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Aguilar JC, Akbar SMF, Al-Mahtab M, Khan MSI, Guzman CA, Fernandez G, Aguiar JA, Michel ML, Bourgine M, Marrero MA, Trittel S, Ebensen T, Riese P, Le Grand R, Herate C, Mauras A, Yoshida O, Hiasa Y, Penton E, Guillen GE. HeberNasvac: Development and Application in the Context of Chronic Hepatitis B. Euroasian J Hepatogastroenterol 2024; 14:221-237. [PMID: 39802853 PMCID: PMC11714097 DOI: 10.5005/jp-journals-10018-1457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 11/28/2024] [Indexed: 01/16/2025] Open
Abstract
The immune system plays a central role in controlling acute hepatitis B infection and in patients resolving chronic hepatitis B (CHB). Given that 221 million (75%) of CHB patients reside in low- and middle-income countries, the development of a vaccine with therapeutic properties represents a rational and cost-effective approach more than a romantic endeavor. This review systematically analyzes the key variables related to the safety, efficacy, and effectiveness of CHB treatments. HeberNasvac experience is revisited for addressing the challenges and potentialities of therapeutic vaccines, as well as the current roadblocks in research and development, registration, and large-scale implementation. How to cite this article Aguilar JC, Akbar SMF, Al-Mahtab M, et al. HeberNasvac: Development and Application in the Context of Chronic Hepatitis B. Euroasian J Hepato-Gastroenterol 2024;14(2):221-237.
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Affiliation(s)
- Julio C Aguilar
- Department of Vaccines, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Sheikh MF Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon City, Japan
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Md Sakirul I Khan
- Department of Research Center for Global and Local Infectious Diseases, Oita University, Oita, Japan
| | - Carlos A Guzman
- Department of Vaccinology and Applied Microbiology, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Guillermo Fernandez
- Department of Gastroenterology, Abel Santamaría Hospital, Pinar del Rio, Cuba
| | - Jorge A Aguiar
- Department of Vaccines, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Marie-Louise Michel
- Laboratory of Hepatitis B Virus Pathogenesis, Institut Pasteur, Paris, France
| | - Maryline Bourgine
- Department of Institut Pasteur-TheraVectys Joint Lab, Institut Pasteur Paris, France
| | - Maria A Marrero
- Department of Clinical Trials, National Coordinating Center for Clinical Trials (CENCEC), Havana, Cuba
| | - Stephanie Trittel
- Department of Vaccinology and Applied Microbiology, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Thomas Ebensen
- Department of Vaccinology and Applied Microbiology, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Peggy Riese
- Department of Vaccinology and Applied Microbiology, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Roger Le Grand
- Department of Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Paris, France
| | - Cecile Herate
- Department of Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Paris, France
| | - Aurelie Mauras
- Department of Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Paris, France
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon City, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon City, Japan
| | - Eduardo Penton
- Department of Vaccines, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Gerardo E Guillen
- Department of Vaccines, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
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Jung CY, Jung HY, Kim HW, Ryu GW, Lee JI, Ahn SH, Kim SU, Kim BS. Fibrotic Burden in Patients With Hepatitis B Virus-Related Cirrhosis Is Independently Associated With Poorer Kidney Outcomes. J Infect Dis 2024; 229:108-116. [PMID: 37470458 DOI: 10.1093/infdis/jiad273] [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: 03/30/2023] [Revised: 07/06/2023] [Accepted: 07/18/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND We investigated whether higher fibrotic burden was independently associated with poorer kidney outcomes in patients with hepatitis B virus (HBV)-related cirrhosis. METHODS A total of 1691 patients with radiologically diagnosed HBV-related cirrhosis but without baseline chronic kidney disease (CKD) who underwent transient elastography (TE) between March 2012 and August 2018 were selected. The study outcome was the composite of development of incident CKD, defined as the occurrence of estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m2 or proteinuria (≥1+ on dipstick test) on 2 consecutive measurements during follow-up, 50% decline in eGFR or onset of end-stage kidney disease (initiation of chronic dialysis), or all-cause mortality. RESULTS The mean age was 53.4 years and 1030 (60.9%) patients were male. During 8379 person-years of follow-up (median 5.2 years), 60 (3.5%) patients experienced study outcomes. When stratified according to TE-defined fibrotic burden, multivariable Cox models revealed that risk of poorer kidney outcomes was 2.77-fold (95% confidence interval, 1.16-6.63; P < .001) higher in patients with liver stiffness range indicating cirrhosis (≥11.7 kPa), compared to those without significant liver fibrosis (<7.9 kPa). These associations remained significant even after adjusting for vigorous confounders. CONCLUSIONS Higher fibrotic burden assessed using TE was independently associated with poorer kidney outcomes in patients with HBV-related cirrhosis.
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Affiliation(s)
- Chan-Young Jung
- Department of Internal Medicine, Yonsei University College of Medicine
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine
| | - Hui-Yun Jung
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Hyung Woo Kim
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Geun Woo Ryu
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Jung Il Lee
- Division of Gastroenterology, Gangnam Severance Hospital
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Beom Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine
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Cho YY, Chang Y, Nam JY, Cho H, Cho EJ, Lee JH, Yu SJ, Yoon JH, Kim YJ. Long-term Nucleotide Analogue Treatment Has Higher Levels of Renal Toxicities than Does Entecavir in Patients with Chronic Hepatitis B. Gut Liver 2021; 14:225-231. [PMID: 31060115 PMCID: PMC7096224 DOI: 10.5009/gnl18474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 02/10/2019] [Accepted: 03/01/2019] [Indexed: 01/10/2023] Open
Abstract
Background/Aims Renal toxicity is a concern in patients with chronic hepatitis B taking nucleotide analogues, such as adefovir (ADV) and tenofovir disoproxil fumarate (TDF). We sought to determine the long-term renal effects of nucleotide analogue treatment versus entecavir (ETV) treatment. Methods In this retrospective single-center study, we selected 87 patients who were treated with ADV and subsequently with TDF from June 2008 to December 2013. ETV-treated patients were matched by treatment duration. We analyzed the creatinine increase over 0.5 mg/dL, glomerular filtration rate (GFR) decrease over 25%, phosphorus decrease under 2.0 mg/dL, and dose reduction of antiviral agents. Results The median follow-up period was 60.0 months for both groups. The incidence of liver cirrhosis was higher in the ADV-TDF group than in the ETV group (32.2% vs 74.7%, p<0.01). Creatinine increased in both groups during follow-up, but the difference was not significant (5.7% and 2.3%, p=0.44). In addition, GFR decreased more often in the ADV-TDF group than in the ETV group (31.0% and 14.9%, p=0.01). After multivariate Cox regression analysis, ADV-TDF treatment was significantly associated with a GFR decrease over 25% (hazard ratio, 2.10; 95% confidence interval, 1.08 to 4.10; p=0.03) after adjusting for the baseline GFR decrease. Conclusions Patients taking nucleotide analogues had a significantly higher number of renal events than did those taking ETV. Clinicians should be aware of the development of renal toxicity in this patient population. Further long-term studies are warranted.
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Affiliation(s)
- Young Youn Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea
| | - Young Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Joon Yeul Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyeki Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Adefovir dipivoxil induced hypophosphatemic osteomalacia in chronic hepatitis B: a comparative study of Chinese and foreign case series. BMC Pharmacol Toxicol 2018; 19:23. [PMID: 29769119 PMCID: PMC5956546 DOI: 10.1186/s40360-018-0212-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 04/30/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Adefovir dipivoxil (ADV)-induced renal tubular dysfunction and hypophosphatemic osteomalacia (HO) have been given great consideration in the past few years. However, no standard guidance is available due to a lack of powerful evidence from appropriate long-term prospective case-control studies and variations in the definition of renal adverse events. The aim of this study is to clarify clinical features of ADV-related HO in Chinese chronic hepatitis B patients with long-term ADV treatment in Chinese and non-Chinese comparative case series. METHODS Retrieval of case reports was based on Pubmed, CNKI, Wan Fang and VIP databases using the key words adefovir dipivoxil, hypophosphatemia, osteomalacia and Fanconi syndrome. We divided patients into Chinese (C group) and Foreign (F group) groups according to their nationality. Comparisons involving demographics, clinical manifestations, tests, treatment and prognosis were conducted between the two groups. RESULTS Of the patients screened, 120 Chinese patients were identified in the C group, and 32 non-Chinese patients were identified in the F group. The average age of the C group was younger than that of the F group (51.89 years ±10.96 years versus 56.47 years ±11.36 years, t = - 2.084, P = 0.039). No significant difference was found in gender (male to female, 3.29:1 versus 3:1, χ 2 = 0.039, P = 0.844). Although there was no significant difference in the duration of ADV therapy before ostalgia onset, the C group tended to develop adverse events earlier, by 2-3 years, while the F group developed adverse events at 4-5 years (Z = - 1.517, P = 0.129). Prognosis was good after adjustment of the ADV dose and supplemental administration of phosphate and calcitriol. Time to resolution of tubular dysfunction was commenced at the first month, and Chinese patients were more prone to recover in the first 3 months than non-Chinese patients (91.3% of patients in the C group versus 56.3% in the F group, Z = - 3.013, P = 0.003). CONCLUSIONS Sufficient attention is required for middle-aged males before and during exposure to long-term ADV therapy, regardless of nationality. The clinical picture, laboratory and radiograph alterations are important clues for those patients and are usually characterized by polyarthralgia, renal tubular dysfunction and mineralization defects. Implementation of an early renal tubular injury index is recommended for patients with higher risk, which would prevent further renal injury.
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Yamamoto T, Maruyama Y, Ohashi N, Yasuda H, Shinozaki M. Hypophosphatemia predicts a failure to recover from adefovir-related renal injury after dose reduction in lamivudine-resistant hepatitis B patients. Hepatol Res 2017; 47:1272-1281. [PMID: 28079295 DOI: 10.1111/hepr.12865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 12/24/2016] [Accepted: 01/09/2017] [Indexed: 02/08/2023]
Abstract
AIM In chronic hepatitis B patients receiving 10 mg adefovir, dose reduction is recommended when renal injury appears. However, recovery is not always achieved and markers that recommend switching to another antiviral agent are unknown. We investigated adefovir-related renal injury, recovery after dose reduction, and their predictors. METHODS The renal injury in 77 chronic hepatitis B patients receiving 10 mg adefovir and recovery after dose reduction to alternate day administration in those with adefovir-related renal injury were assessed. The predictors for >20% estimated glomerular filtration rate (eGFR) decline following treatment with 10 mg adefovir and for >20% eGFR recovery after dose reduction were investigated. RESULTS The adefovir dose was reduced in 26 patients (34%) at 59 ± 30 (mean ± standard deviation) months of 10 mg adefovir treatment because of decreases in eGFR (cumulative incidence 27%), serum phosphorus (9%), and uric acid (16%) levels, and increases in alkaline phosphatase (20%), bone type alkaline phosphatase (18%), urinary α1-microglobulin (18%), and urinary N-acetyl-β-D-glucosaminidase (18%) levels. The only significant predictor for >20% eGFR decline was age ≥50 years at the start of 10 mg adefovir treatment. The cumulative eGFR recovery rate was 42% at 42 ± 27 months after dose reduction, and ≥2.5 mg/dL serum phosphorus level at dose reduction was the only significant predictor for >20% eGFR recovery after dose reduction. CONCLUSION Patients aged ≥50 years are predisposed to adefovir-related renal injury and switching to another antiviral agent rather than adefovir dose reduction is recommended when hypophosphatemia is observed.
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Affiliation(s)
- Tatsuo Yamamoto
- Department of Nephrology, Fujieda Municipal General Hospital, Fujieda, Japan
| | - Yasuhiko Maruyama
- Department of Gastroenterology, Fujieda Municipal General Hospital, Fujieda, Japan
| | - Naro Ohashi
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hideo Yasuda
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masami Shinozaki
- Department of Gastroenterology, Numazu City Hospital, Numazu, Japan
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Lin J, Zhuo Y, Zhang D. Nephrolithiasis and Osteomalacia associated with adefovir-induced Fanconi syndrome in a patient with hepatitis B. BMC Nephrol 2017; 18:275. [PMID: 28851305 PMCID: PMC5576285 DOI: 10.1186/s12882-017-0693-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 08/21/2017] [Indexed: 11/24/2022] Open
Abstract
Background An increasing number of case reports suggest that acquired renal Fanconi syndrome may be associated with prolonged use of adefovir against hepatitis B virus. Renal Fanconi syndrome is an uncommon disease, and its complication with nephrolithiasis is quite rare. Herein, we report a rare coexistence of nephrolithiasis and acquired renal Fanconi syndrome in a chronic hepatitis B-positive patient with prolonged adefovir therapy. Case presentation The patient presented with osteomalacia and nephrolithiasis. Consequently, extracorporeal shock-wave lithotripsy and left double-J ureteral stent insertion were considered for obstructive nephropathy, which was caused by nephrolithiasis. However, osteomalacia had been misdiagnosed as osteoporosis before admission to our hospital. On admission, a complexity of multiple fractures, hypophosphataemia, glycosuria without hyperglycaemia and non–anion-gap metabolic acidosis indicated a diagnosis of acquired renal Fanconi syndrome induced by adefovir. After switching from adefovir to entecavir, the patient’s symptoms and laboratory findings improved significantly. Conclusions The mechanism responsible for nephrolithiasis in renal Fanconi syndrome is still unclear. We recommend regularly monitoring renal function and serum calcium and serum phosphate to prevent renal Fanconi syndrome during the prolonged use of adefovir for hepatitis B virus.
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Affiliation(s)
- Jueying Lin
- Department of Traditional Chinese Medicine, Zhong Shan Hospital Xiamen University, No. 201 Hubin nan Road, Xiamen, Fujian, 361004, China
| | - Yufeng Zhuo
- Department of Traditional Chinese Medicine, Zhong Shan Hospital Xiamen University, No. 201 Hubin nan Road, Xiamen, Fujian, 361004, China
| | - Dongdong Zhang
- Department of Traditional Chinese Medicine, Zhong Shan Hospital Xiamen University, No. 201 Hubin nan Road, Xiamen, Fujian, 361004, China.
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Luo Q, Deng Y, Cheng F, Kang J, Zhong S, Zhang D, Zeng W. Relationship between nephrotoxicity and long-term adefovir dipivoxil therapy for chronic hepatitis B: A meta-analysis. Medicine (Baltimore) 2016; 95:e5578. [PMID: 27977591 PMCID: PMC5268037 DOI: 10.1097/md.0000000000005578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To assess the relationship between adefovir dipivoxil and renal function after anti-hepatitis B virus therapy and elucidate the risk factors involved. METHODS Based on the requirements of the Cochrane systematic review methodology, 21 observational articles on adefovir dipivoxil-associated renal dysfunction were obtained by searching various databases, between January 1, 1995 and July 1, 2016. The Newcastle Ottawa Scale was used to evaluate risk bias. Parameters for 4276 chronic hepatitis B patients were analyzed by Review Manager and R software, and glomerular filtration rate, creatinine clearance, and serum creatinine values were extracted to evaluate renal function. RESULTS Renal dysfunction was more likely to occur in patients receiving the adefovir dipivoxil therapy (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.40-2.80) than the none-adefovir dipivoxil group. Subgroup analysis showed that renal function predictive value is higher for glomerular filtration rate (OR 2.42, 95% CI 1.34-3.14), compared with serum creatinine levels (OR 1.51, 95% CI 0.75-3.04). The rate of adefovir dipivoxil-associated renal dysfunction was 12% (95% CI 0.08-0.16). Older patients and patients with renal insufficiency, hypertension, and diabetes mellitus were more prone to developing adefovir dipivoxil-associated renal dysfunction; however, integrated raw data were insufficient for further detailed analysis. CONCLUSION Long-term adefovir dipivoxil therapy is connected to renal dysfunction in chronic hepatitis B, necessitating the monitoring of kidney function.
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Affiliation(s)
- Qing Luo
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University
| | - Yong Deng
- Department of Gastroenterology, Chongqing General Hospital
| | | | - Juan Kang
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University
| | - Shan Zhong
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University
| | - Dazhi Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weiqiong Zeng
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University
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Uteng M, Mahl A, Beckmann N, Piaia A, Ledieu D, Dubost V, Tritto E, Wolf A, Moulin P, Li L, Chibout SD, Pognan F. Editor's Highlight: Comparative Renal Safety Assessment of the Hepatitis B Drugs, Adefovir, Tenofovir, Telbivudine and Entecavir in Rats. Toxicol Sci 2016; 155:283-297. [PMID: 27742868 DOI: 10.1093/toxsci/kfw208] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The aim of this study was to determine the relative safety of 4 antiviral drugs (telbivudine, tenofovir, adefovir, and entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Sprague Dawley rats. The antiviral drugs were administered once daily for 4 weeks by oral gavage at ∼10 and 25-40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology, and electron microscopic examination. Administration of adefovir at 11 and 28 mg/kg for 4 weeks caused functional and morphological kidney alterations in a time- and dose-dependent manner, affecting mainly the proximal tubules and suggesting a mechanism of toxicity related to mitochondrial degeneration/depletion. Of note, the observed adefovir-induced reduction of kidney function was not detected by the standard method of glomerular filtration rate (GFR) measurements (clearance rate of the endogenous marker, creatinine), thereby emphasizing the superiority of MRI in terms of sensitive detection of GFR in rats. For the low dose of 300 mg/kg of tenofovir, minor kidney effects such as nuclear enlargement in the tubular epithelium, and hyaline droplets accumulation were detected, which was also observed for the low dose (11 mg/kg) of adefovir. No assessments could be done at the higher dose of 600/1000 mg/kg tenofovir due to gastrointestinal tract toxicity which prevented treatment of the animals for longer than 1 week. Entecavir at 1 and 3 mg/kg and telbivudine at 600 and 1600 mg/kg caused no toxicologically relevant effects on the kidney.
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Affiliation(s)
- Marianne Uteng
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland;
| | - Andreas Mahl
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Nicolau Beckmann
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Alessandro Piaia
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - David Ledieu
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Valerie Dubost
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Elaine Tritto
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Armin Wolf
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Pierre Moulin
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Li Li
- Novartis Institutes for BioMedical Research, East Hanover, New Jersey
| | - Salah-Dine Chibout
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Francois Pognan
- Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
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Laho T, Clarke JD, Dzierlenga AL, Li H, Klein DM, Goedken M, Micuda S, Cherrington NJ. Effect of nonalcoholic steatohepatitis on renal filtration and secretion of adefovir. Biochem Pharmacol 2016; 115:144-51. [PMID: 27381944 DOI: 10.1016/j.bcp.2016.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 07/01/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of glomerular filtration with active tubular transport. Nonalcoholic steatohepatitis is a variable in drug disposition, yet the impact on renal transport processes has yet to be fully understood. The goal of this study was to determine the effect of nonalcoholic steatohepatitis on the pharmacokinetics of adefovir in rats given a control or methionine and choline deficient diet to induce nonalcoholic steatohepatitis. METHODS Animals received a bolus dose of 7mg/kg (35μCi/kg) [(3)H] adefovir with consequent measurement of plasma and urine concentrations. Inulin clearance was used to determine glomerular filtration rate. RESULTS Methionine and choline deficient diet-induced nonalcoholic steatohepatitis prolonged the elimination half-life of adefovir. This observation occurred in conjunction with reduced distribution volume and hepatic levels of adefovir. Notably, despite these changes, renal clearance and overall clearance were not changed, despite markedly reduced glomerular filtration rate in nonalcoholic steatohepatitis. Alteration of glomerular filtration rate was fully compensated for by a significant increase in tubular secretion of adefovir. Analysis of renal transporters confirmed transcriptional up-regulation of Mrp4, the major transporter for adefovir tubular secretion. CONCLUSIONS This study demonstrates changes to glomerular filtration and tubular secretion that alter pharmacokinetics of adefovir in nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis-induced changes in renal drug elimination processes could have major implications in variable drug response and the potential for toxicity.
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Affiliation(s)
- Tomas Laho
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ, USA; Charles University, Department of Pharmacology, Hradec Kralove, Czech Republic
| | - John D Clarke
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ, USA
| | - Anika L Dzierlenga
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ, USA
| | - Hui Li
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ, USA
| | - David M Klein
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ, USA
| | - Michael Goedken
- Rutgers University, Department of Translational Sciences Research Pathology Services, New Brunswick, NJ, USA
| | - Stanislav Micuda
- Charles University, Department of Pharmacology, Hradec Kralove, Czech Republic
| | - Nathan J Cherrington
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ, USA.
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Mak LY, Seto WK, Lai CL, Yuen MF. DNA polymerase inhibitors for treating hepatitis B: a safety evaluation. Expert Opin Drug Saf 2016; 15:383-92. [PMID: 26752687 DOI: 10.1517/14740338.2016.1139573] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Oral nucleoside/ nucleotide analogues (NAs) are currently the mainstay of treatment for patients with chronic hepatitis B virus (HBV) infection. They are generally safe to use. However, since their approval in the last decade and a half, the literature has reported adverse effects associated with the use of NA in HBV patients. A comprehensive review on the drug safety is lacking. AREAS COVERED Significant adverse effects associated with NA use in HBV patients including muscle toxicity, peripheral neuropathy, nephrotoxicity and lactic acidosis are discussed. The reported prevalence of each adverse effect, as well as their predictive factors, reversibility and their use in pregnancy and lactating mothers are covered in this review. Novel data regarding reno-protective effect of telbivudine are also discussed. EXPERT OPINION Use of NA in HBV is generally safe. Uncommon adverse effects can be minimized or detected early if clinicians exercise adequate precautions when using NA for at-risk populations with regular monitoring.
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Affiliation(s)
- Lung-Yi Mak
- a Division of Gastroenterology and Hepatology, Department of Medicine , Queen Mary Hospital , Hong Kong , Hong Kong
| | - Wai-Kay Seto
- a Division of Gastroenterology and Hepatology, Department of Medicine , Queen Mary Hospital , Hong Kong , Hong Kong
| | - Ching-Lung Lai
- a Division of Gastroenterology and Hepatology, Department of Medicine , Queen Mary Hospital , Hong Kong , Hong Kong
| | - Man-Fung Yuen
- a Division of Gastroenterology and Hepatology, Department of Medicine , Queen Mary Hospital , Hong Kong , Hong Kong
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11
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Thu AM, Poovorawan K, Kittitrakul C, Nontprasert A, Sriboonvorakul N, Phumratanaprapin W, Tangkijvanich P, Leowattana W, Wilairatana P. Nephrotoxicity caused by oral antiviral agents in patients with chronic hepatitis B treated in a hospital for tropical diseases in Thailand. BMC Pharmacol Toxicol 2015; 16:38. [PMID: 26651337 PMCID: PMC4677430 DOI: 10.1186/s40360-015-0037-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 11/18/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND There is increasing concern about the potential for nephrotoxicity in patients with chronic hepatitis B (CHB) treated long-term with nucleotide analogs. METHODS We examined renal dysfunction and its associated risk factors in patients with CHB treated with antiviral regimens containing either nucleosides or nucleotide analogs. We undertook a retrospective cohort study from 2006 to 2014 at the Hospital for Tropical Diseases, Bangkok, Thailand, and analyzed the data of 102 patients with a median follow-up time of 44.5 months (range 4-101 months). RESULTS Seventy-three patients were treated with an antiviral regime containing a nucleoside analog, and 29 with a regime containing a nucleotide analog. Abnormally elevated serum creatinine concentration was observed in 12 patients (11.8 %) after 8 years of treatment. Thirty one percent of patients treated with nucleotide analogs had elevated serum creatinine levels and three of these patients (10.3 %) developed nephrotoxicity. In contrast, serum creatinine concentrations were elevated in three of the 73 patients treated with a nucleoside analog (4.1 %), and none developed nephrotoxicity. The incidence of renal dysfunction by the nucleotide analog regimen was cumulative, with 11.1, 21.0, 26.5 and 47.6 % of patients affected after 2, 4, 6 and 8 years, respectively. Univariate and multivariate analysis indicated that a nucleotide analog-based regimen significantly predicted renal dysfunction (odds ratio 10.5, 95 % confidence intervals 2.6-42.4, P <0.001). CONCLUSION The long-term use of nucleotide analogs increased the risk of nephrotoxicity in patients with CHB. Thus, the regular assessment of renal function is recommended for all patients with CHB, particularly those treated with a nucleotide analog.
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Affiliation(s)
- Aung Myint Thu
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Kittiyod Poovorawan
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Chatporn Kittitrakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Apichart Nontprasert
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Natthida Sriboonvorakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Weerapong Phumratanaprapin
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Pisit Tangkijvanich
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
| | - Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
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12
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Ozaras R, Khodor H, Yetim N, Unal UK, Demirhan YE, Gultekin G, Isal B. Monotherapy for hepatitis B infection: a review of treatment options. Expert Rev Anti Infect Ther 2015; 13:1457-68. [PMID: 26414781 DOI: 10.1586/14787210.2015.1093934] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Chronic hepatitis B (CHB) is a global health problem, causing liver failure, cirrhosis and hepatocellular carcinoma. CHB treatment aims to prevent liver-related complication. The treatment of CHB infection includes monotherapy with either interferons (IFNs) or nucleos(t)ide (NUC) analogs. IFNs have moderate antiviral effects, and their use is limited by side effects. With the availability of NUCs, IFN-intolerant and decompensated cirrhotic patients began to be treated. Lamivudine and telbivudine, nucleoside analogs, have low genetic barrier to resistance. Adefovir, a nucleotide analog, has moderate potency and potential nephrotoxicity. Entecavir and tenofovir, with their high potency, high genetic barrier to resistance and favorable safety profile are the standard of care in CHB treatment. Long-term use of NUCs with maintained viral suppression results in a decrease in liver-related complications.
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Affiliation(s)
| | - Hawa'a Khodor
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Nergul Yetim
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Umut Kaan Unal
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Yunus Emre Demirhan
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Goknil Gultekin
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Burak Isal
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
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13
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Ridruejo E. Antiviral treatment for chronic hepatitis B in renal transplant patients. World J Hepatol 2015; 7:189-203. [PMID: 25729474 PMCID: PMC4342601 DOI: 10.4254/wjh.v7.i2.189] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 10/17/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B infection is frequent in renal transplant patients. It negatively impacts long term outcomes reducing graft and patient survival. Current guidelines clearly define who needs treatment, when to start, what is the first line therapy, how to monitor treatment response, when to stop, and how patients must be controlled for its safety. There is some data showing a favorable safety and efficacy profile of nucleos(t)ide analogue (NUC) treatment in the renal transplant setting. Entecavir, a drug without major signs of nephrotoxicity, appears to be the first option for NUC naïve patients and tenofovir remains the preferred choice for patients with previous resistance to lamivudine or any other NUC. Renal transplant recipients under antiHBV therapy should be monitored for its efficacy against HBV but also for its safety with a close renal monitoring. Studies including a large number of patients with long term treatment and follow up are still needed to better demonstrate the safety and efficacy of newer NUCs in this population.
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14
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Cho Y, Lee JH, Yu SJ, Yoon JH, Lee HS, Kim YJ. Comparison of the efficacies of entecavir 0.5 and 1.0 mg combined with adefovir in patients with chronic hepatitis B who had failed on prior nucleos(t)ide analogue treatments. J Med Virol 2015; 87:999-1007. [PMID: 25711201 DOI: 10.1002/jmv.24150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2015] [Indexed: 01/05/2023]
Abstract
Entecavir (ETV) plus adefovir (ADV) combination therapy is one of the useful treatment option for the patients with chronic hepatitis B (CHB) who had failed on prior nucleos(t) ide analogue (NA) treatments. This study compared the efficacies of the combinations of ETV 0.5 mg plus ADV and ETV 1.0 mg plus ADV in patients who had failed on prior multiple NA treatments. This retrospective analysis included 148 consecutive patients with CHB infection in Korea (n = 37 with ETV 0.5 mg plus ADV and n = 111 with ETV 1.0 mg plus ADV). The virological and biochemical responses were compared between the two groups. The cumulative probability of viral suppression of ETV 0.5 mg plus ADV was not inferior to that of ETV 1.0 mg plus ADV (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.38-1.08; P = 0.094). The changes in serum HBV DNA level in the ETV 0.5 mg plus ADV group were not different between the two groups over 12 months. Moreover, no significant difference was observed in acquiring ETV-resistant variants between the two groups during the treatment (HR, 0.95; P = 0.953). This study suggests the proof-of-concept that the lower dose of NA in combination with other NA might be the theoretical option for rescue combination therapy in patients with CHB who had failed on prior multiple NA treatments in order to reduce systemic exposure and possible side effects of NA.
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Affiliation(s)
- Yuri Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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15
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Nguyen NH, Trinh HN, Nguyen TT, Do ST, Tran P, Nguyen HA, Nguyen KK, Garcia RT, Lutchman GA, Nguyen MH. Safety and efficacy of entecavir in adefovir-experienced patients. J Gastroenterol Hepatol 2015; 30:43-50. [PMID: 25168842 DOI: 10.1111/jgh.12728] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/10/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Suboptimal viral suppression with adefovir (ADV) poses a challenge in managing chronic hepatitis B. Few studies have evaluated the efficacy of entecavir (ETV) in ADV-experienced patients. Our aim is to assess treatment effectiveness of ETV in ADV-experienced patients. METHODS ADV-experienced patients switched to ETV were enrolled from six US clinics. Patients completed a median of 24 months of ETV after switch. Patients were categorized into partial responders (detectable HBV-DNA at switch) or complete responders (undetectable HBV-DNA at switch) to ADV. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV-DNA < 60 IU/mL) and biochemical response (BR, alanine aminotransferase [ALT] < 40 U/L), respectively. RESULTS A total of 120 patients were included in the analysis (80 ADV partial responders; 40 ADV complete responders). In partial responders, CVS rate was 84% after 24 months of ETV. BR rate was 58% at switch to ETV and increased to 90% after 24 months. All complete responders continued to experience CVS after switch. On multivariate analysis inclusive of age, male gender, ALT level at switch, and history of lamivudine (LAM) exposure, we identified positive, hepatitis B e antigen status before ADV and higher HBV-DNA level at time of switch as significant independent negative predictors of CVS. In eight patients with ADV resistance, seven achieved CVS after 24 months of ETV, and all achieved BR. CONCLUSION In ADV-experienced patients, high rates of CVS and BR can be achieved/sustained after switching to ETV, including those with ADV resistance or with prior exposure to LAM.
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Affiliation(s)
- Nghia H Nguyen
- School of Medicine, University of California San Diego, San Jose, California, USA
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Abstract
There had been remarkable development in nucleos(t)ide analogues (NAs) and evolution in treatment strategies in last 15 years. Currently, there are five NAs available for chronic hepatitis B treatment, namely lamivudine, telbivudine and entecavir (nucleoside analogues), adefovir dipivoxil and tenofovir disoproxil fumarate (nucleotide analogues). The advantages of relatively infrequent side effects and easy administration per oral make NAs popular treatment options. The major drawback of earlier generation NAs is the risk of emergence of drug resistance. Current international guidelines recommend the use of more potent agents with high genetic barriers to resistance including entecavir and tenofovir as first line chronic hepatitis B treatment. However, there is no consensus regarding the subsequent treatment regimens in patients with suboptimal responses to NAs. De novo combination therapy of two NAs, response-guided therapy and roadmap concept in NAs with subsequent switch or add-on therapy can also potentially improve treatment efficacy and avoid resistance.
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Affiliation(s)
- Angeline Oi-Shan Lo
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
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Ramsay ID, Lestner JM, O’Sullivan CP, Cruz AL, Li HK, Barker CI. Antiviral Drugs. SIDE EFFECTS OF DRUGS ANNUAL 2014:401-443. [DOI: 10.1016/b978-0-444-63407-8.00029-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Yu S, Zhou Q, Zhao XM, Yuan M, Wang CT, Cheng XG, Zhang ZH, Li X. Comparison of the antiviral effects of different nucleos(t)ide analogues in chinese patients with chronic hepatitis B: a head-to-head study. Saudi J Gastroenterol 2014; 20:350-5. [PMID: 25434315 PMCID: PMC4271009 DOI: 10.4103/1319-3767.145320] [Citation(s) in RCA: 6] [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] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS To assess the antiviral efficacy of lamivudine (LAM), entecavir (ETV), telbivudine (LDT), and lamivudine and adefovir dipivoxil (CLA) combination in previously untreated hepatitis B patients at different time points during a 52-week treatment period. PATIENTS AND METHODS A total of 164 patients were included in this prospective, open-label, head-to-head study. Serum levels of alanine transaminase (ALT), hepatitis B virus (HBV) DNA, and hepatitis B e antigen (HBeAg) were measured at baseline, and at 12, 24, and 52 weeks of treatment. RESULTS Median reductions in serum HBV DNA levels at 52 weeks (log 10 copies/mL) were as follows: LAM, 3.98; ETV, 3.89; LDT, 4.11; and CLA, 3.36. The corresponding HBV DNA undetectability rates were 83%, 96%, 91%, and 89%, respectively. These two measures showed no significant intergroup differences. Clinical efficacy appeared related to HBV DNA level reduction after 24 weeks of therapy. Patients were divided into three groups based on HBV DNA levels at week 24: Undetectable (<10(3) copies/mL), detectable but <10(4) copies/mL, and >10(4) copies/mL. Patients with levels below quantitation limit (QL) were analyzed at 52 weeks for HBV DNA undetectability rate (94%), ALT normalization rate (83%), and viral breakthrough rate (0%). The corresponding values in the QL-10(4) copies/mL group were 50%, 75%, and 13%, whereas those in the above 10(4) copies/mL group were 53%, 65%, and 18%. There were significant differences at week 52 for HBV DNA levels and viral breakthrough rate between the three groups. CONCLUSIONS Different nucleos(t)ide (NUC) analogues tested exhibited no significant differences in effectiveness for Chinese NUC-naive HBV patients during 1-year treatment period.
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Affiliation(s)
- Shu Yu
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qin Zhou
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiao Miao Zhao
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Min Yuan
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chang Tai Wang
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiao Guang Cheng
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhen Hua Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China,Address for correspondence: Dr. Zhen Hua Zhang, and Xu Li, Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, Anhui Province, China. E-mail: ;
| | - Xu Li
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China,Address for correspondence: Dr. Zhen Hua Zhang, and Xu Li, Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, Anhui Province, China. E-mail: ;
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Elevation in Serum Concentration of Bone-Specific Alkaline Phosphatase without Elevation in Serum Creatinine Concentration Secondary to Adefovir Dipivoxil Therapy in Chronic Hepatitis B Virus Infection. HEPATITIS RESEARCH AND TREATMENT 2013; 2013:739247. [PMID: 24106611 PMCID: PMC3782837 DOI: 10.1155/2013/739247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Revised: 08/06/2013] [Accepted: 08/07/2013] [Indexed: 11/17/2022]
Abstract
Of 168 patients with chronic hepatitis B virus (HBV) infection-related liver disease, 20 patients who had received 100 mg of lamivudine plus 10 mg/day of adefovir dipivoxil (ADV) (ADV group) and 124 patients who had received 0.5 mg/day of entecavir or 100 mg/day of lamivudine (non-ADV group) for >1 year were enrolled. For comparative analyses, 19 well-matched pairs were obtained from the groups by propensity scores. At the time of enrollment, serum creatinine and phosphate concentrations were similar between the ADV and non-ADV groups; however, urinary phosphate (P = 0.0424) and serum bone-specific alkaline phosphatase (BAP) (P = 0.0228) concentrations were significantly higher in the ADV group than in the non-ADV group. Serum BAP was significantly higher at the time of enrollment than before ADV administration in the ADV group (P = 0.0001), although there was no significant change in serum BAP concentration in the non-ADV group. There was a significant positive correlation between the period of ADV therapy and ΔBAP (R (2) = 0.2959, P = 0.0160). Serum BAP concentration increased before increase in serum creatinine concentration and was useful for early detection of adverse events and for developing adequate measures for continuing ADV for chronic HBV infection-related liver disease.
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