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Chen L, Deng M, Yan W, Zeng Z, Chen D, Zhao Y, Wu Y, Li Y, He B. Glycoconjugates of adefovir and tenofovir as asialoglycoprotein-mediated Anti-HBV prodrugs with enhanced liver targeting. Eur J Med Chem 2025; 284:117207. [PMID: 39746236 DOI: 10.1016/j.ejmech.2024.117207] [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: 10/30/2024] [Revised: 12/15/2024] [Accepted: 12/22/2024] [Indexed: 01/04/2025]
Abstract
Hepatitis B virus (HBV) infection remains a significant global health challenge, often leading to severe liver complications such as cirrhosis and cancer. Current treatments rely heavily on nucleos(t)ide analogues like adefovir and tenofovir due to their potent antiviral effects. However, their clinical utility is limited by insufficient liver targeting, leading to off-target side effects, particularly nephrotoxicity. To improve liver-specific drug delivery and reduce adverse effects, we designed novel liver-targeted prodrugs by conjugating adefovir and tenofovir with N-acetylgalactosamine (GalNAc) and tris-GalNAc ligands, which have high affinity for the asialoglycoprotein receptor (ASGPR) predominantly expressed in hepatocytes. Four prodrugs (A1, A2, T1, and T2) were synthesized and evaluated for cytotoxicity, maximum tolerated dose, anti-HBV activity, metabolic stability, pharmacokinetics, and liver-targeting properties. The prodrugs exhibited low cytotoxicity, robust anti-HBV activity, and enhanced selectivity compared to their parent drugs. Notably, the tris-GalNAc conjugates A2 and T2 demonstrated superior liver targeting, showing a threefold higher concentration in the liver compared to the kidneys, thus minimizing renal exposure. These findings suggest that GalNAc and tris-GalNAc conjugation is a promising strategy for enhancing the therapeutic efficacy and safety of adefovir and tenofovir, with potential for further optimization as liver-targeted anti-HBV prodrugs.
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Affiliation(s)
- Lei Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Mingzhenlong Deng
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Wanli Yan
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Ziwei Zeng
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Di Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Yonglong Zhao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Yisong Wu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Yan Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Bin He
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
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Liatsou E, Tatouli I, Mpozikas A, Pavlou MM, Gakiopoulou H, Ntanasis-Stathopoulos I, Gavriatopoulou M, Kontogiannis S, Dimopoulos MA. Tenofovir-Induced Fanconi Syndrome Presenting with Life-Threatening Hypokalemia: Review of the Literature and Recommendations for Early Detection. J Clin Med 2023; 12:7178. [PMID: 38002790 PMCID: PMC10672342 DOI: 10.3390/jcm12227178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/10/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor that has been widely used for the treatment of patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. However, in the HBV monoinfection scenario, only five cases of TDF-associated Fanconi syndrome have been reported thus far, two of them providing a confirmatory kidney biopsy. Here, we describe the case of a 68-year-old woman with chronic hepatitis B (CHB) who developed TDF-induced Fanconi syndrome that reverted after TDF withdrawal from tenofovir alafenamide. Though the overall risk of TDF-associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular functions should be monitored in patients exposed to TDF.
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Affiliation(s)
- Efstathia Liatsou
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.L.); (I.T.); (A.M.); (M.-M.P.); (M.G.); (S.K.)
| | - Ioanna Tatouli
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.L.); (I.T.); (A.M.); (M.-M.P.); (M.G.); (S.K.)
| | - Andreas Mpozikas
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.L.); (I.T.); (A.M.); (M.-M.P.); (M.G.); (S.K.)
| | - Maria-Markella Pavlou
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.L.); (I.T.); (A.M.); (M.-M.P.); (M.G.); (S.K.)
| | - Hariklia Gakiopoulou
- 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.L.); (I.T.); (A.M.); (M.-M.P.); (M.G.); (S.K.)
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.L.); (I.T.); (A.M.); (M.-M.P.); (M.G.); (S.K.)
| | - Sofoklis Kontogiannis
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.L.); (I.T.); (A.M.); (M.-M.P.); (M.G.); (S.K.)
| | - Meletios Athanasios Dimopoulos
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.L.); (I.T.); (A.M.); (M.-M.P.); (M.G.); (S.K.)
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McCormick CD, Sullivan PS, Qato DM, Crawford SY, Schumock GT, Lee TA. Trends of nonoccupational postexposure prophylaxis in the United States. AIDS 2023; 37:2223-2232. [PMID: 37650765 DOI: 10.1097/qad.0000000000003701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
OBJECTIVE To describe national annual rates of nonoccupational postexposure prophylaxis (nPEP) in the United States. DESIGN Retrospective cohort study of commercially insured individuals in the Merative MarketScan Database from January 1, 2010 to December 31, 2019. METHODS Patients at least 13 years old prescribed nPEP per recommended Centers for Disease Control and Prevention guidelines were identified using pharmacy claims. Rates of use were described overall and stratified by sex, age group, and region. These rates were qualitatively compared to the diagnosis rates of human immunodeficiency virus (HIV) observed in the data. Joinpoint analysis identified inflection points of nPEP use. RESULTS Eleven thousand, three hundred and ninety-seven nPEP users were identified, with a mean age of 33.7 years. Most were males (64.6%) and lived in the south (33.2%) and northeast (32.4%). The rate of nPEP use increased 515%, from 1.42 nPEP users per 100 000 enrollees in 2010 to 8.71 nPEP users per 10 000 enrollees in 2019. The comparative nPEP use rates among subgroups largely mirrored their HIV diagnosis rates, that is, subgroups with a higher HIV rate had higher nPEP use. In the Joinpoint analysis significant growth was observed from 2012 to 2015 [estimated annual percentage change (EAPC): 45.8%; 95% confidence interval (CI): 29.4 - 64.3] followed by a more moderate increase from 2015 to 2019 (EAPC 16.0%; 95% CI: 12.6-19.6). CONCLUSIONS nPEP use increased from 2010 to 2019, but not equally across all risk groups. Further policy interventions should be developed to reduce barriers and ensure adequate access to this important HIV prevention tool.
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Affiliation(s)
- Carter D McCormick
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois Chicago, College of Pharmacy, Chicago, Illinois
| | - Patrick S Sullivan
- Department of Epidemiology, Emory University, Rollins School of Public Health, Atlanta, Georgia
| | - Dima M Qato
- Program on Medicines and Public Health, Titus Family Department of Clinical Pharmacy, University of Southern California, School of Pharmacy
- USC Leonard D. Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles, California, USA
| | - Stephanie Y Crawford
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois Chicago, College of Pharmacy, Chicago, Illinois
| | - Glen T Schumock
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois Chicago, College of Pharmacy, Chicago, Illinois
| | - Todd A Lee
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois Chicago, College of Pharmacy, Chicago, Illinois
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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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Stottlemyer BA, Abebe KZ, Palevsky PM, Fried L, Schulman IH, Parikh CR, Poggio E, Siew ED, Gutierrez OM, Horwitz E, Weir MR, Wilson FP, Kane-Gill SL. Expert Consensus on the Nephrotoxic Potential of 195 Medications in the Non-intensive Care Setting: A Modified Delphi Method. Drug Saf 2023; 46:677-687. [PMID: 37223847 PMCID: PMC10208182 DOI: 10.1007/s40264-023-01312-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2023] [Indexed: 05/25/2023]
Abstract
INTRODUCTION Nephrotoxin exposure is significantly associated with acute kidney injury (AKI) development. A standardized list of nephrotoxic medications to surveil and their perceived nephrotoxic potential (NxP) does not exist for non-critically ill patients. OBJECTIVE This study generated consensus on the nephrotoxic effect of 195 medications used in the non-intensive care setting. METHODS Potentially nephrotoxic medications were identified through a comprehensive literature search, and 29 participants with nephrology or pharmacist expertise were identified. The primary outcome was NxP by consensus. Participants rated each drug on a scale of 0-3 (not nephrotoxic to definite nephrotoxicity). Group consensus was met if ≥ 75% of responses were one single rating or a combination of two consecutive ratings. If ≥ 50% of responses indicated "unknown" or not used in the non-intensive care setting, the medication was removed for consideration. Medications not meeting consensus for a given round were included in the subsequent round(s). RESULTS A total of 191 medications were identified in the literature, with 4 medications added after the first round from participants' recommendations. NxP index rating consensus after three rounds was: 14 (7.2%) no NxP in almost all situations (rating 0); 62 (31.8%) unlikely/possibly nephrotoxic (rating 0.5); 21 (10.8%) possibly nephrotoxic (rating 1); 49 (25.1%) possibly/probably nephrotoxic (rating 1.5); 2 (1.0%) probably nephrotoxic (rating 2); 8 (4.1%) probably/definite nephrotoxic (rating 2.5); 0 (0.0%) definitely nephrotoxic (rating 3); and 39 (20.0%) medications were removed from consideration. CONCLUSIONS NxP index rating provides clinical consensus on perceived nephrotoxic medications in the non-intensive care setting and homogeneity for future clinical evaluations and research.
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Affiliation(s)
| | - Kaleab Z Abebe
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Paul M Palevsky
- Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Kidney Medicine Section, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
| | - Linda Fried
- Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Kidney Medicine Section, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
| | - Ivonne H Schulman
- Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Chirag R Parikh
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Emilio Poggio
- Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Edward D Siew
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Tennessee Valley Health Systems (TVHS) Nashville Veterans Affairs Hospital, Nashville, TN, USA
| | - Orlando M Gutierrez
- Department of Medicine, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - F Perry Wilson
- Clinical and Translational Research Accelerator, Department of Medicine, Yale School of Medicine, New Haven, CT, USA
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Kim JH, Kim JH, Choe WH, Kwon SY, Yoo BC, Yoon EL, Kang SH. Switching from Tenofovir-Based Combination Therapy to Tenofovir Monotherapy in Multidrug-Experienced Chronic Hepatitis B Patients: a 5-Year Experience at Two Centers. Antimicrob Agents Chemother 2022; 66:e0027522. [PMID: 35867571 PMCID: PMC9380523 DOI: 10.1128/aac.00275-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/27/2022] [Indexed: 01/16/2023] Open
Abstract
Patients with chronic hepatitis B (CHB) who were administered tenofovir disoproxil fumarate (TDF)-based combination therapy after receiving multiple drugs are frequently switched to TDF monotherapy in South Korea. We evaluated the efficacy and safety of switching to TDF monotherapy from TDF-based combination therapy over 5 years. This was a retrospective study of multidrug-experienced CHB patients who switched from TDF-based combination therapy to TDF monotherapy after achieving a virologic response (VR; <20 IU/mL) at Konkuk University Hospital and Sanggye Paik Hospital. The biochemical response was defined as a normalized serum ALT level during follow-up. Each patient was assessed from the date of switching to TDF monotherapy to the date of the last follow-up over 5 years. A total of 39 patients who received at least one antiviral therapy before TDF-based combination therapy were analyzed. The median duration of VR before switching to TDF monotherapy was 18 months and the median duration of TDF monotherapy was 55 months. In this study, except for one patient who had poor compliance, all patients maintained a VR. Three patients had a temporarily increased HBV DNA level and 91.2% of the patients showed a biochemical response. Switching multidrug-experienced patients to TDF monotherapy is generally safe and effective.
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Affiliation(s)
- Jung Hun Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - Byung-chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - Eileen L. Yoon
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, South Korea
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea
| | - Seong Hee Kang
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, South Korea
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Ullah N, Khan I, Kakakhel MA, Xi L, Bai Y, Kalra BS, Guanlan L, Kumar T, Shah M, Zhang C. Serological prevalence of hepatitis B virus (HBV) in Mardan district, Khyber Pakhtunkhwa, Pakistan. BRAZ J BIOL 2021; 82:e245813. [PMID: 34287527 DOI: 10.1590/1519-6984.245813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 12/04/2020] [Indexed: 11/22/2022] Open
Abstract
Hepatitis B virus infection is perilous among the five types of Hepatitis, as it remains clinically asymptomatic. The present study draws up-to-date prevalence of Hepatitis B virus (HBV) in the general population of Mardan, Khyber Pakhtunkhwa Pakistan. The blood samples from 4803 individuals including 2399 male and 2404 females were investigated. All the suspected samples were analyzed for hepatitis B surface antigen using Immuno-chromatographic test (ICT), Enzyme-linked immunosorbent assay (ELISA), and followed by Reverse transcription-polymerase chain reaction (RT-PCR). Results showed that 312 (13.00%) out of 2399 individuals contained antibodies in their blood against HBV, while among the different age groups, the highest incidences of HBV antibodies were found in the age of 21-30 groups (10.73%). Furthermore, the ICT positive samples were screened by nested polymerase chain reaction to detect the existence of active HBV-DNA. It was observed that 169 (7.04%) out of (2399) male of the total population (4803) tested was positive. On the other hand, the female 463 (19.25%) possessed antibodies in their blood against HBV. Accumulatively, our results showed a higher percentage of HBV prevalence in males than females in the age group 21-30 years. The total HCV infected in Mardan general population was recorded at 5.7% comprising both male and female.
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Affiliation(s)
- N Ullah
- Lanzhou University, School of Life Sciences, MOE Key Laboratory of Cell Activities and Stress Adaptations, Lanzhou, Gansu, China
| | - I Khan
- Lanzhou University, School of Life Sciences, MOE Key Laboratory of Cell Activities and Stress Adaptations, Lanzhou, Gansu, China
| | - M A Kakakhel
- Lanzhou University, School of Life Sciences, MOE Key Laboratory of Cell Activities and Stress Adaptations, Lanzhou, Gansu, China
| | - L Xi
- Lanzhou University, School of Life Sciences, MOE Key Laboratory of Cell Activities and Stress Adaptations, Lanzhou, Gansu, China
| | - Y Bai
- Lanzhou University, School of Life Sciences, MOE Key Laboratory of Cell Activities and Stress Adaptations, Lanzhou, Gansu, China
| | - B S Kalra
- Virtual University of Pakistan, Department of Bioinformatics and Computational Biology, Lahore, Pakistan
| | - L Guanlan
- Lanzhou University, School of Life Sciences, MOE Key Laboratory of Cell Activities and Stress Adaptations, Lanzhou, Gansu, China
| | - T Kumar
- State Key Laboratory of grassland Agro-ecosystem, Key Laboratory of Grassland, Livestock Industry Innovation, , Collage of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - M Shah
- University of Swat, Centre for Animal Sciences & Fisheries, Charbagh, Pakistan
| | - C Zhang
- Lanzhou University, School of Life Sciences, MOE Key Laboratory of Cell Activities and Stress Adaptations, Lanzhou, Gansu, China
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Chen K, Chang C, Lee J, Yang C. Tenofovir disoproxil fumarate for patients with chronic hepatitis B who suboptimal response to non‐tenofovir disoproxil fumarate nucleos(t)ide analogs therapy. ADVANCES IN DIGESTIVE MEDICINE 2020. [DOI: 10.1002/aid2.13171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Kwei‐Ming Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Chi‐Hsien Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Jyong‐Hong Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Chi‐Chieh Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
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Clinical Manifestations and Laboratory Tests of AECHB and Severe Hepatitis (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7418529 DOI: 10.1007/978-94-024-1603-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the clinical symptoms and signs of AECHB and HBV ACLF, classification, grading of HBV ACLF and their features, diagnostic principles and standards in liver pathology, biochemistry, and virology of HBV ACLF.
Liver failure is defined as serious damage to the liver cause by a variety of etiologies, leading to liver function disorder or even decompensation, and clinical syndromes with coagulopathy, jaundice, hepatic encephalopathy, and ascites. Severe hepatitis B can be indicated pathologically by apparent hepatocellular necrosis, including extensive multifocal, confluent, bridging, sub-massive or massive necrosis. Laboratory tests during the course of severe exacerbation of chronic hepatitis B can reflect pathological changes and liver function in a timely manner, providing objective and informative reference data for evaluation of disease severity and treatment efficacy. Among the most important laboratory tests are those for prothrombin activity, international normalized ratio, and increases in total bilirubin concentration. Severe hepatitis B is associated with interactions between the virus and host factors. Detection of HBV DNA, HBV genotype, quasispecies and HBV mutation can provide important theoretical bases for the prevention, control or mitigation of the progress of severe hepatitis B. Noninvasive imaging modalities can be used to visualize the entire liver and parts of it. Measuring liver volume to evaluate liver size and liver reserve capacity is regarded as important in diagnosis, surgical approach and prognostic evaluation of patients with severe exacerbation of chronic hepatitis B and liver failure. Model for End-Stage Liver Disease (MELD) is the first quantitative method developed to assess whether a patient with liver failure requires a liver transplant. The predictive value of the MELD model has been improved by the MELD-Na, iMELD, and MESO models. Several other valuable prognostic models have been developed. For example, for patients with HBV-ACLF, the established TPPM scoring system was found to be more predictive than MELD score.
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10
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Khan NU, Zalan A, Petruzziello A, Ud Din I, Haq F, Hayat Y. Determining the Actual Prevalence of Hepatitis B in Khyber Pakhtunkhwa-Pakistan: A Meta-Analysis. Open Virol J 2018; 12:33-41. [PMID: 29576813 PMCID: PMC5848220 DOI: 10.2174/1874357901812010033] [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: 08/28/2017] [Revised: 09/26/2017] [Accepted: 12/28/2017] [Indexed: 02/07/2023] Open
Abstract
Background: Hepatitis B is considered the most dangerous among the five types of Hepatitis, as it is clinically asymptomatic. It can silently damage the liver over many years without being diagnosed. Hepatitis B is one of the top risks of liver complications in Khyber Pakhtunkhwa (KP), a province of Pakistan, with an average prevalence rate of 2.70%. Aims: We aimed to carefully review the previously published data on prevalence of Hepatitis B Virus (HBV) in KP-Pakistan and use the statistical approach to obtain more precise estimate of the prevalence of HBV in KP-Pakistan. This study on one hand will provide a more reliable and consolidated estimate (pooled estimate) of HBV in the stated region, on the other hand, it enabled us to judge the heterogeneity among the estimates found from these studies. The study is intended to provide more authentic prevalence record and help government/ non-government organizations and health professionals, which plan to initiate HBV prevention programs in KP-Pakistan. Methods: A meta-analysis was performed based on studies found in literature search from electronic databases and bibliography on the prevalence of HBV in KP-Pakistan from 2007 to 2017. Abstracts and results of twenty papers were thoroughly studied and the data were extracted. The findings from these studies were distributed in two groups (general and population at high risk) constituting 15 and 5 studies respectively. Results: The combined prevalence by considering random model for the general population of KP-Pakistan was observed to be 2.71%, while population at high risk was reasonably high i.e. 5.64%. By comparing this prevalence rate to the highest global prevalence of HBV in the adult population of Western Pacific Region (6.2%), significant (p-value= 0.000) heterogeneity was observed among the estimates in each group. However, the funnel plot provides a symmetric look, eliminating the effect of publication bias. We can say that HBV has an alarming prevalence rate in KP-Pakistan. However, HBV is thrice more prevalent in male population of KP-Pakistan than the female population. Conclusion: The above results lead that HBV infection has reached an alarming state in KP-Pakistan, though projects like Prime Minister’s Program for Prevention & Control of Hepatitis which are contributing in improving the health of the people of KP by trying to prevent and control the incidence of HBV. More massive vaccination and awareness programs should be initiated to prevent the spread of HBV on urgent basis. Provision of diagnostics and treatment facilities against HBV in healthcare units of KP-Pakistan should be assured.
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Affiliation(s)
- Najeeb Ullah Khan
- Institute of Biotechnology and Genetic Engineering (Health Division), The University of Agriculture Peshawar, Peshawar, Pakistan
| | - Ali Zalan
- Institute of Biotechnology and Genetic Engineering (Health Division), The University of Agriculture Peshawar, Peshawar, Pakistan
| | - Arnolfo Petruzziello
- Virology and Molecular Biology Unit "V. Tridente", Istituto Nazionale Tumori - Fondazione "G. Pascale", IRCCS Italia, Naples, Italy
| | - Iftikhar Ud Din
- Department of Mathematics, Stats & Computer Science, The University of Agriculture Peshawar, Peshawar, Pakistan
| | - Fazle Haq
- Department of Mathematics, Stats & Computer Science, The University of Agriculture Peshawar, Peshawar, Pakistan
| | - Yousaf Hayat
- Department of Mathematics, Stats & Computer Science, The University of Agriculture Peshawar, Peshawar, Pakistan
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Kimberlin DW. Antiviral Agents. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2018:1551-1567.e6. [DOI: 10.1016/b978-0-323-40181-4.00295-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Straus SE. Unanticipated Risk in Clinical Research ∗ ∗The editors have included Dr. Stephen Straus'original unedited contribution, penned for the book's 2002 edition and published with minor modification in the second edition in 2007, to honor his memory. This is a classic and compelling chapter with a story that remains relevant today. References to regulation and guidelines may not be current. The editors have added current references as of the time of publication to the end of the chapter. PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH 2018:141-159. [DOI: 10.1016/b978-0-12-849905-4.00011-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Lee S, Ahn SH, Jung KS, Kim DY, Kim BK, Kim SU, Baatarkhuu O, Ku HJ, Han K, Park JY. Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance. J Viral Hepat 2017; 24:141-147. [PMID: 27766731 DOI: 10.1111/jvh.12623] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 08/23/2016] [Indexed: 12/29/2022]
Abstract
We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy (TDF group) and TDF plus entecavir (ETV) combination-rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty-three CHB patients with lamivudine and entecavir resistance were investigated. Ninety-six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6-24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono-rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.
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Affiliation(s)
- S Lee
- Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon Metropolitan City, Korea
- Institute for Integrative Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon Metropolitan City, Korea
| | - S H Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - K S Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - D Y Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - B K Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - S U Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - O Baatarkhuu
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Infectious Diseases, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - H J Ku
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - K Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - J Y Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Emtricitabine for adults with lamivudine-resistant chronic hepatitis B virus infection. Hippokratia 2017. [DOI: 10.1002/14651858.cd012496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Shaffer Mok
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Sachin Mohan
- Cooper University Hospital; Department of Internal Medicine; 3rd floor, 401 Haddon Avenue Camden NJ USA 08103
| | - Krystal M Hunter
- Cooper University Hospital; Biostatistics/Research Institute; 1 Cooper Plaza Camden NJ USA 08103
| | - Yize R Wang
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Thomas A Judge
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
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Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, Gurel S, Caruntu FA, Flaherty JF, Massetto B, Kim K, Kitrinos KM, Subramanian GM, McHutchison JG, Yee LJ, Elkhashab M, Berg T, Sporea I, Yurdaydin C, Husa P, Jablkowski MS, Gane E. Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study. J Hepatol 2017; 66:11-18. [PMID: 27545497 DOI: 10.1016/j.jhep.2016.08.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/05/2016] [Accepted: 08/09/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Long-term treatment with tenofovir disoproxil fumarate (TDF) alone, or in combination with emtricitabine (FTC) is associated with sustained viral suppression in patients with lamivudine resistant (LAM-R) chronic hepatitis B (CHB). METHODS LAM-R CHB patients were randomised 1:1 to receive TDF 300mg or FTC 200mg and TDF 300mg once daily in a prospective, double blind, study. The proportion of patients with plasma hepatitis B virus (HBV) DNA<69IU/ml (<400copies/ml) at week 96 (primary efficacy endpoint) was reported previously. Here we present week 240 follow-up data. RESULTS Overall, 280 patients were randomised to receive TDF (n=141) or FTC/TDF (n=139), and 85.4% completed 240weeks of treatment. At week 240, 83.0% of patients in the TDF arm, and 82.7% of patients in the FTC/TDF treatment arm had HBV DNA<69IU/ml (p=0.96). Rates of normal alanine aminotransferase (ALT) and normalised ALT were similar between groups (p=0.41 and p=0.97 respectively). Hepatitis B e antigen loss and seroconversion at week 240 were similar between groups, (p=0.41 and p=0.67 respectively). Overall, six patients achieved hepatitis B surface antigen (HBsAg) loss and one patient (FTC/TDF arm) had HBsAg seroconversion by week 240. No TDF resistance was observed up to week 240. Treatment was generally well tolerated, and renal events were mild and infrequent (∼8.6%). The mean change in bone mineral density at week 240 was -0.98% and -2.54% at the spine and hip, respectively. CONCLUSIONS TDF monotherapy was effective and well tolerated in LAM-R CHB patients for up to 240weeks. LAY SUMMARY The goal of oral antiviral treatment for chronic hepatitis B (CHB) is to achieve and maintain undetectable HBV DNA levels. Treatment options with enhanced potency, and low risk of resistance development for patients infected with lamivudine resistant (LAM-R) HBV are required. Tenofovir disoproxil fumarate (TDF) monotherapy was effective and well tolerated without TDF resistance development in CHB patients with LAM-R, for up to 240weeks. Clinical trial number: NCT00737568.
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Affiliation(s)
- Scott Fung
- Department of Medicine, University of Toronto, Canada.
| | - Peter Kwan
- Department of Medicine, University of British Columbia, Canada
| | - Milotka Fabri
- Clinic for Infectious Diseases, Medical University of Novi Sad, Serbia
| | - Andrzej Horban
- Department of Adult Infectious Diseases, Medical University of Warsaw, Poland
| | - Mijomir Pelemis
- Clinic for Infectious and Tropical Diseases, Clinical Centre of Serbia, Serbia
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University, USA
| | - Selim Gurel
- Department of Internal Medicine, Uludag University, Turkey
| | - Florin A Caruntu
- National Institute for Infectious Diseases, "Prof Dr Matei Bals", Romania
| | | | | | | | | | | | | | | | | | - Thomas Berg
- Clinic of Gastroenterology and Rheumatology, University Hospital Leipzig, Germany
| | - Ioan Sporea
- University of Medicine and Pharmacy, Timisoara, Romania
| | | | - Petr Husa
- University Hospital Brno and Faculty of Medicine, Masaryk University Brno, Czech Republic
| | - Maciej S Jablkowski
- Department of Infectious and Liver Diseases, Medical University of Lodz, Poland
| | - Edward Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
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Drugs to Treat Viral Hepatitis. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00155-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
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Abstract
Chronic hepatitis B virus (HBV) infection has a significant public health impact. There are currently 7 approved therapies for chronic HBV, including standard and pegylated interferon (IFN)-α, and 5 nucleos(t)ide analogs (NUCs). IFN offers benefits over NUCs, including a finite duration of therapy and a higher rate of clearance of hepatitis Be antigen and surface antigen. These benefits need to be weighed against the potential adverse effects of IFN therapy. Some patients should not receive IFN because of advanced liver disease or comorbidities. This article reviews the mechanisms of action, efficacy, and clinical use of IFN therapy for HBV infection.
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Affiliation(s)
- Monica A Konerman
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Anna S Lok
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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Kim HS, Kim BK, Kim SU, Park JY, Kim DY, Song KJ, Park JW, Kim YJ, Baatarkhuu O, Han KH, Ahn SH. Association Between Level of Fibrosis, Rather Than Antiviral Regimen, and Outcomes of Patients With Chronic Hepatitis B. Clin Gastroenterol Hepatol 2016; 14:1647-1656.e6. [PMID: 27305847 DOI: 10.1016/j.cgh.2016.05.039] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 05/27/2016] [Accepted: 05/27/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We performed a propensity-score matched analysis to investigate whether entecavir, compared with lamivudine, can reduce risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B after adjusting for level of fibrosis. METHODS We performed a retrospective study of 1079 patients with chronic hepatitis B who received first-line therapy with lamivudine (n = 435) or entecavir (n = 644) from 2006 through 2013. Only patients with available liver stiffness value measured by transient elastography were recruited. Liver cirrhosis was diagnosed by ultrasonography. To adjust for the imbalance of patients treated with lamivudine versus entecavir, we performed propensity-score matching (PSM), at a ratio of 1:1, using 7 factors (age, sex, hepatitis B e antigen, alanine aminotransferase, serum albumin, platelet count, and liver stiffness; PSM1) or 8 factors (variables of PSM1 plus ultrasonography measurements of cirrhosis; PSM2). Patients with virologic breakthrough or resistance mutations received rescue therapy. RESULTS Over the 7-year period, 91 patients developed HCC and 104 had liver-related events in the entire cohort. In multivariate analyses, level of fibrosis, but not antiviral regimen, was independently associated with risk of HCC (P < .05). The PSM1 group included 342 pairs of patients and the PSM2 group included 338 pairs. Similar proportions of patients given lamivudine versus entecavir developed HCC in each model (10.5% given lamivudine vs 9.9% given entecavir in PSM1 and 11.9% vs 12.6% in PSM2; all P > .05). When PSM was applied to patients with liver stiffness value ≤13 kPa or >13 kPa, patients given lamivudine versus entecavir still had similar cumulative rates of HCC development (all P > .05). CONCLUSIONS In a PSM analysis, we associated level of fibrosis, rather than antiviral regimen, with risk of HCC, when patients received appropriate rescue therapy in case of virologic breakthrough or resistance mutations.
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Affiliation(s)
- Hye Soo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ki Jun Song
- Department of Biostatistics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Won Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yeong Jin Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Oidov Baatarkhuu
- Department of Infectious Diseases, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Ataei B, Khodadoostan M, Pouria B, Adibi P. Tenofovir in treatment of Iranian patients with chronic hepatitis B virus infection: An open-label case series. J Res Pharm Pract 2016; 5:166-70. [PMID: 27512706 PMCID: PMC4966234 DOI: 10.4103/2279-042x.185714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE Tenofovir is among the first-line treatments for chronic hepatitis B (CHB) virus infection. We evaluated the efficacy and safety of Tenofovir in treatment of Iranian patients with CHB. METHODS Forty treatment-native patients with CHB but without concurrent hepatitis C or human immunodeficiency virus infections were treated with Tenobiovir(™) 300 mg/day. The hepatitis B virus (HBV) DNA load, hepatitis B e antigen (HBe Ag), anti-hepatitis B e antibody (HBe Ab), liver enzymes, and creatinine were measured before and at least 3 months after the treatment. FINDINGS The mean age of patients was 38.1 ± 12.4 years and 65% of them were male. Seventeen (42.5%) patients were HBe Ag-positive and 15 (37.5%) patients had alanine aminotransferase (ALT) of two times above the normal. The HBV DNA load was significantly decreased after the treatment (P < 0.001). Twenty-seven (67.5%) patients had viral load of ≤2000 IU/ml and 22 (55%) patients had undetectable HBV DNA level after the treatment. Among positive HBe Ag patients, the HBe Ag became negative in 15 (88.2%) patients after the treatment and HBe Ab became positive in 3 (17.6%) patients. Liver enzymes' levels were significantly decreased after the treatment (P <0.05) and ALT transaminase level became normalized in 86.7% (13 out of 15) of cases with baseline levels twice the normal. CONCLUSION Treatment response rate to Tenofovir in Iranian patients with CHB was high. The virological and serological response rate and safety of Tenofovir in our population was comparable to other populations. Considering availability and costs, Tenobiovir(™) could be recommended as the first-line therapy of chronic HBV infection in Iran.
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Affiliation(s)
- Behrooz Ataei
- Infectious Diseases and Tropical Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahsa Khodadoostan
- Department of Gastroenterology and Hepatology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Babk Pouria
- Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Peyman Adibi
- Department of Gastroenterology and Hepatology, Isfahan University of Medical Sciences, Isfahan, Iran
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Park CH, Jung SW, Shin JW, Bae MA, Lee YI, Park YT, Chung HS, Park NH. Comparison of tenofovir plus lamivudine versus tenofovir monotherapy in patients with lamivudine-resistant chronic hepatitis B. Clin Mol Hepatol 2016; 22:152-9. [PMID: 27044766 PMCID: PMC4825170 DOI: 10.3350/cmh.2016.22.1.152] [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: 09/17/2015] [Revised: 01/21/2016] [Accepted: 02/11/2016] [Indexed: 11/05/2022] Open
Abstract
Background/Aims: Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF–LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB. Methods: We investigated the antiviral efficacy of TDF monotherapy vs. TDF–LAM combination therapy in 103 patients with LAM-resistant CHB. Results: The study subjects were treated with TDF alone (n=40) or TDF–LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8–36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF–LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF–LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank p=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR. Conclusions: TDF monotherapy was as effective as TDF–LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary.
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Affiliation(s)
- Chan Ho Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
| | - Seok Won Jung
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
| | - Jung Woo Shin
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
| | - Mi Ae Bae
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
| | - Yoon Im Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
| | - Yong Tae Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
| | - Hwa Sik Chung
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
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Tavakolpour S, Alavian SM, Sali S. Hepatitis B Reactivation During Immunosuppressive Therapy or Cancer Chemotherapy, Management, and Prevention: A Comprehensive Review-Screened. HEPATITIS MONTHLY 2016; 16:e35810. [PMID: 27257429 PMCID: PMC4887960 DOI: 10.5812/hepatmon.35810] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 01/17/2016] [Accepted: 01/27/2016] [Indexed: 12/11/2022]
Abstract
CONTEXT Due to the close relationship between the immune system and the hepatitis B virus (HBV) replication, it is essential to monitor patients with current or past HBV infection under any type of immunosuppression. Cancer chemotherapy, immunosuppressive therapies in autoimmune diseases, and immunosuppression in solid organ and stem cell transplant recipients are the major reasons for hepatitis B virus reactivation (HBVr). In this review, the challenges associated with HBVr are discussed according to the latest studies and guidelines. We also discuss the role of treatments with different risks, including anti-CD20 agents, tumor necrosis factor-alpha (TNF-α) inhibitors, and other common immunosuppressive agents in various conditions. EVIDENCE ACQUISITION Through an electronic search of the PubMed, Google Scholar, and Scopus databases, we selected the studies associated with HBVr in different conditions. The most recent recommendations were collected in order to reach a consensus on how to manage patients at risk of HBVr. RESULTS It was found that the positive hepatitis B surface antigen (HBsAg), the high baseline HBV DNA level, the positive hepatitis B virus e antigen (HBeAg), and an absent or low hepatitis B surface antibody (HBsAb) titer prior to starting treatment are the most important viral risk factors. Furthermore, rituximab, anthracycline, and different types of TNF-α inhibitors were identified as the high-risk therapies. By analyzing the efficiency of prophylaxis on the prevention of HBVr, it was concluded that those with a high risk of antiviral resistance should not be used in long-term immunosuppressants. Receiving HBV antiviral agents at the commencement of immunosuppressant therapy or chemotherapy was demonstrated to be effective in decreasing the risk of HBVr. Prophylaxis could also be initiated before the start of therapy. For most immune suppressive regimes, antiviral therapy should be kept up for at least 6 months after the cessation of immunosuppressive drugs. However, the optimal time of prophylaxis keeping should be increased in cases associated with rituximab or hematopoietic stem cell transplants. According to the latest studies and guidelines from different bodies, recommendations regarding screening, monitoring, and management of HBVr are outlined. CONCLUSIONS Identification of patients at the risk of HBVr before immunosuppressive therapy is an undeniable part of treatment. Starting the antiviral therapy, based on the type of immunosuppressive drugs and the underlying disease, could lead to better management of disease.
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Affiliation(s)
- Soheil Tavakolpour
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqyiatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqyiatallah University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Seyed Moayed Alavian, Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqyiatallah University of Medical Sciences, Tehran, IR Iran. Tel/Fax: +98-2181264070, E-mail:
| | - Shahnaz Sali
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
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23
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2016; 22:18-75. [PMID: 27044762 PMCID: PMC4825166 DOI: 10.3350/cmh.2016.22.1.18] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 02/22/2016] [Indexed: 01/10/2023] Open
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Weldemhret L, Asmelash T, Belodu R, Gebreegziabiher D. Sero-prevalence of HBV and associated risk factors among HIV positive individuals attending ART clinic at Mekelle hospital, Tigray, Northern Ethiopia. AIDS Res Ther 2016; 13:6. [PMID: 26855663 PMCID: PMC4743406 DOI: 10.1186/s12981-016-0090-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 01/24/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Because of the shared mean of transmission, hepatitis B virus (HBV) is one of an important cause of co-morbidity and mortality in peoples living with HIV/AIDS. Hence, the aim of this study was to determine the sero-prevalence of HBV infection and associated risk factors in HIV/AIDS positive individuals attending ART clinic at Mekelle hospital, Mekelle, Northern Ethiopia. METHODS A cross sectional study was conducted from August to October 2014 in HIV/AIDS positive adult individuals. Socio-demographic data and other explanatory variables were collected from 508 study participants using pre-tested and structured questionnaire-based interviews. Serum hepatitis B surface antigen (HBsAg) was detected using commercially available rapid test and third generation enzyme-linked immunosorbent assay (ELISA). Bivariate and multivariate analysis, using SPSS V.20.0, were performed to assess the variables associated with HBV infection and P value less than 0.05 was considered as statistically significant. RESULTS A total of 508 study participants, 305 females and 203 males were included in this study with the mean (+SD) age of 37.8 + 9.6. The sero-prevalence of HBsAg was 5.9 %. Male gender (AOR = 2.6, 95 % CI 1.2-5.7), multiple sexual partners (AOR = 4.2, 95 % CI 1.3-13.1) and CD4 count <200 cells/μl (AOR = 3.5, 95 % CI 1.1-11.2) were significantly associated with HBsAg positivity. CONCLUSION The prevalence of HBsAg was similar to the general population. However, HIV/AIDS positive individuals with reduced CD4 count, <200 cells/μl, showed a significant association with HBsAg seropositivity. Therefore, we recommended, all HIV/AIDS positive individuals should be screened for HBsAg during their follow for better treatment outcome and minimize risks of HBV transmission.
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Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Adefovir dipivoxil for adults with lamivudine-resistant chronic hepatitis B virus infection. Hippokratia 2015. [DOI: 10.1002/14651858.cd011981] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Shaffer Mok
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Sachin Mohan
- Cooper University Hospital; Department of Internal Medicine; 3rd floor, 401 Haddon Avenue Camden USA 08103
| | - Krystal M Hunter
- Cooper University Hospital; Biostatistics/Research Institute; 1 Cooper Plaza Camden NJ USA 08103
| | - Yize R Wang
- Cooper University Hospital; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Thomas A Judge
- Cooper University Hospital; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
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Toy M, Hutton DW, So SK. Cost-Effectiveness and Cost Thresholds of Generic and Brand Drugs in a National Chronic Hepatitis B Treatment Program in China. PLoS One 2015; 10:e0139876. [PMID: 26536626 PMCID: PMC4633043 DOI: 10.1371/journal.pone.0139876] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 09/02/2015] [Indexed: 12/14/2022] Open
Abstract
Chronic liver disease and liver cancer associated with chronic hepatitis B (CHB) are leading causes of death among adults in China. Although newborn hepatitis B immunization has successfully reduced the prevalence of CHB in children, about 100 million Chinese adults remain chronically infected. If left unmanaged, 15–25% will die from liver cancer or liver cirrhosis. Antiviral treatment is not necessary for all patients with CHB, but when it is indicated, good response to treatment would prevent disease progression and reduce disease mortality and morbidity, and costly complications. The aim of this study is to analyze the cost-effectiveness of generic and brand antiviral drugs for CHB treatment in China, and assessing various thresholds at which a highly potent, low resistance antiviral drug would be cost-saving and/or cost-effective to introduce in a national treatment program. We developed a Markov simulation model of disease progression using effectiveness and cost data from the medical literature. We measured life-time costs, quality adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), and clinical outcomes. The no treatment strategy incurred the highest health care costs ($12,932-$25,293) per patient, and the worst health outcomes, compared to the antiviral treatment strategies. Monotherapy with either entecavir or tenofovir yielded the most QALYs (14.10–19.02) for both HBeAg-positive and negative patients, with or without cirrhosis. Threshold analysis showed entercavir or tenofovir treatment would be cost saving if the drug price is $32–75 (195–460 RMB) per month, highly cost-effective at $62–110 (379–670 RMB) per month and cost-effective at $63–120 (384–734 RMB) per month. This study can support policy decisions regarding the implementation of a national health program for chronic hepatitis B treatment in China at the population level.
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Affiliation(s)
- Mehlika Toy
- Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
- * E-mail:
| | - David W. Hutton
- Department of Health Management and Policy, University of Michigan, Ann Arbor, MI, 48109, United States of America
| | - Samuel K. So
- Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
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Baran B, Soyer OM, Ormeci AC, Gokturk S, Evirgen S, Akyuz F, Karaca C, Demir K, Besisik F, Onel D, Gulluoglu M, Badur S, Kaymakoglu S. Tenofovir disoproxil fumarate has a substantial efficacy against multidrug-resistant strains of hepatitis B virus. Liver Int 2015; 35:2265-74. [PMID: 25800974 DOI: 10.1111/liv.12831] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 03/16/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS To evaluate the efficacy of tenofovir in chronic hepatitis B (CHB) patients with adefovir resistance (ADF-R) and suboptimal response to adefovir (ADF-S). METHODS Nucleos(t)ide analogue (NA)-naïve patients and patients with previous adefovir failure receiving tenofovir therapy for at least 6 months were included in the study. Biochemical and virological tests were obtained at baseline and 3-month intervals in the first year and every 6 months thereafter. The primary outcome measure was complete virological response (CVR) (HBVDNA < 20 IU/ml). CVR rates were calculated by Kaplan-Meier analysis, and a multivariate Cox proportional hazard model was generated to find out factors independently associated with CVR. RESULTS A total of 165 patients (118 men, mean age 42 ± 12, 64 HBeAg(+) ) were included in the study. There were 105 patients in NA-naïve, 32 patients in ADF-S and 28 patients in ADF-R groups. All patients in the ADF-R group had multidrug resistance patterns. Mean duration of tenofovir treatment was 29 ± 14 months. CVR rates in NA-naïve, ADF-S and ADF-R groups were 65% vs. 75% vs. 58% at 12th month, 77% vs. 87% vs. 79% at 24th month and 83% vs. 94% vs. 79% at 36th month respectively. According to multivariate Cox regression model, HBeAg positivity (HR = 0.56, 95%CI 0.36-0.86, P = 0.008), high baseline HBVDNA level (HR = 0.64, 95%CI 0.55-0.74, P < 0.001) and ADF-R (HR = 0.47, 95%CI 0.28-0.81, P = 0.006) were independent predictors for CVR. Seven patients encountered mild renal dysfunction and were managed by dose adjustments. CONCLUSION CVR rates during the follow-up show that tenofovir has a decreased, yet still potent in vivo efficacy against multidrug-resistant strains of HBV.
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Affiliation(s)
- Bulent Baran
- Department of Gastroenterology, Koç University Hospital, Zeytinburnu, Istanbul, Turkey
| | - Ozlem Mutluay Soyer
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Asli Cifcibasi Ormeci
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Suut Gokturk
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Sami Evirgen
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Filiz Akyuz
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Cetin Karaca
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Kadir Demir
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Fatih Besisik
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Derya Onel
- Department of Microbiology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Mine Gulluoglu
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Selim Badur
- Department of Microbiology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
| | - Sabahattin Kaymakoglu
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
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Rahimi R, Hosseini SY, Fattahi MR, Sepehrimanesh M, Safarpour A, Malekhosseini SA, Nejabat M, Khodadad M, Ardebili M. YMDD Motif Mutation Profile Among Patients Receiving Liver Transplant Due to Hepatitis B Virus Infection With Long Term Lamivudine/Immunoglobulin Therapy. HEPATITIS MONTHLY 2015; 15:e27120. [PMID: 26300928 PMCID: PMC4539793 DOI: 10.5812/hepatmon.27120v2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 02/16/2015] [Accepted: 05/10/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recurrence of Hepatitis B Virus infection in patients undergoing liver transplanted (LT) is a serious and often fatal problem. Lamivudine (LAM) and Hepatitis B Immunoglobulin (HBIG) are widely used to manage hepatitis B recurrence after liver transplantation. However, the outcomes in patients are less elucidated. OBJECTIVES The current study aimed to evaluate the YMDD motif mutations profile among the patients undergoing LT infected with HBV and treated with LAM/HBIG at least for one year. PATIENTS AND METHODS Thirty patients with liver transplantation due to HBV were enrolled, while DNA level remained under detection limit of 50 IU/mL before transplantation and abnormal higher levels of liver enzymes after LT. The HBV genome detection was performed by two different Polymerase Chain Reaction methods following viral quantification by commercial Real-Time PCR. HbsAg detection, besides liver function tests were conducted as complementary assays. To assess nucleotide analogue mutations, the major part of polymerase gene (aa 80 - 240) was amplified by Nested-PCR, introduced to sequencing and subjected to phylogenetic analysis. RESULTS Totally, according to the laboratory criteria there were 13 cases with detectable HBV genome, while the mean liver enzyme levels were higher in recurrent patients and HBsAg was detected only in four out of the 13 cases. Phylogenetic analysis demonstrated that all isolated genomes belonged to genotype D. Critical M204I mutation, as a proof for resistance to LAM, was detected among 46% of the subjects and natural entecavir resistance (S202I) was also distinguished in one subject. Viral quantification showed higher titer in LAM resistant group in comparison to the group with undetectable drug resistance mutant (P > 0.05). CONCLUSIONS Although the patients carrying M204I mutation were more likely to show lack of responses to LAM therapy, LAM replacing by other nucleoside/tide analogs plus HBIG maybe still effective in decreasing hepatitis B recurrence after liver transplantation. However, it is suggested that drug resistance test should be considered by clinicians during therapeutic management to avoid the following viral breakthrough.
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Affiliation(s)
- Rahim Rahimi
- Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Seyed Younes Hosseini
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Mohammad Reza Fattahi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
- Corresponding Author: Mohammad Reza Fattahi, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran. Tel/Fax: +98-7116474263, E-mail:
| | - Masood Sepehrimanesh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Alireza Safarpour
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | | | - Maryam Nejabat
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
- Department of Bacteriology and Virology, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Mahboobeh Khodadad
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Maryam Ardebili
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
- National Research Institute for Science Policy Tehran, IR Iran
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Kim HJ, Cho JY, Kim YJ, Gwak GY, Paik YH, Choi MS, Koh KC, Paik SW, Yoo BC, Lee JH. Long-term efficacy of tenofovir disoproxil fumarate therapy after multiple nucleos(t)ide analogue failure in chronic hepatitis B patients. Korean J Intern Med 2015; 30:32-41. [PMID: 25589833 PMCID: PMC4293561 DOI: 10.3904/kjim.2015.30.1.32] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 07/08/2014] [Accepted: 08/01/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS The efficacy of tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B (CHB) patients following prior treatment failure with multiple nucleos(t)ide analogues (NAs) is not well defined, especially in Asian populations. In this study we investigated the efficacy and safety of TDF rescue therapy in CHB patients after multiple NA treatment failure. METHODS The study retrospectively analyzed 52 CHB patients who experienced failure with two or more NAs and who were switched to regimens containing TDF. The efficacy and safety assessments included hepatitis B virus (HBV) DNA undetectability, hepatitis B envelop antigen (HBeAg) seroclearance, alanine transaminase (ALT) normalization and changes in serum creatinine and phosphorus levels. RESULTS The mean HBV DNA level at baseline was 5.4 ± 1.76 log10 IU/mL. At a median duration of 34.5 months of TDF treatment, the cumulative probabilities of achieving complete virological response (CVR) were 25.0%, 51.8%, 74.2%, and 96.7% at 6, 12, 24, and 48 months, respectively. HBeAg seroclearance occurred in seven of 48 patients (14.6%). ALT levels were normalized in 27 of 31 patients (87.1%) with elevated ALT at baseline. Lower levels of HBV DNA at baseline were significantly associated with increased CVR rates (p < 0.001). However, CVR rates did not differ between TDF monotherapy or combination therapy with other NAs, and were not affected by mutations associated with resistance to NAs. No significant adverse events were observed. CONCLUSIONS TDF is an efficient and safe rescue therapy for CHB patients after treatment failure with multiple NAs.
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Affiliation(s)
- Hyo Jin Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ju-Yeon Cho
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yu Jin Kim
- 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
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Cho YK, Cui XJ, Jeong SU, Song BC. Different mechanism of selection of adefovir-resistant mutant viruses during adefovir monotherapy in patients with lamivudine-resistant chronic hepatitis B. Antiviral Res 2014; 112:8-17. [PMID: 25303802 DOI: 10.1016/j.antiviral.2014.09.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Revised: 08/29/2014] [Accepted: 09/29/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Adefovir (ADV) resistance is more frequent in lamivudine (LMV)-resistant chronic hepatitis B (CHB) patients than in nucleos(t)ide analogue-naïve patients. The majority of LMV-resistant mutants harbor the rtM204V/I mutation, while a minor fraction harbor the rtA181V/T mutation. We aimed to elucidate the mechanism of the high rate of ADV resistance in LMV-resistant patients during ADV therapy. METHODS We performed a clonal analysis of HBV reverse transcriptase in treatment-naïve (n = 3) and LMV-resistant patients before ADV therapy (n = 14). Dynamic changes in the viral population (n = 9) during ADV therapy were also analyzed. RESULTS Before ADV therapy, rtA181V/T was observed in 30 of 680 clones (4.4%) from 7 patients with LMV resistance under dominant rt204V/I mutation and in one of 150 clones in treatment-naïve patients. The rtA181V/T mutation was more frequently found in clones from LMV-resistant patients than in treatment-naïve patients (p = 0.029). The rtN236T mutation was not observed in any clone. During ADV therapy, most rtM204V/I mutants were replaced by wild type in all 3 patients without the rtA181V/T mutation and in one patient with the rtA181V/T mutation. Subsequently, wild type was replaced by the rtN236T and/or rtA181V/T mutant. In patients with the rtA181V/T mutation (n = 6), the rtA181V/T mutant overtook the rtM204V/I mutant in 3 of 4 patients with ADV resistance. In 2 patients without ADV resistance, most of the viral population was replaced by wild type by the last follow-up. CONCLUSION The high rate of ADV resistance in patients with LMV-resistance might be attributable to preexisting rtA181V/T mutant virus.
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Affiliation(s)
- Yoo-Kyung Cho
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Xiu-Ji Cui
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Seung Uk Jeong
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Byung-Cheol Song
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea.
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Abstract
BACKGROUND/AIM Treatment practices for patients with chronic hepatitis B (CHB) varies across the world and several professional associations have issued treatment recommendations. This synopsis aims to review the major principles of CHB and its management, and to systematically summarize and compare the recommendations of the major treatment guidelines by: the Asian-Pacific Association for the Study of the Liver, the US Panel, the European Association for the Study of the Liver, and the American Association for the Study of the Liver. METHODS Treatment recommendations were summarized separately for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. CONCLUSIONS Treatment for CHB is recommended on the basis of a variety of host and viral factors, and the ultimate goal of treatment is the prevention of decompensated liver disease, hepatocellular carcinoma, cirrhosis, and premature death. Despite updates and improvements in these guidelines during the past decade, greater patient and physician education as well as better noninvasive markers to identify high-risk patients are still needed. Significant improvements in the application of current practice guidelines, however, can be made by relatively simple educational efforts, and new molecular and genomic techniques may hold promise for more accurate selection of high-risk patients for further therapeutic interventions in a near future.
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Ze E, Baek EK, Lee JJ, Chung HW, Ahn DG, Cho HJ, Kwon JC, Kim HJ, Lee H. Long-term outcomes of two rescue therapies in lamivudine-refractory patients with chronic hepatitis B: combined lamivudine and adefovir, and 1-mg entecavir. Clin Mol Hepatol 2014; 20:267-73. [PMID: 25320730 PMCID: PMC4197175 DOI: 10.3350/cmh.2014.20.3.267] [Citation(s) in RCA: 5] [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: 06/03/2014] [Revised: 08/15/2014] [Accepted: 08/27/2014] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND/AIMS Adefovir (ADV) and lamivudine (LAM) combination therapy (ADV+LAM) has been a useful option for patients with LAM-resistant (LAM-r) chronic hepatitis B (CHB). However, the long-term outcomes of LAM+ADV and 1-mg entecavir (ETV) rescue therapies have still been limited. The aim of this study was to determine the long-term outcomes of these two rescue therapies. METHODS Sixty patients with LAM-r CHB underwent rescue therapy with LAM+ADV (n=36) or 1-mg ETV (n=24). We determined the duration of rescue therapy, timing and type of mutation, undetectable serum hepatitis B virus (HBV) DNA by PCR (lower limitation of detection, < 140 copies/mL), biochemical response (alanine aminotransferase < 40 IU/mL), and the incidence of hepatitis B virus e antigen (HBeAg) seroconversion and virologic breakthrough. RESULTS Baseline characteristics did not differ between the two therapy groups. The duration of rescue therapy was 56 months (range, 14-100 months) in the ADV+LAM group and 42 months (range, 12-73 months) in the ETV group (P=0.036). The cumulative rates of HBV DNA undetectability and HBeAg seroconversion up to 6 years were 88.6% and 43.0%, respectively, in the ADV+LAM group, and 45.8% and 31.8% in the ETV group. The rate of virologic breakthrough and resistance was 14.4% in the ADV+LAM group and 71.9% in the ETV group (P=0.001). CONCLUSIONS Combination of LAM and ADV therapy for up to 6 years achieved modest rates of virological suppression and resistance. ETV is not an optimal therapy because the risk of viral breakthrough to ETV increases over time.
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Affiliation(s)
- EunYoung Ze
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
| | - Eun Kyung Baek
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
| | - Jong Jin Lee
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
| | - Han Wook Chung
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
| | - Dae Geon Ahn
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
| | - Hwan Jun Cho
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
| | - Jae Cheol Kwon
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
| | - Hyung Joon Kim
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
| | - HyunWoong Lee
- Department of Internal Medicine, Chung-Ang University College of Mediciner, Seoul, Korea
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Bang KB, Kim HJ. Management of antiviral drug resistance in chronic hepatitis B. World J Gastroenterol 2014; 20:11641-11649. [PMID: 25206270 PMCID: PMC4155356 DOI: 10.3748/wjg.v20.i33.11641] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 01/10/2014] [Accepted: 05/28/2014] [Indexed: 02/07/2023] Open
Abstract
Rescue antiviral treatment for patients with resistance to preexisting nucleos(t)ide analogues remains a clinical challenge. The correct choice of a first-line treatment of high potency and with a high genetic barrier to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and the emergence of drug resistance. The management of treatment failure and drug resistance requires a precise and accurate clinical and virologic monitoring. Combination treatment with antiviral drugs that belong to different groups is associated with a lower chance of developing resistance to rescue drugs. To guarantee better control of viral replication in patients with drug resistance, the addition of another drug without a cross resistance profile should be given as early as possible, preferably at the time when genotypic resistance emerges. Long-term surveillance for treatment efficacy and possible emergence of drug resistance should be continued to prevent the emergence of multidrug-resistant strains.
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van Hemert FJ, Berkhout B, Zaaijer HL. Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus. PLoS One 2014; 9:e106324. [PMID: 25180507 PMCID: PMC4152281 DOI: 10.1371/journal.pone.0106324] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 07/29/2014] [Indexed: 12/23/2022] Open
Abstract
Introduction Resistance of the reverse transcriptase (RT) of hepatitis B virus (HBV) to the tenofovir nucleotide drug has not been observed since its introduction for treatment of hepatitis B virus (HBV) infection in 2008. In contrast, frequent viral breakthrough and resistance has been documented for adefovir. Our computational study addresses an inventory of the structural differences between these two nucleotide analogues and their binding sites and affinities to wildtype (wt) and mutant RT enzyme structures based on in silico modeling, in comparison with the natural nucleotide substrates. Results Tenofovir and adefovir only differ by an extra CH3-moiety in tenofovir, introducing a center of chirality at the carbon atom linking the purine group with the phosphates. (R)-Tenofovir (and not (S)-tenofovir) binds significantly better to HBV-RT than adefovir. “Single hit” mutations in HBV-RT associated with adefovir resistance may affect the affinity for tenofovir, but to a level that is insufficient for tenofovir resistance. The RT-Surface protein gene overlap in the HBV genome provides an additional genetic constraint that limits the mutational freedom required to generate drug-resistance. Different pockets near the nucleotide binding motif (YMDD) in HBV-RT can bind nucleotides and nucleotide analogues with different affinities and specificities. Conclusion The difference in binding affinity of tenofovir (more than two orders of magnitude in terms of local concentration), a 30x higher dosage of the (R)-tenofovir enantiomer as compared to conformational isomeric or rotameric adefovir, and the constrained mutational space due to gene overlap in HBV may explain the absence of resistance mutations after 6 years of tenofovir monotherapy. In addition, the computational methodology applied here may guide the development of antiviral drugs with better resistance profiles.
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Affiliation(s)
- Formijn J. van Hemert
- Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- * E-mail: (FvH); (HLZ)
| | - Ben Berkhout
- Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Hans L. Zaaijer
- Laboratory of Clinical Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- * E-mail: (FvH); (HLZ)
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Yu W, Wang L, Han N, Zhang X, Mahapatra T, Mahapatra S, Babu GR, Tang W, Detels R, Zhao J. Pre-exposure prophylaxis of HIV: A right way to go or a long way to go? ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2014; 44:201-8. [PMID: 25078629 DOI: 10.3109/21691401.2014.934458] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Antiretroviral drugs are being tried as candidates for the pre-exposure prophylaxis (PrEP) against HIV for a considerable period, due to their potential for immediate inhibition of viral replication. Discrepancies in the findings called for a critical review of the relevant efforts and their outcomes. A systematic literature search identified 143 eligible articles of which only 5 reported complete findings while another 11 were still on-going. Observed moderate efficacy and good safety profile seemed to identify PrEP as a promising step for minimizing the spread of HIV to relatively unaffected population and controlling the epidemic among high risk population groups. But the duration of this efficacy was found to depend heavily on the availability, adherence and other related issues like cost, political commitment, ethical consideration etc. To prevent potential cultural and behavioral modifications, proper pre-administration counseling also seemed critical for the success of PrEP as a cost-effective intervention with adequate coverage.
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Affiliation(s)
- Wenya Yu
- a Shijiazhuang Center for Disease Control and Prevention , Shijia Zhuang , China
| | - Lu Wang
- b National Center for AIDS/STD Control and Prevention, Chinese Centre for Disease Control and Prevention , Beijing , China
| | - Na Han
- c Institute of Clinical Molecular Biology, Peking University People's Hospital , Beijing China
| | - Xiayan Zhang
- b National Center for AIDS/STD Control and Prevention, Chinese Centre for Disease Control and Prevention , Beijing , China
| | - Tanmay Mahapatra
- d Mission Arogya Health and Information Technology Research Foundation , Kolkata , India
| | - Sanchita Mahapatra
- d Mission Arogya Health and Information Technology Research Foundation , Kolkata , India
| | - Giridhar R Babu
- e Public Health Foundation of India, Indian Institutes of Public Health , Hyderabad, Bengaluru Campus, Bengaluru , India
| | - Weiming Tang
- f University of North Carolina , Project-China, Guangzhou , China
| | - Roger Detels
- g Department of Epidemiology , Fielding School of Public Health, University of California , Los Angeles , CA , USA
| | - Jinkou Zhao
- h Impact Results and Evaluation Department, The Global Fund to Fight AIDS , Tuberculosis and Malaria, Geneva , Switzerland
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Virologic and serologic outcomes of mono versus dual HBV therapy and characterization of HIV/HBV coinfection in a US cohort. J Acquir Immune Defic Syndr 2014; 66:172-80. [PMID: 24694927 DOI: 10.1097/qai.0000000000000149] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To characterize HIV/hepatitis B virus (HBV) coinfection in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort and compare long-term HBV outcomes between regimens with 1 (MONO) or 2 (DUAL) anti-HBV agents. DESIGN A retrospective study of coinfected AIDS Clinical Trials Group Longitudinal Linked Randomized Trials subjects who received regimens containing anti-HBV agent(s). METHODS Stored samples at baseline and weeks 16, 32, 48, 144, and 240 were tested for HBV DNA, HBV e antigen (HBeAg), HBV e antibody (HBeAb), and hepatitis D virus (HDV) antibody. Resistance and genotype were tested in samples with HBV DNA >600 IU/mL. MONO versus DUAL analyses were limited to HBV treatment-naive subjects (Naive-MONO, Naive-DUAL). RESULTS Of 150 study subjects, median age was 40 years, 96% were male; 57% white, 26% black, 13% Hispanic. Baseline median CD4 was 224 cells per cubic millimeter, HIV RNA 4.48 log10 copies/mL, HBV DNA 6.30 log10 IU/mL; 59% HBeAg positive and 65% HBeAb negative; HBV genotypes A = 69%, G = 18%, D = 7%, <2% for A/G, B, C, F, H. Coinfection with HDV was 2%. There were 49 Naive-MONO (lamivudine) and 22 Naive-DUAL (11 lamivudine + tenofovir, 11 emtricitabine + tenofovir) with detectable HBV DNA. In the 240-week follow-up, HBV DNA suppression was not significantly higher in Naive-DUAL (P = 0.14); lower baseline HBV DNA (P < 0.01) was associated with suppression. Among 32 Naive-MONO subjects with detectable HBV DNA at baseline and results at week 48, 41% suppressed; among such 15 Naive-DUAL subjects, 53% suppressed. HBeAg and HBeAb analyses showed similar trends. CONCLUSIONS While consistent trends toward increased HBV DNA suppression, HBeAg loss and HBeAb seroconversion were observed in Naive-DUAL compared with Naive-MONO, they were not statistically significant. Overall, HDV coinfection was low.
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Woo HY, Choi JY, Yoon SK, Suh DJ, Paik SW, Han KH, Um SH, Kim BI, Lee HJ, Cho M, Lee CK, Kim DJ, Hwang JS. Rescue therapy with adefovir in decompensated liver cirrhosis patients with lamivudine-resistant hepatitis B virus. Clin Mol Hepatol 2014; 20:168-76. [PMID: 25032183 PMCID: PMC4099332 DOI: 10.3350/cmh.2014.20.2.168] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 05/30/2014] [Accepted: 06/05/2014] [Indexed: 12/14/2022] Open
Abstract
Background/Aims Adefovir dipivoxil (ADV) is a nucleotide analogue that is effective against lamivudine-resistant hepatitis B virus (HBV). The aim of this study was to determine the long-term clinical outcomes after ADV rescue therapy in decompensated patients infected with lamivudine-resistant HBV. Methods In total, 128 patients with a decompensated state and lamivudine-resistant HBV were treated with ADV at a dosage of 10 mg/day for a median of 33 months in this multicenter cohort study. Results Following ADV treatment, 86 (72.3%) of 119 patients experienced a decrease in Child-Pugh score of at least 2 points, and the overall end-stage liver disease score decreased from 16±5 to 14±10 (mean ± SD, P<0.001) during the follow-up period. With ADV treatment, 67 patients (56.3%) had undetectable serum HBV DNA (detection limit, 0.5 pg/mL). Virologic breakthrough occurred in 38 patients (36.1%) and 9 patients had a suboptimal ADV response. The overall survival rate was 89.9% (107/119), and a suboptimal response to ADV treatment was associated with both no improvement in Child-Pugh score (≥2 points; P=0.001) and high mortality following ADV rescue therapy (P=0.012). Conclusions Three years of ADV treatment was effective and safe in decompensated patients with lamivudine-resistant HBV.
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Affiliation(s)
- Hyun Young Woo
- Department of Internal Medicine, Pusan National University College of Medicine, Pusan, Korea
| | - Jong Young Choi
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dong Jin Suh
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Byung Ik Kim
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Mong Cho
- Department of Internal Medicine, Pusan National University College of Medicine, Pusan, Korea
| | - Chun Kyon Lee
- Department of Internal Medicine, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Jae Seok Hwang
- Department of Internal Medicine, Keimyung University College of Medicine, Daegu, Korea
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Dyson JK, Waller J, Turley A, Michael E, Moses S, Valappil M, Hudson M, Bassendine M, McPherson S. Hepatitis B in pregnancy. Frontline Gastroenterol 2014; 5:111-117. [PMID: 24683447 PMCID: PMC3963528 DOI: 10.1136/flgastro-2013-100361] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 09/21/2013] [Accepted: 09/25/2013] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE Vertical transmission of the hepatitis B virus (HBV) is the commonest mode of infection and can be prevented with immunoprophylaxis of the infant and antiviral therapy in the mother. Our aim was to review a cohort of subjects with HBV in pregnancy to determine the prevalence of active disease or high HBV-DNA levels that required treatment to prevent transmission, and to review the management of mothers and infants. METHODS A retrospective case-note review was conducted of all the HBV-infected pregnant women and their infants who attended the Newcastle obstetric services from 2007 to 2011. RESULTS There were 113 pregnancies in 81 women (median age 28 years; 15% hepatitis B e antigen (HBeAg) positive) during 2007-11. 71% of mothers were first diagnosed with HBV during pregnancy. The mothers were born in 28 different countries. 69% of mothers had an HBV-DNA level less than 2000 IU/mL and 13% had HBV-DNA levels greater than 1.0×107 IU/mL so would be eligible for antiviral therapy to prevent transmission to the infant. 9% had active eAg-positive HBV and 3% had active eAg-negative HBV requiring treatment. All infants born to HBeAg-positive mothers received hepatitis B immunoglobulin (HBIG) appropriately and 76% of infants received a full HBV vaccination course. One infant born to an HBeAg-negative mother was hepatitis B surface antigen positive 1 year post-delivery. CONCLUSIONS One in six women had active HBV requiring treatment or high HBV-DNA levels that would benefit from antiviral treatment to reduce the transmission risk. HBIG was administered appropriately but completion of the vaccination course was suboptimal.
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Affiliation(s)
- Jessica Katharine Dyson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Julia Waller
- Health Protection Agency, Newcastle upon Tyne, UK
| | - Andrena Turley
- Department of Obstetrics, Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Enid Michael
- Department of Obstetrics, Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Samuel Moses
- Health Protection Agency, Newcastle upon Tyne, UK,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Manoj Valappil
- Health Protection Agency, Newcastle upon Tyne, UK,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Mark Hudson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Margaret Bassendine
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Stuart McPherson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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Hu CY, Liu YM, Liu Y, Chen Q, Wang W, Wu K, Dong J, Li J, Jia JY, Lu C, Sun SX, Yu C, Li X. Pharmacokinetics and Tolerability of Tenofovir Disoproxil Fumarate 300 mg Once Daily: An Open-Label, Single- and Multiple-Dose Study in Healthy Chinese Subjects. Clin Ther 2013; 35:1884-9. [DOI: 10.1016/j.clinthera.2013.09.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 09/09/2013] [Accepted: 09/24/2013] [Indexed: 11/27/2022]
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[Consensus Statement by GeSIDA/National AIDS Plan Secretariat on antiretroviral treatment in adults infected by the human immunodeficiency virus (Updated January 2013)]. Enferm Infecc Microbiol Clin 2013; 31:602.e1-602.e98. [PMID: 24161378 DOI: 10.1016/j.eimc.2013.04.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 04/08/2013] [Indexed: 02/08/2023]
Abstract
OBJECTIVE This consensus document is an update of combined antiretroviral therapy (cART) guidelines for HIV-1 infected adult patients. METHODS To formulate these recommendations a panel composed of members of the GeSIDA/National AIDS Plan Secretariat (Grupo de Estudio de Sida and the Secretaría del Plan Nacional sobre el Sida) reviewed the efficacy and safety advances in clinical trials, cohort and pharmacokinetic studies published in medical journals (PubMed and Embase) or presented in medical scientific meetings. The strength of the recommendations and the evidence which support them are based on a modification of the criteria of Infectious Diseases Society of America. RESULTS cART is recommended in patients with symptoms of HIV infection, in pregnant women, in serodiscordant couples with high risk of transmission, in hepatitisB co-infection requiring treatment, and in HIV nephropathy. cART is recommended in asymptomatic patients if CD4 is <500cells/μl. If CD4 are >500cells/μl cART should be considered in the case of chronic hepatitisC, cirrhosis, high cardiovascular risk, plasma viral load >100.000 copies/ml, proportion of CD4 cells <14%, neurocognitive deficits, and in people aged >55years. The objective of cART is to achieve an undetectable viral load. The first cART should include 2 reverse transcriptase inhibitors (RTI) nucleoside analogs and a third drug (a non-analog RTI, a ritonavir boosted protease inhibitor, or an integrase inhibitor). The panel has consensually selected some drug combinations, for the first cART and specific criteria for cART in acute HIV infection, in tuberculosis and other HIV related opportunistic infections, for the women and in pregnancy, in hepatitisB or C co-infection, in HIV-2 infection, and in post-exposure prophylaxis. CONCLUSIONS These new guidelines update previous recommendations related to first cART (when to begin and what drugs should be used), how to monitor, and what to do in case of viral failure or adverse drug reactions. cART specific criteria in comorbid patients and special situations are similarly updated.
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Yim HJ, Hwang SG. Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade. Clin Mol Hepatol 2013; 19:195-209. [PMID: 24133659 PMCID: PMC3796671 DOI: 10.3350/cmh.2013.19.3.195] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 08/18/2013] [Indexed: 12/14/2022] Open
Abstract
Although much advancement has been achieved in the treatment of chronic hepatitis B, antiviral resistance is still a challenging issue. Previous generation antiviral agents have already developed resistance in a number of patients, and it is still being used especially in resource limited countries. Once antiviral resistance occurs, it predisposes to subsequent resistance, resulting in multidrug resistance. Therefore, prevention of initial antiviral resistance is the most important strategy, and appropriate choice and modification of therapy would be the cornerstone in avoiding treatment failures. Until now, management of antiviral resistance has been evolving from sequential therapy to combination therapy. In the era of tenofovir, the paradigm shifts again, and we have to decide when to switch and when to combine on the basis of newly emerging clinical data. We expect future eradication of chronic hepatitis B virus infection by proper prevention and optimal management of antiviral resistance.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- Antiviral Resistance Study Group, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA University School of Medicine, Seongnam, Korea
- Antiviral Resistance Study Group, Korea
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Chao DC, Hu KQ. Update on rescue therapies in patients with lamivudine-resistant chronic hepatitis B. Drug Des Devel Ther 2013; 7:777-788. [PMID: 23990707 PMCID: PMC3753145 DOI: 10.2147/dddt.s33947] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis B continues to be a global problem, with an estimated 240 million cases according to the World Health Organization. Chronic infection with the hepatitis B virus (HBV) is associated with cirrhosis, hepatic decompensation, and hepatocellular carcinoma. There are currently several US Food and Drug Administration-approved medications for treating chronic hepatitis B, with Lamivudine (LAM) being the first oral agent made available. The major problem with LAM is significantly decreased effectiveness over time due to the development of anti-HBV resistance that can lead to virologic and biochemical breakthrough as well as hepatitis B flare, progression of liver disease, and decompensation of pre-existing cirrhosis. Despite its high anti-HBV resistant rate, LAM remains widely used in underdeveloped countries due to its wide availability and low cost compared to other antiviral medications, including those that are more effective. Therefore, it is still clinically important to learn how to prevent and treat LAM resistant strains of HBV. Several regimens with the other available antiviral agents have been studied, including switching to monotherapy with either Adefovir, Entecavir, or Tenofovir, adding Adefovir to LAM, and switching to a combination of Adefovir and Entecavir. This review article will examine molecular mechanisms and diagnosis of LAM anti-HBV resistance, risks for and approaches to reduce LAM anti-HBV resistance, and currently available rescue therapy regimens for LAM resistance.
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Affiliation(s)
- Daniel C Chao
- Division of Gastroenterology and Hepatology, University of California, Irvine Medical Center, Orange, CA, USA
| | - Ke-Qin Hu
- Division of Gastroenterology and Hepatology, University of California, Irvine Medical Center, Orange, CA, USA
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Gerlich WH. Medical virology of hepatitis B: how it began and where we are now. Virol J 2013; 10:239. [PMID: 23870415 PMCID: PMC3729363 DOI: 10.1186/1743-422x-10-239] [Citation(s) in RCA: 203] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 07/18/2013] [Indexed: 02/06/2023] Open
Abstract
Infection with hepatitis B virus (HBV) may lead to acute or chronic hepatitis. HBV infections were previously much more frequent but there are still 240 million chronic HBV carriers today and ca. 620,000 die per year from the late sequelae liver cirrhosis or hepatocellular carcinoma. Hepatitis B was recognized as a disease in ancient times, but its etiologic agent was only recently identified. The first clue in unraveling this mystery was the discovery of an enigmatic serum protein named Australia antigen 50 years ago by Baruch Blumberg. Some years later this was recognized to be the HBV surface antigen (HBsAg). Detection of HBsAg allowed for the first time screening of inapparently infected blood donors for a dangerous pathogen. The need to diagnose clinically silent HBV infections was a strong driving force in the development of modern virus diagnostics. HBsAg was the first infection marker to be assayed with a highly sensitive radio immune assay. HBV itself was among the first viruses to be detected by assay of its DNA genome and IgM antibodies against the HBV core antigen were the first to be selectively detected by the anti-μ capture assay. The cloning and sequencing of the HBV genome in 1978 paved the way to understand the viral life cycle, and allowed development of efficient vaccines and drugs. Today’s hepatitis B vaccine was the first vaccine produced by gene technology. Among the problems that still remain today are the inability to achieve a complete cure of chronic HBV infections, the recognition of occult HBV infections, their potential reactivation and the incomplete protection against escape mutants and heterologous HBV genotypes by HBV vaccines.
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Affiliation(s)
- Wolfram H Gerlich
- Institute for Medical Virology, National Reference Center for Hepatitis B and D, Justus Liebig University Giessen, Schubert Str, 81, 35392 Giessen, Germany.
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Price H, Dunn D, Pillay D, Bani-Sadr F, de Vries-Sluijs T, Jain MK, Kuzushita N, Mauss S, Núñez M, Nüesch R, Peters M, Reiberger T, Stephan C, Tan L, Gilson R. Suppression of HBV by tenofovir in HBV/HIV coinfected patients: a systematic review and meta-analysis. PLoS One 2013; 8:e68152. [PMID: 23874527 PMCID: PMC3707972 DOI: 10.1371/journal.pone.0068152] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 05/26/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. METHODS A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. RESULTS Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. INTERPRETATION TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone.
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Affiliation(s)
- Huw Price
- Research Department of Infection and Population Health, University College London, London, United Kingdom.
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Deng XL, Li QL, Guo JJ. Dynamics of lamivudine-resistant hepatitis B virus strains in patients with entecavir rescue therapy. Virus Genes 2013; 47:1-9. [DOI: 10.1007/s11262-013-0915-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Accepted: 04/15/2013] [Indexed: 01/05/2023]
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Management of chronic hepatitis B: Canadian Association for the Study of the Liver consensus guidelines. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2013; 26:917-38. [PMID: 23248795 DOI: 10.1155/2012/506819] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B (CHB) is a dynamic disease that is influenced by host and virological factors. The management of CHB has become more complex with the increasing use of long-term oral nucleos⁄tide analogue antiviral therapies and the availability of novel diagnostic assays. Furthermore, there is often a lack of robust data to guide optimal management such as the selection of therapy, duration of treatment, potential antiviral side effects and the treatment of special populations. In November 2011, the Canadian Liver Foundation and the Canadian Association for the Study of the Liver convened a consensus conference to review the literature and analyze published data, including other international expert guidelines on CHB management. The proceedings of the consensus conference are summarized and provide updated clinical practice guidelines to assist Canadian health care providers in the prevention, diagnosis, assessment and treatment of CHB.
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Efficacy of tenofovir in patients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-naive patients with chronic hepatitis B. Antimicrob Agents Chemother 2013; 57:1790-6. [PMID: 23380725 DOI: 10.1128/aac.02600-12] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
We evaluated the efficacy of tenofovir disoproxil fumarate (TDF) in patients with lamivudine failure (LAM-F) in comparison with that in nucleoside/nucleotide analogue (NA)-naïve patients with chronic hepatitis B (CHB). The criteria for inclusion were being NA naïve or having previous LAM-F and receiving TDF therapy for at least 6 months. Biochemical and virological tests were performed at the baseline, at 3-month intervals in the first year, and every 6 months thereafter. The primary outcome measure for efficacy was a complete virological response (CVR), defined as an HBV DNA level of <20 IU/ml. CVR rates were calculated by Kaplan-Meier analysis, and a multivariate Cox proportional-hazard model was generated in order to find predictive factors independently associated with the time to a CVR. We included 197 patients in the study (136 males; mean age, 43 ± 12 years; 105 patients were NA naïve). Sixty-five patients had hepatitis B e antigen (HBeAg)-positive CHB. The median duration of TDF treatment was 29 (range, 6 to 52) months. Seventy-one patients (77%) in the LAM-F group were treated with TDF add-on therapy. The CVR rates of the NA-naïve and LAM-F groups were comparable in HBeAg-negative (94% versus 96% at month 36, P = 0.10) and HBeAg-positive patients (67% versus 83% at month 36, P = 0.48). According to the multivariate Cox regression model, only HBeAg positivity (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.26 to 0.59; P < 0.001) and a high baseline HBV DNA level (HR, 0.44; 95% CI, 0.29 to 0.67; P < 0.001) had a significant influence on the time to a CVR. The similar cumulative CVR rates during the follow-up show that TDF has comparable efficacy in lamivudine-experienced and NA-naïve patients, and the presence of resistance mutations did not alter the response rates.
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Dusheiko G. Treatment of HBeAg positive chronic hepatitis B: interferon or nucleoside analogues. Liver Int 2013; 33 Suppl 1:137-50. [PMID: 23286858 DOI: 10.1111/liv.12078] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Interferon alpha has restricted efficacy in as much as only a proportion of patients show a response. However, in appropriately selected HBeAg-positive and HBeAg-negative patients, sustained suppression of viral replication can be achieved, and HBeAg or even HBsAg seroconversion can be attained. Thus, finite course of interferon alpha can be successful, and offer an advantage to patient. Interferon (IFN) remains a benchmark therapy for chronic hepatitis B. The main advantages of IFN-α over nucleoside analogues are the absence of resistance and the possibility of immune-mediated clearance of hepatitis B. Unfortunately, side effects preclude the use of interferon alpha in substantial proportions of patients, and prolonged maintenance therapy to suppress hepatitis B virus (HBV) is not feasible. Nucleoside analogues are given by mouth, once per day, and the safety, potency and efficacy have improved and facilitated treatment. However, maintenance of long-term suppression is required for the majority of patients. In general, treatment of chronic hepatitis B should target patients with active disease and viral replication, preferably before the signs and symptoms of cirrhosis or significant injury has occurred. Current EASL guidelines suggest that treatment be based on the evaluation of three criteria: Serum aminotransferase levels, serum HBV DNA levels and histological grade and stage. Many questions remain unanswered on the optimal treatment of patients with chronic hepatitis B with a nucleoside vs interferon alpha. Both forms of treatment have benefits and the choice should be selected and tailored. Stopping or futility rules can be implemented in patients who fail interferon. Recent data suggest the safety and efficacy of nucleoside analogues in the third trimester of pregnancy to reduce the risk of transmission from mothers to their children.
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Affiliation(s)
- Geoffrey Dusheiko
- UCL Division of Liver and Digestive Health, University College London Medical School, and Royal Free Hospital, London, UK.
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Kim YJ, Sinn DH, Gwak GY, Choi MS, Koh KC, Paik SW, Yoo BC, Lee JH. Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures. World J Gastroenterol 2012; 18:6996-7002. [PMID: 23322999 PMCID: PMC3531685 DOI: 10.3748/wjg.v18.i47.6996] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 05/31/2012] [Accepted: 06/08/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB) patients after multiple failures.
METHODS: A total of 29 CHB patients who had a suboptimal response or developed resistance to two or more previous nucleoside/nucleotide analogue (NA) treatments were included. Study subjects were treated with TDF alone (n = 13) or in combination with lamivudine (LAM, n = 12) or entecavir (ETV, n = 4) for ≥ 6 mo. Complete virologic response (CVR) was defined as an achievement of serum hepatitis B virus (HBV) DNA level ≤ 60 IU/mL by real-time polymerase chain reaction method during treatment. Safety assessment was based on serum creatinine and phosphorus level. Eleven patients had histories of LAM and adefovir dipivoxil (ADV) treatment and 18 patients were exposed to LAM, ADV, and ETV. Twenty-seven patients (93.1%) were hepatitis B e antigen (HBeAg) positive and the mean value of the baseline serum HBV DNA level was 5.5 log IU/mL ± 1.7 log IU/mL. The median treatment duration was 16 mo (range 7 to 29 mo).
RESULTS: All the patients had been treated with LAM and developed genotypic and phenotypic resistance to it. Resistance to ADV was present in 7 patients and 10 subjects had a resistance to ETV. One patient had a resistance to both ADV and ETV. The cumulative probabilities of CVR at 12 and 24 mo of TDF containing treatment regimen calculated by the Kaplan Meier method were 86.2% and 96.6%, respectively. Although one patient failed to achieve CVR, serum HBV DNA level decreased by 3.9 log IU/mL from the baseline and the last serum HBV DNA level during treatment was 85 IU/mL, achieving near CVR. No patients in this study showed viral breakthrough or primary non-response during the follow-up period. The cumulative probability of HBeAg clearance in the 27 HBeAg positive patients was 7.4%, 12%, and 27% at 6, 12, and 18 mo of treatment, respectively. Treatment efficacy of TDF containing regimen was not statistically different according to the presence of specific HBV mutations. History of prior exposure to specific antiviral agents did not make a difference to treatment outcome. Treatment efficacy of TDF was not affected by combination therapy with LAM or ETV. No patient developed renal toxicity and no cases of hypophosphatemia associated with TDF therapy were observed. There were no other adverse events related to TDF therapy observed in the study subjects.
CONCLUSION: TDF can be an effective and safe rescue therapy in CHB patients after multiple NA therapy failures.
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Assessing long-term treatment efficacy in chronic hepatitis B and C: between evidence and common sense. J Hepatol 2012; 57:1326-35. [PMID: 22750749 DOI: 10.1016/j.jhep.2012.06.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 06/20/2012] [Accepted: 06/20/2012] [Indexed: 12/18/2022]
Abstract
Chronic infection with the hepatitis B and C virus represents a major health problem worldwide, as it is estimated that roughly 400 and 200 million people respectively, are infected by each virus. By definition, any antiviral therapy that claims to be effective should have as its ultimate efficacy end point an improvement in patients' survival, or at least a reduction in the development rates of liver-related complications. However, this is extremely complicated to prove as the natural course of both viral diseases is extremely slow, requiring decades to evolve in cirrhosis and even more years to lead to liver complications. For this reason, clinicians and health authorities have relied on so called surrogate end points to assess the efficacy of any therapeutic intervention for viral hepatitis. Obviously, this allows for standardization in study designs that ultimately translates into an accelerated time frame for therapeutic drugs as well as healthcare innovations to enter the viral hepatitis clinical practice. However, it also calls for demonstration that surrogate end points in the treatment of patients with chronic hepatitis B or C are good and reliable markers of long-term efficacy.
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