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Rizza G, Glynou K, Eletskaya M. Impact of hepatitis B immunoglobulin mode of administration on treatment experiences of patients after liver transplantation: Results from an online survey. World J Transplant 2024; 14:90949. [PMID: 39295979 PMCID: PMC11317858 DOI: 10.5500/wjt.v14.i3.90949] [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: 12/18/2023] [Revised: 05/02/2024] [Accepted: 06/07/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND Hepatitis B immunoglobulin (HBIG) in combination with a potent nucleos(t)ide analog is considered the standard of care for prophylaxis against hepatitis B virus (HBV) reinfection after liver transplantation for HBV-associated disease. AIM To evaluate patients' satisfaction, preferences, and requirements for subcutaneous (SC), intramuscular (IM), and intravenous (IV) HBIG treatments. METHODS A self-completion, cross-sectional, online, 22-question survey was conducted to examine perceptions and satisfaction with current HBIG treatment in adults receiving HBIG treatment following liver transplantation for HBV-associated disease in France, Italy, and Turkey. Hypothetical HBIG products with different administration modes were evaluated using target product profile assessment and a conjoint (trade-off) exercise. RESULTS Ninety patients were enrolled; 32%, 17%, and 51% were SC, IM, and IV HBIG users, respectively. Mean duration of treatment was 36.2 months. SC HBIG had the least negative impact on emotional well-being and social life and was perceived as the most convenient, easiest to administer, least painful, and had the highest self-rating of treatment compliance. More IM HBIG users than SC or IV HBIG users reported that administration frequency was excessive (67%, 28%, and 28%, respectively). In the target product profile assessment, 76% of patients were likely to use hypothetical SC HBIG. In the conjoint exercise, administration route, frequency, and duration were key drivers of treatment preferences. CONCLUSION Ease, frequency, duration, and side effects of HBIG treatment administration were key drivers of treatment preferences, and SC HBIG appeared advantageous over IM and IV HBIG for administration ease, convenience, and pain. A hypothetical SC HBIG product elicited a favorable response. Patient demographics, personal preferences, and satisfaction with HBIG treatment modalities may influence long-term treatment compliance.
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Affiliation(s)
- Giorgia Rizza
- General Surgery and Liver Transplant Center, S. Giovanni Battista Hospital, Turin I-10126, Italy
| | | | - Masha Eletskaya
- Lumanity Insight (Cello Health Insight), London SE1 1PP, United Kingdom
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Bansal SB, Ramasubramanian V, Prasad N, Saraf N, Soman R, Makharia G, Varughese S, Sahay M, Deswal V, Jeloka T, Gang S, Sharma A, Rupali P, Shah DS, Jha V, Kotton CN. South Asian Transplant Infectious Disease Guidelines for Solid Organ Transplant Candidates, Recipients, and Donors. Transplantation 2023; 107:1910-1934. [PMID: 36749281 DOI: 10.1097/tp.0000000000004521] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
These guidelines discuss the epidemiology, screening, diagnosis, posttransplant prophylaxis, monitoring, and management of endemic infections in solid organ transplant (SOT) candidates, recipients, and donors in South Asia. The guidelines also provide recommendations for SOT recipients traveling to this region. These guidelines are based on literature review and expert opinion by transplant physicians, surgeons, and infectious diseases specialists, mostly from South Asian countries (India, Pakistan, Bangladesh, Nepal, and Sri Lanka) as well as transplant experts from other countries. These guidelines cover relevant endemic bacterial infections (tuberculosis, leptospirosis, melioidosis, typhoid, scrub typhus), viral infections (hepatitis A, B, C, D, and E; rabies; and the arboviruses including dengue, chikungunya, Zika, Japanese encephalitis), endemic fungal infections (mucormycosis, histoplasmosis, talaromycosis, sporotrichosis), and endemic parasitic infections (malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis, strongyloidiasis, and filariasis) as well as travelers' diarrhea and vaccination for SOT candidates and recipients including travelers visiting this region. These guidelines are intended to be an overview of each topic; more detailed reviews are being published as a special supplement in the Indian Journal of Transplantation .
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Affiliation(s)
- Shyam Bihari Bansal
- Department of Nephrology and Kidney Transplantation, Medanta Institute of Kidney and Urology Medanta-Medicity, Gurgaon, India
| | | | - Narayan Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Neeraj Saraf
- Department of Hepatology, Medanta, Medicity, Gurgaon, India
| | - Rajeev Soman
- Department of Infectious Diseases, Jupiter Hospital, Pune, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Santosh Varughese
- Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Manisha Sahay
- Department of Nephrology, Osmania Medical College, and Hospital, Hyderabad, India
| | - Vikas Deswal
- Department of Infectious Diseases, Medanta, Medicity, Gurgaon, India
| | - Tarun Jeloka
- Department of Infectious Diseases, Jupiter Hospital, Pune, India
| | - Sishir Gang
- Department of Nephrology, Muljibhai Patel Urological Hospital, Nadiad, Gujrat, India
| | - Ashish Sharma
- Department of Renal Transplant Surgery, PGIMER, Chandigarh, India
| | - Priscilla Rupali
- Department of Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India
| | - Dibya Singh Shah
- Department of Nephrology and Transplant Medicine, Institute of Medicine, Tribhuvan University of Teaching hospital, Kathmandu, Nepal
| | | | - Camille Nelson Kotton
- Transplant and Immunocompromised Host Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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Liu H, Han CL, Tian BW, Ding ZN, Yang YF, Ma YL, Yang CC, Meng GX, Xue JS, Wang DX, Dong ZR, Chen ZQ, Hong JG, Li T. Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2023:1-11. [PMID: 37148261 DOI: 10.1080/17474124.2023.2212161] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
BACKGROUND Tenofovir (TDF) and entecavir (ETV) are first-line treatments for patients with chronic hepatitis B virus (HBV) infection. However, the effect of TDF versus ETV on the prognosis of HBV-related hepatocellular carcinoma (HCC) has not been fully clarified yet. RESEARCH DESIGN AND METHODS PubMed, Embase and Web of science were searched up to March, 2021. Meta-analyses were performed for overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) to assess the effect of TDF versus ETV on the prognosis of HBV-related HCC. RESULTS A total of 10 studies comprising 4706 Asian patients were included. The pooled results revealed that TDF was associated with better OS (adjusted HR=0.50, 95% CI: 0.40-0.62; I2=36.0%, p=0.167) and better RFS/DFS (adjusted HR=0.70, 95% CI: 0.55-0.89, I2=71.9%, p=0.002) than ETV in treatment of HBV-related HCC. Subgroup analysis revealed that OS benefit from TDF was generally consistent, except for patients who underwent non-surgical treatment for HCC. Subgroup analysis also indicated that TDF reduces the risk of late recurrence (HR=0.41, 95% CI: 0.18-0.0.93; I2=63.0%, p=0.067) rather than early recurrence (HR=0.99, 95% CI: 0.64-1.52; I2=61.3%, p=0.076). CONCLUSIONS Compared with ETV, TDF has the advantage of improving OS and reducing late recurrence of patients with HBV-related HCC patients who underwent resection.
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Affiliation(s)
- Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Ya-Fei Yang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yun-Long Ma
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Chun-Cheng Yang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Guang-Xiao Meng
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Jun-Shuai Xue
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Jian-Guo Hong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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Fuochi E, Anastasio L, Lynch EN, Campani C, Dragoni G, Milani S, Galli A, Innocenti T. Main factors influencing long-term outcomes of liver transplantation in 2022. World J Hepatol 2023; 15:321-352. [PMID: 37034235 PMCID: PMC10075010 DOI: 10.4254/wjh.v15.i3.321] [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: 10/18/2022] [Revised: 11/24/2022] [Accepted: 02/22/2023] [Indexed: 04/11/2023] Open
Abstract
Liver transplant (LT) outcomes have markedly improved in the recent decades, even if long-term morbidity and mortality are still considerable. Most of late deaths are independent from graft function and different comorbidities, including complications of metabolic syndrome and de novo neoplasms, seem to play a key role in determining long-term outcomes in LT recipients. This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation. In particular, the reduction of drug toxicity, the use of tools to identify high-risk patients, and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.
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Affiliation(s)
- Elisa Fuochi
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Lorenzo Anastasio
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Stefano Milani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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Zheng H, Zhu Z, Wang N, Qin J, Guo Y, Xu Z, Li X, Qi C, Yuan X, Wu W, Wang J, Liu L, Nashan B. Entecavir Combined With Short-term Hepatitis B Immunoglobulin in Preventing Hepatitis B Virus Recurrence in Liver Transplant Recipients. Transplant Proc 2023; 55:408-412. [PMID: 36907782 DOI: 10.1016/j.transproceed.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/02/2023] [Indexed: 03/12/2023]
Abstract
BACKGROUND The combination of nucleoside analogs and long-term hepatitis B immunoglobulin (HBIG) is considered to be the standard regimen for preventing hepatitis B virus (HBV) recurrence after liver transplant (LT). However, long-term use of HBIG causes many adverse effects. The aim of this study was to evaluate the effect of nucleoside analogs entecavir combined with short-term HBIG in preventing HBV recurrence after LT. METHODS This retrospective study assessed the effect a combination of entecavir and short-term HBIG in prophylaxis of HBV recurrence among 56 LT recipients who had undergone the procedure because of HBV-associated liver disease at our center between December 2017 and December 2021. All patients received entecavir treatment combined with HBIG for the prevention of hepatitis B recurrence, and HBIG treatment was withdrawn within 1 month. The patients were followed up to determine levels of hepatitis B surface antigen, antibody to hepatitis B surface antigen (HBsAb), and HBV-DNA and the recurrence rate of HBV. RESULTS Only 1 patient appeared positive for hepatitis B surface antigen at 2 months post-LT. The overall HBV recurrence rate was 1.8%. The HBsAb titers of all patients gradually decreased over time, with a median of 376.6 IU/L at 1 month post-LT and a median of 13.47 IU/L at 12 months post-LT. During the follow-up period, the HBsAb titer of the preoperative HBV-DNA-positive patients remained at a lower level than that of HBV-DNA-negative patients. CONCLUSIONS Entecavir combined with short-term HBIG can exert a good effect for the prevention of HBV reinfection post-LT.
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Affiliation(s)
- Hao Zheng
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Zebin Zhu
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Ning Wang
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Jiwei Qin
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Yafei Guo
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Zhijun Xu
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Xuefeng Li
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Can Qi
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Xiaodong Yuan
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Wei Wu
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Jizhou Wang
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Lianxin Liu
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Björn Nashan
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China.
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Neuberger J. Long-term Care of the Adult Liver Transplant Recipient. J Clin Exp Hepatol 2022; 12:1547-1556. [PMID: 36340310 PMCID: PMC9630008 DOI: 10.1016/j.jceh.2022.03.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 03/31/2022] [Indexed: 02/05/2023] Open
Abstract
While outcomes after liver transplantation have increased over the last two decades, this is primarily as a consequence of a reduction in early deaths and survival of those who survive the first 6 months has not significantly changed. Causes of premature death and graft loss include cardiovascular disease, renal impairment, malignancy and some infections. As the number of transplant recipients increase, care is being given by primary and secondary care clinicians. Management of the well patient is crucially dependent on careful assessment and where appropriate intervention, especially of cardiovascular risk - such as advice about avoidance of weight gain; management of hypertension, hyperlipidaemia and diabetes; and provision of appropriate lifestyle advice. Other interventions include surveillance for de novo malignancies, active management of immunosuppressive regimen with the need to tailor immunosuppression to the individual. Prompt investigation of abnormalities of liver function is essential. Immune-mediated graft damage still occurs but is less common as a cause for graft loss. Adherence is sometimes an issue, especially in teenagers and young adults, and should be considered and support given where needed. Immunisations (avoiding live and attenuated vaccines) should be encouraged. Recurrence of disease remains an issue, and some interventions (such as appropriate use of antiviral therapy for those grafted with viral hepatitis, use of ursodeoxycholic acid for those grafted for primary biliary cholangitis or long-term steroids for those grafted for autoimmune disease) may improve and maintain graft function. Close collaboration between recipient and the attending clinicians in primary, secondary and tertiary care and close attention to modifiable conditions will lead to improved outcomes.
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Key Words
- CMV, Cytomegalovirus
- CNI, Calcineurin inhibitor
- DRR-4i, dipeptidyl peptidase-4 inhibitor
- GLP 1RA, glucagon-like peptide-1 receptor agonists
- HBIG, Hepatitis B Immunoglobulin
- HBV, Hepatitis B Virus
- HCC, Hepatocellular carcinoma
- HCV, Hepatitis C virus
- LDL-C, Low-density lipoprotein cholesterol
- LT, Liver transplant
- MDRD, Modification of Diet in Renal Disease
- MRC, Magnetic resonance cholangiography
- NAFLD, Non-alcoholic fatty liver disease
- NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases
- NODAT, New onset diabetes after transplant
- NUC, Nucleos(t)ide analogues
- PBC, Primary Biliary Cholangitis
- PSC, Primary Sclerosing Cholangitis
- SGLT2i, sodium–glucose cotransporter 2 inhibitors
- SRTR, Scientific Registry of Transplant Recipients
- TMPT, Thiopurine S-methyltransferase
- USA, United States of America
- cardiovascular disease
- follow-up
- liver transplant
- mRNA, messenger Ribonucleic acid
- mTORi, mammalian Target of rapamycin inhibitor
- malignancy
- recurrent disease
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Affiliation(s)
- James Neuberger
- Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK
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Detectability of Hepatitis B Virus in Peripheral Blood Mononuclear Cells Among Naive Chronic Hepatitis B Patients With Negative Viremia. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2022. [DOI: 10.1097/ipc.0000000000001153] [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]
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8
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Do Patients with Autoimmune Conditions Have Less Access to Liver Transplantation despite Superior Outcomes? J Pers Med 2022; 12:jpm12071159. [PMID: 35887656 PMCID: PMC9320508 DOI: 10.3390/jpm12071159] [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: 06/15/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022] Open
Abstract
Orthotopic liver transplantation (OLT) is a lifesaving therapy for patients with irreversible liver damage caused by autoimmune liver diseases (AutoD) including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Currently, it is unclear how access to transplantation differs among patients with various etiologies of liver disease. Our aim is to evaluate the likelihood of transplant and the long-term patient and graft survival after OLT for each etiology for transplantation from 2000 to 2021. We conducted a large retrospective study of United Network for Organ Sharing (UNOS) liver transplant patients in five 4-year eras with five cohorts: AutoD (PBC, PSC, AIH cirrhosis), alcohol-related liver disease (ALD), hepatocellular carcinoma (HCC), viral hepatitis, and nonalcoholic steatohepatitis (NASH). We conducted a multivariate analysis for probability of transplant. Intent-to-treat (ITT) analysis was performed to assess the 10-year survival differences for each listing diagnosis while accounting for both waitlist and post-transplant survival. Across all eras, autoimmune conditions had a lower adjusted probability of transplant of 0.92 (0.92, 0.93) compared to ALD 0.97 (0.97, 0.97), HCC 1.08 (1.07, 1.08), viral hepatitis 0.99 (0.99, 0.99), and NASH 0.99 (0.99, 1.00). Patients with AutoD had significantly better post-transplant patient and graft survival than ALD, HCC, viral hepatitis, and NASH in each and across all eras (p-values all < 0.001). Patients with AutoD had superior ITT survival (p-value < 0.001, log rank test). In addition, the waitlist survival for patients with AutoD compared to other listing diagnoses was improved with the exception of ALD, which showed no significant difference (p-value = 0.1056, log rank test). Despite a superior 10-year graft and patient survival in patients transplanted for AutoD, patients with AutoD have a significantly lower probability of receiving a liver transplant compared to those transplanted for HCC, ALD, viral hepatitis, and NASH. Patients with AutoD may benefit from improved liver allocation while maintaining superior waitlist and post-transplant survival. Decreased access in spite of appropriate outcomes for patients poses a significant risk for increased morbidity for patients with AutoD.
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Muhammad H, Zaffar D, Tehreem A, Ting PS, Simsek C, Gokcan H, Gurakar A, Idilman R. HBV/HDV management after liver transplantation: Review. JOURNAL OF LIVER TRANSPLANTATION 2021. [DOI: 10.1016/j.liver.2021.100046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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10
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Current management & future directions in post-liver transplant recurrence of viral hepatitis. JOURNAL OF LIVER TRANSPLANTATION 2021. [DOI: 10.1016/j.liver.2021.100027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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