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Zheng X, Tian S, Li T, Zhang S, Zhou X, Liu Y, Su R, Zhang M, Li B, Qi C, Guo G, Ma S, Sun K, Yang F, Hu Y, Yang C, Cui L, Shang Y, Guo C, Jin B, Guan L, Wang J, Ning W, Han Y. Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages. Signal Transduct Target Ther 2025; 10:81. [PMID: 40050288 PMCID: PMC11885662 DOI: 10.1038/s41392-025-02162-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 12/30/2024] [Accepted: 02/01/2025] [Indexed: 03/09/2025] Open
Abstract
Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies, despite uncertainty about its clinical therapeutic efficacy and unclear underlying mechanisms. Here, we investigated the role of follistatin-like 1 (FSTL1), a profibrotic and proinflammatory matricellular protein, in inflammation-related heterogeneity in stem cell therapy. Our results showed that a high level of circulating FSTL1 is significantly correlated with therapeutic response in patients with cirrhosis. FSTL1 facilitated MSC-mediated early recruitment of Ly6C+ inflammatory macrophages within 24 h postinfusion, which was essential for the empowerment of MSCs and subsequent Ly6C-CX3CR1+ macrophage remodelling at 48 h postinfusion. Fstl1 deficiency abrogated early macrophage recruitment and effective Ly6C-CX3CR1+ macrophage accumulation, resulting in the poor antifibrotic effect of MSCs in mice. Whereas, recombinant FSTL1 protein restored the therapeutic efficacy of MSCs in CCl4-injured Fstl1+/- mice. Mechanistically, host FSTL1 enhanced rapid recycling of CCR2 to the membrane via activation of the CD14/TLR4/NF-κB/ATP6V1G2 axis, leading to early recruitment of Ly6C+ monocytes /macrophages. Taken together, our findings revealed that FSTL1 is a critical regulator of the fibrotic immune microenvironment and facilitates subsequent stem cell therapy. These data suggest that FSTL1 could serve as a predictive biomarker of stem cell therapy response in patients with liver cirrhosis.
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Grants
- 82270551 National Natural Science Foundation of China (National Science Foundation of China)
- 81900570 National Natural Science Foundation of China (National Science Foundation of China)
- 82303155 National Natural Science Foundation of China (National Science Foundation of China)
- 82372882 National Natural Science Foundation of China (National Science Foundation of China)
- This work was supported by the National Key R&D Program of China, 2020YFA0710803 (to J.W.), 2017YFA0105704 (to Y. H.), 2021YFC2500700 and 2024YFA1108500 (to W.N.) National Natural Science Foundation of China (NSFC) grants 81900570, 82470638 (to X.Z.), 82270551 (to Y. H.), 82270616 (to J.W.), 81900502 (to G.G.), 82303155 (T.L.), 82372882 (L.G.) and 82030001 (to W.N.) Key Research and Development Program of Shaanxi province, China No. 2021ZDLSF02-07 (to Y. H.)
- the National Key R&D Program of China, 2020YFA0710803
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Affiliation(s)
- Xiaohong Zheng
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Siyuan Tian
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Ting Li
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Si Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Xia Zhou
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Yansheng Liu
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Rui Su
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Miao Zhang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Bo Li
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Chao Qi
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Guanya Guo
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Shuoyi Ma
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Keshuai Sun
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Fangfang Yang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Yinan Hu
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Chunmei Yang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Lina Cui
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Yulong Shang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Changcun Guo
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Boquan Jin
- Department of Immunology, Fourth Military Medical University, Xi'an, China
| | - Lei Guan
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China
| | - Jingbo Wang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China.
- Science and Technology Innovation Research Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
| | - Wen Ning
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
| | - Ying Han
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, China.
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Pretransplant Hepatitis C Virus Treatment Decreases Access to High-quality Livers. Transplant Direct 2021; 7:e684. [PMID: 34549082 PMCID: PMC8440014 DOI: 10.1097/txd.0000000000001127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 11/27/2022] Open
Abstract
Background Despite the revolutionary role of direct-acting antivirals for hepatitis C virus (HCV), the treatment timing for liver transplant candidates remains controversial. We hypothesize that deferring treatment until after liver transplantation improves access to a larger and higher-quality donor pool without a detrimental impact on post-liver transplantation outcomes. Methods This single-center study includes recipients that underwent deceased-donor liver transplant with HCV as the primary indication January 1, 2014, to December 31, 2018. For recipients that were untreated (n = 87) versus treated (n = 42) pre-LT, we compared post-LT mortality using Cox regression with inverse probability of treatment-weighted data. Results Among pre-LT untreated recipients, 95% were willing to accept an HCV+ donor, and 44.8% received a positive HCV antibody and nucleic acid amplification test (NAT) liver. Among pre-LT treated recipients, 5% were willing to accept an HCV+ donor, and 100% received a negative HCV antibody and NAT liver. The median calculated model for end-stage liver disease at transplant was similar between pre-LT untreated (13, IQR = 9-22) and treated recipients (11, IQR = 8-14) (P = 0.1). Pre-LT treated recipients received livers from older (47 y old versus 37, P < 0.01) and higher body mass index donors (30.2 versus 26.6; P = 0.04) and spent longer on the waiting list (319 d 180, P < 0.001). Unadjusted post-LT mortality at 1 year was higher in the pre-LT treated recipients (14.6% versus 3.5%, P = 0.02). After adjusting for recipient factors, pre-LT treated recipients trended toward a 3.9 times higher risk of mortality compared with the pre-LT untreated recipients (adjusted hazard ratio = 0.973.8615.4) (P = 0.06). Conclusions Deferring HCV treatment improves access to higher-quality donors and may improve post-LT survival.
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Clinical Course and Outcome of Liver Transplantation in Patients with Hepatitis C in Iran. HEPATITIS MONTHLY 2021. [DOI: 10.5812/hepatmon.108405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Hepatitis C is one of the most common causes of end-stage liver disease and liver transplant worldwide. In recent years, with the rapid advances in the treatment of hepatitis C by direct-acting antiviral drugs (DAAs), the clinical course of the disease as well as liver transplantation have had significant improvement. Also, DAAs have completely replaced interferon-based regimens in the treatment and prevention of HCV recurrence after liver transplant. Objectives: This is the first study that aimed to investigate the clinical course of liver transplantation in patients with hepatitis C in Iran. Methods: This retrospective study was conducted on patients with HCV liver transplantation within five years (2012 - 2017) with the age range of 18 to 65 years at Shiraz Organ Transplant Center. All demographic and clinical data were recorded. Pre-transplant viral load, disease recurrence, graft rejection, and mortality rate were the most important indices in this study. Results: Among 55 transplant patients, 49% had received hepatitis C treatment before liver transplantation and interferon-based regimens were more prevalent. Besides, HCV genotype 3, followed by genotype 1, was the most prevalent one. A liver biopsy was performed in patients with elevated liver enzyme levels. The numbers of patients with HCV recurrence at 2, 6, 12, and 24-month intervals were three, two, zero, and two patients, respectively. At these time intervals, eight, eight, one, and three cases of acute graft rejection were found, respectively. Eight patients died with a one-year survival rate of 85%. Sepsis and infectious complications were the most leading causes of death. Conclusions: This study is the first study of liver transplant patients with hepatitis C in Iran. In the five-year study period, rapid development was made in the treatment of HCV patients. It led to the introduction of DAAs, which replaced interferon-based therapies. The results of this study indicated the high success rate of liver transplantation in patients with hepatitis C in Iran. The results of this study could be used to compare the efficacy of DAAs in future research.
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Elzorkany K, Kora MAE, Wahed ASA, Zaghla HES, Zahran AM, Yassein YS, El Naggar AZ, Essa A, Gadallah AA. Assessment of Renal Function in Post-Liver Transplant HCV-Positive Patients Treated with Direct Acting Antivirals. Int J Nephrol Renovasc Dis 2020; 13:351-358. [PMID: 33273842 PMCID: PMC7705253 DOI: 10.2147/ijnrd.s275721] [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: 08/06/2020] [Accepted: 10/21/2020] [Indexed: 11/23/2022] Open
Abstract
Purpose Direct acting antiviral agents (DAAs) have greatly improved the clearance of hepatitis C virus (HCV) infection. The effect of DAAs on renal function in post-liver transplant HCV-positive patients remains questionable, especially considering the possibility of drug interactions between immunosuppressants and DAAs. Patients and methods A retrospective observational study included 84 post-liver transplant patients with HCV infection. Patients were divided into two groups: group I received sofosbuvir plus ribavirin for 24 weeks, group II received sofosbuvir plus daclatasvir for 12 weeks. Laboratory data and eGFR were determined before, at the end, and 6 months after completion of treatment. Results The treatment was well tolerated with 100% sustained virologic response (SVR 12). There was no statistically significant difference between the two groups regarding clinical and laboratory data before treatment. Mean eGFR significantly reduced from 87.36 mL/min to 76.16 mL/min in group I (P=0.001). However, within 6 months after treatment, mean eGFR recovered to 81.51 mL/min, which was not significant when compared to baseline eGFR (P=0.09). Mean eGFR in group II showed non-significant change. There were no significant changes in immunosuppressive drug levels and eGFR in either group of patients, who received either ciclosporin or tacrolimus before and at the end of treatment. Conclusion DDAs in post-liver transplant patients with HCV infection were well tolerated and associated with stable renal function. Moreover, sofosbuvir plus daclatasvir regimen showed relatively better renal safety compared to sofosbuvir plus ribavirin.
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Affiliation(s)
- Khaled Elzorkany
- Internal Medicine Department, Faculty of Medicine, Menoufia University, Shibin El-Kom, Egypt.,Internal Medicine Department, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Mahmoud Abd-Elaziz Kora
- Internal Medicine Department, Faculty of Medicine, Menoufia University, Shibin El-Kom, Egypt
| | - Aliaa Sabry Abdel Wahed
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Shibin El- Kom, Egypt
| | - Hassan El-Sayed Zaghla
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Shibin El- Kom, Egypt
| | - Ahmed Mohamed Zahran
- Internal Medicine Department, Faculty of Medicine, Menoufia University, Shibin El-Kom, Egypt
| | - Yassein Salah Yassein
- Internal Medicine Department, Faculty of Medicine, Menoufia University, Shibin El-Kom, Egypt
| | | | - Abdallah Essa
- Tropical Medicine Department, Faculty of Medicine, Menoufia University, Shibin El-Kom, Egypt
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Comparative analysis of outcomes after liver resection and liver transplantation for early stages hepatocellular carcinoma in HIV-infected patients. An intention-to-treat analysis. HPB (Oxford) 2020; 22:900-910. [PMID: 31734238 DOI: 10.1016/j.hpb.2019.10.014] [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] [Received: 06/01/2019] [Revised: 09/15/2019] [Accepted: 10/01/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND To address the results of resection for hepatocellular carcinoma (HCC) in human immunodeficiency virus (HIV)-carriers, and to compare them against survival after liver transplantation (LT). METHODS All patients with HIV and HCC listed for LT (candidates = LTc+) or resection (LR+) between 2000 and 2017 in our centre were analysed and compared for overall survival (OS) and disease-free survival (DFS). RESULTS The LTc + group (n = 43) presented with higher MELD scores and more advanced portal hypertension and HCC stages than LR + group (n = 15). One-, 3- and 5-year intention-to-treat survival rates were: 81%, 60% and 44%, versus 86%, 58% and 58% in the LTc+ and LR + groups, respectively (p = 0.746). Eleven LTc + patients dropped out. After LT, OS was 81%, 68% and 59% (no difference with LR + group; p = 0.844). There tended to be better DFS after LT, reaching 78%, 68% and 56% versus 53%, 33% and 33% in the LR + group (p = 0.062). CONCLUSION This was the largest series of resections for HCC in HIV + patients and the first intention-to-treat analysis. Although LT and resection do not always concern the same population, they enable equivalent survival. At the price of higher recurrence rate, resection could be integrated in the global armoury of liver surgeons.
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Spearman CW, Dusheiko GM, Hellard M, Sonderup M. Hepatitis C. Lancet 2019; 394:1451-1466. [PMID: 31631857 DOI: 10.1016/s0140-6736(19)32320-7] [Citation(s) in RCA: 270] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/30/2019] [Accepted: 08/09/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis C is a global health problem, and an estimated 71·1 million individuals are chronically infected with hepatitis C virus (HCV). The global incidence of HCV was 23·7 cases per 100 000 population (95% uncertainty interval 21·3-28·7) in 2015, with an estimated 1·75 million new HCV infections diagnosed in 2015. Globally, the most common infections are with HCV genotypes 1 (44% of cases), 3 (25% of cases), and 4 (15% of cases). HCV transmission is most commonly associated with direct percutaneous exposure to blood, via blood transfusions, health-care-related injections, and injecting drug use. Key high-risk populations include people who inject drugs, men who have sex with men, and prisoners. Approximately 10-20% of individuals who are chronically infected with HCV develop complications, such as cirrhosis, liver failure, and hepatocellular carcinoma over a period of 20-30 years. Direct-acting antiviral therapy is now curative, but it is estimated that only 20% of individuals with hepatitis C know their diagnosis, and only 15% of those with known hepatitis C have been treated. Increased diagnosis and linkage to care through universal access to affordable point-of-care diagnostics and pangenotypic direct-acting antiviral therapy is essential to achieve the WHO 2030 elimination targets.
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Affiliation(s)
- C Wendy Spearman
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
| | - Geoffrey M Dusheiko
- Liver Unit, Kings College Hospital, London, UK; Division of Medicine, University College London Medical School, London, UK
| | - Margaret Hellard
- Disease Elimination Program, Burnet Institute, Melbourne, VIC, Australia
| | - Mark Sonderup
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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Samuel D. HCV-positive organ transplants in HCV-negative recipients. Lancet Gastroenterol Hepatol 2019; 4:745-747. [PMID: 31353244 DOI: 10.1016/s2468-1253(19)30250-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 07/18/2019] [Indexed: 12/22/2022]
Affiliation(s)
- Didier Samuel
- Inserm and Université Paris-Sud Research Unit 1193, Centre Hépato-Biliaire, Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Villejuif 94800, France.
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Tanaka T, Voigt MD. Acute cellular rejection in hepatitis C recipients following liver transplantation in the era of direct-acting antivirals: chronological analysis of the United Network for Organ Sharing database. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2019; 26:393-400. [PMID: 31211912 DOI: 10.1002/jhbp.645] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Interferon (IFN) treatment for liver transplant (LT) recipients with hepatitis C virus (HCV) increases acute cellular rejection (ACR) and worsens graft and patient survival. It is unknown if direct-acting antivirals (DAAs) affect rejection rates or post-transplant survival. METHOD The United Network for Organ Sharing STAR files of December 2017 (n = 25,916) were analyzed. RESULTS Compared with non-HCV-LT, HCV-LT survival was worse in the IFN-era (2007-2008) and IFN+DAA-era (2011), but not in the DAA-era (2014-2015). ACR6m rate has been less frequent in newer eras and was lower in HCV-LT than in non-HCV-LT in both the DAA-era (6.9% vs. 9.3%, P < 0.001) and in the IFN+DAA-era (8.8% vs. 11.8%, P = 0.001), but not in the IFN-era (10.8% vs. 11.0%, P = 0.39). HCV-LT recipients who had ACR6m had worse 2-year survival than those without ACR6m, in the IFN-era (80.0% vs. 88.4%, P < 0.0001) and in the IFN+DAA-era (81.4% vs. 89.2%, P < 0.01) but not in the DAA-era (90.4% vs. 93.2%, P = 0.085). Cox proportional hazard model identified ACR6m as independent risk factor for mortality in HCV-LT in the IFN-era (HR = 1.88, P ≤ 0.001) and in the IFN+DAA-era (HR = 1.84, P = 0.005), but not in the DAA-era (P = n.s.). CONCLUSIONS Two-year survival of HCV-LT recipients were significantly better in the DAA-era; these were associated with reduced rate and impact of ACR6m.
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Affiliation(s)
- Tomohiro Tanaka
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
| | - Michael D Voigt
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
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Axelrod DA, Schnitzler MA, Alhamad T, Gordon F, Bloom RD, Hess GP, Xiao H, Nazzal M, Segev DL, Dharnidharka VR, Naik AS, Lam NN, Ouseph R, Kasiske BL, Durand CM, Lentine KL. The impact of direct-acting antiviral agents on liver and kidney transplant costs and outcomes. Am J Transplant 2018; 18:2473-2482. [PMID: 29701909 PMCID: PMC6409105 DOI: 10.1111/ajt.14895] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/14/2018] [Accepted: 04/17/2018] [Indexed: 02/06/2023]
Abstract
Direct-acting antiviral medications (DAAs) have revolutionized care for hepatitis C positive (HCV+) liver (LT) and kidney (KT) transplant recipients. Scientific Registry of Transplant Recipients registry data were integrated with national pharmaceutical claims (2007-2016) to identify HCV treatments before January 2014 (pre-DAA) and after (post-DAA), stratified by donor (D) and recipient (R) serostatus and payer. Pre-DAA, 18% of HCV+ LT recipients were treated within 3 years and without differences by donor serostatus or payer. Post-DAA, only 6% of D-/R+ recipients, 19.8% of D+/R+ recipients with public insurance, and 11.3% with private insurance were treated within 3 years (P < .0001). LT recipients treated for HCV pre-DAA experienced higher rates of graft loss (adjusted hazard ratio [aHR] 1.34 1.852.10 , P < .0001) and death (aHR 1.47 1.681.91 , P < .0001). Post-DAA, HCV treatment was not associated with death (aHR 0.34 0.671.32 , P = .25) or graft failure (aHR 0.32 0.641.26 , P = .20) in D+R+ LT recipients. Treatment increased in D+R+ KT recipients (5.5% pre-DAA vs 12.9% post-DAA), but did not differ by payer status. DAAs reduced the risk of death after D+/R+ KT by 57% (0.19 0.430.95 , P = .04) and graft loss by 46% (0.27 0.541.07 , P = .08). HCV treatment with DAAs appears to improve HCV+ LT and KT outcomes; however, access to these medications appears limited in both LT and KT recipients.
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Affiliation(s)
- D A Axelrod
- Lahey Hospital & Medical Center, Burlington, MA, USA
| | - M A Schnitzler
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
| | - T Alhamad
- Washington University, St. Louis, MO, USA
| | - F Gordon
- Lahey Hospital & Medical Center, Burlington, MA, USA
| | - R D Bloom
- University of Pennsylvania, Philadelphia, PA, USA
| | - G P Hess
- Symphony Health, Conshohocken, PA, USA
| | - H Xiao
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
| | - M Nazzal
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
| | - D L Segev
- Johns Hopkins University, Baltimore, MD, USA
| | | | - A S Naik
- University of Michigan, Ann Arbor, MI, USA
| | - N N Lam
- University of Alberta, Edmonton, AB, Canada
| | - R Ouseph
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
| | - B L Kasiske
- Hennepin County Medical Center, Minneapolis, MN, USA
| | - C M Durand
- Johns Hopkins University, Baltimore, MD, USA
| | - K L Lentine
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
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Shaffer AA, Thomas AG, Bowring MG, Van Pilsum Rasmussen SE, Cash A, Kucirka LM, Alqahtani SA, Gurakar A, Sulkowski MS, Cameron AM, Segev DL, Durand CM. Changes in practice and perception of hepatitis C and liver transplantation: Results of a national survey. Transpl Infect Dis 2018; 20:e12982. [PMID: 30144258 DOI: 10.1111/tid.12982] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/14/2018] [Accepted: 08/12/2018] [Indexed: 12/18/2022]
Abstract
With new practice guidelines, it is important to understand how liver transplant (LT) centers have incorporated direct-acting antivirals (DAAs) into the management of hepatitis C virus-infected (HCV+) candidates and recipients. To explore how DAAs have affected LT centers' willingness to treat HCV+ candidates and recipients and to use HCV+ donors, we surveyed high volume US LT centers (11/2014-12/2015) regarding practices for HCV+ candidates, recipients, and donors, before vs after DAAs. We used the Scientific Registry of Transplant Recipients to compare centers' number of LTs, HCV+ recipients, and HCV+ donors in the years before (1/1/2012-12/31/2013) and after (1/1/2016-12/31/2017) survey administration. Of 80 centers contacted, 57 (71.3%) responded, representing 69.0% of the total volume of LTs in 2013. After DAAs, most centers increased treating candidates with low (≤15) model for end-stage liver disease (MELD) (85.2%), intermediate/high (>15) MELD (92.6%), and hepatocellular carcinoma (79.6%). There was consensus to treat low MELD candidates (90.8% "most of the time/always"), but less certainty for intermediate/high MELD candidates (48.2% "sometimes"). Universal post-LT HCV treatment increased (7.4% vs 57.4%). After DAAs, 42.6% were more willing to use HCV+ donors for HCV+ candidates, and 38.9% were willing to consider using HCV+ donors for HCV- candidates. Overall, with DAAs, centers were more willing to treat HCV+ candidates and recipients and to use HCV+ donors; recent recommendations may help to guide treatment decisions for intermediate/high MELD candidates.
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Affiliation(s)
- Ashton A Shaffer
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland
| | - Alvin G Thomas
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina
| | - Mary Grace Bowring
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Ayla Cash
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lauren M Kucirka
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland
| | - Saleh A Alqahtani
- Department of Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ahmet Gurakar
- Department of Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mark S Sulkowski
- Department of Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Infectious Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andrew M Cameron
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Dorry L Segev
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland
| | - Christine M Durand
- Department of Infectious Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland
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HCV Therapy in Decompensated Cirrhosis before or after Liver Transplantation: A Paradoxical Quandary. Am J Gastroenterol 2018; 113:449-452. [PMID: 29206818 DOI: 10.1038/ajg.2017.435] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Early treatment of recurrent hepatitis C virus infection after liver transplantation in the era of direct-acting antivirals, what we have learned till now? EGYPTIAN LIVER JOURNAL 2018. [DOI: 10.1097/01.elx.0000546496.60509.bf] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Rupp C, Hippchen T, Neuberger M, Sauer P, Pfeiffenberger J, Stremmel W, Gotthardt DN, Mehrabi A, Weiss KH. Successful combination of direct antiviral agents in liver-transplanted patients with recurrent hepatitis C virus. World J Gastroenterol 2018; 24:1353-1360. [PMID: 29599610 PMCID: PMC5871830 DOI: 10.3748/wjg.v24.i12.1353] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/02/2018] [Accepted: 03/18/2018] [Indexed: 02/07/2023] Open
Abstract
AIM To analyze the safety and efficiency of direct-acting antiviral (DAA) regimens in liver-transplanted patients with hepatitis C virus (HCV) reinfection.
METHODS Between January 2014 and December 2016, 39 patients with HCV reinfection after liver transplantation were treated at our tertiary referral center with sofosbuvir (SOF)-based regimens, including various combinations with interferon (IFN), daclatasvir (DAC), simeprivir (SIM) and/or ledipasvir (LDV). Thirteen patients were treated with SOF + IFN ± RBV. Ten patients were treated with SOF + DAC ± RBV. Fiveteen patients were treated with fixed-dose combination of SOF + LDV ± RBV. One patient was treated with SOF + SIM + RBV. Three patients with relapse were retreated with SOF + LDV + RBV. The treatment duration was 12-24 wk in all cases. The decision about the HCV treatment was made by specialists at our transplant center, according to current available or recommended medications.
RESULTS The majority of patients were IFN-experienced (29/39, 74.4%) and had a history of hepatocellular carcinoma (26/39, 66.7%) before liver transplantation. Sustained virological response at 12 wk (SVR12) was achieved in 10/13 (76.9%) of patients treated with SOF + IFN ± RBV. All patients with relapse were treated with fixed-dose combination of SOF + LDV + RBV. Patients treated with SOF + DAC + RBV or SOF + LDV + RBV achieved 100% SVR12. SVR rates after combination treatment with inhibitors of the HCV nonstructural protein (NS)5A and NS5B for 24 wk were significantly higher, as compared to all other therapy regimens (P = 0.007). Liver function was stable or even improved in the majority of patients during treatment. All antiviral therapies were safe and well-tolerated, without need of discontinuation of treatment or dose adjustment of immunosuppression. No serious adverse events or any harm to the liver graft became overt. No patient experienced acute cellular rejection during the study period.
CONCLUSION Our cohort of liver-transplanted patients achieved high rates of SVR12 after a 24-wk course of treatment, especially with combination of NS5A and NS5B inhibitors.
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Affiliation(s)
- Christian Rupp
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
- Interdisciplinary Endoscopy Unit, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Theresa Hippchen
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Manuel Neuberger
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Peter Sauer
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
- Interdisciplinary Endoscopy Unit, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Jan Pfeiffenberger
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Daniel Nils Gotthardt
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg 69120, Germany
| | - Karl-Heinz Weiss
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany
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Ramadori G, Bosio P, Moriconi F, Malik IA. Case report: 8 years after liver transplantation: de novo hepatocellular carcinoma 8 months after HCV clearance through IFN-free antiviral therapy. BMC Cancer 2018; 18:257. [PMID: 29510685 PMCID: PMC5840818 DOI: 10.1186/s12885-018-4175-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 03/01/2018] [Indexed: 12/14/2022] Open
Abstract
Background After orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC), recurrent HCC mostly develops within 2 years. All cases of de novo HCC described so far occurred later than 2 years after OLT. Prevention of post-transplantation HCC has usually been tried to achieve by curing or controlling recurrent liver disease. This has been rationale for treatment with interferon (IFN)/ribavirin of HCV-recurrence in patients after OLT, transplanted for advanced HCV-induced liver disease and/or HCC. The availability of new and more efficient drugs has improved chances also for previously difficult-to-treat HCV-positive patients. Case presentation A 75 year-old male patient who had undergone OLT for decompensated HCV-cirrhosis in 2009, and bilio-digestive surgery in 2011 under tracrolimus (0.5 mg/day) and prednisone (5 mg/day) immunosuppressive therapy, started to receive antiviral treatment for recurrent HCV-infection of graft with 200 mg/day ribavirin in combination with ledipasvir and sofosbuvir by the end of October 2015. Because of multiple side effects (anemia, asthenia, infections, and reduction of kidney functions - palliated by treatment with erythropoietin), treatment was stopped after 16 weeks. At the third control, a minimal increase in alpha-fetoprotein (AFP) serum level to 10 μg/L was measured 8 months after therapy, whereas both liver sonography and serum transaminases were normal. The patient’s general condition; however, remained poor, and a magnetic resonance imaging (MRI) of abdomen was performed 2 months later. A nodule of 3 cm in diameter with a pseudocapsule was found centrally in the liver. The patient had to be hospitalized for recurrent infections of the lung, overt ascites and peritonitis. Rapid tumor growth (10 cm) was detected during last stay in hospital (April 2017), concomitant with a rise of AFP-serum levels to 91 μg/L. The family decided to take the patient home, and best supportive care was provided by a general practitioner, local nurses and the patient’s dedicated wife until his death. Conclusion Before treating OLT patients with HCV graft reinfection one should not only consider possible advantages of newly effective antiviral-therapies, but also life expectancy and possible side effects (difficult to manage at an outpatient service basis), including severe disadvantages such as the development of HCC.
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Affiliation(s)
- Giuliano Ramadori
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Robert-Koch-Street 40, D-37075, Goettingen, Germany.
| | - Patrizia Bosio
- General Practitioner, National health care system, Palazzago, BG, Italy
| | | | - Ihtzaz A Malik
- Institute of Anatomy and Cell Biology, University Medical Center, Kreuzbering 36, 37075, Goettingen, Germany
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Sugawara Y, Hibi T. Direct-acting agents for hepatitis C virus before and after liver transplantation. Biosci Trends 2017; 11:606-611. [PMID: 29238003 DOI: 10.5582/bst.2017.01293] [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: 01/15/2023]
Abstract
Chronic hepatitis C virus (HCV) infection remains a widespread public health concern and many people are infected with HCV. HCV is one of the leading indications for liver transplantation. Direct-acting antiviral agents (DAAs) against HCV have changed the course of chronic HCV infection, however, making it a curable disease. DAA treatment may be initiated before or after liver transplantation. In the present review, we present the available data on DAA treatment of HCV in liver transplant recipients.
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Affiliation(s)
- Yasuhiko Sugawara
- Departments of Transplantation/Pediatric Surgery and Gastroenterology and Hepatology, Postgraduate School of Life Science, Kumamoto University
| | - Taizo Hibi
- Departments of Transplantation/Pediatric Surgery and Gastroenterology and Hepatology, Postgraduate School of Life Science, Kumamoto University
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Ahmed KT, Almashhrawi AA, Ibdah JA, Tahan V. Is the 25-year hepatitis C marathon coming to an end to declare victory? World J Hepatol 2017; 9:921-929. [PMID: 28824743 PMCID: PMC5545137 DOI: 10.4254/wjh.v9.i21.921] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/04/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) which was originally recognized as posttransfusion non-A, non-B hepatitis has been a major global health problem affecting 3% of the world population. Interferon/peginterferon and ribavirin combination therapy was the backbone of chronic HCV therapy for two decades of the journey. However, the interferon based treatment success rate was around 50% with many side effects. Many chronic HCV patients with psychiatric diseases, or even cytopenias, were ineligible for HCV treatment. Now, we no longer need any injectable medicine. New direct-acting antiviral agents against HCV allowed the advance of interferon-free and ribavirin-free oral regimens with high rates of response and tolerability. The cost of the medications should not be a barrier to their access in certain parts of the world. While we are getting closer, we should still focus on preventing the spread of the disease, screening and delivering the cure globally to those in need. In the near future, development of an effective vaccine against HCV would make it possible to eradicate HCV infection worldwide completely.
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Rezaee-Zavareh MS, Hesamizadeh K, Sharafi H, Alavian SM. Treatment of Hepatitis C Infection with Direct-Acting Antiviral Agents in Liver-Transplant Patients: A Systematic Review and Meta-Analysis. HEPATITIS MONTHLY 2017; 17. [DOI: 10.5812/hepatmon.12324] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
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