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Niu YJ, Ai X, Lin XT, Xu WM, Lao SY, Tian ZC, Zhu HY, Zhou W, Huang H, Shi XL. Baicalein inhibits hepatitis B virus through the coiled coil domain containing protein 88A (CCDC88A)-dependent autophagy pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156577. [PMID: 40023973 DOI: 10.1016/j.phymed.2025.156577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Chronic infection with the hepatitis B virus (HBV) represents a significant global health concern. Baicalein, a naturally occurring flavone derived from the roots of Scutellaria baicalensis Georgi, has exhibited both anti-inflammatory and antiviral activities. S. baicalensis is extensively utilized in traditional Chinese medicine for the treatment of various liver disorders, including hepatitis. However, the specific anti-HBV effects of baicalein have not been fully elucidated. PURPOSE This study aimed to investigate the inhibitory effects of baicalein on HBV and to elucidate its underlying mechanisms. MATERIALS AND METHODS The levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were measured using enzyme-linked immunosorbent assay (ELISA) kits. Quantification of HBV DNA was performed using quantitative real-time polymerase chain reaction (qRT-PCR). Western blot analysis was conducted to evaluate proteins involved in autophagy, lysosomal acidification, and autophagy-related signaling pathways. Immunofluorescence microscopy was utilized to assess autophagic flux and lysosomal acidification. RESULTS Baicalein demonstrated significant inhibition of HBsAg, HBeAg, and HBV-DNA secretion in both in vivo and in vitro environments. Subsequent investigations revealed that baicalein disrupted the intracellular trafficking of the hepatitis B virus by inhibiting the CCDC88A-AKT-mTOR (Coiled coil domain containing protein 88A- protein kinase B-mammalian target of rapamycin) signaling pathway. Additionally, baicalein induced autophagy in HepG2 (Human hepatocellular carcinoma cell line 2) and HepG2.215 cell models. The anti-hepatitis B antigen effect of baicalein was partially attenuated when both early and late stages of autophagy were inhibited. A significant correlation was identified between the phosphorylation of AMPKα and the enhanced autophagy observed in baicalein-treated cells. CONCLUSIONS This study elucidates a novel mechanism by which baicalein inhibits the hepatitis B virus (HBV). Specifically, baicalein exerts its antiviral effects by activating autophagy and suppressing the CCDC88A-AKT-mTOR signaling pathway.
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Affiliation(s)
- Yi-Jun Niu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China
| | - Xin Ai
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China
| | - Xiao-Tong Lin
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China
| | - Wei-Ming Xu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China
| | - Su-Ya Lao
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China
| | - Zi-Chen Tian
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China
| | - Hai-Yan Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China
| | - Wei Zhou
- Department of Chemistry, Fudan University, 220 Han Dan Road, Shanghai 200433, China
| | - Hai Huang
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China
| | - Xun-Long Shi
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai 201203, , PR China.
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Niu YJ, Xia CJ, Ai X, Xu WM, Lin XT, Zhu YQ, Zhu HY, Zeng X, Cao ZL, Zhou W, Huang H, Shi XL. Sequential activation of ERα-AMPKα signaling by the flavonoid baicalin down-regulates viral HNF-dependent HBV replication. Acta Pharmacol Sin 2025; 46:653-661. [PMID: 39478159 PMCID: PMC11845607 DOI: 10.1038/s41401-024-01408-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 10/08/2024] [Indexed: 02/23/2025]
Abstract
Baicalin (BA), a natural component found in many traditional Chinese medicines, exerts protective effects against several viruses. Although our previous studies have revealed that the anti-hepatitis B virus (anti-HBV) activity of BA depends on hepatocyte nuclear factor (HNF) signaling, the specific mechanisms remain unclear. The present study explored the potential signaling mechanisms involved in BA-mediated HBV suppression. Transcriptomic analysis suggested that BA significantly modulates the estrogen receptor (ER) and AMPK signaling pathways in HepG2 cells. The ER alpha (ERα) binding affinity of BA and its estrogen-like agonist activity were subsequently verified through molecular docking assays, BA-ERα affinity detection experiments, ERα luciferase reporter gene assays, and qRT-PCR. ERα knockdown (shRNA) and AMPK inhibition (Compound C and doxorubicin [Dox]) experiments revealed that the sequential activation of the ERα-LKB1-AMPK-HNF signaling axis is essential for the anti-HBV effects of BA. This study indicates that BA may trigger the ERα-AMPKα-HNF pathway to inhibit HBV replication, providing insights into its potential protective mechanisms against other viruses.
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Affiliation(s)
- Yi-Jun Niu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Cheng-Jie Xia
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xin Ai
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Wei-Ming Xu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xiao-Tong Lin
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Ying-Qi Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Hai-Yan Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xian Zeng
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Zhong-Lian Cao
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Wei Zhou
- Department of Chemistry, Fudan University, Shanghai, 201203, China
| | - Hai Huang
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xun-Long Shi
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China.
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Li Y, Li YW, Gao Y. Effect of Entecavir, Tenofovir Disoproxil Fumarate, and Tenofovir Alafenamideantiviral Therapy on Renal Function in Chronic Hepatitis B Patients: A Real-World Retrospective Study. Int J Gen Med 2025; 18:1143-1153. [PMID: 40034830 PMCID: PMC11874758 DOI: 10.2147/ijgm.s497550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 02/14/2025] [Indexed: 03/05/2025] Open
Abstract
Background Entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide(TAF) are first-line nucleos(t)ide analogs (NUCs) with chronic hepatitis B (CHB). This study aimed to assess the renal safety profile in NUC-experienced CHB patients who received ETV, TDF or TAF therapy. Methods This retrospective observational cohort study investigated factors related to renal function in 154 patients with NUC-experienced CHB who received ETV, TDF, and TAF therapy for 48 weeks. Changes in UREA, uric acid (UA), creatinine (Cr), and estimated glomerular filtration rate (eGFR) were analyzed using a one-way analysis of variance. A linear mixed-effects model for repeated measures was used to evaluate the correlation between baseline information and eGFR changes 48 weeks following treatment initiation. The model considered sex, baseline age, viral load, aminotransferases, renal function, and treatment group as fixed effects, and incorporated random effects for individual subjects. Results There were no significant differences in UA or Cr levels during therapy over time. The eGFR level was elevated in ETV-treated patients (117.5 ± 16.65 mL/min/1.7m2 vs 109.8 ± 15.69 mL/min/1.7m2, P=0.027), whereas it did not change significantly in TDF- (123.6 ± 28.54 mL/min/1.7m2 vs 115.5 ± 20.44 mL/min/1.7m2, P=0.070) and TAF-treated (121.6 ± 23.44 mL/min/1.7m2 vs 113.4 ± 16.90 mL/min/1.7m2, P=0.053) patients. Younger patients (<30 years) and those with higher HBV DNA (> 7 log10IU/mL) and lower alanine aminotransferase levels (<5 × upper limit of normal) showed a significant improvement in eGFR elevation during NUCs therapy. The linear mixed-effects model showed that the baseline HBV DNA level was an important positive predictor of eGFR elevation at 48 weeks following treatment initiation (estimate was 1.437 and 2.449, P<0.001). Conclusion In real-life experience, ETV, TDF, and TAF therapy may not be associated with eGFR changes in NUC-experienced CHB patients without baseline renal impairment.
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Affiliation(s)
- Yu Li
- Department of Infectious Diseases, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi Province, 710068, People’s Republic of China
| | - Ya-Wei Li
- Division of Medical Affairs, Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, Hubei Province, 442099, People’s Republic of China
| | - Ying Gao
- Department of Hematology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi Province, 710068, People’s Republic of China
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Woodson ME, Walden HF, Mottaleb MA, Makri M, Prifti GM, Moianos D, Pardali V, Zoidis G, Tavis JE. Efficacy and in vitro pharmacological assessment of novel N-hydroxypyridinediones as hepatitis B virus ribonuclease H inhibitors. Antimicrob Agents Chemother 2025; 69:e0145524. [PMID: 39601549 PMCID: PMC11784145 DOI: 10.1128/aac.01455-24] [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: 09/26/2024] [Accepted: 10/23/2024] [Indexed: 11/29/2024] Open
Abstract
We previously reported N-hydroxypyridinedione (HPD) compounds with mid-nanomolar efficacy and selectivity indexes around 300 against hepatitis B virus (HBV) replication. However, they lack pharmacological evaluation. Here, we report in vitro anti-HBV efficacy, cytotoxicity, and pharmacological characterization of 29 novel HPDs within seven subgroups. The best two compounds had EC50s of 61 and 190 nM and selectivity indexes of 526 and 1,071. Compounds with one halogen on the major R group were most effective and compounds with large ether R groups were most cytotoxic. Compounds were not cytotoxic in primary human hepatocytes. All compounds were freely soluble in pHs reflecting plasma (7.4) and the gastrointestinal tract (5 and 6.5). Almost all highly soluble compounds were passively permeable at pH 5.0 and 7.4. Only 2 of 11 compounds tested were likely to be effluxed by p-glycoprotein. The most potent HPDs inhibited HBV replication over human ribonuclease H1 activity by 10-fold. Four of 19 compounds inhibited CYP2D6 >50%, but their CYP2D6 IC50s were >8× higher than their anti-HBV EC50. No compound substantially inhibited CYP3A4. Thirteen of 15 compounds had human microsomal half-lives >30 min with medium to low rates of intrinsic clearance. Eleven of 12 compounds bound plasma proteins by ≥80%; however, effects against HBV replication for only one would likely be physiologically relevant. These results identify two lead candidate HPDs with pharmacological characteristics resembling commercially available drugs that are suitable for in vivo pharmacological and efficacy studies.
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Affiliation(s)
- Molly E. Woodson
- Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri, USA
- Institute for Drug and Biotherapeutic Innovation, St. Louis University, St. Louis, Missouri, USA
| | - Holly F. Walden
- Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri, USA
- Institute for Drug and Biotherapeutic Innovation, St. Louis University, St. Louis, Missouri, USA
| | - M. Abdul Mottaleb
- Institute for Drug and Biotherapeutic Innovation, St. Louis University, St. Louis, Missouri, USA
| | - Maria Makri
- Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
| | - Georgia-Myrto Prifti
- Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
| | - Dimitrios Moianos
- Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
| | - Vasiliki Pardali
- Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
| | - Grigoris Zoidis
- Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
| | - John E. Tavis
- Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri, USA
- Institute for Drug and Biotherapeutic Innovation, St. Louis University, St. Louis, Missouri, USA
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Ismael NY, Usmael SA, Belay NB, Mekonen HD, Johannessen A, Orlien SM. Chronic hepatitis B virus infection in Eastern Ethiopia: Clinical characteristics and determinants of cirrhosis. World J Hepatol 2024; 16:995-1008. [PMID: 39086536 PMCID: PMC11287608 DOI: 10.4254/wjh.v16.i7.995] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 06/14/2024] [Accepted: 07/05/2024] [Indexed: 07/26/2024] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) virus infection is a major cause of liver-associated morbidity and mortality, particularly in low-income countries. A better understanding of the epidemiological, clinical, and virological characteristics of CHB will guide appropriate treatment strategies and improve the control and management of CHB in Ethiopia. AIM To investigate the characteristics of CHB in Eastern Ethiopia and assess the efficacy and safety of antiviral treatment. METHODS This cohort study included 193 adults who were human immunodeficiency virus-negative with CHB between June 2016 and December 2019. Baseline assessments included chemistry, serologic, and viral markers. χ 2 tests, Mann-Whitney U tests, and logistic regression analyses were used to identify the determinants of cirrhosis. Tenofovir disoproxil fumarate (TDF) was initiated using treatment criteria from the Ethiopian CHB pilot program. RESULTS A total of 132 patients (68.4%) were men, with a median age of 30 years [interquartile range (IQR): 24-38]. At enrollment, 60 (31.1%) patients had cirrhosis, of whom 35 (58.3%) had decompensated cirrhosis. Khat use, hepatitis B envelope antigen positivity, and a high viral load were independently associated with cirrhosis. Additionally, 66 patients (33.4%) fulfilled the treatment criteria and 59 (30.6%) started TDF. Among 29 patients who completed 24 months of treatment, the median aspartate aminotransferase to platelet ratio index declined from 1.54 (IQR: 0.66-2.91) to 1.10 (IQR: 0.75-2.53) (P = 0.002), and viral suppression was achieved in 80.9% and 100% of patients after 12 months and 24 months of treatment, respectively. Among the treated patients, 12 (20.3%) died within the first 6 months of treatment, of whom 8 had decompensated cirrhosis. CONCLUSION This study highlights the high prevalence of cirrhosis, initial mortality, and the efficacy of TDF treatment. Scaling up measures to prevent and control CHB infections in Ethiopia is crucial.
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Affiliation(s)
- Nejib Y Ismael
- Department of Internal Medicine, Haramaya University, College of Health and Medical Sciences, Harar 252, Ethiopia
| | - Semir A Usmael
- Department of Internal Medicine, Haramaya University, College of Health and Medical Sciences, Harar 252, Ethiopia.
| | - Nega B Belay
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa 1000, Ethiopia
- Regional Centre for Imported and Tropical Diseases, Oslo University Hospital, Oslo 0450, Ullevål, Norway
| | - Hailemichael Desalegn Mekonen
- Internal Medicine, Gastroenterology and Hepatology Unit, Saint Paul's Hospital Millennium Medical College, Addis Ababa 1000, Ethiopia
- Department of Infectious Disease, Vestfold Hospital Trust, Tønsberg 3103, Norway
| | - Asgeir Johannessen
- Regional Centre for Imported and Tropical Diseases, Oslo University Hospital, Oslo 0450, Ullevål, Norway
- Department of Infectious Disease, Vestfold Hospital Trust, Tønsberg 3103, Norway
- Institute of Clinical Medicine, Oslo University, Oslo 0318, Norway
| | - Stian Ms Orlien
- Regional Centre for Imported and Tropical Diseases, Oslo University Hospital, Oslo 0450, Ullevål, Norway
- Department of Infectious Disease, Vestfold Hospital Trust, Tønsberg 3103, Norway
- Department of Pediatrics, Oslo University, Oslo 0450, Ullevål, Norway
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Jang TY, Liang PC, Jun DW, Jung JH, Toyoda H, Wang CW, Yuen MF, Cheung KS, Yasuda S, Kim SE, Yoon EL, An J, Enomoto M, Kozuka R, Chuma M, Nozaki A, Ishikawa T, Watanabe T, Atsukawa M, Arai T, Hayama K, Ishigami M, Cho YK, Ogawa E, Kim HS, Shim JJ, Uojima H, Jeong SW, Ahn SB, Takaguchi K, Senoh T, Buti M, Vargas-Accarino I E, Abe H, Takahashi H, Inoue K, Yeh ML, Dai CY, Huang JF, Huang CF, Chuang WL, Nguyen MH, Yu ML. Mortality in patients with chronic hepatitis B treated with tenofovir or entecavir: A multinational study. J Gastroenterol Hepatol 2024; 39:1190-1197. [PMID: 38480009 DOI: 10.1111/jgh.16537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/24/2024] [Accepted: 02/27/2024] [Indexed: 06/19/2024]
Abstract
BACKGROUND AND AIM The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. METHODS A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. RESULTS The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. CONCLUSIONS Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.
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Affiliation(s)
- Tyng-Yuan Jang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Program of Environmental and Occupational Medicine and Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, South Korea
| | - Jang Han Jung
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Chih-Wen Wang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Ka Shing Cheung
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Sung Eun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
| | - Eileen L Yoon
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, South Korea
| | - Jihyun An
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, South Korea
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Ritsuzo Kozuka
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Tsunamasa Watanabe
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Taeang Arai
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Korenobu Hayama
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University, Fukuoka, Japan
| | - Hyoung Su Kim
- Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
| | - Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, South Korea
| | - Haruki Uojima
- Department of Gastroenterology and Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, South Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, South Korea
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Maria Buti
- Liver Unit, Hospital Universitari Vall d'Hebron and CIBEREHD del Instituto Carlos III, Barcelona, Spain
| | - Elena Vargas-Accarino I
- Liver Unit, Hospital Universitari Vall d'Hebron and CIBEREHD del Instituto Carlos III, Barcelona, Spain
| | - Hiroshi Abe
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, Saga, Japan
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Kaori Inoue
- Liver Center, Saga University Hospital, Saga, Japan
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Ming-Lun Yeh
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
- PhD Program in Translational Medicine, College of Medicine, Kaohsiung Medical University and Academia Sinica, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Ming-Lung Yu
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Wei T, Zhou BY, Wu XH, Liu XA, Huo MW, Huang XX, Shi LZ, Shi LL, Cao QR. Development of Polyvinyl Alcohol/Polyethylene Glycol Copolymer-based Orodispersible Films Loaded with Entecavir: Formulation and In vitro Characterization. Curr Drug Deliv 2024; 21:1362-1374. [PMID: 37929732 DOI: 10.2174/0115672018261294231024093926] [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: 05/22/2023] [Revised: 08/08/2023] [Accepted: 09/06/2023] [Indexed: 11/07/2023]
Abstract
PURPOSE The aim of the study is to prepare entecavir (ETV)-loaded orodispersible films (ODFs) using polyvinyl alcohol (PVA)/polyethylene glycol (PEG) graft copolymer (Kollicoat® IR) as a film-forming agent, and further to evaluate the dissolution rate, mechanical and physicochemical properties of films. METHODS ETV-ODFs were prepared by a solvent casting method. The amount of film-forming agent, plasticizer, and disintegrating agent was optimized in terms of the appearance, thickness, disintegration time and mechanical properties of ODFs. The compatibility between the drug and each excipient was conducted under high temperature (60 °C), high humidity (RH 92.5%), and strong light (4500 Lx) for 10 days. The dissolution study of optimal ODFs compared with the original commercial tablet (Baraclude®) was performed using a paddle method in pH 1.0, pH 4.5, pH 6.8, and pH 7.4 media at 37 °C. The morphology of ODFs was observed via scanning electron microscopy (SEM). The mechanical properties such as tensile strength (TS), elastic modulus (EM), and percentage elongation (E%) of ODFs were evaluated using the universal testing machine. The physicochemical properties of ODFs were investigated using X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR). RESULTS The related substances were less than 0.5% under high temperature, high humidity, and strong light for 10 days when ETV was mixed with excipients. The optimal formulation of ODFs was set as the quality ratio of Kollicoat® IR, glycerol, sodium alginate (ALG-Na): TiO2: MCC+CMC-Na: ETV was 60:9:12:1:1:1. The drug-loaded ODFs were white and translucent with excellent stripping property. The thickness, disintegration time, EM, TS, and E% were 103.33±7.02 μm, 25.31±1.95 s, 25.34±8.69 Mpa, 2.14±0.26 Mpa, and 65.45±19.41 %, respectively. The cumulative drug release from ODFs was more than 90% in four different media at 10 min. The SEM showed that the drug was highly dispersible in ODFs, and the XRD, DSC, and FT-IR results showed that there occurred some interactions between the drug and excipients. CONCLUSION In conclusion, the developed ETV-loaded ODFs showed relatively short disintegration time, rapid drug dissolution, and excellent mechanical properties. This might be an alternative to conventional ETV Tablets for the treatment of chronic hepatitis B.
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Affiliation(s)
- Teng Wei
- College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China
| | - Bing-Yu Zhou
- Dongliao People's Hospital, Liaoyuan, People's Republic of China
| | - Xin-Hong Wu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China
| | - Xue-Ai Liu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China
| | - Ming-Wei Huo
- College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China
| | - Xiang-Xiang Huang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China
| | - Ling-Zhi Shi
- College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China
| | - Li-Li Shi
- College of Medicine, Jiaxing University, Jiaxing, People's Republic of China
| | - Qin-Ri Cao
- College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China
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8
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Ning Q, Yang T, Guo X, Huang Y, Gao Y, Liu M, Yang P, Guan Y, Liu N, Wang Y, Chen D. CHB patients with rtA181T-mutated HBV infection are associated with higher risk hepatocellular carcinoma due to increases in mutation rates of tumour suppressor genes. J Viral Hepat 2023; 30:951-958. [PMID: 37735836 DOI: 10.1111/jvh.13886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 08/11/2023] [Accepted: 08/24/2023] [Indexed: 09/23/2023]
Abstract
The HBV rtA181T mutation is associated with an increased risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to evaluate the mechanism by which rtA181T mutation increases the risk of HCC. We enrolled 470 CHB patients with rtA181T and rtA181V mutation in this study; 68 (22.15%) of the 307 patients with rtA181T mutation and 22 (13.5%) of the 163 patients with rtA181V mutation developed HCC (p < .05). The median follow-up periods were 8.148 and 8.055 years (p > .05). Serum HBV DNA and HBsAg levels in rtA181T-positive patients were similar to that in rtA181V-positive patients. However, the serum HBeAg levels in the rtA181T-positive patients were significantly higher than that in rtA181V-positive patients. In situ hybridization experiments showed that the HBV cccDNA and HBV RNA levels were significantly higher in the liver cancer tissues of patients with the rtA181T mutation compared to that in the tissues of patients with the rtA181V mutation. The percentage of anti-tumour hot-gene site mutations was significantly higher in the rtA181T-positive HCC liver tissue compared to that in the rtA181T-negative HCC liver tissue (7.65% and 4.3%, p < .05). This is the first study to use a large cohort and a follow-up of more than 5 years (average 8 years) to confirm that the rtA181T mutation increased the risk of HCC, and that it could be related to the increase in the mutation rate of hotspots of tumour suppressor genes (CTNNB1, TP53, NRAS and PIK3CA).
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Affiliation(s)
- Qiqi Ning
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
| | - Tongwang Yang
- Academician Workstation, Changsha Medical University, Changsha, China
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
| | - Xianghua Guo
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
| | - Yanxiang Huang
- Clinical laboratory center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yuxue Gao
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
| | - Mengcheng Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
| | - Pengxiang Yang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
| | - Yuanyue Guan
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
| | - Ning Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
| | - Yang Wang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
| | - Dexi Chen
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing, China
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9
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Liu H, Han CL, Tian BW, Ding ZN, Yang YF, Ma YL, Yang CC, Meng GX, Xue JS, Wang DX, Dong ZR, Chen ZQ, Hong JG, Li T. Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2023:1-11. [PMID: 37148261 DOI: 10.1080/17474124.2023.2212161] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
BACKGROUND Tenofovir (TDF) and entecavir (ETV) are first-line treatments for patients with chronic hepatitis B virus (HBV) infection. However, the effect of TDF versus ETV on the prognosis of HBV-related hepatocellular carcinoma (HCC) has not been fully clarified yet. RESEARCH DESIGN AND METHODS PubMed, Embase and Web of science were searched up to March, 2021. Meta-analyses were performed for overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) to assess the effect of TDF versus ETV on the prognosis of HBV-related HCC. RESULTS A total of 10 studies comprising 4706 Asian patients were included. The pooled results revealed that TDF was associated with better OS (adjusted HR=0.50, 95% CI: 0.40-0.62; I2=36.0%, p=0.167) and better RFS/DFS (adjusted HR=0.70, 95% CI: 0.55-0.89, I2=71.9%, p=0.002) than ETV in treatment of HBV-related HCC. Subgroup analysis revealed that OS benefit from TDF was generally consistent, except for patients who underwent non-surgical treatment for HCC. Subgroup analysis also indicated that TDF reduces the risk of late recurrence (HR=0.41, 95% CI: 0.18-0.0.93; I2=63.0%, p=0.067) rather than early recurrence (HR=0.99, 95% CI: 0.64-1.52; I2=61.3%, p=0.076). CONCLUSIONS Compared with ETV, TDF has the advantage of improving OS and reducing late recurrence of patients with HBV-related HCC patients who underwent resection.
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Affiliation(s)
- Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Ya-Fei Yang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yun-Long Ma
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Chun-Cheng Yang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Guang-Xiao Meng
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Jun-Shuai Xue
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Jian-Guo Hong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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10
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Bi Z, Wang L, Hou H, Lu M, Wang W, Li Z, Liu C. Comparing the efficacy and safety of tenofovir and adefovir or combined drug treatment for the treatment of chronic hepatitis B infection: a systematic review and meta-analysis. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1016. [PMID: 36267714 PMCID: PMC9577806 DOI: 10.21037/atm-22-3747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Chronic hepatitis B (CHB) affects a vast population globally. A variety of drugs are available for the treatment of CHB, including tenofovir (TDF) and adefovir (ADV). However, the efficacy of monotherapy drug treatment is inconclusive, the safety and efficacy of TDF remain unclear, more data are needed to be included and combined drug treatment is considered to exhibit higher efficacy. To explore this issue, we performed a current literature review and meta-analysis to compare the efficacy and safety of ADV vs. TDF, TDF vs. ADV + lamivudine (LAM); TDF vs. ADV + entecavir (ETV). METHODS We systematically searched China National Knowledge Infrastructure, the Cochrane Library, Embase, PubMed, Chinese VIP, and Wanfang Data, for relevant clinical trials since July 2015, all included studies were based on PICOS principles and evaluated independently by the reviewers in accordance with the Cochrane Handbook (Rob2.0). A meta-analysis was performed by using Review Manager 5.4. RESULTS We included a total of 32 studies, including 31 randomized controlled trials and one retrospective study involving 2,473 patients. The results revealed a low risk of bias in included studies, that the virologic response of TDF was superior to ADV (P<0.05). And TDF was also superior to ADV in Serum creatinine levels, Immunologic function, and safety profile. However, when ADV was combined with other medications, it was superior to TDF in alanine aminotransferase (ALT) level and Tbil level and adverse reactions, but on other indicators, TDF was superior to drug combination therapy. CONCLUSIONS Results showed that TDF was superior to ADV in the parameters of ALT, hepatitis B virus (HBV)-DNA reduction, HBeAg-negative conversion rate, safety, and total bilirubin levels in patients with CHB. However, when ADV was combined with LAM or ETV, they often showed the same therapeutic effect as TDF in parameters such as ALT level and Tbil level and combined therapy can effectively reduce the occurrence of adverse reactions. In this study, because the sample source countries were limited, a greater number of global studies are needed in the future to verify the current findings.
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Affiliation(s)
- Zeyu Bi
- Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, School of Environment and Health, Jianghan University, Wuhan, China
| | - Ling Wang
- Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, School of Environment and Health, Jianghan University, Wuhan, China
| | - Huixin Hou
- Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, School of Environment and Health, Jianghan University, Wuhan, China
| | - Miao Lu
- Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, School of Environment and Health, Jianghan University, Wuhan, China
| | - Wei Wang
- Department of outpatients, Wuhan Asian Heart Hospital, Wuhan, China
| | - Zishuo Li
- Department of outpatients, Wuhan Asian Heart Hospital, Wuhan, China
| | - Chengjiang Liu
- Department of Gastroenterology, Anhui Medical University, Hefei, China
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11
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Lim J, Lee JB, An J, Song GW, Kim KM, Lee HC, Shim JH. Extrahepatic carcinogenicity of oral nucleos(t)ide analogues in chronic hepatitis B carriers: A 35,000-Korean outcome study. J Viral Hepat 2022; 29:756-764. [PMID: 35718999 DOI: 10.1111/jvh.13721] [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: 10/12/2021] [Revised: 03/18/2022] [Accepted: 05/21/2022] [Indexed: 12/09/2022]
Abstract
Evidence on the carcinogenicity of oral nucleos(t)ide analogues (NAs) is inconclusive and lacks data on the effects by chemical structure of the NAs in patients with chronic hepatitis B (CHB). We aimed to provide definitive results on this issue using a large set of CHB patients and data on all major NA drugs. The study population consisted of 10,331 patients with CHB receiving primary NA treatment for more than 6 months, and 24,836 untreated controls followed for at least as long as the treated patients. Using the inverse-probability-of-treatment-weighted (IPTW) method, the cumulative incidence of extrahepatic cancers was compared in the treated and untreated patients and across the cyclopentane, L-nucleoside and acyclic phosphonate categories of NAs. Analyses of individual cancers as sub-endpoints were also performed. The cumulative incidence of overall extrahepatic malignancies did not differ between the two groups in the IPTW cohort (hazard ratio [HR] 1.002; 95% confidence interval [CI] [0.859-1.169]). Similar statistical trends were observed in analyses across the three NA chemical subsets and controls. Per-cancer analyses indicated that NA treatment was significantly associated with increased risks of colorectal/anal cancers (HRs [95% CI], 1.538 [1.175-2.013]) and lymphoma (1.784 [1.196-2.662]). Conversely, breast cancer (HRs [95% CI], 0.669 [0.462-0.967]) and prostate cancer (0.521 [0.329-0.825]) were less prevalent in the NA-treated group. In conclusion, prolonged NA treatment presents carcinogenic risks for colorectal/anal and lymphoid tissues in CHB patients, although it does not affect most extrahepatic organs. The protective effect of NAs on breast and prostate cancers should be confirmed.
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Affiliation(s)
- Jihye Lim
- Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jung-Bok Lee
- Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jihyun An
- Gastroenterology, Hanyang University College of Medicine, Guri, Republic of Korea
| | - Gi-Won Song
- Hepatobiliary Surgery and Liver Transplantation, Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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12
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Risks and benefits of oral HIV pre-exposure prophylaxis for people with chronic hepatitis B. THE LANCET HIV 2022; 9:e585-e594. [PMID: 35817068 PMCID: PMC9339532 DOI: 10.1016/s2352-3018(22)00123-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/18/2022] [Accepted: 04/20/2022] [Indexed: 12/20/2022]
Abstract
Individuals with chronic hepatitis B virus (HBV) infection who are at substantial risk of HIV acquisition benefit from pre-exposure prophylaxis (PrEP) with tenofovir-based antiviral therapy. Considering that tenofovir potently inhibits HBV, providing PrEP to individuals with HBV effectively results in treatment of their HBV infection. However, some clinicians might be hesitant to initiate PrEP in people with chronic HBV due to unknown risks of HBV reactivation, hepatitis, and acute liver failure during periods of antiviral cessation. Unfortunately, these knowledge gaps affect scale up of PrEP among people with chronic HBV. Emerging data regarding the risks and benefits of antiviral cessation in people with chronic HBV suggest that PrEP can be safely initiated despite the risks of non-adherence or discontinuation. People with chronic HBV who stop PrEP should be closely monitored for HBV reactivation and hepatitis flares after antiviral cessation.
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13
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Liu M, Shi P, Wang G, Wang G, Song P, Liu Y, Wu S, Gong J. Quantitative analysis of binary mixtures of entecavir using solid-state analytical techniques with chemometric methods. ARAB J CHEM 2021. [DOI: 10.1016/j.arabjc.2021.103360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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14
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Domfeh S, Narkwa P, Quaye O, Kusi K, Rivera O, Danaah M, Musah B, Awandare G, Mensah K, Mutocheluh M. Cryptolepine and Nibima inhibit hepatitis B virus replication. SCIENTIFIC AFRICAN 2021. [DOI: 10.1016/j.sciaf.2021.e00942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
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15
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Mokaya J, Vasylyeva TI, Barnes E, Ansari MA, Pybus OG, Matthews PC. Global prevalence and phylogeny of hepatitis B virus (HBV) drug and vaccine resistance mutations. J Viral Hepat 2021; 28:1110-1120. [PMID: 33893696 PMCID: PMC8581767 DOI: 10.1111/jvh.13525] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/08/2021] [Indexed: 12/29/2022]
Abstract
Vaccination and anti-viral therapy with nucleos(t)ide analogues (NAs) are key approaches to reducing the morbidity, mortality and transmission of hepatitis B virus (HBV) infection. However, the efficacy of these interventions may be reduced by the emergence of drug resistance-associated mutations (RAMs) and/or vaccine escape mutations (VEMs). We have assimilated data on the global prevalence and distribution of HBV RAMs/VEMs from publicly available data and explored the evolution of these mutations. We analysed sequences downloaded from the HBV Database and calculated prevalence of 41 RAMs and 38 VEMs catalogued from published studies. We generated maximum likelihood phylogenetic trees and used treeBreaker to investigate the distribution and estimated the age of selected mutations across tree branches. RAM M204I/V had the highest prevalence, occurring in 3.8% (109/2838) of all HBV sequences in our data set, and a significantly higher rate in genotype C at 5.4% (60/1102, p = 0.0007). VEMs had an overall prevalence of 1.3% (37/2837) and had the highest prevalence in genotype C and in Asia at 2.2% (24/1102; p = 0.002) and 1.6% (34/2109; p = 0.009), respectively. Phylogenetic analysis suggested that RAM/VEMs can arise independently of treatment/vaccine exposure. In conclusion, HBV RAMs/VEMs have been found globally and across genotypes, with the highest prevalence observed in genotype C. Screening for genotype and for resistance-associated mutations may help to improve stratified patient treatment. As NAs and HBV vaccines are increasingly being deployed for HBV prevention and treatment, monitoring for resistance and advocating for better treatment regimens for HBV remains essential.
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Affiliation(s)
| | - Tetyana I. Vasylyeva
- Division of Infectious Diseases & Global Public HealthDepartment of MedicineUniversity of CaliforniaSan DiegoCAUSA
| | - Eleanor Barnes
- Nuffield Department of MedicineOxfordUK
- Department of HepatologyOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK
- National Institutes of Health Research Health Informatics CollaborativeNIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
| | - M. Azim Ansari
- Nuffield Department of MedicineOxfordUK
- Wellcome Centre for Human GeneticsOxfordUK
| | | | - Philippa C. Matthews
- Nuffield Department of MedicineOxfordUK
- National Institutes of Health Research Health Informatics CollaborativeNIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Department of Infectious Diseases and MicrobiologyOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK
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16
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Na JH, Kim JH, Choe WH, Kwon SY, Yoo BC. Changes in the Hepatitis B Surface Antigen Level According to the HBeAg Status and Drug Used in Long-term Nucleos(t)ide Analog-treated Chronic Hepatitis B Patients. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2021; 77:285-293. [PMID: 34158448 DOI: 10.4166/kjg.2021.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/02/2021] [Accepted: 06/04/2021] [Indexed: 12/19/2022]
Abstract
Backgrounds/Aims The HBsAg levels have been used to monitor the chronic hepatitis B (CHB) treatment response to antiviral therapy. On the other hand, it is unclear if the HBsAg quantification levels at each treatment point differ according to the HBeAg status and drug in CHB patients. This study compared the changes in HBsAg in CHB patients according to the HBeAg status and treatment drugs. Methods CHB patients with at least 1 year of follow-up treatment with one drug, either entecavir (ETV) or tenofovir (TDF), were enrolled in this study. The mean HBsAg levels were measured annually for up to 6 years. A linear mixed model was used to compare the HBsAg quantification levels during the follow-up period. An independent samples t-test was used to analyze the differences in the HBsAg quantification levels at each treatment time point. Results Ninety-seven patients were enrolled in this study; 59 among them were HBeAg-positive. Two patients in the TDF group achieved HBsAg seroconversion. The HBsAg level decreased during the follow-up in the ETV and TDF groups. The HBsAg level was lower in the TDF group than the ETV group during the follow-up. On the other hand, subgroup analysis showed that this trend was the same only in the HBeAg-negative patients, not in the HBeAg-positive patients. In the HBeAg-negative patients, HBsAg level in the TDF group was significantly lower than that in the ETV group at 36, 48, and 72 months. The change in HBsAg level from the baseline increased at a decreasing rate during the follow-up in both groups. Furthermore, the change in the HBsAg level in the TDF group was significantly larger than that of the ETV group at 36 months in the HBeAg-negative patients. Conclusions Although TDF might be more efficient than ETV in reducing the HBsAg level in HBeAg-negative patients in a few years, HBsAg seroconversion occurred very rarely. A further large-scale, long-term study will be needed to confirm the antiviral effects on the HBsAg level.
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Affiliation(s)
- Jong Hwa Na
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Byung Chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
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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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Abayli B, Abaylı C, Gencdal G. Histopathological evaluation of long-term tenofovir disoproxil fumarate treatment in patients with hepatitis be antigen-negative chronic hepatitis B. World J Gastrointest Pharmacol Ther 2021; 12:32-39. [PMID: 33815864 PMCID: PMC8008959 DOI: 10.4292/wjgpt.v12.i2.32] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/10/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus is a universal health problem. There are approximately 250 million people living with hepatitis B worldwide, and approximately 600000 of these people die every year due to the virus.
AIM To compare the pretreatment and post-treatment histopathological results of patients with hepatitis be antigen (HBeAg)-negative chronic hepatitis B (CHB) who had been receiving tenofovir disoproxil fumarate (TDF) treatment at our clinic for at least 5 years.
METHODS Patients with HBeAg-negative CHB who were being treated with TDF (245 mg/d) were included in the study. Liver biopsies of patients before TDF treatment and liver biopsies after 5 years of TDF treatment were retrospectively compared.
RESULTS A total of 50 HBeAg-negative CHB patients were included in the study (mean age: 47.9 ± 10.4 years, men: 27.54%). Histological improvement was observed in 78% (39) of the patients after 5 years of treatment. After the 5 years of treatment, the mean Ishak score of the patients was 1.3 ± 1.3, and the mean histologic activity index score was 4.1 ± 2.8. A 1.53 point reduction in Ishak fibrosis score was detected after long-term TDF treatment.
CONCLUSION Liver biopsies after 5 years of TDF treatment revealed a significant histological response and a regression of the necroinflammatory score compared to pretreatment liver biopsies. To better understand the effects of antiviral treatments on the improvement of liver histology, long-term studies involving larger numbers of patients are needed.
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Affiliation(s)
| | | | - Genco Gencdal
- Department of Gastroenterology, Hepatology and Liver Transplantation, Koc University, School of Medicine, İstanbul 34300, Turkey
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19
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Monty MA, Islam MA, Nan X, Tan J, Tuhin IJ, Tang X, Miao M, Wu D, Yu L. Emerging role of RNA interference in immune cells engineering and its therapeutic synergism in immunotherapy. Br J Pharmacol 2021; 178:1741-1755. [PMID: 33608889 DOI: 10.1111/bph.15414] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 02/09/2021] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
RNAi effectors (e.g. siRNA, shRNA and miRNA) can trigger the silencing of specific genes causing alteration of genomic functions becoming a new therapeutic area for the treatment of infectious diseases, neurodegenerative disorders and cancer. In cancer treatment, RNAi effectors showed potential immunomodulatory actions by down-regulating immuno-suppressive proteins, such as PD-1 and CTLA-4, which restrict immune cell function and present challenges in cancer immunotherapy. Therefore, compared with extracellular targeting by antibodies, RNAi-mediated cell-intrinsic disruption of inhibitory pathways in immune cells could promote an increased anti-tumour immune response. Along with non-viral vectors, DNA-based RNAi strategies might be a more promising method for immunomodulation to silence multiple inhibitory pathways in T cells than immune checkpoint blockade antibodies. Thus, in this review, we discuss diverse RNAi implementation strategies, with recent viral and non-viral mediated RNAi synergism to immunotherapy that augments the anti-tumour immunity. Finally, we provide the current progress of RNAi in clinical pipeline.
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Affiliation(s)
- Masuma Akter Monty
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
| | - Md Ariful Islam
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Xu Nan
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
| | - Jingwen Tan
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
| | - Israth Jahan Tuhin
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
| | - Xiaowen Tang
- The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Miao Miao
- The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Depei Wu
- The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Yu
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
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20
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Treem WR, Palmer M, Lonjon-Domanec I, Seekins D, Dimick-Santos L, Avigan MI, Marcinak JF, Dash A, Regev A, Maller E, Patwardhan M, Lewis JH, Rockey DC, Di Bisceglie AM, Freston JW, Andrade RJ, Chalasani N. Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis. Drug Saf 2021; 44:133-165. [PMID: 33141341 PMCID: PMC7847464 DOI: 10.1007/s40264-020-01014-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.
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Affiliation(s)
| | - Melissa Palmer
- Takeda, Cambridge, MA, USA
- Liver Consulting LLC, New York, NY, USA
| | | | | | | | - Mark I Avigan
- US Food and Drug Administration, Silver Spring, MD, USA
| | | | - Ajit Dash
- , Genentech, South San Francisco, CA, USA
| | - Arie Regev
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Eric Maller
- Pfizer, Collegeville, PA, USA
- MEMS Biopharma Consulting, LLC, Wynnewood, PA, USA
| | | | | | - Don C Rockey
- Medical University of South Carolina, Charleston, SC, USA
| | | | - James W Freston
- University of Connecticut Health Center, Farmington, CT, USA
| | - Raul J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd, Universidad de Málaga, Málaga, Spain
| | - Naga Chalasani
- Indiana University School of Medicine, Indianapolis, IN, USA.
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21
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Siakavellas S, Goulis J, Manolakopoulos S, Triantos C, Gatselis N, Tsentemidou E, Kranidioti H, Ζisimopoulos Κ, Τsoulas C, Dalekos G, Papatheodoridis G. Monitoring and comorbidities in patients with chronic hepatitis B currently treated with nucleos(t)ide analogs. Ann Gastroenterol 2021; 34:73-79. [PMID: 33414625 PMCID: PMC7774663 DOI: 10.20524/aog.2020.0525] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 06/25/2020] [Indexed: 12/16/2022] Open
Abstract
Background Long-term monotherapy with nucleos(t)ide analogs (NAs) represents the treatment option for the majority of patients with chronic hepatitis B (CHB), an aging population with a greater likelihood of comorbidities. We assessed the prevalence of concurrent non-hepatic diseases and the safety monitoring in a large cohort of CHB patients receiving NAs and their potential impact on disease outcomes. Methods We included 500 consecutive CHB patients from 5 major tertiary Greek centers, under long-term therapy with an NA. Epidemiological/clinical characteristics and data on concomitant disease, drug use and investigations ordered were collected. Results The mean age was 58 years and 66% were male. Most patients were receiving tenofovir disoproxil fumarate (TDF, 60%) or entecavir (ETV, 37%) monotherapy. Decompensated cirrhosis at baseline was present in 10%, while hepatocellular carcinoma (HCC) under therapy developed in 21 patients. The median duration of total NA therapy was 56 and of latest therapy 42 months. The most common (prevalence >10%) comorbidities were hypertension (28%), non-HCC cancer(s) (12%), and diabetes (11%). Patients with a longer duration of latest therapy (≥4 vs. <4 years) were older (mean age: 58 vs. 56 years, P=0.004), had more frequent history of prior use of NA(s) (53% vs. 35%, P<0.001), and less frequent liver decompensation (5% vs. 13%, P=0.008) and non-HCC cancers (8% vs. 15%, P=0.020). HCC developed more frequently in patients with than in those without diabetes (11% vs. 3%, P=0.022). Conclusion Greek CHB patients currently treated with NAs, almost exclusively ETV or TDF, are often older than 60 years, have several comorbidities, and thus require careful management.
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Affiliation(s)
- Spyros Siakavellas
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital of Athens, Athens (Spyros Siakavellas, Spilios Manolakopoulos, George Papatheodoridis)
| | - John Goulis
- 4 Department of Internal Medicine, Medical School of Aristotle University of Thessaloniki (John Goulis, Eva Tsentemidou)
| | - Spilios Manolakopoulos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital of Athens, Athens (Spyros Siakavellas, Spilios Manolakopoulos, George Papatheodoridis).,2 Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Hippokratio General Hospital, Athens (Spilios Manolakopoulos, Hariklia Kranidioti)
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Rio (Christos Triantos, Konstantinos Zisimopoulos)
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa (Nikolaos Gatselis, George Dalekos)
| | - Eva Tsentemidou
- 4 Department of Internal Medicine, Medical School of Aristotle University of Thessaloniki (John Goulis, Eva Tsentemidou)
| | - Hariklia Kranidioti
- 2 Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Hippokratio General Hospital, Athens (Spilios Manolakopoulos, Hariklia Kranidioti)
| | - Κonstantinos Ζisimopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Rio (Christos Triantos, Konstantinos Zisimopoulos)
| | - Christos Τsoulas
- Medical Department, Gilead Sciences Hellas (Christos Tsoulas), Greece
| | - George Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa (Nikolaos Gatselis, George Dalekos)
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital of Athens, Athens (Spyros Siakavellas, Spilios Manolakopoulos, George Papatheodoridis)
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22
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Tenofovir is Superior to Entecavir in Patients with Treatment-naïve Hepatitis B e-Antigen-Positive Chronic Hepatitis B. J Clin Exp Hepatol 2021; 11:37-44. [PMID: 33679047 PMCID: PMC7897859 DOI: 10.1016/j.jceh.2020.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/01/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIM Chronic Hepatitis B (CHB) is a global health problem affecting around 400 million of people worldwide. Two available first-line antiviral drugs are tenofovir disoproxil fumarate (TDF) and Entecavir (ETV). Till date,there are few published reports from India comparing efficacy of TDF and ETV in CHB cases. Therefore, this present study was carried out with an aim to compare the efficacy of ETV and TDF in patients with nucleos(t)ide naïve CHB. MATERIALS AND METHODS This retrospective cohort study was carried out in 192 treatment naïve CHB cases, who completed 24 months of treatment with either TDF or ETV between March 2015 and August 2017. The primary end point of the study was undetectable hepatitis B virus DNA after 24 months of therapy. RESULTS Of total 192 patients with CHB, 38 hepatitis B e-antigen (HBeAg)-positive and 53 HBeAg-negative patients were treated with tenofovir, whereas 40 HBeAg-positive and 61 HBeAg-negative patients were treated with ETV. Pretreatment characteristics at baseline were not statistically different between the TDF and ETV groups. Patients treated with TDF achieved significantly higher complete viral suppression as compared with ETV-treated patients (Log rank: 7.04, P = 0.008) in HBeAg-positive CHB during the 24 months follow-up time; whereas no significant difference in viral suppression rate could be noticed in HBeAg-negative patients (Log rank: 0.98, P = 0.38). Both univariate and multivariate analysis by cox proportional hazard model confirmed that tenofovir had significant rate of complete viral suppression in comparison with ETV in HBeAg-positive patients (P < 0.05); whereas complete viral suppression rates were similar in HBeAg-negative patients. CONCLUSION In our study, tenofovir had more effective antiviral suppressive effect compared with ETV in HBeAg-positive, nucleos(t)ide-naïve CHB cases.
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Key Words
- ALT, alanine aminotransferase
- APRI, AST-to-platelet Ratio Index
- BMI, body mass index
- CHB, chronic hepatitis B
- CI, confidence interval
- ETV, entecavir
- HBV, hepatitis B virus
- HBVDNA, hepatitis B DNA
- HBeAg, hepatitis B e antigen
- HBsAg, hepatitis B surface antigen
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HIV, human immunodeficiency virus
- Hb, hemoglobin
- TDF, tenofovir disoproxil fumarate
- antiviral therapy
- chronic hepatitis B
- entecavir
- tenofovir
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23
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Liu H, Shi Y, Hayden JC, Ryan PM, Rahmani J, Yu G. Tenofovir Treatment Has Lower Risk of Hepatocellular Carcinoma than Entecavir Treatment in Patients with Chronic Hepatitis B: A Systematic Review and Meta-Analysis. Liver Cancer 2020; 9:468-476. [PMID: 32999872 PMCID: PMC7506291 DOI: 10.1159/000507253] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 03/15/2020] [Indexed: 02/04/2023] Open
Abstract
PURPOSE Tenofovir (TDF) and entecavir (ETV) are both equally recommended as first-line treatments for patients with chronic hepatitis B (CHB). They have comparable efficacy in virologic response, but their effect on the development of hepatocellular carcinoma (HCC) in CHB is controversial. Therefore, we aimed to compare TDF and ETV evaluating the risk of HCC development in CHB patients. METHODS A systematic literature search was conducted up to November 2019 in MEDLINE/PubMed, SCOPUS, and Web of Science databases without language and time restrictions. DerSimonian and Laird random-effects models were used to estimate combined hazard ratios (HRs) and 95% CIs. RESULTS Seven studies containing 35,785 participants were included in this systematic review and meta-analysis. The pooled HR (95% CI) of HCC in the patients who used TDF versus patients who used ETV was 0.75 (0.56-0.96). There was no significant heterogeneity detected among the included studies results (I2 = 47.5%). There was no significant publication bias detected among the included studies (Begg's p = 0.88 and Egger's regression test p = 0.96). CONCLUSIONS Evidence to date suggests that TDF treatment is associated with significantly fewer cases of HCC when compared to ETV.
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Affiliation(s)
- Hairong Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Yu Shi
- Department of General Surgery, ShanXian Hospital of Traditional Chinese Medicine, Heze City, China
| | - John C. Hayden
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Paul M. Ryan
- School of Medicine, University College Cork, Cork, Ireland
| | - Jamal Rahmani
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Guangsheng Yu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China,*Guangsheng Yu, Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwu Road, Huaiyin District, Jinan, Shandong 250021 (China), or
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24
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Allard NL, MacLachlan JH, Dev A, Dwyer J, Srivatsa G, Spelman T, Thompson AJ, Cowie BC. Adherence in chronic hepatitis B: associations between medication possession ratio and adverse viral outcomes. BMC Gastroenterol 2020; 20:140. [PMID: 32381025 PMCID: PMC7203797 DOI: 10.1186/s12876-020-01219-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 03/11/2020] [Indexed: 01/08/2023] Open
Abstract
Background Antiviral therapy for chronic hepatitis B (CHB) is effective and can substantially reduce the risk of progressive liver disease and hepatocellular carcinoma but is often administered for an indefinite duration. Adherence has been shown in clinical trials to maximize the benefit of therapy and prevent the development of resistance, however the optimal threshold for predicting clinical outcomes has not been identified. The aim of this study was to analyse adherence using the medication possession ration (MPR) and its relation to virological outcomes in a large multi-centre hospital outpatient population, and guide development of an evidence-based threshold for optimal adherence. Methods Pharmacy and pathology records of patients dispensed CHB antiviral therapy from 4 major hospitals in Melbourne between 2010 and 2013 were extracted and analysed to determine their MPR and identify instances of unfavourable viral outcomes. Viral outcomes were classified categorically, with unfavourable outcomes including HBV DNA remaining detectable after 2 years treatment or experiencing viral breakthrough. The association between MPR and unfavourable outcomes was assessed according to various thresholds using ROC analysis and time-to-event regression. Results Six hundred forty-two individuals were included in the analysis. Median age was 46.6 years, 68% were male, 77% were born in Asia, and the median time on treatment was 27.5 months. The majority had favourable viral outcomes (91.06%), with most having undetectable HBV DNA at the end of the study period. The most common unfavourable outcome was a rise of < 1 log in HBV DNA (6.54% of the total), while 2.49% of participants experienced viral breakthrough. Adherence was linearly associated with favourable outcomes, with increasing risk of virological breakthrough as MPR fell. Decreasing the value of MPR, at which a cut-point was taken, was associated with a progressively larger reduction in the rate of unfavourable event; from a 60% reduction under a cut-point of 1.00 to a 79% reduction when the MPR cut-point was set at 0.8. Conclusion Lower adherence as measured using the MPR was strongly associated with unfavourable therapeutic outcomes, including virological failure. Optimising adherence is therefore important for preventing viral rebound and potential complications such as antiviral resistance. The evidence of dose-response highlights the need for nuanced interventions.
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Affiliation(s)
- Nicole L Allard
- WHO Collaborating Centre for Viral Hepatitis, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne Victoria, 3000, Australia. .,University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia.
| | - Jennifer H MacLachlan
- WHO Collaborating Centre for Viral Hepatitis, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne Victoria, 3000, Australia.,University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia
| | - Anouk Dev
- Department of Gastroenterology, Monash Health, and Monash University, Victoria, 3168, Clayton, Australia
| | - James Dwyer
- Mercy Hospital for Women, Victoria, 3084, Australia
| | - Geeta Srivatsa
- Western Health and Footscray Hospital, Footscray, Victoria, 3011, Australia
| | - Timothy Spelman
- University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia.,Burnet Institute, Melbourne, 3000, Australia
| | - Alexander J Thompson
- University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia.,St. Vincent's Hospital, Melbourne, 3000, Australia
| | - Benjamin C Cowie
- WHO Collaborating Centre for Viral Hepatitis, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne Victoria, 3000, Australia.,University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia
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25
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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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26
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Liu B, Shen B, Mei M, Li L, Wang X, Zhao H. Potential Effects of Telbivudine Versus Entecavir on Renal Function in Patients With Chronic Hepatitis B Virus Receiving Glucocorticoids Therapy. Ther Apher Dial 2019; 24:56-63. [PMID: 31090170 DOI: 10.1111/1744-9987.12839] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 04/05/2019] [Accepted: 05/13/2019] [Indexed: 12/17/2022]
Abstract
Data remains limited about the optimal nucleos(t)ide analogue therapy for patients infected with hepatitis B virus (HBV) while treated with glucocorticoids because of kidney diseases. We aim to evaluate the safety and efficacy of long-term antiviral therapy with telbivudine (LdT) and entecavir (ETV) in this specific population. In this prospective randomized controlled study, a total of 60 patients with both kidney diseases and chronic hepatitis B were randomly divided into LdT group and ETV group. We analyzed changes in estimated glomerular filtration rate (eGFR), variation in HBV DNA, seroconversion of hepatitis B e antigen (HbeAg) and hepatitis B surface antigen (HBsAg). During the 18 month follow-up period, serum HBV DNA load was decreased significantly at 3, 6, 12, 18 months, compared to the pre-treatment value in both LdT and ETV cohorts. No patients achieved HBeAg loss-seroconversion or HBsAg loss-seroconversion with ETV therapy whilst one patient experienced HBeAg and HBsAg loss-seroconversion with LdT therapy. No significant changes in eGFR were seen in patients with ETV therapy compared to baseline. However, eGFR increased 7.43, 18.97 mL/min/1.73m2 , respectively at 12 and 18 months in LdT group and the changes were significant compared to baseline. Further analysis also demonstrated that eGFR significantly improved 11.8, 23.25 mL/min/1.73m2 at 12 and 18 months in LdT group for patients with impaired renal function. LdT is superior to ETV in patients with chronic hepatitis B and kidney diseases because of the renal protection it confers by increasing eGFR.
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Affiliation(s)
- Baolian Liu
- Department of Nephrology, The First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Bingbing Shen
- Department of Nephrology, The First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Mei Mei
- Department of Nephrology, The First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Lina Li
- Department of Nephrology, The First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Xiaohong Wang
- Department of Epidemiology, The First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Hongwen Zhao
- Department of Nephrology, The First Affiliated Hospital of the Army Medical University, Chongqing, China
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Wei MT, Le AK, Chang MS, Hsu H, Nguyen P, Zhang JQ, Wong C, Wong C, Cheung R, Nguyen MH. Antiviral therapy and the development of osteopenia/osteoporosis among Asians with chronic hepatitis B. J Med Virol 2019; 91:1288-1294. [PMID: 30776311 DOI: 10.1002/jmv.25433] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 02/12/2019] [Accepted: 02/15/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Recent studies have suggested a potential increase in the incidence of osteoporosis for patients receiving tenofovir disoproxil fumarate (TDF), but this issue remains controversial. METHODS The retrospective cohort study of 1224 Asian chronic hepatitis B (CHB) patients greater than 18 years without baseline osteopenia/osteoporosis seen at four US centers from 2008 to 2016. Patients were categorized into three groups-treatment-naive patients who initiated therapy with TDF (1) or entecavir (ETV) (2), or untreated patients (3). Patients were followed until the development of osteopenia/osteoporosis or end of the study. RESULTS Of the 1224 study patients, 276 were treated with TDF, 335 with ETV, and 613 were untreated. The prevalence of cirrhosis was lower for untreated patients (2.6% vs 16.3% for TDF and 17.6% for ETV; P < 0.001). The 8-year cumulative incidence rate of osteopenia/osteoporosis was 13.17% for TDF, 15.09% for ETV, and 10.17% for untreated patients, with no statistically significant difference among the three groups ( P = 0.218). On multivariate Cox regression controlling for demographics, osteoporosis risk factors, albumin, and hepatitis B virus (HBV) DNA levels, neither TDF (adjusted hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.34 and 1.59) nor ETV (adjusted HR = 0.98; 95% CI: 0.51 and 1.90) were associated with increased osteopenia/osteoporosis risk compared with untreated patients. CONCLUSIONS Our retrospective study suggests that there is no significant increase in the incidence of osteopenia/osteoporosis for patients with CHB treated with TDF or ETV during a median follow-up of about 4 to 5 years. However, further study with longer follow-up is needed as an anti-HBV therapy, which is often lifelong or long-term and the development of osteopenia/osteoporosis can be a slow process.
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Affiliation(s)
- Mike T Wei
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | - An K Le
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | - Matthew S Chang
- Department of Gastroenterology, Kaiser Permanente, Northern California, Santa Clara, California
| | - Holden Hsu
- Department of Medical Research, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Pauline Nguyen
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | | | - Chris Wong
- C. Wong Clinic, San Francisco, California
| | | | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
| | - Mindie H Nguyen
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
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Lee HM, Ahn J, Kim WR, Lim JK, Nguyen M, Pan CQ, Kim D, Mannalithara A, Te H, Trinh H, Chu D, Tran T, Woog J, Lok AS. A Comparison Between Community and Academic Practices in the USA in the Management of Chronic Hepatitis B Patients Receiving Entecavir: Results of the ENUMERATE Study. Dig Dis Sci 2019; 64:358-366. [PMID: 30238203 DOI: 10.1007/s10620-018-5281-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/07/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The management of chronic hepatitis B patients is not well characterized in real-world practice. We compared baseline characteristics of CHB patients on entecavir, the frequency of on-treatment monitoring, and the effectiveness of ETV treatment between academic and community practices. METHODS Treatment-naïve CHB patients ≥18 years old, treated with ETV for ≥12 months from 2005 to 2013, in 26 community and academic practices throughout the USA were retrospectively evaluated. RESULTS Of 841 patients enrolled, 658 (65% male, 83% Asian, median age 47, 9% with cirrhosis) met inclusion criteria. Half of the patients (52%) were from community practices. A lower percentage of patients in community practices had cirrhosis or liver cancer (5 vs. 14%). Community practices more often treated patients with baseline ALT < 2 × ULN. Over a median follow-up of 4 years, community practices were more likely to discontinue ETV with less frequent laboratory monitoring compared to academic practices. The 5-year cumulative probability of ALT normalization was greater among patients treated in community practices (70 vs. 50%, p < 0.001), but the 5-year cumulative probability of undetectable HBV DNA was lower (45 vs. 70%, p < 0.001) than those treated in academic practices. CONCLUSION Academic practices saw CHB patients with more advanced liver disease, more often followed AASLD guidelines, and monitored patients on ETV treatment more frequently than community practices. While patients in community practices were less likely to achieve undetectable HBV DNA and more likely to achieve ALT normalization, the rates of HBeAg loss and seroconversion as well as HBsAg loss were similar.
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Affiliation(s)
- Hannah M Lee
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, 1200 E. Broad St., 14th Floor, P.O. Box 980341, Richmond, VA, 23298, USA.
| | - Joseph Ahn
- Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, OR, USA
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | | | - Mindie Nguyen
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Calvin Q Pan
- Division of Gastroenterology and Hepatology, NYU Langone Health, NYU School of Medicine, New York, USA
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Ajitha Mannalithara
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Helen Te
- Digestive Disease Center, University of Chicago, Chicago, IL, USA
| | - Huy Trinh
- San Jose Gastroenterology, San Jose, CA, USA
| | - Danny Chu
- Albert Einstein College of Medicine, New York, NY, USA
| | - Tram Tran
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | | | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
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Desalegn H, Aberra H, Berhe N, Mekasha B, Stene-Johansen K, Krarup H, Pereira AP, Gundersen SG, Johannessen A. Treatment of chronic hepatitis B in sub-Saharan Africa: 1-year results of a pilot program in Ethiopia. BMC Med 2018; 16:234. [PMID: 30554571 PMCID: PMC6296040 DOI: 10.1186/s12916-018-1229-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 11/30/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The World Health Organization has set an ambitious goal of eliminating viral hepatitis as a major public health threat by 2030. However, in sub-Saharan Africa, antiviral treatment of chronic hepatitis B (CHB) is virtually unavailable. Herein, we present the 1-year results of a pilot CHB treatment program in Ethiopia. METHODS At a public hospital in Addis Ababa, CHB patients were treated with tenofovir disoproxil fumarate based on simplified eligibility criteria. Baseline assessment included liver function tests, viral markers, and transient elastography (Fibroscan). Changes in laboratory markers were analyzed using Wilcoxon signed-rank tests. Adherence to therapy was measured by pharmacy refill data. RESULTS Out of 1303 patients, 328 (25.2%) fulfilled the treatment criteria and 254 (19.5%) had started tenofovir disoproxil fumarate therapy prior to September 1, 2016. Of the patients who started therapy, 30 (11.8%) died within the first year of follow-up (28 of whom had decompensated cirrhosis), 9 (3.5%) self-stopped treatment, 7 (2.8%) were lost to follow-up, and 4 (1.6%) were transferred out. In patients who completed 12 months of treatment, the median Fibroscan value declined from 12.8 to 10.4 kPa (p < 0.001), 172 of 202 (85.1%) patients with available pharmacy refill data had taken ≥ 95% of their tablets, and 161 of 189 (85.2%) patients with viral load results had suppressed viremia. Virologic failure (≥ 69 IU/mL) at 12 months was associated with high baseline HBV viral load (> 1,000,000 IU/mL; adjusted OR 2.41; 95% CI 1.04-5.55) and suboptimal adherence (< 95%; adjusted OR 3.43, 95% CI 1.33-8.88). CONCLUSIONS This pilot program demonstrated that antiviral therapy of CHB can be realized in Ethiopia with good clinical and virologic response. Early mortality was high in patients with decompensated cirrhosis, underscoring the need for earlier detection of hepatitis B virus infection and timely initiation of treatment, prior to the development of irreversible complications, in sub-Saharan Africa. TRIAL REGISTRATION NCT02344498 (ClinicalTrials.gov identifier). Registered 16 January 2015.
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Affiliation(s)
- Hailemichael Desalegn
- Medical Department, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Hanna Aberra
- Medical Department, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Nega Berhe
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia.,Centre for Imported and Tropical Diseases, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, 0424, Oslo, Norway
| | - Bitsatab Mekasha
- Medical Department, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | | | - Henrik Krarup
- Section of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark
| | | | - Svein Gunnar Gundersen
- Research Unit, Sørlandet Hospital HF, Kristiansand, Norway.,Department of Global Development and Planning, University of Agder, Kristiansand, Norway
| | - Asgeir Johannessen
- Centre for Imported and Tropical Diseases, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, 0424, Oslo, Norway. .,Department of Infectious Diseases, Vestfold Hospital Trust, Tønsberg, Norway.
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Kostyusheva A, Kostyushev D, Brezgin S, Volchkova E, Chulanov V. Clinical Implications of Hepatitis B Virus RNA and Covalently Closed Circular DNA in Monitoring Patients with Chronic Hepatitis B Today with a Gaze into the Future: The Field Is Unprepared for a Sterilizing Cure. Genes (Basel) 2018; 9:E483. [PMID: 30301171 PMCID: PMC6210151 DOI: 10.3390/genes9100483] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 09/30/2018] [Accepted: 10/03/2018] [Indexed: 12/12/2022] Open
Abstract
. Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come.
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Affiliation(s)
| | | | - Sergey Brezgin
- Central Research Institute of Epidemiology, Moscow, 111123, Russia.
- National Research Centre, Institute of Immunology, Federal Medical Biological Agency, Moscow, 115478, Russia.
| | - Elena Volchkova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, 119146, Russia.
| | - Vladimir Chulanov
- Central Research Institute of Epidemiology, Moscow, 111123, Russia.
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, 119146, Russia.
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31
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Pazgan-Simon M, Simon KA, Jarowicz E, Rotter K, Szymanek-Pasternak A, Zuwała-Jagiełło J. Hepatitis B virus treatment in hepatocellular carcinoma patients prolongs survival and reduces the risk of cancer recurrence. Clin Exp Hepatol 2018; 4:210-216. [PMID: 30324148 PMCID: PMC6185928 DOI: 10.5114/ceh.2018.78127] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 02/15/2018] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection and HBV-related liver disease are estimated to affect about 240 million people worldwide. Now that a vaccine is available, the number of new HBV infection cases has plummeted. Yet, there are still regions with very high incidence of HBV. Hepatocellular carcinoma (HCC) is the fourth to six most common malignancy in men and the ninth most common malignancy in women worldwide. 54% of all HCC cases are HBV-associated, making it the most common cause of cancer worldwide. Hepatitis B therapy prevents progression of chronic hepatitis to cirrhosis and HCC development, but even with the best HBV treatment, such patients are still at risk of HCC. Also in patients after transarterial chemoembolization (TACE), liver resection (hepatectomy) or liver transplant, suppression of hepatitis B virus (HBV) improves patient survival. In this paper we present current possibilities of HCC and HBV treatment, which lead to improved survival and quality of life.
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Affiliation(s)
- Monika Pazgan-Simon
- Department of Infectious Disease 1, Regional Specialistic Hospital, Wroclaw, Poland
| | - Krzysztof A. Simon
- Department of Infectious Disease and Hepatology, Wroclaw Medical University, Wroclaw, Poland
| | - Ewa Jarowicz
- Department of Infectious Disease 2, Regional Specialistic Hospital, Wroclaw, Poland
| | - Katarzyna Rotter
- Department of Infectious Disease 1, Regional Specialistic Hospital, Wroclaw, Poland
| | - Anna Szymanek-Pasternak
- Department of Infectious Disease and Hepatology, Wroclaw Medical University, Wroclaw, Poland
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Singh L, Indermun S, Govender M, Kumar P, du Toit LC, Choonara YE, Pillay V. Drug Delivery Strategies for Antivirals against Hepatitis B Virus. Viruses 2018; 10:E267. [PMID: 29772748 PMCID: PMC5977260 DOI: 10.3390/v10050267] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 05/04/2018] [Accepted: 05/08/2018] [Indexed: 12/16/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection poses a significant health challenge due to associated morbidity and mortality from cirrhosis and hepatocellular cancer that eventually results in the breakdown of liver functionality. Nanotechnology has the potential to play a pivotal role in reducing viral load levels and drug-resistant HBV through drug targeting, thus reducing the rate of evolution of the disease. Apart from tissue targeting, intracellular delivery of a wide range of drugs is necessary to exert a therapeutic action in the affected organelles. This review encompasses the strategies and techniques that have been utilized to target the HBV-infected nuclei in liver hepatocytes, with a significant look at the new insights and most recent advances in drug carriers and their role in anti-HBV therapy.
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Affiliation(s)
- Latavia Singh
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Sunaina Indermun
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Mershen Govender
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Pradeep Kumar
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Lisa C du Toit
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Yahya E Choonara
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Viness Pillay
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
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Wang X, Xu HJ, Jia XD, Yang YT, Zhang XJ. Crystal structure and Hirshfeld surface analysis of the anhydrous form of the nucleoside analogue entecavir. ACTA CRYSTALLOGRAPHICA SECTION C-STRUCTURAL CHEMISTRY 2018; 74:381-385. [PMID: 29504569 DOI: 10.1107/s2053229618002528] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 02/12/2018] [Indexed: 11/10/2022]
Abstract
The nucleoside analogue entecavir {systematic name: 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one}, C12H15N5O3, is an antihepatitis B virus drug that has been approved in the US, EU and several countries worldwide. We report here the single-crystal structure of the anhydrous form and compare it with that of the previously reported monohydrate form [Jiang & Liu (2009). Acta Cryst. E65, o2232]. Hirshfeld surface analysis has been employed to understand and visualize the subtle packing differences between the two crystalline forms. The results show that, compared to the previously reported hydrated form, the anhydrous crystal has significantly different intermolecular interactions and packing patterns.
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Affiliation(s)
- Xiaojuan Wang
- Department of Phamacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Hai Jiang Xu
- Department of Phamacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Xue Dong Jia
- Department of Phamacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Yan Tao Yang
- Department of Phamacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Xiao Jian Zhang
- Department of Phamacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
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Angelbello AJ, Chen JL, Childs-Disney JL, Zhang P, Wang ZF, Disney MD. Using Genome Sequence to Enable the Design of Medicines and Chemical Probes. Chem Rev 2018; 118:1599-1663. [PMID: 29322778 DOI: 10.1021/acs.chemrev.7b00504] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Rapid progress in genome sequencing technology has put us firmly into a postgenomic era. A key challenge in biomedical research is harnessing genome sequence to fulfill the promise of personalized medicine. This Review describes how genome sequencing has enabled the identification of disease-causing biomolecules and how these data have been converted into chemical probes of function, preclinical lead modalities, and ultimately U.S. Food and Drug Administration (FDA)-approved drugs. In particular, we focus on the use of oligonucleotide-based modalities to target disease-causing RNAs; small molecules that target DNA, RNA, or protein; the rational repurposing of known therapeutic modalities; and the advantages of pharmacogenetics. Lastly, we discuss the remaining challenges and opportunities in the direct utilization of genome sequence to enable design of medicines.
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Affiliation(s)
- Alicia J Angelbello
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Jonathan L Chen
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Jessica L Childs-Disney
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Peiyuan Zhang
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Zi-Fu Wang
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Matthew D Disney
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
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Kim CW, Kim CS, Kim HY, Lee CD, Yu K, Llamoso C, Lee HJ. Large-scale surveillance study of the safety and effectiveness of entecavir in Korean patients with chronic hepatitis B. Korean J Intern Med 2018; 33:91-101. [PMID: 29228519 PMCID: PMC5768541 DOI: 10.3904/kjim.2016.111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 09/03/2016] [Accepted: 10/15/2016] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND/AIMS Entecavir (ETV) is effective and safe antiviral agent against hepatitis B virus (HBV) in clinical and real-world setting but, most studies were performed in single institute or have limitation in patient's number. A large-scale nation-wide real-world surveillance study was carried out to investigate safety, efficacy and clinical effectiveness of ETV in Korean patients with chronic hepatitis B (CHB). METHODS Between 2006 and 2012, 3,444 patients were enrolled from 132 Korean institutions. For the safety assessment, investigators recorded the occurrence of observed and patient-reported adverse events (AEs), as well as laboratory abnormalities. Efficacy, which consisted of change in HBV DNA and alanine aminotransferase (ALT), was evaluated in patients who had received at least 16 weeks of ETV treatment. Overall clinical effectiveness, based on improvement of ALT, HBV DNA and patient's symptoms, was evaluated by physicians. RESULTS Of the patients, 3,367 were evaluated for safety and 3,115 for efficacy and clinical effectiveness. Three hundred and eighty AEs were reported in 255 cases (7.57%), and 67 adverse drug reactions in 54 cases (1.6%). Serious AEs (SAE) were 19 events in nine cases (0.27%). Serious adverse drug reactions (SADR) were three events in two cases (0.06%), and unexpected SAE/SADR were three events in two cases (0.06%). Medical history and concomitant medications were factors inf luencing incidence rates of AEs. Overall clinical effectiveness rate was 96.53%, which was clinically assessed as marked improved or improved state. CONCLUSIONS This study showed that ETV was well tolerated and clinically effective in Korean patients with CHB in a real-world nation-wide setting.
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Affiliation(s)
- Chang Wook Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | | | - Hee Yeon Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang Don Lee
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | | | | | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
- Correspondence to Heon Ju Lee, M.D. Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: +82-53-623-8000 Fax: +82-53-654-8386 E-mail:
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Kim MN, Hwang SG, Rim KS, Kim BK, Park JY, Kim DY, Ahn SH, Han KH, Kim SU. Validation of PAGE-B model in Asian chronic hepatitis B patients receiving entecavir or tenofovir. Liver Int 2017; 37:1788-1795. [PMID: 28418595 DOI: 10.1111/liv.13450] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 04/07/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS A new hepatocellular carcinoma risk prediction model, PAGE-B, which includes age, gender and platelet count as constituent variables, has recently been proposed in Caucasian chronic hepatitis B patients. We validated PAGE-B model and compared its accuracy with that of conventional risk prediction models in Asian chronic hepatitis B patients. METHODS Chronic hepatitis B patients treated with entecavir or tenofovir were consecutively recruited. The performance of PAGE-B and three conventional risk prediction models (CU-HCC, GAG-HCC and REACH-B) were analysed. RESULTS A total of 1092 chronic hepatitis B patients (668 men, 61.2%) were selected between August 2006 and January 2015. The mean age was 48 years. During the follow-up period (median, 43.6 months), 36 (3.3%) patients developed hepatocellular carcinoma. Older age (hazard ratio [HR]=1.077), male gender (HR=3.676) and lower platelet count (HR=0.984) were independent predictors of hepatocellular carcinoma development. The PAGE-B showed similar area under receiver operating characteristic curves (AUROCs) to GAG-HCC and CU-HCC at 3 years (0.777 vs 0.793 and 0.743, respectively; all P>.05) and 5 years (0.799 vs 0.803 and 0.744, respectively; all P>.05), whereas the AUROCs of PAGE-B were significantly higher than those of the REACH-B (0.602 at 3 years and 0.572 at 5 years, P<.05). CONCLUSIONS Our study demonstrated that PAGE-B is applicable to Asian chronic hepatitis B patients receiving ETV or TDF therapy. The PAGE-B showed similar predictive performance to GAG-HCC and CU-HCC.
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Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Kyu Sung Rim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Yang YM, Choi EJ. Renal safety of tenofovir and/or entecavir in patients with chronic HBV monoinfection. Ther Clin Risk Manag 2017; 13:1273-1285. [PMID: 29033575 PMCID: PMC5628694 DOI: 10.2147/tcrm.s143286] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Background Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are recommended as the first-line therapy for chronic hepatitis B (CHB) due to their genetic barrier to resistance and effectiveness of virological suppression. TDF and ETV may cause renal toxicity through various mechanisms such as renal tubular injury, apoptosis, and mitochondrial toxicity. The aims of the current review were to assess the potential renal toxicity associated with the use of TDF and ETV in patients infected with chronic hepatitis B virus (HBV) and to provide clinical perspectives on these two agents in the treatment of CHB. Methods A literature search of clinical studies published in PubMed and posted on ClinicalTrials.gov website was implemented to find studies evaluating the potential renal toxicity of TDF and ETV. Results Twenty-one studies were examined in this review. The TDF dose used in the studies was 245 or 300 mg/day and that of ETV was 0.5 or 1 mg/day. Based on the markers of renal function, patients treated with TDF were not more likely to show changes in renal function than those treated with ETV; however, the estimated glomerular filtration rates (eGFRs) of patients receiving TDF tended to be more clearly reduced than those of patients receiving ETV. The eGFRs of patients treated with TDF decreased in a time-dependent manner, whereas those of patients treated with ETV increased or decreased across various time points. Conclusion The data shown in this study suggest that use of TDF and ETV could be at least associated with reductions in renal function in patients with chronic HBV infection. However, various risk factors, such as pre-existing renal failure and comorbidities, are also associated with decreased renal function during the treatment of TDF and ETV. Thus, studies of management strategies for HBV-infected patients with these risk factors are necessary in the near future.
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Affiliation(s)
- Young-Mo Yang
- Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, South Korea
| | - Eun Joo Choi
- Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, South Korea
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Truong J, Shadbolt B, Ooi M, Chitturi S, Kaye G, Farrell GC, Teoh NC. Week 4 viral load predicts long-term suppression of hepatitis B virus DNA during antiviral therapy: improving hepatitis B treatment in the real world. Intern Med J 2017; 47:50-56. [PMID: 27571991 DOI: 10.1111/imj.13244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 08/15/2016] [Accepted: 08/22/2016] [Indexed: 01/01/2023]
Abstract
BACKGROUND Entecavir and tenofovir potently suppress hepatitis B virus (HBV) replication so that serum HBV DNA levels <20 IU/mL can be achieved after 2 years. Despite this, inadequate suppression is reported in >20% of cases for unclear reasons. AIM We tested whether 4-week viral load (VL) assessment could improve 96-week treatment outcome. METHODS Data on all chronic hepatitis B patients treated with entecavir or tenofovir between 2005 and 2014 were entered prospectively. Full data capture included pre-treatment, weeks 4, 24, 48 and 96 HBV DNA titre, HBeAg, age, gender, antiviral agent and dose escalation. Compliance data were compiled from pharmacy records, doctors' letters and clinic bookings/attendance. Time to achieve complete viral suppression (HBV DNA < 20 IU/mL) was graphed using Kaplan-Meier curves. Factors affecting this were examined using a multivariate Cox Proportional Hazard model. RESULTS Among 156 patients treated, 72 received entecavir and 84 tenofovir. Pre-treatment HBV DNA titre, 4-week assessment and compliance impacted significantly on time to complete viral suppression. At 96 weeks, 90% of those assessed as compliant by 4-week HBV DNA had complete viral suppression versus 50% followed by 6-month VL estimation. Continuing care by the same physician was related to 4-week VL testing and optimal compliance. CONCLUSIONS Medium-term outcomes of HBV antiviral therapy are improved by early on-treatment VL testing, facilitating patient engagement and improved compliance. The observation that 90% complete viral suppression after 2 years monotherapy is achievable in a routine clinic setting questions the need for combination therapy in HBV cases with suboptimal response.
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Affiliation(s)
- J Truong
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - B Shadbolt
- Centre for Advances in Epidemiology and Information Technology, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - M Ooi
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - S Chitturi
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - G Kaye
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - G C Farrell
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - N C Teoh
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
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Using Population Pharmacokinetic and Pharmacodynamic Analyses of Entecavir in Pediatric Subjects to Simplify Dosing Recommendations. Clin Pharmacokinet 2017; 55:1559-1572. [PMID: 27319000 DOI: 10.1007/s40262-016-0420-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Entecavir is an orally administered guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase, which is approved for the treatment of chronic hepatitis B (CHB) infection in adults and children ≥2 years old (USA and EU). OBJECTIVE To develop simplified entecavir dosing recommendations for young children infected with CHB. METHODS Data from recent clinical trials were used to develop a population pharmacokinetic (PPK) model, which allowed us to estimate entecavir exposures in children and compare them to ranges known to be efficacious in adults. A population pharmacodynamic (PPD) model was generated to describe the concentration/effect relationship for entecavir in lamivudine treatment-naïve children. The PPK dataset comprised three pediatric cohorts: 2 to <6 years (n = 36); 6 to <12 years (n = 43); and 12 to <18 years (n = 74). Data from 177 adults were also included to enhance model stability and to aid in the covariate search. RESULTS Entecavir concentration-time profiles were well-described by a two-compartment model with first-order absorption and first-order elimination. Age was not a statistically significant covariate after accounting for weight. For the PPD model, the HBV DNA concentration following entecavir exposure was adequately described using a direct effect inhibitory maximum effect (E max) model with additive residual error. CONCLUSION Model-estimated, steady-state entecavir area under the concentration-time curve, in both the original (15 weight groups) and simplified (eight weight groups) pediatric dosing regimens, provided entecavir exposures consistent with those observed to be efficacious in adults, and resulted in the simplified dose algorithm for pediatric patients that is approved for the current entecavir label.
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Yoo EH, Cho HJ. Clinical response to long-term tenofovir monotherapy in Korean chronic hepatitis B patients. Clin Chim Acta 2017; 471:308-313. [PMID: 28687350 DOI: 10.1016/j.cca.2017.06.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 06/22/2017] [Accepted: 06/27/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) is a potent nucleotide analogue recommended as first-line monotherapy for chronic hepatitis B (CHB). We investigated the clinical response to TDF monotherapy in Korean CHB patients. METHODS A total of 90 CHB patients [55 hepatitis B e antigen (HBeAg)-positive and 35 HBeAg-negative] who received TDF monotherapy for >2year, were enrolled. Quantitative hepatitis B surface antigen (qHBsAg) levels, serum alanine aminotransferase (ALT), HBeAg, anti-HBe and HBV DNA levels were measured during treatment. Virologic response (VR) was defined as undetectable HBV DNA level. RESULTS The cumulative incidences of complete virologic response (CVR) were 75.6% and 89.9% at months 12 and 24, respectively. The cumulative CVR rates were significantly higher in HBeAg-negative than HBeAg-positive group (P<0.001). HBeAg loss/seroconversion was observed in 21 (38.2%) out of 55 HBeAg-positive patients. One HBeAg-positive and 1 HBeAg-negative patients (2.2%) achieved HBsAg loss at months 6 and 8 of TDF therapy, respectively. Baseline HBV DNA level and qHBsAg were significant predictive factors for a CVR (P=0.001 and P<0.001, respectively). CONCLUSIONS Virologic, serologic, biochemical responses were achieved in both HBeAg-positive and HBeAg-negative patients under 24-month TDF therapy. Monitoring using baseline HBV DNA and qHBsAg levels would be helpful to predict CVR.
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Affiliation(s)
- Eun-Hyung Yoo
- Department of Laboratory Medicine, Konyang University School of Medicine, Daejeon, Republic of Korea
| | - Hyun-Jung Cho
- Department of Laboratory Medicine, Konyang University School of Medicine, Daejeon, Republic of Korea.
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Evolutionary trends of resistance mutational patterns of HBV reverse transcriptase over years (2002–2012) of different treatment regimens: The legacy of lamivudine/adefovir combination treatment. Antiviral Res 2017; 143:62-68. [DOI: 10.1016/j.antiviral.2017.03.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 03/10/2017] [Indexed: 02/07/2023]
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Cho JY, Sohn W, Sinn DH, Gwak GY, Paik YH, Choi MS, Koh KC, Paik SW, Yoo BC, Lee JH. Long-term real-world entecavir therapy in treatment-naïve hepatitis B patients: base-line hepatitis B virus DNA and hepatitis B surface antigen levels predict virologic response. Korean J Intern Med 2017; 32:636-646. [PMID: 27809454 PMCID: PMC5511938 DOI: 10.3904/kjim.2016.096] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/22/2016] [Accepted: 06/04/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS Entecavir is a potent nucleoside analogue with high efficacy and barrier for resistance. We aimed to investigate the long-term efficacy and viral resistance rate of entecavir and explore the factors associated with virologic response, including quantitative hepatitis B surface antigen (qHBsAg) levels. METHODS One thousand and nine treatment-naïve chronic hepatitis B (CHB) patients were evaluated for cumulative rates of virologic response, biochemical response, and entecavir mutations. The role of baseline qHBsAg for virologic response was assessed in 271 patients with qHBsAg prior to entecavir treatment. RESULTS The median duration of entecavir treatment was 26.5 months. The cumulative rate of virologic response at years 1, 3, and 5 were 79.0%, 95.6%, and 99.4%, respectively. The cumulative rate of entecavir resistance was 1.0% and 2.1% in years 3 and 5. Multivariate analysis identified baseline hepatitis B e antigen (HBeAg) negative status (p < 0.001) and lower hepatitis B virus (HBV) DNA (p < 0.001) as predictors of virologic response. Lower qHBsAg was an independent predictor of virologic response in patients with baseline qHBsAg. There were no serious adverse events during treatment. CONCLUSIONS Long-term entecavir treatment of nucleos(t)ide-naïve CHB patients was associated with an excellent virologic response and a low rate of entecavir-resistant mutations at 5 years. Baseline HBV DNA load, qHBsAg levels, and HBeAg status were predictors of virologic response during entecavir treatment.
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Affiliation(s)
- Ju-Yeon Cho
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Medicine, Chosun University Hospital, Gwangju, Korea
| | - Won Sohn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Hepatology, Daejin Medical Center, Bundang Jesaeng Hospital, Seongnam, Korea
| | - Dong-Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung Chul Yoo
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Correspondence to Joon Hyeok Lee, M.D. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3409 Fax: +82-2-3410-6983 E-mail:
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Aberra H, Desalegn H, Berhe N, Medhin G, Stene-Johansen K, Gundersen SG, Johannessen A. Early experiences from one of the first treatment programs for chronic hepatitis B in sub-Saharan Africa. BMC Infect Dis 2017. [PMID: 28629395 PMCID: PMC5477340 DOI: 10.1186/s12879-017-2549-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Treatment for chronic hepatitis B (CHB) is virtually absent in sub-Saharan Africa. Here we present early experiences from a pilot program for treatment of CHB in Ethiopia. METHODS Adults (≥18 years) with CHB were included in a cohort study at St. Paul's Hospital Millennium Medical College, Addis Ababa, from February 2015. The baseline assessment included liver function tests, viral markers and transient elastography (Fibroscan 402, Echosense, France). Logistic regression models were used to identify predictors of fibrosis. Tenofovir disoproxil fumarate (TDF) was initiated based on the European Association for the Study of the Liver (EASL) criteria, with some modifications. The initial 300 patients underwent a more comprehensive evaluation and are presented here. RESULTS One-hundred-and-thirty-eight patients (46.0%) were women and median age was 30 years (interquartile range 26-40). Co-infections were rare: four patients (1.3%) were anti-HCV positive, 11 (3.7%) were anti-HDV positive, whereas 5 (1.7%) had HIV-infection. The majority were hepatitis B e-antigen (HBeAg) negative (n = 262; 90.7%) and had a normal (≤40 U/L) alanine aminotransferase (ALT) (n = 245; 83.1%). Of 268 patients with a valid Fibroscan result, 79 (29.5%) had significant fibrosis (>7.9 kPa). Independent predictors of fibrosis were male sex, age > 35 years and viral load >20,000 IU/ml. In total, 74 patients (24.7%) started TDF therapy, of whom 46 (62.2%) had cirrhosis. CONCLUSIONS The majority were HBeAg negative and had normal ALT. However, one quarter of the patients were in need of antiviral treatment, underscoring the need to scale up CHB treatment on the African continent. TRIAL REGISTRATION NCT02344498 ( ClinicalTrials.gov identifier). Registered 16 January 2015.
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Affiliation(s)
- Hanna Aberra
- Medical Department, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Hailemichael Desalegn
- Medical Department, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Nega Berhe
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia.,Centre for Imported and Tropical Diseases, Oslo University Hospital, Ullevål, Box 4956 Nydalen, 0424, Oslo, PO, Norway
| | - Girmay Medhin
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | | | - Svein Gunnar Gundersen
- Research Unit, Sørlandet Hospital HF, Kristiansand, Norway.,Department of Global Development and Planning, University of Agder, Kristiansand, Norway
| | - Asgeir Johannessen
- Centre for Imported and Tropical Diseases, Oslo University Hospital, Ullevål, Box 4956 Nydalen, 0424, Oslo, PO, Norway.
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Kim D, Lee J, Kim DH, Kang K, Suh SJ, Jung YK, Yim HJ. [A Case of Tenofovir-associated Fanconi Syndrome in Patient with Chronic Hepatitis B]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 68:317-320. [PMID: 28025475 DOI: 10.4166/kjg.2016.68.6.317] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) is one of the most widely used treatment options for human immunodeficiency virus (HIV) and HBV infections. Despite its efficacy and safety, some cases of nephrotoxicity have been reported in the treatment of HIV patients. Even more recently, very few cases of Fanconi syndrome associated with tenofovir therapy in HBV monoinfection have been reported. Herein, we report a case of a 47-year-old male with an HBV monoinfection, who developed Fanconi syndrome and a secondary osteomalacia with multiple bone pain. After TDF withdrawal and supplementation of calcitriol, his renal function was reverted. Although the overall risk of TDF-associated nephrotoxicity is very low, both glomerular and tubular function should be monitored in patients undergoing TDF treatment.
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Affiliation(s)
- Dongwoo Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jongjin Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Dae Ha Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kyuho Kang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sang Jun Suh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Young Kul Jung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyung Joon Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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Kim DH, Choi JW, Seo JH, Cho YS, Won SY, Park BK, Jeon HH, Shin SY, Lee CK. Entecavir to Telbivudine Switch Therapy in Entecavir-Treated Patients with Undetectable Hepatitis B Viral DNA. Yonsei Med J 2017; 58:552-556. [PMID: 28332360 PMCID: PMC5368140 DOI: 10.3349/ymj.2017.58.3.552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 01/17/2017] [Accepted: 01/18/2017] [Indexed: 01/17/2023] Open
Abstract
PURPOSE This study examined 2-year outcome of consecutive therapy using entecavir (ETV) followed by telbivudine (LdT) in subjects with undetectable hepatitis B virus (HBV) DNA level and normal alanine aminotransferase level after the initial 6 months of ETV treatment. MATERIALS AND METHODS Sixty subjects were randomized to continue with ETV or switch to LdT. Significant difference in baseline characteristics was not found between the two groups. Persistent HBV DNA level of 20-60 IU/mL in three consecutive samples collected three months apart or singly measured HBV DNA level of >60 IU/mL was defined as virological rebound. RESULTS During 96 weeks of follow-up, all subjects of the ETV-only group (n=30) resulted in undetectable HBV DNA level. On the other hand, 83.3% (n=25) of the LdT-switched group showed treatment success. Virological rebound time varied from week 24 to 84 after switching to LdT. HBV DNA level was 180 to 2940 IU/mL at rebound time. All subjects with virological rebound (n=5) showed drug-resistant mutation: three had mutation rtM204I, and two had mutation rtM204V. Consecutive treatment using ETV followed by LdT showed virological rebound in 16.7% of subjects during 96 weeks of follow-up. HBV DNA negativity during initial ETV therapy could not be achieved in patients who switched to LdT. CONCLUSION Consecutive treatment using ETV followed by lamivudine was ineffective for treating chronic hepatitis B. LdT was found as a more potent antiviral agent than lamivudine. However, this conclusion requires larger-scale, long-term prospective reviews of the treatment effects of ETV-LdT switch therapy.
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Affiliation(s)
- Dong Hyun Kim
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Jong Won Choi
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Jeong Hun Seo
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Yong Suk Cho
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Sun Young Won
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Byung Kyu Park
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Han Ho Jeon
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Sang Yun Shin
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Chun Kyon Lee
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea.
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On-treatment HBV DNA dynamics predict virological breakthrough in entecavir-treated HBeAg-positive chronic hepatitis B. PLoS One 2017; 12:e0174046. [PMID: 28350873 PMCID: PMC5369759 DOI: 10.1371/journal.pone.0174046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Accepted: 03/02/2017] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND & AIMS Virological breakthrough (VBT) could be a manifestation of chronic hepatitis B (CHB) in patients treated with long-term nucleot(s)ide analogues. We aimed to determine the association of on-treatment serum hepatitis B virus (HBV) DNA with VBT in HBeAg-positive CHB patients receiving entecavir (ETV) treatment. METHODS A retrospective cohort study, including 162 consecutive patients (95 men and 67 women; mean age, 43.1±13.4 years) with HBeAg-positive CHB treated with ETV for at least 48 weeks between August 2008 and May 2015, was conducted. Univariate and multivariate cox regression analysis were used to identify associations with VBT and clinical factors, including HBV DNA and HBeAg serum status. RESULTS Among the 162 ETV-treated HBeAg-positive CHB patients, eighteen patients (11.1%) experienced VBT (VBT group), whereas the other 144 patients were without VBT (non-VBT group). The cumulative rate of HBV DNA < 100 IU/mL in the VBT group and the non-VBT group at week 48 were 44.44% and 70.14%, and at week 96 were 58.33% and 92.56%, respectively (p = 0.015). The cumulative rate of HBeAg seroclearance in the VBT group and non-VBT group at week 48 and week 96 were statistically significant (p = 0.014). Multivariate analysis disclosed that failure to achieve HBeAg seroclearance were the factors significantly associated with VBT. CONCLUSIONS Our results demonstrated that on-treatment HBV DNA could probably predict VBT in ETV-treated HBeAg-positive chronic hepatitis B patients. Failure to achieve HBeAg seroclearance was associated with VBT in ETV-treated HBeAg-positive CHB patients. HBV DNA >100IU/mL at 48 weeks is potentially a predictor for VBT.
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Huang Y. Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics. MOLECULAR THERAPY. NUCLEIC ACIDS 2017; 6:116-132. [PMID: 28325278 PMCID: PMC5363494 DOI: 10.1016/j.omtn.2016.12.003] [Citation(s) in RCA: 207] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 12/04/2016] [Accepted: 12/04/2016] [Indexed: 01/03/2023]
Abstract
A main challenge in realizing the full potential of nucleic acid therapeutics is efficient delivery of them into targeted tissues and cells. N-acetylgalactosamine (GalNAc) is a well-defined liver-targeted moiety benefiting from its high affinity with asialoglycoprotein receptor (ASGPR). By conjugating it directly to the oligonucleotides or decorating it to a certain delivery system as a targeting moiety, GalNAc has achieved compelling successes in the development of nucleic acid therapeutics in recent years. Several oligonucleotide modalities are undergoing pivotal clinical studies, followed by a blooming pipeline in the preclinical stage. This review covers the progress of GalNAc-decorated oligonucleotide drugs, including siRNAs, anti-miRs, and ASOs, which provides a panorama for this field.
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Affiliation(s)
- Yuanyu Huang
- Advanced Research Institute for Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
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Kayaaslan B, Guner R. Adverse effects of oral antiviral therapy in chronic hepatitis B. World J Hepatol 2017; 9:227-241. [PMID: 28261380 PMCID: PMC5316843 DOI: 10.4254/wjh.v9.i5.227] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 11/22/2016] [Accepted: 12/09/2016] [Indexed: 02/06/2023] Open
Abstract
Oral nucleoside/nucleotide analogues (NAs) are currently the backbone of chronic hepatitis B (CHB) infection treatment. They are generally well-tolerated by patients and safe to use. To date, a significant number of patients have been treated with NAs. Safety data has accumulated over the years. The aim of this article is to review and update the adverse effects of oral NAs. NAs can cause class adverse effects (i.e., myopathy, neuropathy, lactic acidosis) and dissimilar adverse effects. All NAs carry a “Black Box” warning because of the potential risk for mitochondrial dysfunction. However, these adverse effects are rarely reported. The majority of cases are associated with lamivudine and telbivudine. Adefovir can lead to dose- and time-dependent nephrotoxicity, even at low doses. Tenofovir has significant renal and bone toxicity in patients with human immunodeficiency virus (HIV) infection. However, bone and renal toxicity in patients with CHB are not as prominent as in HIV infection. Entecavir and lamivudine are not generally associated with renal adverse events. Entecavir has been claimed to increase the risk of lactic acidosis in decompensated liver disease and high Model for End-Stage Liver Disease scores. However, current studies reported that entecavir could be safely used in decompensated cirrhosis. An increase in fetal adverse events has not been reported with lamivudine, telbivudine and tenofovir use in pregnant women, while there is no adequate data regarding entecavir and adefovir. Further long-term experience is required to highlight the adverse effects of NAs, especially in special patient populations, including pregnant women, elderly and patients with renal impairment.
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Zhang XX, Li MR, Xi HL, Cao Y, Zhang RW, Zhang Y, Xu XY. Dynamic Characteristics of Serum Hepatitis B Surface Antigen in Chinese Chronic Hepatitis B Patients Receiving 7 Years of Entecavir Therapy. Chin Med J (Engl) 2017; 129:929-35. [PMID: 27064037 PMCID: PMC4831527 DOI: 10.4103/0366-6999.179802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: The ultimate goal of hepatitis B treatment is hepatitis B surface antigen (HBsAg) seroclearance. Several factors have been suggested to be associated with the rate of HBsAg reduction in antiviral-naive or lamivudine therapy cohorts. However, there are few studies evaluating the factors during long-term entecavir (ETV) therapy. In the present study, we aimed to evaluate the factors to predict the outcome of ETV therapy for 7 years. Methods: A total of 47 chronic hepatitis B (CHB) patients treated with ETV monotherapy were included in this study. Liver biochemistry, hepatitis B virus (HBV) serological markers, serum HBV DNA, and HBsAg titers were tested at baseline, 3 months, 6 months, and yearly from 1 to 7. The associations between factors and HBsAg reduction were assessed using multivariate tests with repeated measure analysis of variance. Results: At baseline, serum HBsAg levels showed a positive correlation with baseline HBV DNA levels (r = 0.625, P < 0.001). The mean HBsAg titers after ETV treatment were significantly lower than the baseline titers (P ranges from 0.025 to 0.000,000,6). The HBsAg reduction rate during the 1st year was greater compared to after 1 year of treatment (P < 0.05). Multivariate test showed that hepatitis B e antigen (HBeAg) seroclearance and/or HBsAg reduction ≥0.5 log10 IU/ml at 6 months had a high negative predictive value (96.77%) for HBsAg seroclearance (P = 0.002, P = 0.012, respectively). Conclusions: The HBsAg reduction rate during the 1st year was greater than that after 1 year of treatment. Further, HBeAg status and HBsAg levels at month 6 are the optimal factors for the early prediction of HBsAg seroclearance after long-term ETV therapy in CHB patients.
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Affiliation(s)
| | | | | | | | | | | | - Xiao-Yuan Xu
- Department of Infectious Disease, Peking University First Hospital, Beijing 100034, China
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Lovett GC, Nguyen T, Iser DM, Holmes JA, Chen R, Demediuk B, Shaw G, Bell SJ, Desmond PV, Thompson AJ. Efficacy and safety of tenofovir in chronic hepatitis B: Australian real world experience. World J Hepatol 2017; 9:48-56. [PMID: 28105258 PMCID: PMC5220271 DOI: 10.4254/wjh.v9.i1.48] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 07/21/2016] [Accepted: 09/22/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the long-term treatment outcomes of tenofovir therapy in patients in a real world Australian tertiary care setting.
METHODS We performed a retrospective analysis of treatment outcomes among treatment-naïve and treatment-experienced patients receiving a minimum 3 mo tenofovir therapy through St Vincent’s Hospital Melbourne, Australia. We included patients receiving tenofovir [tenofovir disoproxil fumarate (TDF)] monotherapy, as well as patients treated with TDF in combination with a second antiviral agent. Patients were excluded if they demonstrated human immune-deficiency virus/hepatitis C virus/hepatitis delta virus coinfection or were less than 18 years of age. We considered virological and biochemical response, as well as safety outcomes. Virological response was determined by measurement of hepatitis B virus (HBV) DNA using sensitive assays; biochemical response was determined via serum liver function tests; histological response was determined from liver biopsy and fibroscan; safety analysis focused on glomerular renal function and bone mineral density. The primary efficacy endpoint was complete virological suppression over time, defined by HBV DNA < 20 IU/mL. Secondary efficacy endpoints included rates of biochemical response, and HB e antigen (HBeAg)/HB surface antigen loss and seroconversion over time.
RESULTS Ninety-two patients were identified who fulfilled the enrolment criteria. Median follow-up was 26 mo (range 3-114). Mean age was 46 (24-78) years, 64 (70%) were male and 77 (84%) were of Asian origin. 55 (60%) patients were treatment-naïve and 62 patients (67%) were HBeAg-negative. Complete virological suppression was achieved by 45/65 (71%) patients at 12 mo, 37/46 (80%) at 24 mo and 25/28 (89%) at 36 mo. Partial virological response (HBV DNA 20-2000 IU/mL) was achieved by 89/92 (96.7%) of patients. Multivariate analysis showed a significant relationship between virological suppression at end of follow-up and baseline HBV DNA level (OR = 0.897, 95%CI: 0.833-0.967, P = 0.0046) and HBeAg positive status (OR = 0.373, 95%CI: 0.183-0.762, P = 0.0069). There was no difference in response comparing treatment-naïve and treatment-experienced patients. Three episodes of virological breakthrough occurred in the setting of non-compliance. Tenofovir therapy was well tolerated.
CONCLUSION Tenofovir is an efficacious, safe and well-tolerated treatment in an Australian real-world tertiary care setting. Our data are similar to the reported experience from registration trials.
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