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Ali SH, Shah MH, Roy S, Bharadwaj HR, Tan JK, Rao MS, Fuad M, Ahluwalia A, Gaur A, Dalal P, Dhali A, Gopakumar H. Efficacy and Safety of Tenofovir Plus Entecavir Combination Therapy Versus Tenofovir Monotherapy in Chronic Hepatitis B Virus Patients With Resistance or Partial Response to Entecavir: A Systematic Review and Meta-analysis. J Clin Exp Hepatol 2025; 15:102541. [PMID: 40248347 PMCID: PMC12002651 DOI: 10.1016/j.jceh.2025.102541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/01/2025] [Indexed: 04/19/2025] Open
Abstract
Background and objectives Chronic hepatitis B virus remains a significant cause of liver disease in the developing world, leading to sequelae such as hepatocellular carcinoma. While entecavir (ETV) serves as a first-line treatment, its growing resistance rates underscore the need to explore viable alternatives. Tenofovir disoproxil fumarate (TDF) monotherapy and entecavir plus tenofovir (TDF + ETV) combination therapy are both employed as treatments, but one's efficacy over another is in question. This meta-analysis aims to investigate any primacy of either treatment. Methods We conducted a comprehensive literature search across PubMed/Medline, Embase, Cochrane Central, Web of Science, and China National Knowledge Infrastructure from inception till 7th October 2024. Studies comparing the safety and efficacy of TDF monotherapy versus TDF + ETV combination therapy in patients resistant to entecavir were considered. Data about the virologic response (VR), virologic breakthrough, HbeAg seroconversion, HbeAg/HbsAg seroclearance, and alanine aminotransferase normalization were extracted. Relative risks (RRs) and their corresponding 95% confidence intervals (CIs) were calculated, pooled, and analyzed in a random-effects model. P-value <0.05 was regarded as significant for all analyses. Results Nine studies, comprising 335 patients undergoing monotherapy and 352 patients undergoing combination therapy, satisfied the criteria. TDF + ETV combination therapy was found slightly advantageous to TDF monotherapy, stimulating a VR at 48 weeks (RR 1.081 95% CI: [1.001-1.167] P = 0.046, I2 = 0%), along with the HbeAg seroconversion rate (RR 1.711 95% CI: [1.005-2.913] P = 0.048, I2 = 0%). There were no significant adverse events in individual studies to warrant a meta-analysis. Conclusions TDF + ETV shows slightly better efficacy to TDF monotherapy over a 48-week treatment regimen, with minimal safety concerns. However, further high-quality studies like randomized controlled trials are needed to further solidify conclusions, with this meta-analysis only achieving borderline significances. Registration This review is registered on the PROSPERO database (ID: CRD42024581443).
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Affiliation(s)
- Syed H. Ali
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Muhammad H. Shah
- School of Medicine, Queen's University Belfast, Belfast, United Kingdom
| | - Sakshi Roy
- School of Medicine, Queen's University Belfast, Belfast, United Kingdom
| | - Hareesha R. Bharadwaj
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Joecelyn K. Tan
- Faculty of Medicine, University of St Andrews, St Andrews, Scotland, United Kingdom
| | - Medha S. Rao
- School of Medicine, Queen's University Belfast, Belfast, United Kingdom
| | - Muhtasim Fuad
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Arjun Ahluwalia
- School of Medicine, Queen's University Belfast, Belfast, United Kingdom
| | - Aditya Gaur
- Yeovil District Hospital, Somerset NHS Foundation Trust, Higher Kingston, Yeovil, UK
| | - Priyal Dalal
- School of Medicine and Dentistry, University of Central Lancashire, Preston, UK
| | - Arkadeep Dhali
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, UK
- School of Medicine and Population Health, The University of Sheffield, Sheffield, UK
| | - Harishankar Gopakumar
- Department of Gastroenterology, University of Illinois College of Medicine Peoria, Peoria, IL, USA
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Lim J, Lee HY, Sang H, Jeong SJ, Kim HI. Association of nucleos(t)ide analogue therapy with Parkinson disease in chronic hepatitis B patients. Sci Rep 2025; 15:15192. [PMID: 40307244 PMCID: PMC12044151 DOI: 10.1038/s41598-025-00110-6] [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: 02/20/2025] [Accepted: 04/24/2025] [Indexed: 05/02/2025] Open
Abstract
Prolonged therapy using nucleos(t)ide analogs (NUC) is inevitable in patients with chronic hepatitis B (CHB) infection, but its long-term impact on Parkinson's disease (PD) risk remains unclear. This study evaluated the association between NUC therapy and PD incidence in a nationwide CHB cohort. The study population comprised the National Health Insurance Service claims database from January 1, 2013, to December 31, 2013, only included treatment naïve CHB patients and those without previously diagnosed with PD. Participants were followed until PD diagnosis or study completion. The primary outcome was PD incidence, comparing patients who initiated NUC therapy at cohort entry with those who did not. Over the 7.9-year study period, the incidence rate of PD in NUC-treated patients was 1.48 per 1000 persons, compared to 1.95 per 1000 persons in the untreated group. In an adjusted competing risk model, the 3-year follow-up showed a statistically significant reduction in risk (hazard ratio [HR]: 0.61; 95% confidence interval [CI] 0.39-0.97). In the propensity score-matched cohort of 18,365 pairs, the cumulative incidence during 2-4 years of follow-up was significantly lower in the NUC-treated group compared to the untreated group. However, no statistically significant difference in cumulative PD incidence was observed between the groups at the early or late stages of the follow-up period. NUC therapy initially reduced PD incidence, but this protective effect diminished over time, indicating a time-varying effect. Regular PD screening may be needed for long-term NUC users.
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Affiliation(s)
- Jihye Lim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyo Young Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Hyunji Sang
- Department of Endocrinology and Metabolism, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea
- Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea
| | - Su Jin Jeong
- Clinical Research Institute, Kyung Hee University Medical Center, 24, Kyunghee dae-ro, Dongdaemun-gu, Seoul, 02453, Republic of Korea.
| | - Ha Il Kim
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea.
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, 153, Gyeongchun-ro, Guri, 11923, Republic of Korea.
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Lim J, Gu H, Sang H, Jeong SJ, Kim HI. Impact of nucleos(t)ide analogue therapy on the incidence of Alzheimer's disease in patients with chronic hepatitis B virus infection. Alzheimers Res Ther 2025; 17:84. [PMID: 40241196 PMCID: PMC12004639 DOI: 10.1186/s13195-025-01729-3] [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: 12/28/2024] [Accepted: 03/31/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND Long-term therapy with nucleos(t)ide analogs (NUCs) is inevitable for chronic hepatitis B (CHB) patients. However, how NUC therapy on the developing Alzheimer's disease (AD) in these patients remains controversial. METHODS This retrospective cohort study used the Korean National Health Insurance Service claims database from January 1, 2013, to December 31, 2013, treatment naïve CHB patients and those without previously diagnosed with AD. Participants were followed from the index date until either the diagnosis of AD or the study's conclusion on December 31, 2021. The primary outcome was the incidence of AD, compared between the group with initiated NUC therapy (n = 18,365) at cohort entry and the group without NUC therapy (n = 212,820). RESULTS During the study, 416 patients were diagnosed with AD. After propensity-score matching (18,365 pairs), the 5- to 7-year follow-up showed a significantly lower hazard ratio (HR) in the NUC-treated group compared to the untreated group (HR 0.31-0.40), with HRs remaining constant over time. Subgroup analysis showed more pronounced benefits of NUC therapy in patients under 65 years (HRs: 0.22 vs. 1.23; P < 0.05) and those without dyslipidemia (HRs: 0.14 vs. 1.09; P < 0.05). Protective effects were also observed across subgroups with hypertension, chronic kidney disease, heart disease, and a history of brain trauma, consistent with AD risk factor trends. CONCLUSIONS Our study analyses suggest that NUC therapy appears to have a protective effect against the development of AD in patients with CHB.
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Affiliation(s)
- Jihye Lim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyundam Gu
- Epidemiologic & Biostatistical Methods for Public Health & Clinical Research, Bloomberg School of Public Health, Johns Hopkins, Baltimore, Maryland, USA
| | - Hyunji Sang
- Department of Endocrinology and Metabolism, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, South Korea
- Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, South Korea
| | - Su Jin Jeong
- Clinical Research Institute, Kyung Hee University Medical Center, 24 Kyunghee dae-ro, Seoul, , Dongdaemun-gu 02453, South Korea.
| | - Ha Il Kim
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea.
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Guri, , 153 Gyeongchun-ro 11923, South Korea.
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Ugbaja SC, Mokoena AT, Mushebenge AGA, Kumalo HM, Ngcobo M, Gqaleni N. Evaluation of the Potency of Repurposed Antiretrovirals in HBV Therapy: A Narrative Investigation of the Traditional Medicine Alternatives. Int J Mol Sci 2025; 26:1523. [PMID: 40003989 PMCID: PMC11855344 DOI: 10.3390/ijms26041523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Hepatitis B is one of the killer communicable diseases, with a global estimation of 1.1 million deaths resulting from liver diseases annually. The search for HBV therapeutics has resulted in repurposing the existing antiretrovirals (ARVs) for HBV treatment, considering their shared common replication mechanisms. This review is aimed at evaluating the potencies of some of the repurposed ARVs used for HBV treatment, analyzing the common mechanisms of viral replications in HBV and HIV, and investigating the potentials of traditional medicines as an alternative treatment for HBV patients. The topical keywords drug repurposing, drug repositioning, antiretrovirals, hepatitis B treatment, HBV, natural products, traditional medicines, title, and abstract were searched in PubMed, Web of Science, and Google Scholar. The advanced search included the five years, 2019-2024. The search result was filtered from 377 to 110 relevant articles. The evaluation reveals that CD4+ T cells are targeted by HIV, while HBV targets the liver with its associated diseases (cirrhosis and hepatocellular carcinoma (HCC)). Furthermore, treatments with the available repurposed ARVs only prevent or slow down the progression to cirrhosis, reduce the HCC incidence, and can improve the quality of life and increase life expectancy; however, they are not curative for HBV. Traditional medicines/natural product extracts or their phytochemicals exert anti-HBV effects through different mechanisms. Traditional medicines exert improved therapeutic effects when combined properly. The investigation further reveals that consideration of an in silico approach in HBV therapeutics might not only streamline drug development but also contribute to a deeper understanding of viral pathogenesis. Therefore, we recommend the integration of computational drug design methods with traditional medicine and natural product screening for discovering new bioactive HBV drug candidates.
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Affiliation(s)
- Samuel Chima Ugbaja
- Discipline of Traditional Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Ata Thabo Mokoena
- Discipline of Traditional Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4000, South Africa
- Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Aganze Gloire-Aimé Mushebenge
- Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
- Faculty of Pharmaceutical Sciences, University of Lubumbashi, Lubumbashi 1825, Democratic Republic of the Congo
| | - Hezekiel M. Kumalo
- Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Mlungisi Ngcobo
- Discipline of Traditional Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Nceba Gqaleni
- Discipline of Traditional Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4000, South Africa
- Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4000, South Africa
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Rani S, Dandu H, Yadav A, Lamba M, Goel A, Ali W, Atam V, Rungta S, Gautam M, Singhai A. Urinary Levels of Neutrophil Gelatinase-associated Lipocalin and Cystatin C in Patients with Hepatitis B on Tenofovir Treatment. THE JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA 2025; 73:13-15. [PMID: 39927991 DOI: 10.59556/japi.73.0828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
INTRODUCTION Tenofovir disoproxil fumarate (TDF) is a third-generation nucleoside analogue commonly used as a first-line therapy for chronic hepatitis B virus (HBV) infection. However, it is associated with nephrotoxicity, which can occur through mechanisms such as mitochondrial deoxyribonucleic acid (DNA) depletion and damage to renal tubules. This nephrotoxic effect typically manifests as a mild increase in serum creatinine and a decrease in serum phosphate, usually within 4-12 months after starting treatment. Recent studies suggest that novel biomarkers, such as urinary neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, may predict acute kidney injury (AKI) earlier and more accurately than traditional markers like serum creatinine. In line with this, we investigated NGAL and cystatin C levels in HBV patients receiving TDF therapy to assess their potential in monitoring kidney function. MATERIALS AND METHODS The study included 350 cases in total. Each participant underwent a thorough assessment, including a detailed medical history, clinical examination, and routine blood tests, as outlined in the study's working proforma. Based on the above details, 226 cases fulfilling the inclusion criteria were enrolled for the second step of the study, where a 5 mL urine sample from each case was taken and sent to the pathology laboratory for estimation of cystatin C and NGAL by the ELISA method with the help of a kit. RESULTS The average age of the participants was 37.93 years, with 124 individuals falling within the 18-35-year age-group. After accounting for confounding factors, 87 cases were identified, predominantly young males, who exhibited elevated levels of both urinary NGAL and cystatin C. CONCLUSION In this cross-sectional study, after controlling for confounding factors, we observed that TDF treatment was linked to elevated levels of urinary NGAL and cystatin C in 87 (38.4%) of the cases. Notably, increased levels of these biomarkers were also found in the younger age-group (18-35 years). These findings suggest the need for further prospective studies with larger sample sizes to better understand the direct impact of TDF on kidney function in hepatitis B patients.
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Affiliation(s)
- Shivani Rani
- Senior Resident, Department of Internal Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Himanshu Dandu
- Professor, Department of Internal Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Ambuj Yadav
- Assistant Professor, Department of Internal Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India, Corresponding Author
| | - Mahak Lamba
- Assistant Professor, Department of Internal Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Amit Goel
- Professor, Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Wahid Ali
- Professor, Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Virendra Atam
- Professor, Department of Internal Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Sumit Rungta
- Professor, Department of Gastroenterology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Medhavi Gautam
- Associate Professor, Department of Internal Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Atin Singhai
- Professor, Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
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Jiang C, Zhang ZH, Li JX. Current status of drug therapy for chronic hepatitis B. World J Gastroenterol 2025; 31:99443. [PMID: 39811512 PMCID: PMC11684199 DOI: 10.3748/wjg.v31.i2.99443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/04/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024] Open
Abstract
In this editorial, we comment on the article by Meng et al. Chronic hepatitis B (CHB) is a significant global health problem, particularly in developing countries. Hepatitis B virus (HBV) infection is one of the most important risk factors for cirrhosis and hepatocellular carcinoma. Prevention and treatment of HBV are key measures to reduce complications. At present, drug therapy can effectively control virus replication and slow disease progression, but completely eliminating the virus remains a challenge. Anti-HBV treatment is a long-term process, and there are many kinds of antiviral drugs with different mechanisms of action, it is essential to evaluate the safety and efficacy of these drugs to reduce side effects and improve patients' compliance. We will summarize the current status of CHB drug treatment, hoping to provide a reference for the selection of clinical antiviral drugs.
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Affiliation(s)
- Chuang Jiang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zhi-Hong Zhang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Xin Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of General Surgery, Dafang County People's Hospital, Bijie 551600, Guizhou Province, China
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Yamada S, Uchida Y, Kouyama JI, Naiki K, Tsuji S, Uemura H, Sugawara K, Nakayama N, Imai Y, Tomiya T, Mizuno S, Mochida S. Switching from combination therapy with entecavir hydrate plus tenofovir alafenamide fumarate to tenofovir alafenamide fumarate monotherapy in patients with chronic hepatitis B based on nucleotide sequences of hepatitis B virus pregenome RNA. Hepatol Res 2024; 54:877-887. [PMID: 38517681 DOI: 10.1111/hepr.14036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/09/2024] [Accepted: 02/28/2024] [Indexed: 03/24/2024]
Abstract
AIM Patients with chronic hepatitis B virus (HBV) infection experiencing viral breakthrough (BTH) or partial response (PR) during lamivudine (LAM) or entecavir hydrate (ETV) administration often took ETV plus tenofovir alafenamide fumarate (TAF) due to the emergence of a drug-resistance mutation. However, in patients lacking drug-resistance mutation against TAF, sufficient antiviral effects may be achievable with TAF monotherapy. We assessed the drug-resistance profile through nucleotide sequences of HBV pregenome RNA, and subsequently changed to TAF monotherapy from ETV plus TAF. METHODS This prospective study included 25 patients with serum HBV-DNA below 20 IU/mL under ETV plus TAF administration. Pregenome RNA nucleotide sequences of HBV in the sera were analyzed using direct sequencing and deep sequencing. ETV was discontinued in patients without rtA194T and rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutations in direct sequencing. RESULTS LAM-PR, LAM-BTH, ETV-PR, and ETV-BTH were observed in 1, 16, 7, and 1 patient(s), respectively. Pregenome RNA nucleotide sequences were analyzable in 20 patients. Among the 12 patients classified as LAM-BTH, six patients showed rtL180M + rtM204V/I in direct sequencing, and one patient showed minor clones containing rtL180M + rtM204V + A194T in deep sequencing at a frequency of 0.3%. In the six patients classified as ETV-PR, one patient harbored rtM204I. No clones showing rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutation were detected in deep sequencing. Subsequently, ETV was discontinued, and serum HBV-DNA remained undetectable up to 48 weeks in all patients. CONCLUSION Patients receiving ETV plus TAF due to partial response or BTH during initial LAM or ETV administration were able to safely transition to TAF monotherapy based on nucleotide sequences of HBV pregenome RNA in the sera.
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Affiliation(s)
- Shunsuke Yamada
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Yoshihito Uchida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Jun-Ichi Kouyama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Kayoko Naiki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Shohei Tsuji
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Hayato Uemura
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Kayoko Sugawara
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Nobuaki Nakayama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Yukinori Imai
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Tomoaki Tomiya
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Suguru Mizuno
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Japan
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Korkmaz Sezer S, Yuksel S, Koc A, Ulu A, Ates B. Evaluation of genotoxic and mitotoxic effects of TAF-loaded chitosan nanoparticles in HepG2 cells. Drug Chem Toxicol 2024; 47:516-526. [PMID: 38726977 DOI: 10.1080/01480545.2024.2349663] [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] [Received: 09/30/2023] [Revised: 04/04/2024] [Accepted: 04/24/2024] [Indexed: 09/04/2024]
Abstract
Tenofovir alafenamide (TAF) is a new drug from the nucleotide reverse transcriptase inhibitor group approved for the treatment of chronic Hepatitis B in 2016. With this study, we aimed to test whether possible cellular toxicity can be reduced by controlled drug release as a result of loading with chitosan nanoparticles (CHS). We investigated the genotoxic and mitotoxic effects of 45 µM TAF-loaded CHS and TAF-only on HepG2 cells by micronucleus (MN), comet assay, determination of mtDNA quantification, mitochondrial membrane potential (ΔΨm), and ROS levels. Additionally, we compared the samples by RNAseq analyses to reveal the transcriptional responses to each regimen. In terms of genotoxic tests, although MN and comet were found higher in all experimental treatment conditions, the encapsulation of CHS reduced the genotoxicity of TAF. MtDNA level was found to be lower in the TAF treatment, whereas it was higher in CHS and CHS-TAF treatments. The TAF-loaded CHS and TAF treatments had an impaired ΔΨm value. Cellular ROS levels were higher in all treatment conditions. According to the analyses of gene expression patterns; CHS-only changed the expression of relatively few genes (187 genes), while TAF changed the expression of the 1974 genes and TAF-loaded CHS changed the expression of 734 genes. Considering the gene expression numbers, CHS encapsulation of TAF significantly reduced the number of genes that were differentially expressed by TAF-only. Overall, we observed that TAF has genotoxic and mitotoxic effects on HepG2 cells, and upon encapsulation with CHS, its genotoxic and mitotoxic effects were decreased.
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Affiliation(s)
- Selcen Korkmaz Sezer
- Faculty of Medicine, Department of Medical Genetics, Inonu University, Malatya, Turkey
| | - Sengul Yuksel
- Faculty of Medicine, Department of Medical Genetics, Inonu University, Malatya, Turkey
| | - Ahmet Koc
- Faculty of Medicine, Department of Medical Genetics, Inonu University, Malatya, Turkey
- Inonu University, Drug Research and Application Center, Malatya, Turkey
| | - Ahmet Ulu
- Faculty of Arts and Science, Department of Chemistry, Malatya, Turkey
| | - Burhan Ates
- Faculty of Arts and Science, Department of Chemistry, Malatya, Turkey
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Hossain MG, Ueda K. Regulation of Hepatitis B Virus Replication by Modulating Endoplasmic Reticulum Stress (ER-Stress). Int J Microbiol 2024; 2024:9117453. [PMID: 39246409 PMCID: PMC11379510 DOI: 10.1155/2024/9117453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 08/21/2024] [Indexed: 09/10/2024] Open
Abstract
Hepatitis B virus (HBV), resistant to several antiviral drugs due to viral genomic mutations, has been reported, which aggravates chronic infection and leads to hepatocellular carcinoma. Therefore, host cellular factors/signaling modulation might be an alternative way of treatment for drug-resistant HBV. Here, we investigated the viral protein expression, replication, and virion production using endoplasmic reticulum (ER) stress-modulating chemicals, tunicamycin (an ER-stress inducer), and salubrinal (an ER-stress inhibitor). We found that ER-stress could be induced by HBV replication in transfected HepG2 cells as well as by tunicamycin as demonstrated by dual luciferase assay. HBV intracellular core-associated DNA quantified by qPCR has been significantly increased by tunicamycin in transfected HepG2 cells. Inversely, intracellular core associated and extracellular particle DNA has been significantly decreased in a dose-dependent manner in salubrinal-treated HepG2 cells transfected with HBV-replicating plasmid pHBI. Similar results were found in stably HBV-expressing hepatoblastoma (HB611) cells treated with salubrinal. However, increased or decreased ER-stress by tunicamycin or salubrinal treatment, respectively, has been confirmed by expression analysis of grp78 using Western blot. In addition, Western blot results demonstrated that the expression of HBV core protein and large HBsAg is increased and decreased by tunicamycin and salubrinal, respectively. In conclusion, the sal-mediated inhibition of the HBV replication and virion production might be due to the simultaneous reduction of core and large HBsAg expression and maintaining the ER homeostasis. These results of HBV replication regulation by modulation of ER-stress dynamics would be useful for designing/identifying anti-HBV drugs targeting cellular signaling pathways.
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Affiliation(s)
- Md Golzar Hossain
- Department of Microbiology and Hygiene Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
| | - Keiji Ueda
- Division of Virology Department of Microbiology and Immunology Graduate School of Medicine Osaka University, Osaka, Japan
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Patil VS, Harish DR, Charla R, Vetrivel U, Jalalpure SS, Bhandare VV, Deshpande SH, Hegde HV, Roy S. Structural insights into modeling of hepatitis B virus reverse transcriptase and identification of its inhibitors from potential medicinal plants of Western Ghats: an in silico and in vitro study. J Biomol Struct Dyn 2023; 42:11731-11749. [PMID: 37811543 DOI: 10.1080/07391102.2023.2264400] [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] [Received: 07/07/2023] [Accepted: 09/21/2023] [Indexed: 10/10/2023]
Abstract
The present study was proposed to model full-length HBV-RT and investigate the intermolecular interactions of known inhibitor and libraries of phytocompounds to probe the potential natural leads by in silico and in vitro studies. Homology modeling of RT was performed by Phyre2 and Modeller and virtual screening of ligands implemented through POAP pipeline. Molecular dynamics (MD) simulation (100 ns) and MM-GBSA calculations were performed using Schrodinger Desmond and Prime, respectively. Phytocompounds probable host protein targets gene set pathway enrichment and network analysis were executed by KEGG database and Cytoscape software. Prioritized plant extracts/enriched fraction LC-MS analysis was performed and along with pure compound, RT inhibitory activity, time-dependent HBsAg and HBeAg secretion, and intracellular HBV DNA, and pgRNA by qRT-PCR was performed in HepG2.2.15 cell line. Among the screened chemical library of 268 phytocompounds from 18 medicinal plants, 15 molecules from Terminalia chebula (6), Bidens pilosa (5), and Centella asiatica (4)) were identified as potential inhibitors of YMDD and RT1 motif of HBV-RT. MD simulation demonstrated stable interactions of 15 phytocompounds with HBV-RT, of which 1,2,3,4,6-Pentagalloyl Glucose (PGG) was identified as lead molecule. Out of 15 compounds, 11 were predicted to modulate 39 proteins and 15 molecular pathways associated with HBV infection. TCN and TCW (500 µg/mL) showed potent RT inhibition, decreased intracellular HBV DNA, and pgRNA, and time-dependent inhibition of HBsAg and HBeAg levels compared to PGG and Tenofovir Disoproxil Fumarate. We propose that the identified lead molecules from T. chebula as promising and cost-effective moieties for the management of HBV infection.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Vishal S Patil
- ICMR-National Institute of Traditional Medicine, Belagavi, Karnataka, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi, Karnataka, India
| | | | - Rajitha Charla
- ICMR-National Institute of Traditional Medicine, Belagavi, Karnataka, India
| | - Umashankar Vetrivel
- ICMR-National Institute of Traditional Medicine, Belagavi, Karnataka, India
- ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India
| | - Sunil S Jalalpure
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi, Karnataka, India
| | - Vishwambhar Vishnu Bhandare
- ICMR-National Institute of Traditional Medicine, Belagavi, Karnataka, India
- Department of Microbiology, Shivaji University, Kolhapur, Maharashtra, India
| | - Sanjay H Deshpande
- ICMR-National Institute of Traditional Medicine, Belagavi, Karnataka, India
- Regional Centre for Biotechnology, NCR-Biotech Science Cluster, Faridabad, India
| | - Harsha V Hegde
- ICMR-National Institute of Traditional Medicine, Belagavi, Karnataka, India
| | - Subarna Roy
- ICMR-National Institute of Traditional Medicine, Belagavi, Karnataka, India
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Yu W, Li Z, Wu W, Zhao D, Yan C, Lin P. Insights into the mechanisms of telbivudine-induced myopathy associated with mitochondrial dysfunction. Chem Biol Interact 2023; 383:110692. [PMID: 37659625 DOI: 10.1016/j.cbi.2023.110692] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/10/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023]
Abstract
As a nucleotide analogue (NA), telbivudine was widely used in the treatment for chronic hepatitis B (CHB) by interfering with reverse transcriptase of hepatitis B virus. However, the use of NAs for hepatitis B treatment has been accompanied by numerous reports highlighting the occurrence of neuromyopathy, particularly in the case of telbivudine. This study aimed to investigate the underlying mechanisms responsible for telbivudine-induced myopathy. We established animal and cell models of telbivudine-induced myopathy using C57BL/6 mice and C2C12 cells, respectively. Our findings revealed that telbivudine significantly reduced mitochondrial DNA (mtDNA) copy number and caused increase of oxidative stress. Telbivudine treatment significantly inhibited mitochondrial complex I and IV expression, impairing the oxidative phosphorylation function of the respiratory chain. Modified Gomori trichrome (MGT) staining of the muscle sections displayed an increase in ragged red fibers (RRFs), indicating abnormal mitochondrial accumulation. In conclusion, our study provides compelling evidence suggesting that telbivudine-induced myopathy is associated with mitochondrial toxicity and impaired energy metabolism. The observed muscle pathology, depletion of mtDNA, elevation of oxidative stress and altered mitochondrial function support the hypothesis that telbivudine disrupts mitochondrial homeostasis, ultimately leading to muscle damage. This may be also a common mechanism for NAs to cause neuromyopathy.
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Affiliation(s)
- Wenfei Yu
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China; University of Health and Rehabilitation Sciences, No. 17, Shandong Road, Shinan District, Qingdao City, Shandong Province, China
| | - Zhuxun Li
- Shandong University Cheeloo College of Medicine, Jinan, 250012, Shandong Province, China
| | - Wenjing Wu
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China
| | - Dandan Zhao
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China
| | - Chuanzhu Yan
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China
| | - Pengfei Lin
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China.
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Li J, Zang X, Heng H, Liu X, Geng H, Liang J. Fanconi syndrome induced by the long-term use of tenofovir disoproxil fumarate: a case report and literature review. J Int Med Res 2023; 51:3000605231195469. [PMID: 37666224 PMCID: PMC10478560 DOI: 10.1177/03000605231195469] [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] [Received: 04/12/2023] [Accepted: 07/28/2023] [Indexed: 09/06/2023] Open
Abstract
We present the case of a woman of 50 years of age who experienced widespread bone pain along with digestive symptoms, including nausea and vomiting. She had been prescribed tenofovir disoproxil fumarate (TDF) tablets for the treatment of hepatitis B. Laboratory testing revealed low circulating phosphorus and potassium concentrations and acidosis. A whole-body bone scan revealed abnormal bone metabolism. Rheumatologic and urologic conditions were ruled out, and therefore TDF-induced Fanconi syndrome (FS) and related bone pain was diagnosed. After the TDF was discontinued, the patient's symptoms and laboratory indices significantly improved. In this manuscript, we highlight the clinical manifestations of and laboratory test results associated with FS and summarize the cases of TDF-induced FS reported on PubMed between 2013 and 2022 to improve understanding of FS.
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Affiliation(s)
- Jiayi Li
- Graduate School, Bengbu Medical College, Anhui, China
| | - Xiu Zang
- Department of Endocrinology, Xuzhou Central Hospital, Jiangsu, China
| | - Hao Heng
- Department of Endocrinology, Xuzhou Central Hospital, Jiangsu, China
| | - Xuekui Liu
- Department of Endocrinology, Xuzhou Central Hospital, Jiangsu, China
| | - Houfa Geng
- Department of Endocrinology, Xuzhou Central Hospital, Jiangsu, China
| | - Jun Liang
- Graduate School, Bengbu Medical College, Anhui, China
- Department of Endocrinology, Xuzhou Central Hospital, Jiangsu, China
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13
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Obrecht M, Zurbruegg S, Accart N, Lambert C, Doelemeyer A, Ledermann B, Beckmann N. Magnetic resonance imaging and ultrasound elastography in the context of preclinical pharmacological research: significance for the 3R principles. Front Pharmacol 2023; 14:1177421. [PMID: 37448960 PMCID: PMC10337591 DOI: 10.3389/fphar.2023.1177421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/16/2023] [Indexed: 07/18/2023] Open
Abstract
The 3Rs principles-reduction, refinement, replacement-are at the core of preclinical research within drug discovery, which still relies to a great extent on the availability of models of disease in animals. Minimizing their distress, reducing their number as well as searching for means to replace them in experimental studies are constant objectives in this area. Due to its non-invasive character in vivo imaging supports these efforts by enabling repeated longitudinal assessments in each animal which serves as its own control, thereby enabling to reduce considerably the animal utilization in the experiments. The repetitive monitoring of pathology progression and the effects of therapy becomes feasible by assessment of quantitative biomarkers. Moreover, imaging has translational prospects by facilitating the comparison of studies performed in small rodents and humans. Also, learnings from the clinic may be potentially back-translated to preclinical settings and therefore contribute to refining animal investigations. By concentrating on activities around the application of magnetic resonance imaging (MRI) and ultrasound elastography to small rodent models of disease, we aim to illustrate how in vivo imaging contributes primarily to reduction and refinement in the context of pharmacological research.
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Affiliation(s)
- Michael Obrecht
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Stefan Zurbruegg
- Neurosciences Department, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Nathalie Accart
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Christian Lambert
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Arno Doelemeyer
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Birgit Ledermann
- 3Rs Leader, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Nicolau Beckmann
- Diseases of Aging and Regenerative Medicines, Novartis Institutes for BioMedical Research, Basel, Switzerland
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Mali A, Franci G, Zannella C, Chianese A, Anthiya S, López-Estévez AM, Monti A, De Filippis A, Doti N, Alonso MJ, Galdiero M. Antiviral Peptides Delivered by Chitosan-Based Nanoparticles to Neutralize SARS-CoV-2 and HCoV-OC43. Pharmaceutics 2023; 15:1621. [PMID: 37376070 DOI: 10.3390/pharmaceutics15061621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 03/29/2023] [Accepted: 04/07/2023] [Indexed: 06/29/2023] Open
Abstract
The COVID-19 pandemic has made it clear that there is a crucial need for the design and development of antiviral agents that can efficiently reduce the fatality rate caused by infectious diseases. The fact that coronavirus mainly enters through the nasal epithelial cells and spreads through the nasal passage makes the nasal delivery of antiviral agents a promising strategy not only to reduce viral infection but also its transmission. Peptides are emerging as powerful candidates for antiviral treatments, showing not only a strong antiviral activity, but also improved safety, efficacy, and higher specificity against viral pathogens. Based on our previous experience on the use of chitosan-based nanoparticles to deliver peptides intra-nasally the current study aimed to explore the delivery of two-novel antiviral peptides making use of nanoparticles consisting of HA/CS and DS/CS. The antiviral peptides were chemically synthesized, and the optimal conditions for encapsulating them were selected through a combination of physical entrapment and chemical conjugation using HA/CS and DS/CS nanocomplexes. Finally, we evaluated the in vitro neutralization capacity against SARS-CoV-2 and HCoV-OC43 for potential use as prophylaxis or therapy.
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Affiliation(s)
- Avinash Mali
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Gianluigi Franci
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy
| | - Carla Zannella
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Annalisa Chianese
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Shubaash Anthiya
- Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Ana M López-Estévez
- Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Alessandra Monti
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), 80131 Naples, Italy
- CIRPEB, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, 80134 Naples, Italy
| | - Anna De Filippis
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Nunzianna Doti
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), 80131 Naples, Italy
- CIRPEB, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, 80134 Naples, Italy
| | - María José Alonso
- Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Massimiliano Galdiero
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
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Lu L, Lu T, Wu Y, Wang Y, Ke X, Yang R. Research on the effectiveness and material basis of Ligusticum chuanxiong in alleviating acute liver injury. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116643. [PMID: 37220808 DOI: 10.1016/j.jep.2023.116643] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/08/2023] [Accepted: 05/14/2023] [Indexed: 05/25/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE As an effective medicinal plant, Ligusticum chuanxiong (L. chuanxiong) is traditionally used in China to treat various kinds of dysesthesia caused by liver qi stagnation, chest paralysis and heart pain caused by liver blood stagnation, and bruises and injuries caused by blood stasis. Recent research has confirmed the efficacy of L. chuanxiong in treating liver injury. AIM OF THE STUDY L. chuanxiong has significant hepatoprotective effects, but its material basis and mechanism of action are still ambiguous. This work was to reveal the potential active ingredients (parts) of L. chuanxiong for liver protection and to investigate the pharmacological mechanism of its liver protection. MATERIALS AND METHODS The hepatoprotective substance basis and mechanism of L. chuanxiong were investigated using network pharmacology, and the active components of L. chuanxiong extract were studied using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analytical techniques. Molecular docking was adopted to verify the interaction between the active ingredients in L. chuanxiong and the key targets involved in liver injury. To confirm the hepatoprotective effects of the effective part in L. chuanxiong, a carbon tetrachloride (CCl4)-induced acute liver injury model in mice was used. RESULTS As a result, network pharmacological analysis techniques were used to screen out potential active ingredients such as ferulic acid, caffeic acid, and p-coumaric acid, which were concentrated in the organic acid site and acted on 19 key targets related to liver protection. The biological process involved the positive regulation of nitric oxide biosynthesis, and various signaling pathways were implicated, including the Toll-like receptor signaling pathway, the NOD-like receptor signaling pathway, the TNF signaling pathway, and others. LC-MS and GC-MS qualitatively analyzed the effective components from L. chuanxiong extract, and 50 active components were identified. The molecular docking of key components with the core targets showed good activity, which validated the predicted results. In the final analysis, a mouse model of acute liver injury induced by CCl4 further verified the greater protective effect of the organic acid fraction of L. chuanxiong on liver injury in mice compared with other parts. CONCLUSION The results reveal that L. chuanxiong may relieve liver damage, and the organic acids were the main active part in it. Its mechanism of alleviating liver injury is related to positive regulation of nitric oxide biosynthesis, the Toll-like receptor signaling pathway, the NOD-like receptor signaling pathway, the TNF signaling pathway, and so on.
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Affiliation(s)
- Lingzhi Lu
- School of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Taotao Lu
- School of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Yajing Wu
- School of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Yunhong Wang
- Chongqing Academy of Chinese Materia Medica, Chongqing, China
| | - Xiumei Ke
- Chongqing Medical University, Chongqing, China.
| | - Rongping Yang
- School of Pharmaceutical Sciences, Southwest University, Chongqing, China.
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Yang X, Yan H, Zhang X, Qin X, Guo P. Comparison of renal safety and bone mineral density of tenofovir and entecavir in patients with chronic hepatitis B: A Systematic Review and Meta-analysis. Int J Infect Dis 2022; 124:133-142. [PMID: 36122671 DOI: 10.1016/j.ijid.2022.09.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/29/2022] [Accepted: 09/13/2022] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are recommended as first-line treatments for chronic hepatitis B (CHB). However, the safety of these two drugs remains controversial. This study aims to evaluate and compare renal function and bone mineral density in CHB patients who took TDF or ETV. METHODS The electronic databases of the Cochrane Library, PubMed, and Embase were searched. The key words were: "CHB," "tenofovir," and "entecavir". Heterogeneity and subgroups were analyzed. RESULTS 16 studies met the inclusion criteria. There was no significant difference in serum creatinine levels between the TDF and the ETV group. There was a significant standardized mean difference in serum estimated glomerular filtration rate (eGFR) between months (12 months: SMD [95%CI] = -0.07 [-0.12, -0.01]; 18-24 months: SMD [95%CI]=-0.11[-0.17],-0.05]), but no significant difference emerged in the long-term drug use for over 24 months. There was no significant difference in the incidence of osteopenia/osteoporosis (I2=41%, RR [95%CI]=1.29[0.93,1.77], p=0.13>0.05). CONCLUSIONS Compared with the ETV group, a greater reduction in eGFR and serum phosphorus levels was observed in the TDF group. There was no significant difference in the incidence of osteopenia/osteoporosis between the two groups.
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Affiliation(s)
- Xiaoxian Yang
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Haiyi Yan
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Xiuju Zhang
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Xueying Qin
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Peng Guo
- Department of Hepatology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China.
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Tang Z, Li T, Dai H, Feng C, Xie X, Peng F, Lan G, Yu S, Wang Y, Fang C, Nie M, Yuan X, Tang X, Jiang X, Zhu X, Fan Y, Peng J, Sun S, Zhong M, Zhang H, Peng L. Drug-induced Fanconi syndrome in patients with kidney allograft transplantation. Front Immunol 2022; 13:979983. [PMID: 36059468 PMCID: PMC9437944 DOI: 10.3389/fimmu.2022.979983] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundPatients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical.MethodsThis retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis.ResultsThe onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A.ConclusionsFor the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.
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Affiliation(s)
- Zhouqi Tang
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Tengfang Li
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Helong Dai
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
- Clinical Immunology Center, Central South University, Changsha, China
- Department of Organ Transplantation, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou Peole’s Hosital), Zhengzhou, China
| | - Chen Feng
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Xubiao Xie
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Fenghua Peng
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Gongbin Lan
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Shaojie Yu
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Yu Wang
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Chunhua Fang
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Manhua Nie
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Xiaoqiong Yuan
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Xiaotian Tang
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Xin Jiang
- Department of Organ Transplantation, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou Peole’s Hosital), Zhengzhou, China
| | - Xuejing Zhu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yuxi Fan
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Jiawei Peng
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Siyu Sun
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Mingda Zhong
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Hedong Zhang
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
| | - Longkai Peng
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China
- *Correspondence: Longkai Peng,
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Fang HW, Yen YH, Hung CH, Wang JH, Hu TH, Lu SN, Chen CH. Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir. Dig Dis Sci 2022; 67:3402-3411. [PMID: 34241753 DOI: 10.1007/s10620-021-07128-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/20/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The predictors of persistent virological suppression after clinical relapse remain unclear. AIMS To investigate the predictors of retreatment or persistent virological suppression after clinical relapse in chronic hepatitis B (CHB) patients who discontinued entecavir or tenofovir disoproxil fumarate (TDF). METHODS A total of 243 hepatitis B e antigen-negative CHB patients without cirrhosis who experienced clinical relapse after entecavir or TDF cessation were enrolled. RESULTS Of the 243 CHB patients, 192 received retreatment and 51 did not receive retreatment after clinical relapse. Of the 51 patients without retreatment, 23 achieved persistent virological suppression (persistent HBV DNA < 2000 IU/mL at least 2 years) and 10 experienced hepatitis B surface antigen (HBsAg) loss. The Cox regression analysis showed that short consolidation duration, short duration of the first clinical relapse from the end of treatment (EOT), and high bilirubin and HBV DNA levels at the first clinical relapse were independent predictors of retreatment. Long duration of the first clinical relapse from the EOT and low HBsAg levels at the first clinical relapse were independent factors of patients with persistent virological suppression. The rates of persistent virological suppression at the first clinical relapse among patients with HBsAg < 100 and ≥ 100 IU/mL were 44.4% (12/27) and 5.1% (11/216) (P < 0.001), respectively. Baseline HBsAg levels and no retreatment requirement were independent factors associated with HBsAg loss. CONCLUSIONS The HBsAg of 100 IU/mL at the first clinical relapse could predict persistent virological suppression after clinical relapse in patients who discontinued entecavir or TDF therapy.
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Affiliation(s)
- Hsin-Wei Fang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.
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19
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Mally A, Jarzina S. Mapping Adverse Outcome Pathways for Kidney Injury as a Basis for the Development of Mechanism-Based Animal-Sparing Approaches to Assessment of Nephrotoxicity. FRONTIERS IN TOXICOLOGY 2022; 4:863643. [PMID: 35785263 PMCID: PMC9242087 DOI: 10.3389/ftox.2022.863643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/11/2022] [Indexed: 02/04/2023] Open
Abstract
In line with recent OECD activities on the use of AOPs in developing Integrated Approaches to Testing and Assessment (IATAs), it is expected that systematic mapping of AOPs leading to systemic toxicity may provide a mechanistic framework for the development and implementation of mechanism-based in vitro endpoints. These may form part of an integrated testing strategy to reduce the need for repeated dose toxicity studies. Focusing on kidney and in particular the proximal tubule epithelium as a key target site of chemical-induced injury, the overall aim of this work is to contribute to building a network of AOPs leading to nephrotoxicity. Current mechanistic understanding of kidney injury initiated by 1) inhibition of mitochondrial DNA polymerase γ (mtDNA Polγ), 2) receptor mediated endocytosis and lysosomal overload, and 3) covalent protein binding, which all present fairly well established, common mechanisms by which certain chemicals or drugs may cause nephrotoxicity, is presented and systematically captured in a formal description of AOPs in line with the OECD AOP development programme and in accordance with the harmonized terminology provided by the Collaborative Adverse Outcome Pathway Wiki. The relative level of confidence in the established AOPs is assessed based on evolved Bradford-Hill weight of evidence considerations of biological plausibility, essentiality and empirical support (temporal and dose-response concordance).
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20
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Li C, Li H, Gong M, Wei J. Osteopenia in a young man associated with the use of tenofovir disoproxil fumarate. Clin Case Rep 2022; 10:e05641. [PMID: 35356169 PMCID: PMC8956931 DOI: 10.1002/ccr3.5641] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/02/2022] [Accepted: 03/09/2022] [Indexed: 12/13/2022] Open
Abstract
Tenofovir disoproxil fumarate is a recommended first-line therapy for patients with chronic hepatitis B, although the frequent Tenofovir disoproxil fumarate related adverse drug reactions are nephrotoxicity and bone toxicity. We described the case of a 21-year-old Han Chinese male patient with chronic hepatitis B with tenofovir disoproxil fumarate-associated osteopenia. The patient presented osteopenia at the site of his femoral neck with bone mineral density 0.865g/cm2 (Z = -1.9) in January 2020. Nine months after switching to TAF, bone mineral density at left femoral neck improved to 0.978g/cm2 (Z = -1.0) in September 2020. Bone mineral density of this patients was normal in January 2021. This is the first report in very young man presenting tenofovir disoproxil fumarate-associated osteopenia.
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Affiliation(s)
- Chunmei Li
- Department of Infectious disease and hepatologyHospital of Yunnan UniversityYunnanChina
| | - Hui Li
- Department of Infectious disease and hepatologyHospital of Yunnan UniversityYunnanChina
| | - Ming Gong
- Department of Infectious disease and hepatologyHospital of Yunnan UniversityYunnanChina
| | - Jia Wei
- Department of Infectious disease and hepatologyHospital of Yunnan UniversityYunnanChina
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21
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Nečasová I, Stojaspal M, Motyčáková E, Brom T, Janovič T, Hofr C. Transcriptional regulators of human oncoviruses: structural and functional implications for anticancer therapy. NAR Cancer 2022; 4:zcac005. [PMID: 35252867 PMCID: PMC8892037 DOI: 10.1093/narcan/zcac005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/04/2022] [Accepted: 02/15/2022] [Indexed: 11/26/2022] Open
Abstract
Transcription is often the first biosynthetic event of viral infection. Viruses produce preferentially viral transcriptional regulators (vTRs) essential for expressing viral genes and regulating essential host cell proteins to enable viral genome replication. As vTRs are unique viral proteins that promote the transcription of viral nucleic acid, vTRs interact with host proteins to suppress detection and immune reactions to viral infection. Thus, vTRs are promising therapeutic targets that are sequentially and structurally distinct from host cell proteins. Here, we review vTRs of three human oncoviruses: HBx of hepatitis B virus, HBZ of human T-lymphotropic virus type 1, and Rta of Epstein-Barr virus. We present three cunningly exciting and dangerous transcription strategies that make viral infections so efficient. We use available structural and functional knowledge to critically examine the potential of vTRs as new antiviral-anticancer therapy targets. For each oncovirus, we describe (i) the strategy of viral genome transcription; (ii) vTRs' structure and binding partners essential for transcription regulation; and (iii) advantages and challenges of vTR targeting in antiviral therapies. We discuss the implications of vTR regulation for oncogenesis and perspectives on developing novel antiviral and anticancer strategies.
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Affiliation(s)
- Ivona Nečasová
- Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, Královopolská 135, Brno 612 65, Czech Republic
| | - Martin Stojaspal
- Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, Královopolská 135, Brno 612 65, Czech Republic
| | - Edita Motyčáková
- Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, Královopolská 135, Brno 612 65, Czech Republic
| | - Tomáš Brom
- LifeB, Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 753/5, Brno 625 00, Czech Republic
| | - Tomáš Janovič
- LifeB, Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 753/5, Brno 625 00, Czech Republic
| | - Ctirad Hofr
- Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, Královopolská 135, Brno 612 65, Czech Republic
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22
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Masetti C, Pugliese N, Aghemo A, Viganò M. Safety of current antiviral drugs for chronic hepatitis B. Expert Opin Drug Saf 2022; 21:939-945. [PMID: 35209776 DOI: 10.1080/14740338.2022.2045271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Oral nucleos(t)ide analogues (NUCs) are recommended as first-line therapy for chronic hepatitis B due to higher HBV-DNA suppression rates and safety profile. Long-term treatment with NUCs is often necessary to achieve durable viral suppression. AREAS COVERED This review provides an overview of the long-term safety data that have become available since entecavir (ETV) and tenofovir disoproxil fumarate (TDF) were first approved, and recent data on tenofovir alafenamide (TAF) in patients with CHB. EXPERT OPINION NUCs generally show remarkable safety in patients taking them for long periods. Nevertheless, renal and bone toxicity may occur in a minority of patients on TDF therapy. These effects have been overcome by the recent release of TAF. Moreover, the currently available data do not allow firm conclusions on superiority of TDF on ETV about HCC risk reduction. Observational studies involving more homogeneous cohorts are therefore needed; furthermore long-term studies assessing impact of TAF on this important topic are warranted.
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Affiliation(s)
- Chiara Masetti
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy
| | - Nicola Pugliese
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Mauro Viganò
- 3Division of Hepatology, Ospedale San Giuseppe, Milan, Italy
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23
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Nagura Y, Matsuura K, Iio E, Fujita K, Inoue T, Matsumoto A, Tanaka E, Nishiguchi S, Kang JH, Matsui T, Enomoto M, Ikeda H, Watanabe T, Okuse C, Tsuge M, Atsukawa M, Tateyama M, Kataoka H, Tanaka Y. Serum miR-192-5p levels predict the efficacy of pegylated interferon therapy for chronic hepatitis B. PLoS One 2022; 17:e0263844. [PMID: 35157730 PMCID: PMC8843190 DOI: 10.1371/journal.pone.0263844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/27/2022] [Indexed: 12/30/2022] Open
Abstract
We examined the association between serum miRNA (-192-5p, -122-3p, -320a and -6126-5p) levels and the efficacy of pegylated interferon (Peg-IFN) monotherapy for chronic hepatitis B (CHB) patients. We enrolled 61 CHB patients treated with Peg-IFNα-2a weekly for 48 weeks, of whom 12 had a virological response (VR) and 49 did not VR (non-VR). A VR was defined as HBV DNA < 2,000 IU/ml, hepatitis B e antigen (HBeAg)-negative, and nucleos(t)ide analogue free at 48 weeks after the end of treatment. The non-VR group showed a significantly higher HBeAg-positivity rate, ALT, HBV DNA, and serum miR-192-5p levels at baseline (P = 0.024, P = 0.020, P = 0.007, P = 0.021, respectively). Serum miR-192-5p levels at 24-weeks after the start of treatment were also significantly higher in the non-VR than the VR group (P = 0.011). Multivariate logistic regression analysis for predicting VR showed that miR-192-5p level at baseline was an independent factor (Odds 4.5, P = 0.041). Serum miR-192-5p levels were significantly correlated with the levels of HBV DNA, hepatitis B core-related antigen, and hepatitis B surface antigen (r = 0.484, 0.384 and 0.759, respectively). The serum miR-192-5p level was useful as a biomarker for the therapeutic efficacy of Peg-IFN in CHB treatment.
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Affiliation(s)
- Yoshihito Nagura
- Departments of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Etsuko Iio
- Departments of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Aichi, Japan
| | - Akihiro Matsumoto
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Jong-Hon Kang
- Division of Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Takeshi Matsui
- Division of Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Osaka, Japan
| | - Hiroki Ikeda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Tsunamasa Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Chiaki Okuse
- Division of General Internal Medicine, Department of Internal Medicine, Kawasaki Municipal Tama Hospital, Kawasaki, Kanagawa, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Masakuni Tateyama
- Department of Gastroenterology and Hepatology Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Yasuhito Tanaka
- Departments of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
- Department of Gastroenterology and Hepatology Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
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24
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Hosaka T, Suzuki F, Kobayashi M, Fujiyama S, Kawamura Y, Sezaki H, Akuta N, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H. Renal safety and biochemical changes for 2 years after switching to tenofovir alafenamide from long-term other nucleotide analog treatment in patients with chronic hepatitis B. Hepatol Res 2022; 52:153-164. [PMID: 34687121 DOI: 10.1111/hepr.13726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/24/2021] [Accepted: 10/20/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Long-term use of nucleotide analogs such as adefovir (ADV) or tenofovir disoproxil fumarate (TDF) may cause renal impairment. Tenofovir alafenamide (TAF) has less systemic exposure than TDF did. The aims were to examine longitudinal changes in renal function and biochemical parameters for 2 years after switching from long-term ADV and TDF to TAF, and to explore factors associated with improved renal function after TAF in patients with chronic hepatitis B. METHODS The prospective observational cohort study included 306 patients with chronic hepatitis B who underwent switching from long-term TDF or ADV to TAF. The primary outcome was the changes in estimated glomerular filtration rate (eGFR) after TAF. RESULTS Among 306 patients, 190 (65.3%) and 106 (34.7%) had chronic kidney disease (CKD) stages 1-2 and 3a-4 at baseline. In patients with CKD stages 3a-4, the mean eGFR significantly increased until week 12 and plateaued from week 12 to year 2 (adjusted slope using linear mixed effect models: +9.01 ml/min/1.73 m2 /year until week 12; p < 0.001). In contrast, the mean eGFR plateaued from baseline to year 2 in the CKD stages 1-2 subgroup. Multivariate logistic regression showed that baseline CKD stage ≥3a, steeper decline in eGFR 1 year before TAF, and shorter duration of any nucleotide analog use was significantly associated with ≥10% improvement in eGFR in year 1. CONCLUSIONS Switching from TDF or ADV to TAF resulted in favorable renal safety for 2 years. In CKD stage 3a-4 subgroup, eGFR after TAF was recovered in the first 12 weeks and subsequently stabilized.
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Affiliation(s)
- Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | | | | | | | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan
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25
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Sequential HBV treatment with tenofovir alafenamide for patients with chronic hepatitis B: week 96 results from a real-world, multicenter cohort study. Hepatol Int 2022; 16:282-293. [PMID: 35075593 DOI: 10.1007/s12072-021-10295-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023]
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26
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Ulu A, Sezer SK, Yüksel Ş, Koç A, Ateş B. Preparation, Controlled Drug Release, and Cell Viability Evaluation of Tenofovir Alafenamide‐Loaded Chitosan Nanoparticles. STARCH-STARKE 2021. [DOI: 10.1002/star.202100144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Ahmet Ulu
- Biochemistry and Biomaterials Research Laboratory Department of Chemistry Faculty of Arts and Science İnönü University Malatya 44280 Turkey
| | - Selcen Korkmaz Sezer
- Department of Medical Genetics Faculty of Medicine Turgut Ozal Medical Center İnönü University Malatya 44280 Turkey
| | - Şengül Yüksel
- Department of Medical Genetics Faculty of Medicine Turgut Ozal Medical Center İnönü University Malatya 44280 Turkey
| | - Ahmet Koç
- Department of Medical Genetics Faculty of Medicine Turgut Ozal Medical Center İnönü University Malatya 44280 Turkey
| | - Burhan Ateş
- Biochemistry and Biomaterials Research Laboratory Department of Chemistry Faculty of Arts and Science İnönü University Malatya 44280 Turkey
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27
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Abstract
This article reviews the incidence of acute hepatitis B virus (HBV) infection, its clinical course, strategies to prevent acute HBV infection in susceptible individuals, and the management of patients with acute HBV.
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Affiliation(s)
- Simone E Dekker
- Department of Medicine, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
| | - Ellen W Green
- Department of Medicine, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
| | - Joseph Ahn
- Division of Gastroenterology and Hepatology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, MNP 4112, Portland, OR 97239, USA.
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28
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Birk B, Haake V, Sperber S, Herold M, Wallisch SK, Huener HA, Verlohner A, Amma MM, Walk T, Hernandez TR, Hewitt NJ, Kamp H, van Ravenzwaay B. Use of in vitro metabolomics in NRK cells to help predicting nephrotoxicity and differentiating the MoA of nephrotoxicants. Toxicol Lett 2021; 353:43-59. [PMID: 34626816 DOI: 10.1016/j.toxlet.2021.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 08/06/2021] [Accepted: 09/29/2021] [Indexed: 12/25/2022]
Abstract
We describe a strategy using an in vitro metabolomics assay with tubular rat NRK-52E cells to investigate the Modes of Action (MoAs) of nephrotoxic compounds. Chemicals were selected according to their MoAs based on literature information: acetaminophen, 4-aminophenol and S-(trichlorovinyl-)L-cysteine (TCVC), (covalent protein binding); gentamycin, vancomycin, polymycin B and CdCl2 (lysosomal overload) and tenofovir and cidofovir (mitochondrial DNA-interaction). After treatment and harvesting of the cells, intracellular endogenous metabolites were quantified relative to vehicle control. Metabolite patterns were evaluated in a purely data-driven pattern generation process excluding published information. This strategy confirmed the assignment of the chemicals to the respective MoA except for TCVC and CdCl2. Finally, TCVC was defined as unidentified and CdCl2 was reclassified to the MoA "covalent protein binding". Hierarchical cluster analysis of 58 distinct metabolites from the patterns enabled a clear visual separation of chemicals in each MoA. The assay reproducibility was very good and metabolic responses were consistent. These results support the use of metabolome analysis in NRK-52E cells as a suitable tool for understanding and investigating the MoA of nephrotoxicants. This assay could enable the early identification of nephrotoxic compounds and finally reduce animal testing.
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Affiliation(s)
- Barbara Birk
- Experimental Toxicology and Ecology, BASF SE, Ludwigshafen, Germany.
| | | | - Saskia Sperber
- Experimental Toxicology and Ecology, BASF SE, Ludwigshafen, Germany
| | | | | | | | | | - Meike M Amma
- Experimental Toxicology and Ecology, BASF SE, Ludwigshafen, Germany
| | | | | | | | - Hennicke Kamp
- Experimental Toxicology and Ecology, BASF SE, Ludwigshafen, Germany; BASF Metabolome Solutions GmbH, Berlin, Germany
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29
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Lee YS, Bang SM, Lee YS. Benefits and Risks of Antiviral Treatment during Pregnancy in Patients with Chronic Hepatitis B. J Clin Med 2021; 10:2320. [PMID: 34073357 PMCID: PMC8198811 DOI: 10.3390/jcm10112320] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a main cause of chronic liver disease worldwide and can lead to severe liver diseases. The World Health Organization has planned to eliminate viral hepatitis, including hepatitis caused by HBV and hepatitis C virus, by 2030. As mother-to-child transmission (MTCT) of HBV is a main cause of chronic HBV infection, MTCT prevention is the main target to reduce the risk of chronic HBV infection and eliminate the disease. Recent clinical trials and meta-analyses found that antiviral therapy could prevent MTCT effectively in mothers with ≥200,000 IU/mL of HBV DNA, in combination with serial vaccination and hepatitis B immune globulin administration in infants. Despite the preventive role of antivirals for MTCT of HBV, there are several concerns regarding antiviral therapy with respect to the safety of the mother and fetus during pregnancy. This review summarizes the benefits and risks of antiviral treatment during pregnancy in women with chronic HBV infection.
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Affiliation(s)
| | | | - Young-Sun Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea; (Y.S.L.); (S.M.B.)
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Risk of disease transmission in an expanded donor population: the potential of hepatitis B virus donors. Curr Opin Organ Transplant 2021; 25:631-639. [PMID: 33027191 DOI: 10.1097/mot.0000000000000810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Lack of availability of donor organs is a constant challenge that patients and providers face in transplantation. To address this shortage, donors that test positive for hepatitis B, in particular those with resolved infection, have been increasingly utilized in clinical practice. We review here the potential risks for the recipient and the advances in hepatitis B management that have made use of these donors a well tolerated and advisable proposition. RECENT FINDINGS As routine administration of antiviral prophylaxis in the posttransplant setting among those deemed high risk for transmission, outcomes for recipients of hepatitis B donors, including liver transplant recipients, have been comparable to uninfected donors. Universal hepatitis B nucleic acid testing of donors has also enhanced our ability to accurately inform recipients regarding transmission risk. Appropriate use of prophylaxis and careful monitoring for transmission posttransplant is key to ensuring no adverse outcomes occur. SUMMARY Treatment of hepatitis B has evolved over the past two decades. Expanding the donor pool with hepatitis B donors is now well tolerated, ethical, and advantageous to the transplant community at large. A clear discussion with recipients on the substantial benefit and low harm of using hepatitis B donors will lead to greater acceptance and utilization of these organs.
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31
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Song K, Yan Q, Yang Y, Lv M, Chen Y, Dai Y, Zhang L, Huang Y, Zhang C, Gao H. Fanconi syndrome induced by adefovir dipivoxil: a case report and clinical review. J Int Med Res 2021; 48:300060520954713. [PMID: 33100076 PMCID: PMC7607140 DOI: 10.1177/0300060520954713] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
More than 150 cases of Fanconi syndrome (FS) or hypophosphatemia osteomalacia induced by low-dose adefovir dipivoxil (ADV) have been reported since 2002, when ADV was introduced for the long-term treatment of hepatitis B virus (HBV) infection. Because the life expectancy of HBV-infected individuals has increased, the adverse effects of long-term treatment with antiviral therapies are increasingly observed, and nephrotoxicity is one of the most severe adverse effects of ADV. Therefore, the number of cases may be far higher than reported. Moreover, ADV-induced FS is often misdiagnosed or diagnosed long after it first develops. ADV-induced FS may seriously decrease patient quality of life and lead to bone fractures and even disability. Although progress has been made in the identification of biomarkers and treatments, few systematic clinical guidelines or clinical reviews for FS induced by ADV have been reported. In this study, we highlighted the recent progress toward understanding of FS induced by ADV, described a clinical case, and summarized the primary characteristics and laboratory findings of this disease.
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Affiliation(s)
- Kaixin Song
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Yan
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Yang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengyue Lv
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuting Chen
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue Dai
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Le Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Huang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cuntai Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyu Gao
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Bone loss in hepatitis B virus-infected patients can be associated with greater osteoclastic activity independently of the retroviral use. Sci Rep 2021; 11:10162. [PMID: 33986322 PMCID: PMC8119499 DOI: 10.1038/s41598-021-89486-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 04/20/2021] [Indexed: 01/04/2023] Open
Abstract
Nucleoside/nucleotide analogs such as tenofovir, have been used as long-term therapy for the treatment of hepatitis B and side effects such as the reduction in bone mineral density have been associated with their use. To determine the relationships between bone, hormonal, biochemical, and mineral parameters in patients with hepatitis B treated with nucleoside/nucleotide antiviral. A cross-sectional study was conducted with 81 adult patients with chronic hepatitis B infection. Dual-energy X-ray absorptiometry (DXA) was performed to assess bone mineral density. Biochemical analyses were performed for osteocalcin, deoxypyridinoline, parathyroid hormone, vitamin D, IGF-1, TSH, testosterone, estradiol, FSH, transaminases, urea, creatinine, calcium, serum and urinary phosphorus, magnesium, and FGF-23, body composition was performed by DXA. Participants, both gender, were divided according to the use of antiretrovirals: Group1: 27 inactive virus carriers without medication; Group2: 27 patients using tenofovir; and Group3: 27 patients using lamivudine or entecavir. DXA readings diagnosed osteopenia in the lumbar spine for 7.4% of individuals in Group1, 15% in Group2, and 3.7% in Group3. For all groups, we observed normal values in bone formation markers, osteocalcin levels as well as parathyroid hormone, insulin growth factor 1, and FGF-23. In all groups, we found increased levels of urinary deoxypyridinoline, a bone resorption marker. Increased levels in the bone resorption markers indicated a high resorptive activity of bone tissue. These data suggested high resorption activity of bone tissue in hepatitis B virus-infected patients independent of the use of antiretrovirals.
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Huang PY, Chiu SYH, Chang KC, Tseng PL, Yen YH, Tsai MC, Wang JH, Kee KM, Chen CH, Hung CH, Chiu KW, Hu TH. A novel evidence of serial changes of bone mineral density in chronic hepatitis B patients treated with entecavir. Hepatol Int 2021; 15:310-317. [PMID: 33907949 DOI: 10.1007/s12072-021-10148-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 01/18/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND AIMS Tenofovir disoproxil fumarate (TDF) and Entecavir (ETV) are commonly used for patients with chronic hepatitis B (CHB), and renal or bone toxicity are possible concerns. This study is to evaluate the renal and bone effect of TDF compared with ETV in CHB patients. METHODS This is a retrospective study at Kaohsiung Chung-Gung memorial hospital, Taiwan, from June 2013 to December 2018. Patients with CHB were prescribed with TDF or ETV for 3 years or above. Renal function was assessed at 12-week intervals. Dual-energy X-ray absorptiometry scans of the spine and femurs were performed at 48-week intervals. The propensity score analysis was conducted to balance the baseline characteristics of patients in both treatment groups. RESULTS A total of 258 patients were included in this study: TDF (n = 135) and ETV (n = 123). The prevalence of osteopenia was much higher in the TDF group at week 48 and week 96. The TDF group showed significant mean percentage decrease from baseline in bone mineral density throughout the treatment course. Logistic regression analysis adjusted for the propensity score demonstrated that the use of TDF was the only predictive factor of significant bone density loss at week 144. The mean percentage decline of estimated glomerular filtration rate was significant in the TDF group at all time points. Renal threshold phosphate concentration was similar among both treatment groups. CONCLUSIONS This study suggested CHB patients treated with TDF may experience increased risks of bone loss and renal deficits compared to those treated with ETV.
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Affiliation(s)
- Pao-Yuan Huang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
| | - Sherry Yueh-Hsia Chiu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- Department of Health Care Management, College of Management; and Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Po-Lin Tseng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Hao Yen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kwong-Ming Kee
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - King-Wah Chiu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan.
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Delshadi R, Bahrami A, McClements DJ, Moore MD, Williams L. Development of nanoparticle-delivery systems for antiviral agents: A review. J Control Release 2021; 331:30-44. [PMID: 33450319 PMCID: PMC7803629 DOI: 10.1016/j.jconrel.2021.01.017] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 01/07/2021] [Accepted: 01/10/2021] [Indexed: 02/07/2023]
Abstract
The COVID-19 pandemic has resulted in unprecedented increases in sickness, death, economic disruption, and social disturbances globally. However, the virus (SARS-CoV-2) that caused this pandemic is only one of many viruses threatening public health. Consequently, it is important to have effective means of preventing viral transmission and reducing its devastating effects on human and animal health. Although many antivirals are already available, their efficacy is often limited because of factors such as poor solubility, low permeability, poor bioavailability, un-targeted release, adverse side effects, and antiviral resistance. Many of these problems can be overcome using advanced antiviral delivery systems constructed using nanotechnology principles. These delivery systems consist of antivirals loaded into nanoparticles, which may be fabricated from either synthetic or natural materials. Nevertheless, there is increasing emphasis on the development of antiviral delivery systems from natural substances, such as lipids, phospholipids, surfactants, proteins, and polysaccharides, due to health and environmental issues. The composition, morphology, dimensions, and interfacial characteristics of nanoparticles can be manipulated to improve the handling, stability, and potency of antivirals. This article outlines the major classes of antivirals, summarizes the challenges currently limiting their efficacy, and highlights how nanoparticles can be used to overcome these challenges. Recent studies on the application of antiviral nanoparticle-based delivery systems are reviewed and future directions are described.
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Affiliation(s)
- Rana Delshadi
- Food Science and Technology Graduate, Menomonie, WI, USA
| | - Akbar Bahrami
- Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University, North Carolina Research Campus, Kannapolis, NC 28081, USA
| | | | - Matthew D Moore
- Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
| | - Leonard Williams
- Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University, North Carolina Research Campus, Kannapolis, NC 28081, USA.
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Brayette A, Essig M, Carrier P, Debette-Gratien M, Labrunie A, Alain S, Maynard M, Ganne-Carrié N, Nguyen-Khac E, Pinet P, De Ledinghen V, Renou C, Mathurin P, Vanlemmens C, Di Martino V, Gervais A, Foucher J, Isabelle FH, Vergniol J, Hourmand-Ollivier I, Cohen D, Duval X, Poynard T, Bardou M, Abergel A, Dao MT, Thévenot T, Hiriart JB, Canva V, Lassailly G, Aurières C, Boyer N, Thabut D, Bernard PH, Schnee M, Larrey D, Hanslik B, Hommel S, Jacques J, Loustaud-Ratti V. Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus. World J Hepatol 2020; 12:1326-1340. [PMID: 33442458 PMCID: PMC7772739 DOI: 10.4254/wjh.v12.i12.1326] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 10/07/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use. AIM To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients. METHODS A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors. RESULTS Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo. CONCLUSION The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.
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Affiliation(s)
- Anaïs Brayette
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
| | - Marie Essig
- U1248 INSERM, Department of Nephrology and Transplantation, CHU Limoges, Limoges F-87000, France
| | - Paul Carrier
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
| | - Marilyne Debette-Gratien
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
| | - Anaïs Labrunie
- Department of Center of Epidemiology, Biostatistics and Research Methodology, CHU Limoges, Limoges F-87000, France
| | - Sophie Alain
- U1092 INSERM, Department of Virology, CHU Limoges, Limoges F-87000, France
| | - Marianne Maynard
- Department of Hepatology, Croix-Rousse University Hospital of Lyon, Lyon 69004, France
| | - Nathalie Ganne-Carrié
- Department of Hepatology, Jean Verdier University Hospital of Bondy, Bondy 93140, France
| | - Eric Nguyen-Khac
- Department of Hepato-Gastroenterology, Amiens University Hospital, Amiens 80054, France
| | - Pauline Pinet
- Department of Infectious Diseases, CHU Limoges, Limoges F-87000, France
| | - Victor De Ledinghen
- Department of Hepatology, Haut Leveque Hospital, Bordeaux University Hospital, Pessac 33604, France
| | - Christophe Renou
- Department of Gastroenterology, Hyeres Hospital, Hyeres 83407, France
| | - Philippe Mathurin
- Department of Hepato-Gastroenterology, Claude Huriez University Hospital, Lille 59037, France
| | - Claire Vanlemmens
- Department of Hepatology, Jean Minjoz University Hospital, Besançon 25030, France
| | - Vincent Di Martino
- Department of Hepatology, Jean Minjoz University Hospital, Besançon 25030, France
| | - Anne Gervais
- Department of Infectious Diseases, Bichat University Hospital, Paris 75018, France
| | - Juliette Foucher
- Department of Hepatology, Haut Leveque Hospital, Bordeaux University Hospital, Pessac 33604, France
| | | | - Julien Vergniol
- Department of Hepatology, Haut Leveque Hospital, Bordeaux University Hospital, Pessac 33604, France
| | | | - Daniel Cohen
- Department of General Medecine, University Hospital of Caen, Caen 14000, France
| | - Xavier Duval
- Department of Infectious Diseases, Bichat University Hospital, Paris 75018, France
| | - Thierry Poynard
- Department of Hepatology, La Pitié-Salpêtrière University Hospital, Paris 75651, France
| | - Marc Bardou
- Department of Hepatology and Gastroenterology, Dijon University Hospital, Dijon 21079, France
| | - Armand Abergel
- Department of Hepatology and Gastroenterology, Estaing University Hospital, Clermont Ferrand 63003, France
| | - Manh-Thong Dao
- Department of Hepato-Gastroenterology and Nutrition, University Hospital of Caen, Caen 14033, France
| | - Thierry Thévenot
- Department of Hepatology, Jean Minjoz University Hospital, Besançon 25030, France
| | - Jean-Baptiste Hiriart
- Department of Hepatology, Haut Leveque Hospital, Bordeaux University Hospital, Pessac 33604, France
| | - Valérie Canva
- Department of Hepato-Gastroenterology, Claude Huriez University Hospital, Lille 59037, France
| | - Guillaume Lassailly
- Department of Hepato-Gastroenterology, Claude Huriez University Hospital, Lille 59037, France
| | - Christine Aurières
- Department of Hepatology, Beaujon University Hospital, Clichy 92110, France
| | - Nathalie Boyer
- Department of Hepatology, Beaujon University Hospital, Clichy 92110, France
| | - Dominique Thabut
- Department of Hepatology, La Pitié-Salpêtrière University Hospital, Paris 75651, France
| | - Pierre-Henri Bernard
- Department of Hepatology, Saint-André University Hospital, Bordeaux 33000, France
| | - Matthieu Schnee
- Department of Hepatology and Gastroenterology, La Roche-Sur-Yon Hospital Center, La Roche-Sur-Yon 85000, France
| | - Dominique Larrey
- Department of Hepatology and Gastroenterology, University Hospital of Montpellier, Montpellier 34295, France
| | - Bertrand Hanslik
- Department of Addictology, Hospital of Montpellier, Montpellier 34295, France
| | - Séverine Hommel
- Department of Hepatology and Gastroenterology, Hospital Center of Aix en Provence, Aix-en-Provence 13100, France
| | - Jérémie Jacques
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
| | - Véronique Loustaud-Ratti
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France.
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Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B. Antiviral Res 2020; 185:104992. [PMID: 33279523 DOI: 10.1016/j.antiviral.2020.104992] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
Long-term treatment with nucleos(t)ide analogs (NAs) is the current first line therapy for patients with chronic hepatitis B (CHB), recommended by most of the current guidelines. NAs prevent disease progression, liver failure, decrease the risk of hepatocellular carcinoma (HCC), and have favorable safety profiles. However, low rates of on-therapy functional cure (hepatitis B surface antigen [HBsAg] loss), which is regarded as the optimal end point, prevent many patients from stopping NA therapy with the need for a lifelong treatment. The higher likelihood of HBsAg loss associated with stopping as compared to continuing NAs has got a lot of attention recently. Recommendations regarding endpoints allowing for safely stopping NA therapy differ between international guidelines. Whereas in HBeAg-positive patients, HBeAg seroconversion with at least one year of consolidation therapy is an acceptable endpoint of treatment, the recommendations for HBeAg-negative ones differ. Some guidelines propose ≥3 years of HBV DNA undetectability to stop NA while others regard HBsAg loss as the only acceptable endpoint. Stopping NA can lead to substantial rates of virologic relapses and consequent ALT flares in some cases. Moreover, no reliable predictor(s) of post-NA relapses have been identified so far. Quantitative HBsAg is becoming an increasingly promising marker to predict safe NA cessation. On the other hand, investigating the role of the immune system in mediating sustained virologic responses after NA withdrawal is needed to suggest immunological biomarkers to safely stop NA. In this article, we will review relevant literature regarding NA stopping strategy and discuss promising viral and immunological biomarkers to predict antiviral responses and thus to help identify patients who are more likely to achieve HBsAg seroclearance.
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Oh KK, Adnan M, Cho DH. Network pharmacology approach to bioactive chemical compounds identified from Lespedeza bicolor lignum methanol extract by GC–MS for amelioration of hepatitis. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100851] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Olejarz P, Chwatko G, Kubalczyk P, Purgat K, Głowacki R, Borowczyk K. Application of High-Performance Liquid Chromatography for Simultaneous Determination of Tenofovir and Creatinine in Human Urine and Plasma Samples. Pharmaceuticals (Basel) 2020; 13:ph13110367. [PMID: 33167541 PMCID: PMC7694483 DOI: 10.3390/ph13110367] [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: 09/30/2020] [Revised: 11/01/2020] [Accepted: 11/04/2020] [Indexed: 11/16/2022] Open
Abstract
Tenofovir disoproxil fumarate is widely used in the therapy of human immunodeficiency virus and hepatitis B virus; however, a high concentration of the prodrug effects kidney function damage. To control the effectiveness of kidney functions in treated patients, the level of creatinine in the body must be controlled. This work describes a simple, fast, and “plastic-waste” reducing method for the simultaneous determination of tenofovir and creatinine in human urine and plasma. In both assays, only 50 µL of body fluid was required. The tests were carried out by reversed phase high-performance liquid chromatography with UV detection. In urine samples, the limits of detection for tenofovir and creatinine were 4 µg mL−1 and 0.03 µmol mL−1, respectively. In plasma samples, the limits of detection were 0.15 µg mL−1 for tenofovir and 0.0003 µmol mL−1 for creatinine. The method was applied for the determination of tenofovir and creatinine in human urine and plasma samples. The biggest advantage of the elaborated method is the possibility to determine tenofovir and creatinine in one analytical run in both urine and plasma sample collected from HIV and HBV patients. The possibility to reduce the level of laboratory waste in a sample preparation protocol is in the mainstream of a new trend of analytical chemistry which is based on green chemistry.
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Yu HC, Lin KH, Tsay FW, Tsai TJ, Wu PC, Chen YH, Chen YH. Kinetics of hepatitis B surface antigen and estimated glomerular filtration rate in telbivudine-treated hepatitis B patients with different rescue strategies. PLoS One 2020; 15:e0237586. [PMID: 32785260 PMCID: PMC7423127 DOI: 10.1371/journal.pone.0237586] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 07/29/2020] [Indexed: 01/09/2023] Open
Abstract
This study investigated the kinetics of estimated glomerular filtration rate (eGFR) and quantitative hepatitis B surface antigen (qHBsAg) in telbivudine (LdT)-treated chronic hepatitis B (CHB) patients whose treatment was subsequently adjusted with the adding on adefovir or by switching to tenofovir disoproxil fumarate (TDF) as rescue. Of 295 CHB patients initially treated with LdT, 102 of them who subsequently receiving either adding-on adefovir (group A, n = 58) or switching to TDF (group B, n = 44) for more than 24 months were enrolled. Serial eGFR and qHBsAg levels (3 to 6 monthly) in both LdT monotherapy and rescue therapy periods were analyzed retrospectively. Subsequent decline of qHBsAg especially in rescue therapy period were noted (p<0.001 and p = 0.068 in group A and B). However, patients in group B achieved a significant increase of eGFR (p = 0.010) in LdT monotherapy period but had a significant decline of eGFR (p<0.001) in rescue therapy period. In contrast, patients in group A maintained eGFR levels in both periods. Meanwhile, switch to TDF (hazard ratio: 3.036; 95% confidence interval: 1.040-8.861; p = 0.042) was the sole factor related to the decrease of eGFR>20% from baseline. Both rescue therapies achieved subsequent declines of qHBsAg over time but caused different changes in eGFR. LdT-based rescue therapy maintained eGFR but TDF switching therapy descended eGFR. Therefore, it is essential to monitor patient's renal function intensively when switching from LdT to TDF as a rescue strategy.
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Affiliation(s)
- Hsien-Chung Yu
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Chung Shan Medical University, Taichung, Taiwan
- Institute of Health Care Management, Department of Business Management, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Kung-Hung Lin
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Feng-Woei Tsay
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Chung Shan Medical University, Taichung, Taiwan
| | - Tzung-Jiun Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Chung Shan Medical University, Taichung, Taiwan
| | - Pin-Chieh Wu
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
- Department of Family Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Yu-Hsun Chen
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Yan-Hua Chen
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- * E-mail:
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Wang Z, Wang W, Wang L. Epigenetic regulation of covalently closed circular DNA minichromosome in hepatitis B virus infection. BIOPHYSICS REPORTS 2020. [DOI: 10.1007/s41048-020-00112-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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41
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Maponga TG, McNaughton AL, van Schalkwyk M, Hugo S, Nwankwo C, Taljaard J, Mokaya J, Smith DA, van Vuuren C, Goedhals D, Gabriel S, Andersson MI, Preiser W, van Rensburg C, Matthews PC. Treatment advantage in HBV/HIV coinfection compared to HBV monoinfection in a South African cohort. J Infect 2020; 81:121-130. [PMID: 32360882 PMCID: PMC7308798 DOI: 10.1016/j.jinf.2020.04.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 04/17/2020] [Accepted: 04/26/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Prompted by international targets for elimination of hepatitis B virus (HBV), we set out to characterise individuals with HBV monoinfection vs. those coinfected with HBV/HIV, to evaluate the impact of therapy and to guide improvements in clinical care. METHODS We report observational data from a real world cross-sectional cohort of 115 adults with chronic hepatitis B infection (CHB), at a university hospital in Cape Town, South Africa. HIV coinfection was present in 39 (34%) subjects. We recorded cross-sectional demographic, clinical and laboratory data. RESULTS Compared to those with HIV coinfection, HBV monoinfected adults were less likely to be HBeAg-positive (p=0.01), less likely to have had assessment with elastography (p<0.0001), and less likely to be on antiviral treatment (p<0.0001); they were more likely to have detectable HBV viraemia (p=0.04), and more likely to have features of liver disease including moderate/severe thrombocytopaenia (p=0.007), elevated bilirubin (p=0.004), and elevated APRI score (p=0.02). Three cases of hepatocellular carcinoma all arose in HBV monoinfection. CONCLUSIONS Our data demonstrate that individuals with HBV monoinfection may be disadvantaged compared to those with HIV coinfection, highlighting potential systematic inequities in referral, monitoring and treatment.
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Affiliation(s)
- Tongai G Maponga
- Division of Medical Virology, Stellenbosch University / National Health Laboratory Service Tygerberg, Cape Town, South Africa
| | - Anna L McNaughton
- Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford, UK
| | - Marije van Schalkwyk
- Division of Infectious Diseases, Department of Medicine, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, South Africa
| | - Susan Hugo
- Division of Infectious Diseases, Department of Medicine, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, South Africa
| | - Chikezie Nwankwo
- Division of Gastroenterology, Department of Medicine, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, South Africa
| | - Jantjie Taljaard
- Division of Infectious Diseases, Department of Medicine, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, South Africa
| | - Jolynne Mokaya
- Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford, UK
| | - David A Smith
- Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford, UK
| | - Cloete van Vuuren
- Division of Infectious Diseases, Department of Internal Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa
| | - Dominique Goedhals
- Division of Virology, Universitas Academic Laboratories, National Health Laboratory Service/University of the Free State, Bloemfontein, South Africa
| | - Shiraaz Gabriel
- Division of Gastroenterology, Department of Medicine, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, South Africa
| | - Monique I Andersson
- Division of Medical Virology, Stellenbosch University / National Health Laboratory Service Tygerberg, Cape Town, South Africa; Department of Microbiology and Infectious Diseases, Oxford University Hospitals, John Radcliffe Hospital, Headington, Oxford, UK
| | - Wolfgang Preiser
- Division of Medical Virology, Stellenbosch University / National Health Laboratory Service Tygerberg, Cape Town, South Africa
| | - Christo van Rensburg
- Division of Gastroenterology, Department of Medicine, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, South Africa
| | - Philippa C Matthews
- Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford, UK; Department of Microbiology and Infectious Diseases, Oxford University Hospitals, John Radcliffe Hospital, Headington, Oxford, UK; NIHR British Research Council, John Radcliffe Hospital, Headington, Oxford, UK.
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Hajiani E, Parsi A, Seyedian SS, Rajaei E, Jolodarian P. Comparing the frequency of osteoporosis and osteopenia in chronic hepatitis B patients with and without Tenofovir treatment. CLINICAL EPIDEMIOLOGY AND GLOBAL HEALTH 2020. [DOI: 10.1016/j.cegh.2019.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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43
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Sun L, Yi D, Sun W, Wang C. Retrospective analysis of the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population. J Clin Pharm Ther 2020; 45:722-728. [PMID: 32406123 DOI: 10.1111/jcpt.13154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 12/19/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE To explore the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population and provide a reference for rational drug use in the clinic. METHODS By searching the CNKI, Wanfang, Chinese VIP, PubMed/MEDLINE, Web of Knowledge, Ovid, Elsevier and SpringerLink databases during 1 January 2008 to 31 December 2019, 78 studies of ADV-induced Fanconi's syndrome involving a total of 110 patients were collected and analysed retrospectively. RESULTS AND DISCUSSION Prolonged usage of adefovir dipivoxil at low doses to treat hepatitis B might cause Fanconi's syndrome as the first symptom, especially for use over 12 months.The main clinical manifestation was bone pain accompanied by hypophosphataemia, elevated alkaline phosphatase (ALP), urine glycosuria and urine protein. X-rays and bone mineral density (BMD) examinations were mainly used to characterized osteoporosis. The patients had pain relief within 1 week to 1 month, and the biochemical indicators returned to normal within from 2 to 4 months. WHAT IS NEW AND CONCLUSION Sufficient attention is required before and during exposure to long-term ADV therapy. The clinical picture, laboratory and radiograph alterations are important clues for ADV-induced Fanconi's syndrome.
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Affiliation(s)
- Linli Sun
- Department of general surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Dan Yi
- Drug clinical trial center, Zhuzhou central hospital, Zhuzhou, China
| | - Wei Sun
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Chunjiang Wang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
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Hayashi S, Higashi-Kuwata N, Das D, Tomaya K, Yamada K, Murakami S, Venzon DJ, Hattori SI, Isogawa M, Sarafianos SG, Mitsuya H, Tanaka Y. 7-Deaza-7-fluoro modification confers on 4'-cyano-nucleosides potent activity against entecavir/adefovir-resistant HBV variants and favorable safety. Antiviral Res 2020; 176:104744. [PMID: 32084506 PMCID: PMC7164687 DOI: 10.1016/j.antiviral.2020.104744] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/20/2020] [Accepted: 02/10/2020] [Indexed: 12/15/2022]
Abstract
We designed, synthesized and identified a novel nucleoside derivative, 4'-C-cyano-7-deaza-7-fluoro-2'-deoxyadenosine (CdFA), which exerts potent anti-HBV activity (IC50 ~26 nM) with favorable hepatocytotoxicity (CC50 ~56 μM). Southern blot analysis using wild-type HBV (HBVWT)-encoding-plasmid-transfected HepG2 cells revealed that CdFA efficiently suppresses the production of HBVWT (IC50 = 153.7 nM), entecavir (ETV)-resistant HBV carrying L180M/S202G/M204V substitutions (HBVETVR; IC50 = 373.2 nM), and adefovir dipivoxil (ADV)-resistant HBV carrying A181T/N236T substitutions (HBVADVR; IC50=192.6 nM), whereas ETV and ADV were less potent against HBVETVR and HBVADVR (IC50: >1,000 and 4,022.5 nM, respectively). Once-daily peroral administration of CdFA to human-liver-chimeric mice over 14 days (1 mg/kg/day) comparably blocked HBVWT and HBVETVR viremia by 0.7 and 1.2 logs, respectively, without significant changes in body-weight or serum human-albumin levels, although ETV only slightly suppressed HBVETVR viremia (CdFA vs ETV; p = 0.032). Molecular modeling suggested that ETV-TP has good nonpolar interactions with HBVWT reverse transcriptase (RTWT)'s Met204 and Asp205, while CdFA-TP fails to interact with Met204, in line with the relatively inferior activity against HBVWT of CdFA compared to ETV (IC50: 0.026 versus 0.003 nM). In contrast, the 4'-cyano of CdFA-TP forms good nonpolar contacts with RTWT's Leu180 and RTETVR's Met180, while ETV-TP loses interactions with RTETVR's Met180, explaining in part why ETV is less potent against HBVETVR than CdFA. The present results show that CdFA exerts potent activity against HBVWT, HBVETVR and HBVADVR with enhanced safety and that 7-deaza-7-fluoro modification confers potent activity against drug-resistant HBV variants and favorable safety, shedding light to further design more potent and safer anti-HBV nucleoside analogs.
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Affiliation(s)
- Sanae Hayashi
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Nobuyo Higashi-Kuwata
- Department of Refractory Viral Infections, National Center for Global Health & Medicine Research Institute, Tokyo, Japan
| | - Debananda Das
- Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kota Tomaya
- Biochemicals Division, Yamasa Corporation, Choshi, Chiba, Japan
| | - Kohei Yamada
- Biochemicals Division, Yamasa Corporation, Choshi, Chiba, Japan
| | - Shuko Murakami
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - David J Venzon
- Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shin-Ichiro Hattori
- Department of Refractory Viral Infections, National Center for Global Health & Medicine Research Institute, Tokyo, Japan
| | - Masanori Isogawa
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Stefan G Sarafianos
- Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
| | - Hiroaki Mitsuya
- Department of Refractory Viral Infections, National Center for Global Health & Medicine Research Institute, Tokyo, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Clinical Sciences, Kumamoto University Hospital, Kumamoto, Japan.
| | - Yasuhito Tanaka
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
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Wang YH, Liao J, Zhang DM, Wu DB, Tao YC, Wang ML, Chen EQ, Tang H. Tenofovir monotherapy versus tenofovir plus entecavir combination therapy in HBeAg-positive chronic hepatitis patients with partial virological response to entecavir. J Med Virol 2020; 92:302-308. [PMID: 31609007 DOI: 10.1002/jmv.25608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 09/24/2019] [Accepted: 10/08/2019] [Indexed: 02/05/2023]
Abstract
AIMS The aim of this retrospective study was to compare the efficacy and safety of tenofovir disoproxil fumarate (TDF) monotherapy and TDF + entecavir (ETV) combination therapy for chronic hepatitis B (CHB) patients with the partial virological response (PVR) to ETV. METHODS CHB patients with PVR to ETV were switched to TDF monotherapy or TDF + ETV combination therapy. The primary efficacy outcome was a virological response (VR), and the secondary efficacy outcomes were hepatitis B e antigen (HBeAg) seroconversion and alanine aminotransferase (ALT) normalization. The primary safety outcomes were changes in serum creatinine and serum phosphorus levels. RESULTS A total of 143 patients were investigated, including 63 patients in the TDF monotherapy group and 80 patients in the TDF + ETV combination therapy group. Baseline demographics and clinical characteristics were comparable between groups. The median age of patients was 44.5 years, and 76.2% of them were male. The VR rate in TDF + ETV group was higher than that of the TDF group at 48 weeks (88.8% vs 71.4%; P = .009). At 48 weeks, the HBeAg seroconversion rate of TDF + ETV group was higher than that of the TDF group (30% vs 15.9%; P = .049). There was no significant difference in the proportion of patients with elevated ALT in the TDF group and TDF + ETV group at 48 weeks (9.5% vs 7.5%; P = .665). After adjusting the treatment regimen, serum creatinine levels increased slightly and serum phosphorus level decreased slightly in both groups. CONCLUSIONS TDF + ETV combination therapy for 48 weeks had a higher VR rate than TDF monotherapy in CHB patients with PVR to ETV.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Juan Liao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Dong-Mei Zhang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Dong-Bo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Meng-Lan Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Adverse events of nucleos(t)ide analogues for chronic hepatitis B: a systematic review. J Gastroenterol 2020; 55:496-514. [PMID: 32185517 PMCID: PMC7188775 DOI: 10.1007/s00535-020-01680-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 02/26/2020] [Indexed: 02/04/2023]
Abstract
Nucleos(t)ide analogues (NAs) are the main drug category used in chronic hepatitis B (CHB) treatment. Despite the fact that NAs have a favourable safety profile, undesired adverse events (AEs) may occur during the treatment of CHB. Given the eminent number of patients currently receiving NAs, even a small risk of any of these toxicities can represent a major medical issue. The main objective of this review was to analyse information available on AEs associated with the use of NAs in published studies. We choose the following MesH terms for this systematic review: chronic hepatitis B, side effects and treatment. All articles published from 1 January 1990 up to 19 February 2018 in MEDLINE of PubMed, EMBASE, the Cochrane Library and LILACS databases were searched. A total of 120 articles were selected for analysis, comprising 6419 patients treated with lamivudine (LAM), 5947 with entecavir (ETV), 3566 with tenofovir disoproxil fumarate (TDF), 3096 with telbivudine (LdT), 1178 with adefovir dipivoxil (ADV) and 876 with tenofovir alafenamide (TAF). The most common AEs in all NAs assessed were abdominal pain/discomfort, nasopharyngitis/upper respiratory tract infections, fatigue, and headache. TAF displays the highest density of AEs per patient treated among NAs (1.14 AE/treated patient). In conclusion, treatment of CHB with NAs is safe, with a low incidence of AEs. Despite the general understanding TAF being safer than TDF, the number of patients treated with TAF still is too small in comparison to other NAs to consolidate an accurate safety profile. PROSPERO Registration No. CRD42018086471.
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Lee D, Yun BC, Seo KI, Han BH, Lee SU, Park ET, Lee JW, Jeong J. Risk factors associated with hypophosphatemia in chronic Hepatitis B patients treated with tenofovir disoproxil fumarate. Medicine (Baltimore) 2019; 98:e18351. [PMID: 31852136 PMCID: PMC6922420 DOI: 10.1097/md.0000000000018351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is thought to cause varying degrees of hypophosphatemia in patients with chronic hepatitis B (CHB). Therefore, we investigated factors that cause hypophosphatemia in patients treated with TDF and methods to increase serum phosphorus concentrations in clinical practice.We completed a retrospective review of patients with CHB treated with TDF initially at Kosin University Gospel Hospital, Busan, Korea from January 2012 to January 2017. Subclinical hypophosphatemia and hypophosphatemia were defined as serum phosphorus below 3.0 mg/dL and 2.5 mg/dL, respectively.We screened 206 patients with CHB treated with TDF, among which 135 were excluded for the following reasons: baseline malignancy (59), limited data (50), co-administered other antivirals (14), hypophosphatemia at baseline (7), and other reasons (5). The final study population comprised 71 patients. Subclinical hypophosphatemia developed in 43 (60.5%) patients. Hypophosphatemia occurred in 18 patients (25.3%). Liver cirrhosis was the most significant predictor of hypophosphatemia (P = .038, OR = 3.440, CI = 1.082-10.937) Patients diagnosed with subclinical hypophosphatemia were encouraged to increase their intake of nuts and dairy products (25 patients) or reduce their alcohol intake (2), dose reduction of TDF (4) or placed under observation (4). Among patients with subclinical hypophosphatemia, serum phosphorus concentrations were elevated (>3.0 mg/dL) in 23 of 36 patients (63.8%). Increased nut and dairy intake increased phosphorus concentrations to more than 3.0 mg/dl in 16 of 25 patients (64.0%).Entecavir or tenofovir alafenamide fumarate (TAF) should be considered rather than TDF in patients with liver cirrhosis because of the risk of hypophosphatemia. Instead of stopping TDF treatment, encouraging increased intake of phosphorus-rich foods could increase serum phosphorus concentrations in clinical practice.
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Dessordi R, Santana RDC, Navarro AM. Influence of antiretroviral therapy on bone metabolism of patients with chronic hepatitis B: a review. Rev Soc Bras Med Trop 2019; 52:e20180441. [PMID: 31596347 DOI: 10.1590/0037-8682-0441-2018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 08/21/2019] [Indexed: 11/21/2022] Open
Abstract
Hepatitis B is a major public health problem worldwide and associated with significant mortality. To prevent or delay the deleterious effects of chronic infection by the hepatitis B virus, patients should be carefully followed, and antiviral therapy indicated according to specific recommendations. Currently, available drugs inhibit viral replication and slow or stop the progression of inflammation and fibrosis of the liver. However, the drugs for oral use in the treatment of hepatitis B, jointly referred to as nucleoside/nucleotide analogs, are indicated for prolonged use and have potential side effects. The reduction in bone mineral density was associated with the use of tenofovir, already evaluated in patients infected with HIV because the drug is also part of the therapeutic arsenal for this viral infection. There are few studies on the effects of tenofovir in patients with mono hepatitis B. Therefore, this literature review proposes to examine how hepatitis B acts in the body and the mechanisms by which antiretroviral drugs (especially tenofovir) can affect bone metabolism.
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Affiliation(s)
- Renata Dessordi
- Universidade Estadual Paulista "Júlio de Mesquita Filho", Programa de Pós-Graduação Stricto Sensu em Alimentos e Nutrição, São Paulo, SP, Brasil.,Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas do Estado de São Paulo, Departamento de Alimentos e Nutrição, São Paulo, SP, Brasil
| | - Rodrigo de Carvalho Santana
- Universidade de São Paulo, Escola de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil
| | - Anderson Marliere Navarro
- Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas do Estado de São Paulo, Departamento de Alimentos e Nutrição, São Paulo, SP, Brasil.,Universidade de São Paulo, Escola de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil
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49
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Jeong HM, Kim DJ. Bone Diseases in Patients with Chronic Liver Disease. Int J Mol Sci 2019; 20:4270. [PMID: 31480433 PMCID: PMC6747370 DOI: 10.3390/ijms20174270] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 08/25/2019] [Accepted: 08/28/2019] [Indexed: 02/07/2023] Open
Abstract
Osteoporosis is a frequently observed complication in patients with chronic liver disease, particularly liver cirrhosis and cholestatic liver diseases. In addition, osteoporosis is critical in patients receiving a liver transplant. Nevertheless, few studies have evaluated bone diseases in patients with more frequently observed chronic liver disease, such as chronic viral hepatitis, nonalcoholic fatty liver disease and alcoholic liver disease. Osteoporosis is a disease caused by an imbalance in the activities of osteoblasts and osteoclasts. Over the last few decades, many advances have improved our knowledge of the pathogenesis of osteoporosis. Importantly, activated immune cells affect the progression of osteoporosis, and chronic inflammation may exert an additional effect on the existing pathophysiology of osteoporosis. The microbiota of the intestinal tract may also affect the progression of bone loss in patients with chronic liver disease. Recently, studies regarding the effects of chronic inflammation on dysbiosis in bone diseases have been conducted. However, mechanisms underlying osteoporosis in patients with chronic liver disease are complex and precise mechanisms remain unknown. The following special considerations in patients with chronic liver disease are reviewed: bone diseases in patients who underwent a liver transplant, the association between chronic hepatitis B virus infection treatment and bone diseases, the association between sarcopenia and bone diseases in patients with chronic liver disease, and the association between chronic liver disease and avascular necrosis of the hip. Few guidelines are currently available for the management of low bone mineral density or bone diseases in patients with chronic liver disease. Due to increased life expectancy and therapeutic advances in chronic liver disease, the importance of managing osteoporosis and other bone diseases in patients with chronic liver disease is expected to increase. Consequently, specific guidelines need to be established in the near future.
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Affiliation(s)
- Hae Min Jeong
- Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do 24253, Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Gangwon-do 24253, Korea
| | - Dong Joon Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Gangwon-do 24253, Korea.
- Department of Internal Medicine, Hallym University College of Medicine, Seoul 05355, Korea.
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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