapruk
- School of Pharmacy, Monash University Malaysia, Malaysia.,Centre of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.,School of Population Health, University of Queensland, Brisbane, Australia.,School of Pharmacy, University of Wisconsin-Madison, Madison, WI
| | | | - Jorg Petersen
- IFI Institut für Interdisziplinäre Medizin, Asklepios Klinik St. Georg, Hamburg, Germany
| | - Peter Buggisch
- IFI Institut für Interdisziplinäre Medizin, Asklepios Klinik St. Georg, Hamburg, Germany
| |
Collapse
|
|
41
|
Mangia A, Foster GR, Berg CP, Curescu M, Ledinghen VD, Habersetzer F, Manolakopoulos S, Negri E, Papatheodoridis G, Ahlers S, Castillo M, Bakalos G, Mauss S. Efficacy and safety profile of boceprevir- or telaprevir-based triple therapy or dual peginterferon alfa-2a or alfa-2b plus ribavirin therapy in chronic hepatitis C: the real-world PegBase observational study. Ann Gastroenterol 2017; 30:327-343. [PMID: 28469364 PMCID: PMC5411384 DOI: 10.20524/aog.2017.0136] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 02/19/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice. METHODS PegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naïve and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12). RESULTS SVR12 rates in treatment-naïve genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naïve patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports. CONCLUSION The efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies.
Collapse
Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - Graham R Foster
- Institute of Cellular and Molecular Sciences, Queen Mary University of London, London, UK
| | - Christoph P Berg
- Department of Internal Medicine, Medizinische Universitätsklinik Tübingen, Tübingen, Germany
| | - Manuela Curescu
- Clinic of Infectious Diseases, University of Medicine and Pharmacy Timişoara, Timişoara, Romania
| | | | - François Habersetzer
- Unité Hépatologie, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Inserm 1110, Université de Strasbourg, Strasbourg, France
| | | | - Elisa Negri
- UO Malattie Infettive ed Epatologia, Azienda Ospedaliero - Universitaria di Parma, Parma, Italy
| | | | | | | | | | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Düsseldorf, Germany
| | | |
Collapse
|
|
42
|
Terrault NA, Zeuzem S, Di Bisceglie AM, Lim JK, Pockros PJ, Frazier LM, Kuo A, Lok AS, Shiffman ML, Ben Ari Z, Akushevich L, Vainorius M, Sulkowski MS, Fried MW, Nelson DR. Effectiveness of Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection and Factors Associated With Sustained Virologic Response. Gastroenterology 2016; 151:1131-1140.e5. [PMID: 27565882 PMCID: PMC5300778 DOI: 10.1053/j.gastro.2016.08.004] [Citation(s) in RCA: 169] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 07/22/2016] [Accepted: 08/05/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS The combination of ledipasvir and sofosbuvir has been approved for treatment of genotype 1 hepatitis C virus (HCV) infection, including an 8-week regimen for treatment-naïve patients without cirrhosis and a baseline level of HCV RNA <6 million IU/mL. We analyzed data from a multicenter, prospective, observational study to determine real-world sustained virologic responses 12 weeks after treatment (SVR12) with regimens containing ledipasvir and sofosbuvir and identify factors associated with treatment failure. METHODS We collected data from 2099 participants in the HCV-TARGET study with complete virologic data (per-protocol population). We analyzed data from 1788 patients receiving ledipasvir-sofosbuvir (282 for 8 weeks, 910 for 12 weeks, 510 for 24 weeks, and 86 for a different duration) and 311 receiving ledipasvir-sofosbuvir plus ribavirin (212 for 12 weeks and 81 for 24 weeks, 18 for other duration) to estimate SVR12 (with 95% confidence interval [CI]), and logistic regression methods to identify factors that predicted an SVR12. RESULTS The overall study population was 25% black, 66% with HCV genotype 1A infection, 41% with cirrhosis, 50% treatment-experienced, and 30% receiving proton pump inhibitors at start of treatment. In the per-protocol population, SVR12s were achieved by 96% of patients receiving ledipasvir-sofosbuvir for 8 weeks (95% CI, 93%-98%), 97% receiving the drugs for 12 weeks (95% CI, 96%-98%), and 95% receiving the drugs for 24 weeks (95% CI, 93%-97%). Among patients also receiving ribavirin, SVR12 was achieved by 97% of the patients receiving the drugs for 12 weeks (95% CI, 94%-99%) and 95% receiving the drugs for 24 weeks (95% CI, 88%-99%). Of the 586 patients who qualified for 8 weeks of treatment, only 255 (44%) received the drugs for 8 weeks. The rate of SVR12 among those who qualified for and received 8 weeks of therapy was similar in those who qualified for 8 weeks but received 12 weeks therapy (96%; 95% CI, 92%-99% vs 98%; 95% CI, 95%-99%). Factors that predicted SVR12 were higher albumin (≥3.5 g/dL), lower total bilirubin (≤1.2 g/dL), absence of cirrhosis, and absence of proton pump inhibitor use. CONCLUSIONS Regimens containing ledipasvir and sofosbuvir are highly effective for a broad spectrum of patients with HCV genotype 1 infection treated in different clinical practice settings. Expanded use of 8-week treatment regimens for eligible patients is supported by these real-world results. Modification of proton pump inhibitor use may increase rates of SVR. ClinicalTrials.gov no. NCT01474811.
Collapse
Affiliation(s)
- Norah A Terrault
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, California.
| | | | - Adrian M Di Bisceglie
- Department of Medicine, Saint Louis University School of Medicine, St Louis, Missouri
| | - Joseph K Lim
- Yale University School of Medicine, New Haven, Connecticut
| | - Paul J Pockros
- Liver Disease Center, Scripps Clinic, La Jolla, California
| | | | - Alexander Kuo
- University of California San Diego, San Diego, California
| | - Anna S Lok
- University of Michigan Health System, Ann Arbor, Michigan
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Gray E, Norris S, Schmitz S, O'Leary A. Do disparities between populations in randomized controlled trials and the real world lead to differences in outcomes? J Comp Eff Res 2016; 6:65-82. [PMID: 27854129 DOI: 10.2217/cer-2016-0042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To conduct a systematic review investigating reasons for the disparity between the efficacy and effectiveness rates reported in randomized controlled trials (RCTs) and observational studies of direct-acting antiviral treatment regimens licensed for use in genotype1 hepatitis C virus-infected individuals. METHODS This systematic review was conducted in accordance with the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group. RESULTS Statistically significant (p < 0.05) differences in the baseline demographics and sustained virological response rates were observed between RCT and observational studies. CONCLUSION In order for outcomes from RCTs to be generalizable to the real world, greater consideration needs to be taken to include patient populations that are more representative of those awaiting treatment in the clinical setting.
Collapse
Affiliation(s)
- Emma Gray
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Suzanne Norris
- School of Medicine, Trinity College Dublin, Dublin, Ireland.,Departmentof Hepatology, St James' Hospital, Dublin, Ireland
| | - Susanne Schmitz
- HealthEconomics & Evidence Synthesis Research Unit, Department of PopulationHealth, Luxembourg Health Institute, Luxembourg
| | - Aisling O'Leary
- Schoolof Pharmacy, Royal College of Surgeons of Ireland, Dublin, Ireland.,NationalCentre for Pharmacoeconomics, St James' Hospital, Dublin, Ireland
| |
Collapse
|
|
44
|
Gentile I, Maraolo AE, Niola M, Graziano V, Borgia G, Paternoster M. Limiting the access to direct-acting antivirals against HCV: an ethical dilemma. Expert Rev Gastroenterol Hepatol 2016; 10:1227-1234. [PMID: 27607920 DOI: 10.1080/17474124.2016.1234375] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection affects about 200 million people worldwide and represents a leading cause of liver-related mortality. Eradication of HCV infection, achieved mainly through direct-acting antivirals (DAA), results in a decrease of mortality and an improvement of quality of life. These drugs have a maximal efficacy and an optimal tolerability. However, their high cost precludes a universal access even in wealthy countries. Areas covered: This article deals with the policies adopted for the use of the new anti-HCV drugs, especially in Europe and most of all in Italy, supposedly the developed country with the highest HCV prevalence. The literature search was performed using Pubmed and Web of Science. Moreover, national regulatory institutional websites were consulted. Expert commentary: The current policy of limitation to the access of the DAA presents a series of ethical issues that makes it non-applicable. A 'treat-all' strategy should resolve all ethical dilemmas, by virtue of the wide benefits of anti-HCV treatment not only for the advanced stage of infection, but also for the initial stages. A reduction in price of the drugs is the actual condition to achieve such a change.
Collapse
Affiliation(s)
- Ivan Gentile
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Alberto E Maraolo
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Massimo Niola
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| | - Vincenzo Graziano
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| | - Guglielmo Borgia
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Mariano Paternoster
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| |
Collapse
|
|
45
|
Rutter K, Etschmaier A, Ferlitsch M, Maieron A, Hametner S, Horvatits T, Paternostro R, Salzl P, Reiberger T, Peck-Radosavljevic M, Quehenberger P, Hofer H, Trauner M, Ferenci P, Ferlitsch A. von Willebrand factor antigen (vWF-Ag): A non-invasive predictor of treatment response and serious adverse events in HCV patients with interferon triple therapy. Dig Liver Dis 2016; 48:1194-1199. [PMID: 27476467 DOI: 10.1016/j.dld.2016.06.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 05/26/2016] [Accepted: 06/28/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Treatment of chronic hepatitis C virus (HCV) infection was revolutionized within the last years. Interferon free antiviral regimens are not accessible without limitations. Combination of peginterferon/ribavirin with first generation direct acting antivirals is less effective and associated with serious adverse events. AIM We have shown that vWF-Ag is associated with portal hypertension and treatment response to PEG/RBV and we evaluated if vWF-Ag is a predictive marker for treatment response and safety in patients with triple therapy. METHODS 222 HCV-GT 1 patients and DAA based triple therapy were included in this retrospective, multicenter study. RESULTS Median vWF-Ag levels were 167.0% [IQR: 124.0-210.0%]. Significantly higher levels were seen in patients without SVR; median 190% [IQR: 146.0-259.5%] versus SVR: 142.5% [IQR: 114.3-196.8%], p<0.001. Furthermore levels of vWF-Ag were identified as independent predictor of non SVR; (OR: 1.009; 95%CI: 1.016-1.3, p=0.005). In patients with cirrhosis elevated vWF-Ag levels were associated with increased incidence of SAEs (OR: 1.016; 95%CI: 1.004-1.028; p=0.007). Best cut off for prediction of SAEs was vWF-Ag>281.5% with a sensitivity of 78% and a specificity of 90%. CONCLUSION Baseline vWF-Ag levels predict outcome of DAA based treatment in HCV-1 patients and identify patients with a risk of SAEs. Therefore vWF-Ag may be an additional marker for selecting patients for interferon free therapeutic regimens.
Collapse
Affiliation(s)
- Karoline Rutter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexandra Etschmaier
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Monika Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | | | | | - Thomas Horvatits
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Petra Salzl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Quehenberger
- Department of Laboratory Medicine, Medical University of Vienna, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Arnulf Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
| |
Collapse
|
|
46
|
Fagundes RN, Ferreira LEVVDC, Pace FHDL. [Health-Related Quality of Life in patients with hepatitis C treated with dual and triple therapy]. Rev Esc Enferm USP 2016; 49:939-45. [PMID: 27419677 DOI: 10.1590/s0080-623420150000600009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 09/23/2015] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Comparing Health-Related Quality of Life (HRQoL) scores in patients with chronic hepatitis C undergoing double and triple antiviral therapy and analyzing possible factors related to HRQoL. METHOD HRQoL was assessed using the Short Form 36 and Chronic Liver Disease Questionnaire, which were applied at baseline and at weeks 4, 12 and 16 of treatment to 32 patients divided into two groups: double therapy with pegylated interferon (IFN-PEG) and ribavirin, and triple therapy with PEG-IFN, ribavirin and telaprevir. RESULTS The reduction of HRQoL was greater in patients receiving triple therapy compared to those treated with two drugs, the most critical time is at 12 weeks in both groups. After removal of telaprevir, the triple therapy group significantly improved their HRQoL scores. Anxiety and depression before treatment, employment status and race are significantly related to diminished HRQoL. CONCLUSION Patients undergoing double and triple therapy have diminished HRQoL indexes, but the addition of telaprevir chooses a more significant decrease.
Collapse
Affiliation(s)
- Raíssa Neves Fagundes
- Universidade Federal de Juiz de Fora, Departamento de Gastroenterologia, Juiz de Fora, MG, Brazil
| | | | | |
Collapse
|
|
47
|
Feld JJ, Maan R, Zeuzem S, Kuo A, Nelson DR, Di Bisceglie AM, Manns MP, Sherman K, Frazier LM, Sterling R, Mailliard M, Schmidt M, Akushevich L, Vainorius M, Fried MW. Effectiveness and Safety of Sofosbuvir-Based Regimens for Chronic HCV Genotype 3 Infection: Results of the HCV-TARGET Study. Clin Infect Dis 2016; 63:776-783. [PMID: 27325691 PMCID: PMC4996139 DOI: 10.1093/cid/ciw387] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 06/06/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Sofosbuvir (SOF) is active against all hepatitis C virus (HCV) genotypes, and SOF-based therapies lead to high rates of sustained virologic response (SVR). However, genotype 3 (GT3) HCV remains a challenge with lower SVR rates reported, particularly in patients with cirrhosis. This study reports the effectiveness and safety of SOF-based therapy in patients with GT3 HCV treated in clinical practice. METHODS Hepatitis C Virus Therapeutic Registry and Research Network is an international, prospective observational study evaluating patients treated in usual clinical practice. Patients with GT3 HCV were analyzed to assess predictors of treatment response and adverse events using descriptive statistics and multivariable logistic regression. RESULTS Treatment outcomes were available for 197 patients treated with SOF and ribavirin (RBV), with or without peginterferon, including 54% with cirrhosis and 49% who failed prior therapy. Of 178 patients treated with SOF/RBV, 60% achieved SVR at 12 weeks (SVR12), compared with 84% of 19 patients treated with SOF/peginterferon/RBV. For patients treated with SOF/RBV, the SVR12 rate was 58% in treatment-naive patients with cirrhosis, and 42% in those with cirrhosis who failed prior therapy. In noncirrhotic patients, SVR12 rates were 89% in treatment-naive and 88% in treatment-experienced patients. After controlling for age and sex, absence of cirrhosis (odds ratio [OR], 6.4; 95% confidence interval [CI], 2.78-14.74), albumin levels ≥3.2 g/dL (OR, 12.48; 95% CI, 3.86-40.33), and platelet count >10(5) cells/µL (OR, 7.44; 95% CI, 3.51-15.78) were associated with greater odds of SVR12 CONCLUSIONS: SVR rates were acceptable in patients with GT3 HCV without cirrhosis; however, in those with cirrhosis, treatment with SOF/RBV was suboptimal, highlighting the need for new therapies for this population.
Collapse
Affiliation(s)
- Jordan J Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Ontario, Canada
| | - Raoel Maan
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study. PLoS One 2016; 11:e0161821. [PMID: 27598789 PMCID: PMC5012685 DOI: 10.1371/journal.pone.0161821] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 08/14/2016] [Indexed: 02/06/2023] Open
Abstract
Background Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. Methods We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. Results In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45–2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. Conclusions Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.
Collapse
|
|
49
|
Sepúlveda-Crespo D, Jiménez JL, Gómez R, De La Mata FJ, Majano PL, Muñoz-Fernández MÁ, Gastaminza P. Polyanionic carbosilane dendrimers prevent hepatitis C virus infection in cell culture. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 13:49-58. [PMID: 27562210 DOI: 10.1016/j.nano.2016.08.018] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 07/11/2016] [Accepted: 08/11/2016] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is a major biomedical problem worldwide. Although new direct antiviral agents (DAAs) have been developed for the treatment of chronic HCV infection, the potential emergence of resistant virus variants and the difficulties to implement their administration worldwide make the development of novel antiviral agents an urgent need. Moreover, no effective vaccine is available against HCV and transmission of the virus still occurs particularly when prophylactic measures are not taken. We used a cell-based system to screen a battery of polyanionic carbosilane dendrimers (PCDs) to identify compounds with antiviral activity against HCV and show that they inhibit effective virus adsorption of major HCV genotypes. Interestingly, one of the PCDs irreversibly destabilized infectious virions. This compound displays additive effect in combination with a clinically relevant DAA, sofosbuvir. Our results support further characterization of these molecules as nanotools for the control of hepatitis C virus spread.
Collapse
Affiliation(s)
- Daniel Sepúlveda-Crespo
- Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Spanish HIV-HGM BioBank, Madrid, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; Plataforma de Laboratorio, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - José Luis Jiménez
- Plataforma de Laboratorio, Hospital General Universitario Gregorio Marañón, Madrid, Spain; CIBER-BBN, Instituto de Salud Carlos III, Madrid, Spain
| | - Rafael Gómez
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Campus Universitario, Alcalá de Henares, Madrid, Spain; CIBER-BBN, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Javier De La Mata
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Campus Universitario, Alcalá de Henares, Madrid, Spain; CIBER-BBN, Instituto de Salud Carlos III, Madrid, Spain
| | - Pedro L Majano
- Molecular Biology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Ma Ángeles Muñoz-Fernández
- Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Spanish HIV-HGM BioBank, Madrid, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; Plataforma de Laboratorio, Hospital General Universitario Gregorio Marañón, Madrid, Spain; CIBER-BBN, Instituto de Salud Carlos III, Madrid, Spain
| | - Pablo Gastaminza
- Centro Nacional De Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Campus Cantoblanco, Madrid, Spain.
| |
Collapse
|
|
50
|
Meanwell NA. 2015 Philip S. Portoghese Medicinal Chemistry Lectureship. Curing Hepatitis C Virus Infection with Direct-Acting Antiviral Agents: The Arc of a Medicinal Chemistry Triumph. J Med Chem 2016; 59:7311-51. [PMID: 27501244 DOI: 10.1021/acs.jmedchem.6b00915] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The development of direct-acting antiviral agents that can cure a chronic hepatitis C virus (HCV) infection after 8-12 weeks of daily, well-tolerated therapy has revolutionized the treatment of this insidious disease. In this article, three of Bristol-Myers Squibb's HCV programs are summarized, each of which produced a clinical candidate: the NS3 protease inhibitor asunaprevir (64), marketed as Sunvepra, the NS5A replication complex inhibitor daclatasvir (117), marketed as Daklinza, and the allosteric NS5B polymerase inhibitor beclabuvir (142), which is in late stage clinical studies. A clinical study with 64 and 117 established for the first time that a chronic HCV infection could be cured by treatment with direct-acting antiviral agents alone in the absence of interferon. The development of small molecule HCV therapeutics, designed by medicinal chemists, has been hailed as "the arc of a medical triumph" but may equally well be described as "the arc of a medicinal chemistry triumph".
Collapse
Affiliation(s)
- Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research & Development , Wallingford, Connecticut 06492, United States
| |
Collapse
|