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Lumley SF, Mokaya J, Maponga TG, Kramvis A, Dusheiko G, Irving W, Delphin M, Said Mohammed K, Downs LO, Waddilove E, Anderson M, Iwuji C, Msomi N, Ocama P, Hamid S, Adda D, Halford R, Kabagambe K, Benschop KSM, Inzaule S, Chan P, Paul MAS, Izumi K, Nisa T, De Dieu Iragena J, Girón-Callejas A, Kpossou AR, Jamiyu G, Emmanuel O, Balkissa M, Keita M, Prabdial-Sing N, Martinez A, Magongo EN, Shao Y, Sued O, Sereno LS, Shafer RW, Lesi O, Faini D, Easterbrook P, Duncombe C, Jordan MR, Matthews PC. Hepatitis B virus resistance to nucleos(t)ide analogue therapy: WHO consultation on questions, challenges, and a roadmap for the field. THE LANCET. MICROBE 2025:101076. [PMID: 40220768 DOI: 10.1016/j.lanmic.2025.101076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 04/14/2025]
Abstract
In this Review, we summarise outputs from a multidisciplinary consultation convened by WHO between July 11 and 13, 2023, to discuss hepatitis B virus (HBV) drug resistance (HBVDR). Treatment of chronic HBV infection with highly effective nucleos(t)ide analogue agents, tenofovir and entecavir, is a crucial intervention that supports the global goal of elimination of HBV infection as a public health threat. The risk of HBVDR as a threat to treatment outcomes is currently considered low from a public health perspective; however, drug resistance can influence individual outcomes, particularly among those who are treatment-experienced. We highlight the need to develop appropriate prevention, monitoring, and surveillance approaches for HBVDR, to support investment in the global scale-up of HBV diagnosis and treatment. Recommendations for the HBVDR field will ultimately be incorporated into a WHO integrated Global Action Plan for drug-resistant HIV, viral hepatitis, and priority sexually transmitted infections.
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Affiliation(s)
- Sheila F Lumley
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals, Oxford, UK
| | - Jolynne Mokaya
- Parasites and Microbes, Wellcome Sanger Institute, Cambridge, UK
| | - Tongai G Maponga
- Division of Medical Virology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; National Health Laboratory Service, Tygerberg Business Unit, Cape Town, South Africa
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Geoffrey Dusheiko
- University of the Witwatersrand, Johannesburg, South Africa; Institute of Liver Studies, King's College Hospital, London, UK
| | - William Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | | | | | - Louise O Downs
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals, Oxford, UK; Kenya Medical Research Institute Wellcome Trust, Kilifi, Kenya
| | | | - Motswedi Anderson
- The Francis Crick Institute, London, UK; Africa Health Research Institute, Durban, South Africa; Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Collins Iwuji
- Africa Health Research Institute, Durban, South Africa; Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Nokukhanya Msomi
- Discipline of Virology, University of KwaZulu-Natal and National Health Laboratory Service, Durban, South Africa
| | - Ponsiano Ocama
- Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Saeed Hamid
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Danjuma Adda
- World Hepatitis Alliance, Geneva, Switzerland; Center for Initiative and Development and Chagro-Care Trust, Jalingo, Nigeria
| | | | - Kenneth Kabagambe
- The National Organisation for People Living with Hepatitis B, Kampala, Uganda
| | | | - Seth Inzaule
- Amsterdam Institute for Global Health and Development and Department of Global Health, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Polin Chan
- Department of Communicable Diseases, WHO South-East Asia Regional Office, New Delhi, India
| | | | - Kiyohiko Izumi
- Division of Programmes for Disease Control, WHO Western Pacific Regional Office, Manila, Philippines
| | - Tiara Nisa
- Division of Programmes for Disease Control, WHO Western Pacific Regional Office, Manila, Philippines
| | - Jean De Dieu Iragena
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Amalia Girón-Callejas
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | | | - Ganiyu Jamiyu
- National AIDS, Viral Hepatitis and STIs Control Programme, Abuja, Nigeria
| | - Omolara Emmanuel
- National AIDS, Viral Hepatitis and STIs Control Programme, Abuja, Nigeria
| | - Mahamadou Balkissa
- Programme National de Lutte contre le Sida et les Hépatites (PNLSH), Ministère de la Santé Publique, de la Population et des Affaires Sociales, Niamey, Niger
| | - Mamadou Keita
- The Sectoral Unit for the Fight against HIV, Tuberculosis and Viral Hepatitis, Ministry of Health, Bamako, Mali
| | - Nishi Prabdial-Sing
- National Institute for Communicable Diseases and National Health Laboratory Service and the Faculty of Health Sciences, Witwatersrand University, Johannesburg, South Africa; National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa
| | - Alexander Martinez
- Gorgas Memorial Institute for Health Studies, Panama City, Panama; Department of Microbiology and Immunology, University of Panama, Panama City, Panama
| | | | - Yiming Shao
- National Centre for AIDS/STD Control and Prevention A, Chinese Center for Disease Control and Prevention, Changping Laboratory, Beijing, China
| | - Omar Sued
- HIV, STI, Viral Hepatitis and TB Unit, Department of Communicable Disease Prevention, Control, and Elimination, Pan American Health Organization, Washington, DC, USA
| | - Leandro Soares Sereno
- HIV, STI, Viral Hepatitis and TB Unit, Department of Communicable Disease Prevention, Control, and Elimination, Pan American Health Organization, Washington, DC, USA
| | - Robert W Shafer
- Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA
| | - Olufunmilayo Lesi
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland; University of Lagos, Lagos, Nigeria
| | - Diana Faini
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Philippa Easterbrook
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Chris Duncombe
- International Association of Providers of AIDS Care, Washington DC, USA
| | - Michael R Jordan
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA; Collaboratory for Emerging Infectious Diseases and Response, Tufts University, Medford, MA, USA
| | - Philippa C Matthews
- Kenya Medical Research Institute Wellcome Trust, Kilifi, Kenya; Division of Infection and Immunity, University College London, London, UK; Department of Infectious Diseases, University College London Hospital, London, UK.
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Ravanbakhsh N, Rivera Campana A, Chapin C, Jhaveri R. Hepatitis B Virus Treatment in Children: Common Challenges and Management Options in a Case-Based Format. J Pediatric Infect Dis Soc 2024; 13:S142-S147. [PMID: 39171575 DOI: 10.1093/jpids/piae084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/19/2024] [Indexed: 08/23/2024]
Abstract
The management of hepatitis B virus (HBV) in pediatrics presents many challenges, given the potential sequelae of untreated infection including hepatic fibrosis, cirrhosis, and malignancy, and a lack of clear guidance on the timing of treatment initiation. The goal of this review is to feature common clinical scenarios that occur in the evaluation and treatment of HBV infection in children. Each vignette presents an opportunity to discuss guidelines and evidence-based practices as well as review landmark studies and evolving practices.
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Affiliation(s)
- Naseem Ravanbakhsh
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Andres Rivera Campana
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Catherine Chapin
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Ravi Jhaveri
- Division of Pediatric Infectious Diseases, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Hige S, Aoki K, Nakamoto D, Flaherty JF, Botros I, Mizutani H, Ishizaki A, Konishi H, Yuan J, Jinushi M, Ng LJ. Real-world safety and effectiveness of tenofovir alafenamide for 144 weeks in Japanese patients with chronic hepatitis B. J Viral Hepat 2024; 31:165-175. [PMID: 38163911 DOI: 10.1111/jvh.13912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/17/2023] [Accepted: 12/13/2023] [Indexed: 01/03/2024]
Abstract
Tenofovir alafenamide (TAF), a prodrug of tenofovir, delivers high levels of active drug to hepatocytes and is given in a lower dose than tenofovir disoproxil fumarate (TDF). TAF reduces viral replication in patients with chronic hepatitis B (CHB) similar to TDF and has shown a lower risk of the renal and bone toxicities associated with TDF use. This post-marketing surveillance study examined the safety and effectiveness of TAF in treatment-naïve and -experienced CHB patients who received TAF for 144 weeks at real-world clinical sites in Japan. Safety assessments included the incidence of adverse drug reactions (ADRs), renal and bone events, and changes in selected laboratory parameters. Effectiveness was based on the proportion of patients with HBV DNA levels below the lower limit of quantitation or <29 IU/mL. This analysis included 580 patients; 18.4% of whom were treatment-naïve. The cumulative incidence of ADRs was 0.21 per 100 person-months, and the incidence of serious ADRs was 0.01 (95% CI, 0.00-0.04) per 100 person-months. There were no ADRs of declines in estimated glomerular filtration rates, renal failure or proximal tubulopathy. The most common ADR was hypophosphataemia in seven (1.2%) patients. Two (0.4%) patients each had decreased blood phosphorus, bone mineral density decreased, dizziness and alopecia. Overall, the proportion of virologically suppressed patients increased from 68.8% at baseline to 97.5% at Week 144. These results confirm the real-world safety and effectiveness of TAF in Japanese patients with CHB and are consistent with the findings of other evaluations of the safety and efficacy of TAF in CHB.
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Affiliation(s)
- Shuhei Hige
- Department of Gastroenterology, Sapporo-Kosei General Hospital, Sapporo, Japan
| | - Kouji Aoki
- Gilead Sciences K.K., Chiyoda-Ku, Tokyo, Japan
| | | | | | - Irina Botros
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | | | - Jason Yuan
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Leslie J Ng
- Gilead Sciences, Inc., Foster City, California, USA
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Jagarlamudi N, Reyes M, Fung S, Wong F. The Use of Tenofovir Disoproxil Fumarate in the Management of eAg-Negative Chronic Hepatitis B Infection. J Clin Med 2024; 13:1864. [PMID: 38610629 PMCID: PMC11012673 DOI: 10.3390/jcm13071864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
Background/Objectives: Currently, there are insufficient data to recommend the treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic infection who have normal ALT and low HBV DNA, since the prognosis is generally regarded as favorable. The aim of this pilot study was to determine whether the use of tenofovir disoproxil fumarate (TDF) 300 mg/day for 3 years was able to achieve functional cure (HBsAg loss) and HBsAg seroconversion in HBeAb-positive individuals. Methods: Fifty patients not on antiviral therapy (40% men, mean age 48.9 ± 10.9 years, 84% Asians) with minimal fibrosis were enrolled. Results: TDF reduced HBV DNA significantly to undetectable levels after 6 months. Overall, 48.3% of inactive carriers (baseline HBV DNA < 2000 IU/mL) remained HBV DNA negative 6 months after treatment withdrawal, which was significantly higher than the 5.6% in those who were not inactive carriers (baseline HBV DNA ≥ 2000 IU/mL) (p = 0.003). The HBsAg levels did not drop throughout the study period with no difference between inactive carriers versus those who were not. Five inactive carriers achieved functional cure, but none of these were amongst those who were not inactive carriers. No renal dysfunction or ALT flare on treatment withdrawal was observed. Conclusions: TDF could potentially be used to induce functional cure in patients who are inactive carriers with normal ALT, low HBV DNA and without advanced fibrosis.
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Affiliation(s)
| | | | | | - Florence Wong
- Division of Gastroenterology and Hepatology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON M5G2C4, Canada (M.R.); (S.F.)
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Abstract
Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - George V Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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Giordano C, Picardi M, Pugliese N, Vincenzi A, Abagnale DP, De Fazio L, Giannattasio ML, Fatigati C, Ciriello M, Salemme A, Muccioli Casadei G, Vigliar E, Mascolo M, Troncone G, Pane F. Lamivudine 24-month-long prophylaxis is a safe and efficient choice for the prevention of hepatitis B virus reactivation in HBsAg-negative/HBcAb-positive patients with advanced DLBCL undergoing upfront R-CHOP-21. Front Oncol 2023; 13:1130899. [PMID: 36890828 PMCID: PMC9986962 DOI: 10.3389/fonc.2023.1130899] [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: 12/23/2022] [Accepted: 01/30/2023] [Indexed: 02/17/2023] Open
Abstract
Introduction Occult hepatitis B infection (OBI) is a condition where replication-competent hepatitis B virus-DNA (HBV-DNA) is present in the liver, with or without HBV-DNA in the blood [<200 international units (IU)/ml or absent] in HB surface antigen (HBsAg)-negative/HB core antibody (HBcAb)-positive individuals. In patients with advanced stage diffuse large B-cell lymphoma (DLBCL) undergoing 6 cycles of R-CHOP-21+2 additional R, OBI reactivation is a frequent and severe complication. There is no consensus among recent guidelines on whether a pre-emptive approach or primary antiviral prophylaxis is the best solution in this setting of patients. In addition, questions still unresolved are the type of prophylactic drug against HBV and adequate prophylaxis duration. Methods In this case-cohort study, we compared a prospective series of 31 HBsAg-/HBcAb+ patients with newly diagnosed high-risk DLBCL receiving lamivudine (LAM) prophylaxis 1 week before R-CHOP-21+2R until 18 months after (24-month LAM series) versus 96 HBsAg-/HBcAb+ patients (from January 2005 to December 2011) undergoing a pre-emptive approach (pre-emptive cohort) and versus 60 HBsAg-/HBcAb+ patients, from January 2012 to December 2017, receiving LAM prophylaxis [1 week before immunochemotherapy (ICHT) start until 6 months after] (12-month LAM cohort). Efficacy analysis focused primarily on ICHT disruption and secondarily on OBI reactivation and/or acute hepatitis. Results In the 24-month LAM series and in the 12-month LAM cohort, there were no episodes of ICHT disruption versus 7% in the pre-emptive cohort (P = 0.05). OBI reactivation did not occur in any of the 31 patients in the 24-month LAM series versus 7 out of 60 patients (10%) in the 12-month LAM cohort or 12 out of 96 (12%) patients in the pre-emptive cohort (P = 0.04, by χ 2 test). No patients in the 24-month LAM series developed acute hepatitis compared with three in the 12-month LAM cohort and six in the pre-emptive cohort. Discussion This is the first study collecting data regarding a consistent and homogeneous large sample of 187 HBsAg-/HBcAb+ patients undergoing standard R-CHOP-21 for aggressive lymphoma. In our study, 24-month-long prophylaxis with LAM appears to be the most effective approach with a null risk of OBI reactivation, hepatitis flare-up, and ICHT disruption.
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Affiliation(s)
- Claudia Giordano
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Marco Picardi
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Novella Pugliese
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Annamaria Vincenzi
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Davide Pio Abagnale
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Laura De Fazio
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Maria Luisa Giannattasio
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Carmina Fatigati
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Mauro Ciriello
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Alessia Salemme
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Giada Muccioli Casadei
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Elena Vigliar
- Department of Public Health, Federico II University Medical School Naples, Naples, Italy
| | - Massimo Mascolo
- Department of Advanced Biomedical Sciences, Federico II University Medical School, Naples, Italy
| | - Giancarlo Troncone
- Department of Public Health, Federico II University Medical School Naples, Naples, Italy
| | - Fabrizio Pane
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
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Virological responses to tenofovir-alafenamide-containing antiretroviral therapy in people living with HIV co-infected with lamivudine-resistant or lamivudine-susceptible hepatitis B virus. Int J Antimicrob Agents 2022; 60:106682. [PMID: 36279976 DOI: 10.1016/j.ijantimicag.2022.106682] [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: 12/01/2021] [Revised: 08/11/2022] [Accepted: 10/17/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Data on the effectiveness of tenofovir alafenamide (TAF) against lamivudine-resistant (LAM-R) hepatitis B virus (HBV) among patients co-infected with human immunodeficiency virus (HIV) and HBV are limited. METHODS Between April and December 2018, HIV-positive patients co-infected with LAM-R or lamivudine-susceptible (LAM-S) HBV who switched from tenofovir-disoproxil-fumarate-containing antiretroviral therapy (ART) to TAF-containing ART were followed for 96 weeks. Plasma HBV and HIV loads, HBV serological markers, and liver function before and after the switch were analysed. RESULTS In total, 182 patients co-infected with HIV and HBV were included in this study: 45 with LAM-R HBV and 137 with LAM-S HBV. At baseline, 28.9% and 7.4% of patients in the LAM-R and LAM-S groups, respectively, tested positive for hepatitis B virus envelope antigen (HBeAg) (P<0.001), and the respective percentages of patients who had achieved plasma HBV DNA <20 IU/mL were 95.5% and 97.1%. At weeks 48 and 96, 100% and 94.9% of patients in the LAM-R group, respectively, and 97.1% and 95.6% of patients in the LAM-S group, respectively, maintained plasma HBV DNA <20 IU/mL. Lamivudine resistance of HBV and baseline hepatitis B virus surface antigen (HBsAg) level were associated with HBsAg decrement at week 96 at a degree of 0.25 log10 IU/mL [95% confidence interval (CI) 0.059-0.246] and 0.22 log10 IU/mL (per 1-log10IU/mL increase, 95% CI 0.018-0.101), respectively. At week 96, 2.2% (4/182) of patients had HBsAg loss; no patients in the LAM-R group and 25.0% (2/8) of patients in the LAM-S group had HBeAg seroconversion. CONCLUSIONS Switching to TAF-containing regimens maintained high rates of HBV viral suppression in patients co-infected with either LAM-R or LAM-S HBV. The decrease in HBsAg was minimal, and HBsAg seroconversion occurred infrequently.
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Clinical Efficacy and Safety of Tenofovir in the Treatment of Patients with Chronic Hepatitis B. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1673453. [PMID: 35774746 PMCID: PMC9239785 DOI: 10.1155/2022/1673453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/22/2022] [Accepted: 05/26/2022] [Indexed: 11/24/2022]
Abstract
The negative rate of serum HBV DNA, HBeAg, and ALT in the tenofovir group was significantly higher than that in the entecavir group (86.67%, 3.33%, and 80.00%) (all P < 0.05). In the tenofovir group, 2cases were considered. Objective. The aim of this study is to analyze the clinical effect and safety of tenofovir in the treatment of chronic hepatitis B (CHB) patients. Methods. A total of 60 patients with CHB who were admitted and treated in Anqing First People's Hospital Affiliated to Anhui Medical University from January 2019 to July 2020 were randomly assigned at a ratio of 1 : 1 into the tenofovir group (treated with tenofovir) and the entecavir group (treated with entecavir) via the random number table method. The clinical therapeutic effect and safety of the two groups were compared. Results. The serum hepatitis B virus (HBV) DNA levels in the two groups decreased after treatment, but there was no significant difference. Ths (2.50%) had nausea, 1 (1.25%) had headache, and 0 had an elevated creatine kinase. In the tenofovir group,1(3.33%) had nausea, 0 had headache, and 0 had an elevated creatine kinase. In the entecavir group, there were 3 (10.00%) cases of nausea, 2 (6.67%) cases of headache, and 1 (3.33%) case of elevated creatine kinase. The overall incidence of adverse reactions in the tenofovir group (3.33%) was significantly lower than that in the entecavir group (20.00%) (all P < 0.05). Conclusion. Tenofovir is more effective than entecavir in the treatment of patients with CHB due to low incidence of adverse events and a good safety profile.
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Lim Y, Seto W, Kurosaki M, Fung S, Kao J, Hou J, Gordon SC, Flaherty JF, Yee LJ, Zhao Y, Agarwal K, Lampertico P. Review article: switching patients with chronic hepatitis B to tenofovir alafenamide-a review of current data. Aliment Pharmacol Ther 2022; 55:921-943. [PMID: 35178711 PMCID: PMC9304567 DOI: 10.1111/apt.16788] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/29/2021] [Accepted: 01/12/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND The nucleos(t)ide analogues (NAs) entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are preferred treatment options for patients with chronic hepatitis B infection (CHB). However, resistance to ETV has been reported, especially with prior exposure to other NAs, and long-term TDF treatment has been associated with decline in renal function and loss of bone mineral density in some patients. Consequently, TAF may be preferable to ETV, TDF or other NAs in specific circumstances such as in patients with risk of bone or renal complications, elderly patients or those with previous NA experience. AIM To provide a summary of the available efficacy and safety data following switch to TAF from other NAs in patients with CHB in clinical studies and real-world settings. METHODS Literature searches were performed on PubMed and abstracts from three major international liver congresses between 2019 and 2021. Studies that included efficacy and/or safety data for patients with CHB switching from any NA to TAF were selected. RESULTS Thirty-six papers and abstracts were included in this narrative review. Switching from TDF to TAF maintained or improved virological and biochemical responses with improved bone and renal safety. Switching from ETV or other NAs to TAF maintained or improved virological and biochemical responses and varying results for bone and renal safety. CONCLUSIONS Switching to TAF appears to maintain or improve virological, biochemical and bone- and renal-related safety outcomes. These data support the concept of switching to TAF in some patients with CHB based on their individual circumstances.
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Affiliation(s)
- Young‐Suk Lim
- University of Ulsan College of MedicineSeoulSouth Korea
| | - Wai‐Kay Seto
- The University of Hong KongHong Kong
- The University of Hong Kong‐Shenzhen HospitalShenzenChina
| | | | | | | | - Jinlin Hou
- Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Stuart C. Gordon
- Henry Ford Health System and Wayne State University School of MedicineDetroitMIUSA
| | | | | | | | | | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
- University of MilanMilanItaly
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Masetti C, Pugliese N, Aghemo A, Viganò M. Safety of current antiviral drugs for chronic hepatitis B. Expert Opin Drug Saf 2022; 21:939-945. [PMID: 35209776 DOI: 10.1080/14740338.2022.2045271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Oral nucleos(t)ide analogues (NUCs) are recommended as first-line therapy for chronic hepatitis B due to higher HBV-DNA suppression rates and safety profile. Long-term treatment with NUCs is often necessary to achieve durable viral suppression. AREAS COVERED This review provides an overview of the long-term safety data that have become available since entecavir (ETV) and tenofovir disoproxil fumarate (TDF) were first approved, and recent data on tenofovir alafenamide (TAF) in patients with CHB. EXPERT OPINION NUCs generally show remarkable safety in patients taking them for long periods. Nevertheless, renal and bone toxicity may occur in a minority of patients on TDF therapy. These effects have been overcome by the recent release of TAF. Moreover, the currently available data do not allow firm conclusions on superiority of TDF on ETV about HCC risk reduction. Observational studies involving more homogeneous cohorts are therefore needed; furthermore long-term studies assessing impact of TAF on this important topic are warranted.
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Affiliation(s)
- Chiara Masetti
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy
| | - Nicola Pugliese
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Mauro Viganò
- 3Division of Hepatology, Ospedale San Giuseppe, Milan, Italy
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Zhang Q, Cai DC, Hu P, Ren H. Low-level viremia in nucleoside analog-treated chronic hepatitis B patients. Chin Med J (Engl) 2021; 134:2810-2817. [PMID: 34759219 PMCID: PMC8668013 DOI: 10.1097/cm9.0000000000001793] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Indexed: 12/14/2022] Open
Abstract
ABSTRACT Low-level viremia (LLV) was defined as persistent or intermittent episodes of detectable hepatitis B virus (HBV) DNA (<2000 IU/mL, detection limit of 10 IU/mL) after 48 weeks of antiviral treatment. Effective antiviral therapies for chronic hepatitis B (CHB) patients, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), have been shown to inhibit the replication of HBV DNA and prevent liver-related complications. However, even with long-term antiviral therapy, there are still a number of patients with persistent or intermittent LLV. At present, the research on LLV to address whether adversely affect the clinical outcome is limited, and the follow-up treatment for these patients is open to question. At the same time, the mechanism of LLV is not clear. In this review, we summarize the incidence of LLV, the association between LLV and long-term outcomes, possible mechanisms, and management strategies in these patient populations.
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Affiliation(s)
- Qian Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
- Department of Infectious Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550001, China
| | - Da-Chuan Cai
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Hong Ren
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
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12
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de Almeida NAA, de Paula VS. Occult Hepatitis B virus (HBV) infection and challenges for hepatitis elimination: A literature review. J Appl Microbiol 2021; 132:1616-1635. [PMID: 34724308 DOI: 10.1111/jam.15351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/08/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Occult hepatitis B infection (OBI) is characterized by the detection of hepatitis B virus (HBV) DNA in serum or liver but negativity for hepatitis B surface antigen. OBI, which is thought to be maintained by host, immunological, viral and/or epigenetic factors, is one of the most challenging clinical features in the study of viral hepatitis. Currently, there is no validated detection test for OBI. It is believed that OBI is widely distributed throughout the world, with a higher prevalence in populations at high-risk HBV, but the detailed worldwide prevalence patterns are unknown. We conducted a survey of recently published studies on OBI rates across all continents. High prevalence rates of OBI are observed in some specific groups, including patients with hepatitis C virus, human immunodeficiency virus co-infection or hepatocellular carcinoma. In 2016, the World Health Organization adopted strategies to eliminate viral hepatitis by 2030, but the difficulties in detecting and treating OBI currently challenge this goal. Subjects with OBI can transmit HBV, and episodes of reactivation can occur. Further studies to understanding the mechanisms that drive the development of OBI are needed and can contribute to efforts at eliminating viral hepatitis.
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Tsai HJ, Chuang YW, Yang SS, Chang YZ, Chang HR, Lee TY. Evaluating the renal safety of tenofovir disoproxil fumarate in hepatitis B patients without chronic kidney disease. J Viral Hepat 2021; 28:1579-1586. [PMID: 34464999 DOI: 10.1111/jvh.13603] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 08/27/2021] [Indexed: 12/13/2022]
Abstract
The nephrotoxicity of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients without chronic kidney disease (CKD) remains controversial. We aimed to evaluate nephrotoxicity of TDF in this population. In this hospital-based cohort study, CHB patients who received either TDF or entecavir (ETV) therapy, and did not have underlying CKD, were retrospectively recruited from January, 2008 to January, 2019. After excluding those with confounding conditions, 257 TDF-treated patients were matched through propensity scores with 514 ETV-treated patients. Cumulative incidences of, and hazard ratios (HRs) for the CKD guideline-defined renal dysfunction, were analysed. The mean decline in glomerular filtration rate was similar over 60 months (TDF vs. ETV: 10.1 ml/min/1.73 m2 , 95% confidence interval [CI]: 7.4-12.7 vs. 8.0 ml/min/1.73 m2 , 95% CI: 6.4-9.6; p = .34). The 5-year cumulative incidence of renal dysfunction was not significantly different (TDF vs. ETV: 10.4%, 95% CI: 5.6-18.0 vs. 5.8%, 95% CI: 3.6-9.0; p = .18). However, in multivariable stratified analysis, TDF was associated with an increased risk of renal dysfunction in the elderly (age ≥60 years), when compared to ETV (HR 2.86, 95% CI: 1.02-8.01; p < .05). For confirming the effect of TDF amongst the elderly, 61 TDF-treated patients were further matched with 183 ETV-treated patients, with 5-year cumulative incidence of renal dysfunction being significantly higher in TDF users (TDF vs. ETV: 34.4%, 95% CI: 17.7-59.8 vs. 15.5%, 95% CI: 9.4-25.1; p < .05). TDF use was independently related to renal dysfunction (HR 2.71, 95% CI: 1.19-6.14; p < .05). Although TDF is generally safe for CHB patients without CKD, it is best to be avoided in the elderly.
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Affiliation(s)
- Hsin-Ju Tsai
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ya-Wen Chuang
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yan-Zin Chang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Clinical Laboratory, Drug Testing Center, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Horng-Rong Chang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Nephrology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Wang G, Duan Z. Guidelines for Prevention and Treatment of Chronic Hepatitis B. J Clin Transl Hepatol 2021; 9:769-791. [PMID: 34722192 PMCID: PMC8516840 DOI: 10.14218/jcth.2021.00209] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/20/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022] Open
Abstract
To achieve the goal of the World Health Organization to eliminate viral hepatitis as a major public health threat by 2030, the Chinese Society of Infectious Diseases and the Chinese Society of Hepatology convened an expert panel in 2019 to update the guidelines for the prevention and treatment of chronic hepatitis B (CHB). The current guidelines cover recent advances in basic, clinical, and preventive studies of CHB infection and consider the actual situation in China. These guidelines are intended to provide support for the prevention, diagnosis, and treatment of CHB.
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Affiliation(s)
- Guiqiang Wang
- Center for Liver Diseases, Department of Infectious Diseases, Peking University First Hospital; Department of Infectious and Liver Diseases, Peking University International Hospital, Beijing, China
| | - Zhongping Duan
- Center for Difficult and Complicated Liver Diseases and Artificial Liver, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Atencio P, Conesa-Buendía FM, Cabello-Ubeda A, Llamas-Granda P, Pérez-Tanoira R, Prieto-Pérez L, Álvarez BÁ, Acosta IC, Arboiro-Pinel R, Díaz-Curiel M, Largo R, Herrero-Beaumont G, Górgolas M, Mediero A. Bone deleterious effects of different nrtis in treatment-naïve HIV patients after 12 and 48 weeks of treatment. Curr HIV Res 2021; 19:434-447. [PMID: 34353266 PMCID: PMC9175084 DOI: 10.2174/1570162x19666210805094434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 11/22/2022]
Abstract
Background Bone alterations have been observed in the course of HIV infection, characterized by a marked decrease in bone mineral density (BMD) and an increase in the frequency of fractures as a result of fragility. We aim to evaluate early changes in bone metabolic profile and the possible association with tenofovir and other nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) in treatment-naïve HIV patients. Methods We conducted a prospective study in naïve HIV-infected adults (under 50 years), separated into three groups according to NRTI therapy: tenofovir disoproxil fumarate (TDF); tenofovir alafenamide (TAF) and abacavir (ABC). BMD and epidemiological, immunological and metabolic bone parameters were evaluated. Bone markers were analyzed in plasma at baseline, 12 and 48 weeks after initiating treatment. Results Average age of patients was 34.8 years (± 9.6). 92.4% of them with CD4 count > 200 cel/μL. At week 12 after starting treatment, both TDF [increase in PN1P (31.7%, p = 0.004), TRAP (11.1%, p = 0.003), OPN (19.3%, p = 0.045) and OC (38.6%, p = 0.001); decrease in OPG (-23.4%, p = 0.003)] and TAF [increase in 42.6% for CTX (p = 0.011), 27.3% for OC (p = 0.001) and 21% for TRAP (p = 0.008); decrease in OPG (-28.8%, p = 0.049)] presented a deep resorption profile compared to ABC, these differences in bone molecular markers, a tendency to equalize at week 48, where no significant differences were observed. Patients treated with TDF showed the greatest decrease in Z-score in both lumbar spine (LS) and femoral neck (FN) at week 48 without statistically significant differences. Conclusion Treatment-naïve HIV patients have a high prevalence of low bone density. Treatment with TDF is associated with greater bone deterioration at 12 and 48 weeks. TAF seems to present similar early bone deterioration at 12 weeks which disappears at 48 weeks.
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Affiliation(s)
- Patricia Atencio
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | | | - Alfonso Cabello-Ubeda
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Patricia Llamas-Granda
- Bone and Joint Research Unit. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Ramón Pérez-Tanoira
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Laura Prieto-Pérez
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Beatriz Álvarez Álvarez
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Irene Carrillo Acosta
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Rosa Arboiro-Pinel
- Internal Medicine, Bone Disease Department. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Manuel Díaz-Curiel
- Internal Medicine, Bone Disease Department. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Raquel Largo
- Bone and Joint Research Unit. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Gabriel Herrero-Beaumont
- Bone and Joint Research Unit. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Miguel Górgolas
- Internal Medicine, Bone Disease Department. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Aránzazu Mediero
- Bone and Joint Research Unit. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
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Lee J, Kim GA, Kim HJ, Cho S, Ko MJ, Lim YS. Tenofovir disoproxil fumarate on the risk of hepatocellular carcinoma in chronic hepatitis B patients with failure to preceding treatments: A nationwide cohort study. J Viral Hepat 2021; 28:1150-1159. [PMID: 33934466 DOI: 10.1111/jvh.13530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/09/2021] [Accepted: 04/17/2021] [Indexed: 12/12/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) monotherapy is recommended for the treatment of chronic hepatitis B (CHB) patients who are refractory to other drugs. Yet, little data are available for the effectiveness of TDF monotherapy compared with TDF-based combination therapy on the risk of hepatocellular carcinoma (HCC) and death/transplantation. This nationwide population-based cohort study included 11,289 CHB patients who initiated TDF rescue therapy after failure of preceding treatments between 2012 and 2014 in Korea. The risks of HCC and death/transplantation were compared between TDF combotherapy (n = 2,499) and TDF monotherapy (n = 8,790) groups. The findings were validated in a hospital cohort of 1,163 CHB patients. In the nationwide cohort, during 44.2 months of overall treatment duration, 529 patients developed HCC and 190 died or received transplantation. In the 2,499 propensity score-matched pairs, compared with TDF combotherapy, TDF monotherapy showed no significantly different risks of HCC (1.11/100 person-year [PY] vs. 1.32/100 PY; HR 1.23, 95% CI 0.95-1.60, p = .12) and death/transplant (0.43/100 PY vs. 0.42/100 PY; HR 1.04, 95% CI 0.67-1.60, p = .87). However, in the 469 propensity score-matched pairs of cirrhosis subcohort, TDF monotherapy was associated with a higher risk of HCC than TDF combotherapy (HR 1.46, 95% CI 1.002-2.12, p = .049). In the validation hospital cohort, TDF monotherapy was not associated with significantly different risks of HCC and death/transplant in the entire cohort and cirrhosis subcohort. In CHB patients with failure to preceding treatments, TDF monotherapy showed no higher risks of HCC and death/transplantation compared with TDF combotherapy. However, the comparative effectiveness of rescue TDF monotherapy should be further clarified in cirrhotic patients since the findings were not consistent in the nationwide and hospital cohorts.
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Affiliation(s)
- Jayoun Lee
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Gi-Ae Kim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Hyo Jeong Kim
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Songhee Cho
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Min Jung Ko
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Young-Suk Lim
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea.,Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Lai Q, Mennini G, Giovanardi F, Rossi M, Giannini EG. Immunoglobulin, nucleos(t)ide analogues and hepatitis B virus recurrence after liver transplant: A meta-analysis. Eur J Clin Invest 2021; 51:e13575. [PMID: 33866547 PMCID: PMC8365701 DOI: 10.1111/eci.13575] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/04/2021] [Accepted: 04/13/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Prophylaxis with hepatitis B immunoglobulin (HBIG) represents an efficient strategy for reducing the risk of hepatitis B virus (HBV) recurrence after liver transplantation (LT). Unfortunately, the long-term use of HBIG presents high costs. Therefore, the use of prophylaxis based only on nucleos(t)ide analogues (NUC) has been recently postulated. The present meta-analysis aimed to evaluate the impact of HBIG ± NUC vs HBIG alone or NUC alone in post-LT HBV recurrence prophylaxis. MATERIALS AND METHODS A systematic literature search was performed using PubMed and Cochrane databases. The primary outcome investigated was the HBV recurrence after LT. Three analyses were done comparing the effect of (a) HBIG + NUC vs HBIG alone; (b) HBIG+NUC vs NUC alone; and (c) HBIG alone vs NUC alone. Sub-analyses were also performed investigating the effect of low and high genetic barrierto-recurrence NUC. RESULTS Fifty-one studies were included. The summary OR (95%CI) showed a decreased risk with the combination of HBIG + NUC vs HBIG alone for HBV recurrence, being 0.36 (95% CI = 0.22-0.61; P < .001). HBIG + NUC combined treatment reduced HBV reappearance respect to NUC alone (OR = 0.22; 95% CI = 0.16-0.30; P < .0001). Similarly, HBIG alone was significantly better than NUC alone in preventing HBV recurrence (OR = 0.20; 95% CI = 0.09-0.44; P < .0001). CONCLUSIONS Prophylaxis with HBIG is relevant in preventing post-LT HBV recurrence. Its combination with NUC gives the best results in terms of protection. The present results should be considered in light of the fact that also old studies based on lamivudine use were included. Studies exploring in detail high genetic barrier-to-recurrence NUC and protocols with definite use of HBIG are needed.
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Affiliation(s)
- Quirino Lai
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Gianluca Mennini
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Massimo Rossi
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Edoardo G. Giannini
- Gastroenterology UnitDepartment of Internal MedicineUniversity of GenoaIRCCS Ospedale Policlinico San MartinoGenoaItaly
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Wassner C, Bradley N, Lee Y. A Review and Clinical Understanding of Tenofovir: Tenofovir Disoproxil Fumarate versus Tenofovir Alafenamide. J Int Assoc Provid AIDS Care 2021; 19:2325958220919231. [PMID: 32295453 PMCID: PMC7163232 DOI: 10.1177/2325958220919231] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
HIV is a serious chronic medical condition. Significant improvements in antiretroviral
therapy have led to a transformation in its management. No curative treatment is available
for HIV, and lifelong therapy is required with a combination of agents to control viral
replication and prevent complications. Some of the older agents are notorious for many
side effects, making patient compliance difficult, which is critical to preventing HIV
resistance. Tenofovir is one of the newer, more tolerable, nucleotide reverse
transcriptase inhibitors on the market; is a mainstay of many antiretroviral therapy
combinations; and is now available in 2 different formulations, tenofovir disoproxil
fumarate (TDF) and, the more recent, tenofovir alafenamide (TAF). These 2 formulations
have very different pharmacokinetics, which seem to affect their efficacy and safety. This
manuscript provides insight into the history of TDF and TAF development, their unique
pharmacokinetics and pharmacology, clinically important adverse effects, monitoring,
interactions, resistance, review of clinical studies, and guideline recommendations and
clinical applications for tenofovir’s various indications.
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Affiliation(s)
- Chanie Wassner
- Department of Pharmacy, NYU Langone Hospital, Brooklyn, NY, USA
| | - Nicole Bradley
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Yuman Lee
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
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Analysis of long-term safety and efficacy of nucleos(t)ide analogue therapy for chronic hepatitis B throughout pregnancy. Int J Infect Dis 2021; 105:626-631. [PMID: 33722684 DOI: 10.1016/j.ijid.2021.03.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/06/2021] [Accepted: 03/09/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Limited data exist regarding the efficacy and long-term safety of nucleos(t)ide analogue therapy throughout pregnancy for women with chronic hepatitis B and their children. METHODS This retrospective cohort study included 165 women in total: 91 women received telbivudine (LDT) and 74 women received tenofovir (TDF) throughout pregnancy. The virological response and safety in women were recorded, and the physical development and bone mineral density in children were evaluated up to 5 years of age. RESULTS The rate of virological breakthrough in women was 4.24% overall (7.70% in LDT group and 0% in TDF group; P < 0.05). No cases of renal injury or other obstetric adverse events occurred in either group of women. Among the children, only one child had a significantly low Z score for weight for age (<-2), and no children had a significantly low Z score for height for age or bone mineral density. No significant difference was found between the children in the two groups. CONCLUSIONS Nucleos(t)ide analogue therapy with TDF or LDT throughout pregnancy had no effect on the long-term physical development and bone development of children. In addition, the use of TDF throughout pregnancy had better long-term antiviral efficacy than LDT in women, with no evidence of renal toxicity.
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Yang SS, Cai CW, Ma XQ, Xu J, Yu CB. Efficacy and cost-effectiveness of antiviral regimens for entecavir-resistant hepatitis B: A systematic review and network meta-analysis. Hepatobiliary Pancreat Dis Int 2020; 19:507-514. [PMID: 33051132 DOI: 10.1016/j.hbpd.2020.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic hepatitis B (CHB) patients who had exposed to lamivudine (LAM) and telbivudine (LdT) had high risk of developing entecavir (ETV)-resistance after long-term treatment. We aimed to conduct a systematic review and a network meta-analysis on the efficacy and cost-effectiveness on antiviral regimens in CHB patients with ETV-resistance. DATA SOURCES We searched PubMed, EMBASE and Web of Science for studies on nucleos(t)ide analogues (NAs) treatment [including tenofovir disoproxil fumarate (TDF)-based rescue therapies, adefovir (ADV)-based rescue therapies and double-dose ETV therapy] in CHB patients with ETV-resistance. The network meta-analysis was conducted for 1-year complete virological response (CVR) and biological response (BR) rates using GeMTC and ADDIS. A cost-effective analysis was conducted to select an economic and effective treatment regimen based on the 1-year CVR rate. RESULTS A total of 6 studies were finally included in this analysis. The antiviral efficacy was estimated. On network meta-analysis, the 1-year CVR rate in ETV-TDF [odds ratio (OR) = 22.30; 95 % confidence interval (CI): 2.78-241.93], LAM-TDF (OR = 70.67; 95 % CI: 5.16-1307.45) and TDF (OR = 16.90; 95 % CI: 2.28-186.30) groups were significantly higher than that in the ETV double-dose group; the 1-year CVR rate in the LAM-TDF group (OR = 14.82; 95 % CI: 1.03-220.31) was significantly higher than that in the LAM/LdT-ADV group. The 1-year BR rate of ETV-TDF (OR = 28.68; 95 % CI: 1.70-1505.08) and TDF (OR = 21.79; 95 % CI: 1.43-1070.09) therapies were significantly higher than that of ETV double-dose therapy. TDF-based therapies had the highest possibility to achieve the CVR and BR at 1 year, in which LAM-TDF combined therapy was the most effective regimen. The ratio of cost/effectiveness for 1-year treatment was 8 526, 17 649, 20 651 Yuan in the TDF group, TDF-ETV group, and ETV-ADV group, respectively. CONCLUSIONS TDF-based combined therapies such as ETV-TDF and LAM-TDF therapies were the first-line treatment if financial condition is allowed.
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Affiliation(s)
- Si-Si Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Cheng-Wei Cai
- Department of Neurosurgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xue-Qing Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jia Xu
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Cheng-Bo Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Huang BY, Tsai MR, Hsu JK, Lin CY, Lin CL, Hu JT, Huang YW, Liu CJ, Wu WJ, Wu CF, Sung FY, Chen PJ, Liang HJ, Lin SM, Yu MW. Longitudinal change of metabolite profile and its relation to multiple risk factors for the risk of developing hepatitis B-related hepatocellular carcinoma. Mol Carcinog 2020; 59:1269-1279. [PMID: 32914490 DOI: 10.1002/mc.23255] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/03/2020] [Accepted: 08/26/2020] [Indexed: 12/19/2022]
Abstract
Despite considerable knowledge of viral pathogenesis, the pathophysiological changes related to the multifactorial, multistep process of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) development remains unclear. Longitudinal metabolomics study can reveal biological process for disease progression. We performed metabolite profiling with longitudinal prediagnostic plasma samples from two nested case-control studies of hepatitis B surface antigen carriers participating in ultrasound screening for HCC, one within a government employee cohort (870 samples from 109 HCC cases and 107 controls) and the other within a hospital-based cohort (266 samples from 63 HCC cases and 114 controls). Of the 34 measured metabolites, tyrosine, isoleucine, and glutamine were consistently associated with HCC. In analyses combining longitudinal data, a high metabolic risk score based on the three amino acids was robustly associated with increased risk of HCC (OR = 3.71, 95% confidence interval: 2.53-5.42), even after adjustment for clinical factors, or when assessed for different times up to ≥8 years before diagnosis. Similar association was observed in an independent, prospective analysis comprising 633 randomly selected individuals of the government employee cohort. More importantly, this metabolite signature was longitudinally influenced by HBV-infection phase and involved in gradual progression to liver fibrosis and cirrhosis. Furthermore, mediation analysis showed that the score mediated substantial proportions of the associations of key viral factors, insulin resistance, and diabetes status with HCC risk. Our results suggest that an amino-acid dysregulation metabotype may play a role in HBV-related HCC development, and may also be linked to common pathways that mediate increased HCC risks.
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Affiliation(s)
- Bo-Yuan Huang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Min-Ru Tsai
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Jia-Kai Hsu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Ching-Yu Lin
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Jui-Ting Hu
- Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Yi-Wen Huang
- Department of Internal Medicine, Division of Gastroenterology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Internal Medicine, Division of Gastroenterology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, Division of Gastroenterology, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wan-Jung Wu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Feng Wu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Feng-Yu Sung
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, Division of Gastroenterology, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hao-Jan Liang
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Shi-Ming Lin
- Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, College of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Ming-Whei Yu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
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22
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Rodríguez M, Buti M, Esteban R, Lens S, Prieto M, Suárez E, García-Samaniego J. Consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B virus infection (2020). GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:559-587. [PMID: 32778356 DOI: 10.1016/j.gastrohep.2020.03.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) infection remains a global public health problem. HBV vaccination is the most effective tool to reduce the incidence of HBV disease. Despite there has not been new clinical developments for the treatment of chronic hepatitis B in the last few years, changing epidemiology and current insights on natural history, diagnostic tools and therapy indications make necessary an update of the former version of the consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B infection published in 2012. The current document updates the management of chronic hepatitis B. The treatment of choice is the long-term administration of a nucleos(t)ide analogue with high barrier to resistance (entecavir, tenofovir or tenofovir alafenamide). Pegylated interferon may be an option in patients with non-advanced liver disease, but its applicability is limited due to the low efficacy and poor tolerability. All patients must be monitored for the risk of progression to advanced liver disease and development of hepatocellular carcinoma.
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Affiliation(s)
- Manuel Rodríguez
- Sección de Hepatología, Servicio de Digestivo, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España.
| | - María Buti
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Rafael Esteban
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Sabela Lens
- Servicio de Hepatología, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Universidad de Barcelona, Barcelona, España
| | - Martín Prieto
- Sección de Hepatología, Servicio de Medicina Digestiva, Hospital Universitari ì Politècnic La Fe, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Valencia, España
| | - Emilio Suárez
- Unidad de Enfermedades Digestivas, Hospital Universitario Virgen de Valme, Sevilla, España
| | - Javier García-Samaniego
- Unidad de Hepatología, Hospital Universitario La Paz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, España.
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Lampertico P, Berg T, Buti M, Pathil A, Petersen J, Ryder SD, Zoulim F, Botros I, Flaherty JF, Jump B, Op den Brouw ML, van Troostenburg A, Ramroth H. Treatment with tenofovir disoproxil fumarate or entecavir in chronic hepatitis B virus-infected patients with renal impairment: results from a 7-year, multicentre retrospective cohort study. Aliment Pharmacol Ther 2020; 52:500-512. [PMID: 32583915 PMCID: PMC7383725 DOI: 10.1111/apt.15901] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/02/2020] [Accepted: 05/30/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Limited data exist regarding tenofovir disoproxil fumarate (TDF) safety and effectiveness in chronic hepatitis B virus-infected (CHB) patients with renal impairment (RI). AIMS To compare real-world data on renal safety and effectiveness of TDF vs entecavir (ETV) in CHB patients with moderate-to-severe RI. METHODS Retrospective, non-interventional, cohort study analysing medical records for TDF/ETV-treated CHB patients (54 European centres). Included patients experienced moderate-to-severe RI (creatinine clearance 20-60 mL/min [Cockcroft-Gault]) either before TDF/ETV initiation ('before' subgroup [baseline = treatment initiation]) or after TDF/ETV initiation ('after' subgroup [baseline = first RI occurrence]). The primary objective was TDF safety, particularly renal-related adverse events of special interest (AESI). TDF and ETV safety and effectiveness were compared and multivariate analyses were performed using inverse probability treatment weighting. RESULTS 'Before' subgroup included 107 TDF- and 91 ETV-treated patients; 'after' subgroup included 212 TDF- and 77 ETV-treated patients. Mean baseline creatinine clearance was higher for TDF- vs ETV-treated patients (both subgroups). Median follow-up was 3.1 years (both treatments). AESI were more frequent with TDF vs ETV ('before': 18.7% vs 8.8%; 'after': 9.9% vs 3.9%); however, differences were not significant by multivariate analysis. Only TDF-treated patients experienced renal tubular dysfunction (6.5% 'before'; 1.9% 'after') as well as renal adverse events leading to treatment discontinuation (8.4% 'before'; 7.1% 'after'). Effectiveness was similar between treatments. CONCLUSIONS Overall safety was similar for TDF vs ETV (both subgroups). Given that renal tubular dysfunction occurred with TDF and not with ETV, renal safety concerns may be greater with TDF in CHB patients with RI.
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Wen WH, Chen HL, Shih TTF, Wu JF, Ni YH, Lee CN, Zhao LL, Lai MW, Mu SC, Tung YC, Hsu HY, Chang MH. Long-term growth and bone development in children of HBV-infected mothers with and without fetal exposure to tenofovir disoproxil fumarate. J Hepatol 2020; 72:1082-1087. [PMID: 32044401 DOI: 10.1016/j.jhep.2020.01.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 12/08/2019] [Accepted: 01/09/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent maternal transmission of HBV, owing to its efficacy and safety. However, data are lacking on the long-term safety outcomes in children following fetal exposure to TDF. METHODS Children participating in a prospective, multisite trial of maternal TDF treatment during late pregnancy were recruited for follow-up visits once a year. Growth parameters, serum biochemistry, HBV serology, and bone mineral density (BMD) by dual-energy x-ray absorptiometery scan were measured. RESULTS One hundred and twenty-eight children, 71 in the TDF and 57 in the control group, completed 255 follow-up visits at the age of 2 to 7 (median, 4.08) years. No differences in z-scores for weight-for-age (0.26 ± 0.90 vs. 0.22 ± 0.99, p = 0.481), z-scores for height-for-age (0.20 ± 1.02 vs. 0.25 ± 0.98, p = 0.812), and estimated glomerular filtration rate (169.12 ± 50.48 vs. 169.06 ± 34.46 ml/min/1.73m2, p = 0.479) were detected. After adjustment for age, sex and HBV status by multiple linear regression, children in the TDF and control group had comparable levels of serum calcium, phosphorus, bone-specific alkaline phosphatase, calcidiol and BMD of lumbar spines (0.55 ± 0.01 vs. 0.57 ± 0.01 g/cm2, p = 0.159) and left hip (0.56 ± 0.01 vs. 0.56 ± 0.01 g/cm2, p = 0.926). CONCLUSIONS Children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6-7 years after delivery. CLINICAL TRIAL NUMBER NCT01312012 (ClinicalTrials.gov) LAY SUMMARY: Currently there are insufficient long-term safety data in children born to mothers who took antiviral agents during pregnancy to prevent mother-to-infant transmission of hepatitis B virus (HBV). In this study, we found that children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6-7 years after delivery.
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Affiliation(s)
- Wan-Hsin Wen
- Department of Pediatrics, Cardinal Tien Hospital, New Taipei City, Taiwan; School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Department and Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tiffany Ting-Fang Shih
- Department of Radiology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Chien-Nan Lee
- Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Lu-Lu Zhao
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Ming-Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics; Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Shu-Chi Mu
- Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Yi-Ching Tung
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Department and Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.
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25
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Hajiani E, Parsi A, Seyedian SS, Rajaei E, Jolodarian P. Comparing the frequency of osteoporosis and osteopenia in chronic hepatitis B patients with and without Tenofovir treatment. CLINICAL EPIDEMIOLOGY AND GLOBAL HEALTH 2020. [DOI: 10.1016/j.cegh.2019.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Adverse events of nucleos(t)ide analogues for chronic hepatitis B: a systematic review. J Gastroenterol 2020; 55:496-514. [PMID: 32185517 PMCID: PMC7188775 DOI: 10.1007/s00535-020-01680-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 02/26/2020] [Indexed: 02/04/2023]
Abstract
Nucleos(t)ide analogues (NAs) are the main drug category used in chronic hepatitis B (CHB) treatment. Despite the fact that NAs have a favourable safety profile, undesired adverse events (AEs) may occur during the treatment of CHB. Given the eminent number of patients currently receiving NAs, even a small risk of any of these toxicities can represent a major medical issue. The main objective of this review was to analyse information available on AEs associated with the use of NAs in published studies. We choose the following MesH terms for this systematic review: chronic hepatitis B, side effects and treatment. All articles published from 1 January 1990 up to 19 February 2018 in MEDLINE of PubMed, EMBASE, the Cochrane Library and LILACS databases were searched. A total of 120 articles were selected for analysis, comprising 6419 patients treated with lamivudine (LAM), 5947 with entecavir (ETV), 3566 with tenofovir disoproxil fumarate (TDF), 3096 with telbivudine (LdT), 1178 with adefovir dipivoxil (ADV) and 876 with tenofovir alafenamide (TAF). The most common AEs in all NAs assessed were abdominal pain/discomfort, nasopharyngitis/upper respiratory tract infections, fatigue, and headache. TAF displays the highest density of AEs per patient treated among NAs (1.14 AE/treated patient). In conclusion, treatment of CHB with NAs is safe, with a low incidence of AEs. Despite the general understanding TAF being safer than TDF, the number of patients treated with TAF still is too small in comparison to other NAs to consolidate an accurate safety profile. PROSPERO Registration No. CRD42018086471.
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Marcellin P, Wong DK, Sievert W, Buggisch P, Petersen J, Flisiak R, Manns M, Kaita K, Krastev Z, Lee SS, Cathcart AL, Crans G, Op den Brouw M, Jump B, Gaggar A, Flaherty J, Buti M. Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int 2019; 39:1868-1875. [PMID: 31136052 DOI: 10.1111/liv.14155] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 05/08/2019] [Accepted: 05/09/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) is a first-line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well-described cohort of CHB patients. METHODS Hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients from two randomised, double-blind trials (ClinicalTrials.gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open-label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety and tolerability. RESULTS Of 641 randomised and treated patients, 585 (91%) entered the open-label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg-negative patients and 78/80 (98%) of HBeAg-positive patients with available data achieved hepatitis B virus (HBV) DNA < 69 IU/mL, while 88/106 (83%) and 60/77 (78%) patients achieved ALT normalisation, respectively. Of the 23 patients with HBeAg status available at Year 10, 12 (52%) and six (27%) experienced HBeAg loss and seroconversion, respectively. No resistance to TDF was documented up to Year 10. In the period between Year 8 and Year 10, the safety profile of TDF was similar to previous reports, with few patients experiencing renal- or bone-related adverse events. CONCLUSIONS Over 10 years, TDF had a favourable safety profile, was well tolerated, and resulted in continued maintenance of virological suppression with no documented resistance.
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Affiliation(s)
| | - David K Wong
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - William Sievert
- Gastroenterology and Hepatology Unit, Monash Health and Monash University, Melbourne, Australia
| | - Peter Buggisch
- Liver Unit, IFI-Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany
| | - Jörg Petersen
- Liver Unit, IFI-Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University Bialystok, Bialystok, Poland
| | - Michael Manns
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.,Helmholtz Center for Infection Research (HZI), Hannover, Germany
| | - Kelly Kaita
- Viral Hepatitis Investigative Unit, University of Manitoba, Winnipeg, Canada
| | - Zahari Krastev
- Clinic of Gastroenterology, St Ivan Rilsky University Hospital, Medical University, Sofia, Bulgaria
| | - Samuel S Lee
- Liver Unit, University of Calgary, Calgary, Alberta, Canada
| | | | | | | | | | - Anuj Gaggar
- Gilead Sciences Inc, Foster City, California
| | | | - Maria Buti
- Liver Unit, Hospital Universitario Vall d'Hebron and CIBEREHD del Instituto Carlos III, Barcelona, Spain
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Tafesh ZH, Brown RS. Management of Virologic Failure in Patients with Chronic Hepatitis B Treated with Nucleos(t)ide Analogues. CURRENT HEPATOLOGY REPORTS 2019; 18:363-369. [DOI: 10.1007/s11901-019-00483-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Vittal A, Ghany MG. WHO Guidelines for Prevention, Care and Treatment of Individuals Infected with HBV: A US Perspective. Clin Liver Dis 2019; 23:417-432. [PMID: 31266617 PMCID: PMC9616205 DOI: 10.1016/j.cld.2019.04.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The prevalence of chronic hepatitis B (CHB) differs globally. CHB is responsible for 30% of all deaths from cirrhosis and 40% from hepatocellular carcinoma. The WHO developed guidelines in 2015 on prevention, care, and treatment of chronic HBV infection targeted to program managers in all health care settings, particularly in low- and middle-income countries. Several of the recommendations differ from those of the major Liver Societies, including the American Association for the Study of Liver Diseases (AASLD). This review highlights key differences between the AASLD and WHO guidelines and discusses the impact on management of CHB.
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Lim YS, Gwak GY, Choi J, Lee YS, Byun KS, Kim YJ, Yoo BC, Kwon SY, Lee HC. Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial. J Hepatol 2019; 71:35-44. [PMID: 30876946 DOI: 10.1016/j.jhep.2019.02.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 02/06/2019] [Accepted: 02/22/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or adefovir (ADV). Nonetheless, the virologic response rate was suboptimal in patients receiving up to 144 weeks of TDF monotherapy. We aimed to assess the efficacy and safety of TDF monotherapy given for up to 240 weeks. METHODS One trial enrolled patients with ETV resistance without ADV resistance (n = 90), and another trial included patients with ADV resistance (n = 102). Most patients (91.2%) also had lamivudine resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then TDF monotherapy until week 240. We compared efficacy between the studies and safety in the pooled population at 240 weeks. RESULTS At week 240, the proportion of patients with serum HBV DNA <15 IU/ml was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; p = 0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; p = 0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBV e antigen (HBeAg)-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBV surface antigen seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (-3.21 ml/min/1.73 m2 by the CKD-EPI equation, p <0.001) and bone mineral density (g/cm2) at the femur (-2.48%, p <0.001). CONCLUSIONS Up to 240 weeks of TDF monotherapy provided an increasing virologic response rate in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density. (ClinicalTrials.gov No, NCT01639066 and NCT01639092). LAY SUMMARY In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy of TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but it was associated with poor serological responses and decreasing renal function and bone mineral density.
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Affiliation(s)
- Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Byung Chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Chan HLY. Okuda lecture: Challenges of hepatitis B in the era of antiviral therapy. J Gastroenterol Hepatol 2019; 34:501-506. [PMID: 30402981 DOI: 10.1111/jgh.14534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/25/2018] [Accepted: 10/30/2018] [Indexed: 12/13/2022]
Abstract
Nucleos(t)ide analogs (NAs) are effective, safe, and convenient antiviral therapy to suppress replication of hepatitis B virus, which can be translated into improved long-term outcome of chronic hepatitis B patients. The current recommended first-line NAs, namely, entecavir and tenofovir, are largely free from problems of drug resistance. Nonetheless, there are still a few challenges in the era of NA. First, the risk of hepatocellular carcinoma can only be reduced but not eliminated, particularly among cirrhotic patients. For cirrhotic patients who have persistent low-level viremia on NA, that is, partial responders, the risk of hepatocellular carcinoma is higher than those with complete viral suppression. The best strategy to manage partial responders to entecavir or tenofovir is uncertain. Second, immune-tolerant patients are very difficult to treat with NA. A significant proportion of immune-tolerant patients will have detectable viremia despite a few years of continuous NA treatment, and the rate of hepatitis B e-antigen seroconversion is very low. Third, most patients need long-term treatment as NA cannot eliminate covalently closed circular DNA in the hepatocytes. Some patients can consider stop NA according to treatment guidelines, but viral and clinical relapses often occur after treatment cessation. There is no concrete consensus on when one should stop NA in a hepatitis B e-antigen-negative patient among different treatment guidelines. New biomarkers such as hepatitis B surface antigen level can be used to select patients to stop NA, but the data are still preliminary.
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Affiliation(s)
- Henry Lik Yuen Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
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Suk‐Fong Lok A. Hepatitis B Treatment: What We Know Now and What Remains to Be Researched. Hepatol Commun 2019; 3:8-19. [PMID: 30619990 PMCID: PMC6312657 DOI: 10.1002/hep4.1281] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 10/24/2018] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, two types of treatment, interferons (IFNs) and nucleos(t)ide analogues (NAs), have been approved. These treatments are effective in suppressing HBV replication and in decreasing the risk of developing cirrhosis, liver failure, hepatocellular carcinoma (HCC), and death. However, these treatments do not eliminate the virus, and the risk of HCC remains. This review article summarizes current knowledge about the safety, efficacy, and clinical indications of hepatitis B treatment. It also discusses limitations of existing treatment, gaps in knowledge, and feasibility of a hepatitis B cure.
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Affiliation(s)
- Anna Suk‐Fong Lok
- Division of Gastroenterology and HepatologyUniversity of MichiganAnn ArborMI
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No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection. Antimicrob Agents Chemother 2018; 62:AAC.01064-18. [PMID: 30038044 DOI: 10.1128/aac.01064-18] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 06/14/2018] [Indexed: 12/19/2022] Open
Abstract
Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In two clinical trials, 1,298 hepatitis E antigen-positive and -negative patients with CHB were randomized 2:1 and treated with TAF (n = 866) or TDF (n = 432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (Pol/RT) were assessed using INNO-LiPA Multi-DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥ 69IU/ml) by HBV Pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to the study drug. At baseline, the majority of patients harbored virus with wild-type Pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF, 11.1%; TDF, 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF, 2.8%; TDF, 3.2%) that was often associated with drug nonadherence (TAF, 30%; TDF, 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96, with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA < 69 IU/ml) was similar across treatment groups, and no substitutions associated with resistance to TAF or TDF were detected. (These studies have been registered at ClinicalTrials.gov under identifiers NCT01940471 and NCT01940341.).
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Seto WK, Asahina Y, Brown TT, Peng CY, Stanciu C, Abdurakhmanov D, Tabak F, Nguyen TT, Chuang WL, Inokuma T, Ikeda F, Santantonio TA, Habersetzer F, Ramji A, Lau AH, Suri V, Flaherty JF, Wang H, Gaggar A, Subramanian GM, Mukewar S, Brunetto MR, Fung S, Chan HLY. Improved Bone Safety of Tenofovir Alafenamide Compared to Tenofovir Disoproxil Fumarate Over 2 Years in Patients With Chronic HBV Infection. Clin Gastroenterol Hepatol 2018:S1542-3565(18)30633-5. [PMID: 29933096 DOI: 10.1016/j.cgh.2018.06.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 04/25/2018] [Accepted: 06/09/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Long-term use of tenofovir disoproxil fumarate (TDF) reduces bone mineral density (BMD). Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has shown non-inferior efficacy to TDF in patients with chronic hepatitis B virus (HBV) infection, with improved bone effects at 48 weeks. We performed a randomized trial to evaluate the bone safety of TAF compared with TDF over 2 years, assessing baseline risk factors for bone loss, were evaluated after 2 years of treatment. METHODS In a double-blind study, hepatitis B e antigen (HBeAg)-positive patients (n = 873) and HBeAg-negative patients (n = 425) were randomly assigned (2:1) to groups given TAF (25 mg; n = 866) or TDF (300 mg; n = 432) once daily. We assessed bone safety, including hip and spine BMD, using dual-energy X-ray absorptiometry and measured changes in serum markers of bone turnover over 96 weeks. RESULTS At baseline, treatment groups were well matched. At week 96, patients receiving TAF had significantly smaller decreases in hip BMD (mean reduction of 0.33%) than patients receiving TDF (mean reduction of 2.51%) (P < .001) and spine BMD (reduction of 0.75% in patients receiving patients receiving TAF vs reduction of 2.57% in patients receiving TDF) (P < .001). For hip BMD, the magnitude of difference in bone loss between the TAF and TDF groups increased at week 96 compared to week 48 (P < .001). The TAF group had minimal changes in markers of bone turnover by 12 weeks of treatment, but the TDF group had significant changes, compared to baseline. Risk factors for bone loss had fewer effects in patients receiving TAF than TDF at week 96. CONCLUSIONS In double-blind randomized trials, we found that after 2 years of treatment, patients receiving TAF had continued improvements in bone safety compared with patients receiving TDF. Clinicaltrial.gov ID NCT01940471 and NCT01940341.
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Affiliation(s)
- Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong.
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology and Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Todd T Brown
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Carol Stanciu
- Institute of Gastroenterology and Hepatology, University of Medicine and Pharmacy "Grigore T. Popa," Iasi, Romania
| | | | - Fehmi Tabak
- Deparment of Infectious Diseases, Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey
| | | | - Wan-Long Chuang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tetsuro Inokuma
- Department of Gastroenterology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Fusao Ikeda
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Teresa Antonia Santantonio
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Foggia, Fogia, Italy
| | - François Habersetzer
- Pôle Hépato-digestif, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Institut Hospitalo-Universitaire, Inserm U 1110, Institut sur les Maladies Virales et Hépatiques, Université de Strasbourg, Strasbourg, France
| | - Alnoor Ramji
- Gastrointestinal Research Institute, Vancouver, British Columbia, Canada
| | | | | | | | | | | | | | | | - Maurizia R Brunetto
- Clinical and Experimental Medicine Department, University of Pisa, Pisa, Italy
| | - Scott Fung
- Toronto General Hospital, Toronto, Ontario, Canada
| | - Henry Lik-Yuen Chan
- Department of Medicine & Therapeutics, Prince of Wales Hospital, Hong Kong, Hong Kong
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Abstract
IMPORTANCE More than 240 million individuals worldwide are infected with chronic hepatitis B virus (HBV). Among individuals with chronic HBV infection who are untreated, 15% to 40% progress to cirrhosis, which may lead to liver failure and liver cancer. OBSERVATIONS Pegylated interferon and nucleos(t)ide analogues (lamivudine, adefovir, entecavir, tenofovir disoproxil, and tenofovir alafenamide) suppress HBV DNA replication and improve liver inflammation and fibrosis. Long-term viral suppression is associated with regression of liver fibrosis and reduced risk of hepatocellular carcinoma in cohort studies. The cure (defined as hepatitis B surface antigen loss with undetectable HBV DNA) rates after treatment remain low (3%-7% with pegylated interferon and 1%-12% with nucleos[t]ide analogue therapy). Pegylated interferon therapy can be completed in 48 weeks and is not associated with the development of resistance; however, its use is limited by poor tolerability and adverse effects such as bone marrow suppression and exacerbation of existing neuropsychiatric symptoms such as depression. Newer agents (entecavir, tenofovir disoproxil, and tenofovir alafenamide) may be associated with a significantly reduced risk of drug resistance compared with older agents (lamivudine and adefovir) and should be considered as the first-line treatment. CONCLUSIONS AND RELEVANCE Antiviral treatment with either pegylated interferon or a nucleos(t)ide analogue (lamivudine, adefovir, entecavir, tenofovir disoproxil, or tenofovir alafenamide) should be offered to patients with chronic HBV infection and liver inflammation in an effort to reduce progression of liver disease. Nucleos(t)ide analogues should be considered as first-line therapy. Because cure rates are low, most patients will require therapy indefinitely.
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Affiliation(s)
- Lydia S Y Tang
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore
| | - Emily Covert
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore
| | - Eleanor Wilson
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore
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Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018; 67:1560-1599. [PMID: 29405329 PMCID: PMC5975958 DOI: 10.1002/hep.29800] [Citation(s) in RCA: 2780] [Impact Index Per Article: 397.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 01/11/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Norah A Terrault
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, CA
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Brian J McMahon
- Liver Diseases and Hepatitis Program, Alaska NativeTribal Health Consortium, Anchorage, AK
| | - Kyong-Mi Chang
- Division of Gastroenterology, Corporal Michael J. Crescenz VA Medical Center & University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Jessica P Hwang
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Maureen M Jonas
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | | | - John B Wong
- Division of Clinical Decision Making, Tufts Medical Center, Tufts University School of Medicine, Boston, MA
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Bielen R, Robaeys G, Schelfhout S, Monbaliu D, Van der Merwe S, Pirenne J, Nevens F. Personalized subcutaneous administration of hepatitis B surface antibodies without nucleos(t)ide analogs for patients at risk of renal failure after liver transplantation: a prospective single center cohort study. Transpl Int 2018; 31:503-509. [PMID: 29359868 DOI: 10.1111/tri.13112] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/02/2017] [Accepted: 01/08/2018] [Indexed: 12/29/2022]
Abstract
Currently, nucleos(t)ide analogs (NAs) in monotherapy are favored as prophylaxis against hepatitis B recurrence after liver transplantation. However, in patients at risk of renal failure, renal safety of NAs is of concern. We investigated the safety and efficacy of subcutaneous (SC) hepatitis B immunoglobulins (HBIG) in monotherapy. This is a single-arm prospective trial in patients transplanted >1 year. We included 43 Caucasian patients. The majority was treated with calcineurin inhibitors, and several patients had other risk factors for renal impairment as well: diabetes mellitus (n = 10/43), arterial hypertension (n = 11/43), and hyperlipidemia (=10/43). At inclusion, 42% (n = 18) had chronic kidney disease ≥ grade 3a. All patients were switched from IV HBIG with or without NAs to SC HBIG without NAs. After one year, the targeted titer was lowered to ≥150 IU/l in patients with low risk of recurrence. Mean follow-up time was 36 ± 5 months. None of the patients had a relapse of HBsAg or HBV DNA. The treatment was well tolerated, safe and the renal function remained unchanged both in patients with (n = 18) or without (n = 25) renal impairment at baseline. The mean HBsAb titer could be decreased from 343 ± 163 to 199 ± 81 IU/l in the low-risk group (n = 17) and 218 ± 71 IU/l in the high-risk group (n = 26). In 86% (n = 37) doses, reductions were possible, which significantly lowered the cost of treatment. SC HBIG without NAs had a 100% success rate in the long-term prevention of HBsAg and HBV DNA reappearance, without deterioration of renal function.
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Affiliation(s)
- Rob Bielen
- Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.,Department of Gastroenterology and Hepatology, Ziekenhuis Oost Limburg, Genk, Belgium
| | - Geert Robaeys
- Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.,Department of Gastroenterology and Hepatology, Ziekenhuis Oost Limburg, Genk, Belgium.,Department of Gastroenterology & Hepatology, University Hospitals KULeuven, Leuven, Belgium
| | - Sigrid Schelfhout
- Department of Gastroenterology & Hepatology, University Hospitals KULeuven, Leuven, Belgium
| | - Diethard Monbaliu
- Department of Abdominal Transplant Surgery, University Hospitals KULeuven, Leuven, Belgium
| | - Schalk Van der Merwe
- Department of Gastroenterology & Hepatology, University Hospitals KULeuven, Leuven, Belgium
| | - Jacques Pirenne
- Department of Abdominal Transplant Surgery, University Hospitals KULeuven, Leuven, Belgium
| | - Frederik Nevens
- Department of Gastroenterology & Hepatology, University Hospitals KULeuven, Leuven, Belgium
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Rodríguez M, Pascasio JM, Fraga E, Fuentes J, Prieto M, Sánchez-Antolín G, Calleja JL, Molina E, García-Buey ML, Blanco MÁ, Salmerón J, Bonet ML, Pons JA, González JM, Casado MÁ, Jorquera F. Tenofovir vs lamivudine plus adefovir in chronic hepatitis B: TENOSIMP-B study. World J Gastroenterol 2017; 23:7459-7469. [PMID: 29151700 PMCID: PMC5685852 DOI: 10.3748/wjg.v23.i41.7459] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 05/22/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM.
METHODS This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed.
RESULTS Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA (HBV-DNA) remained undetectable, all patients remained HBeAg negative, and hepatitis B surface antigen (HBsAg) positive. Alanine aminotransferase (ALT) values at the end of the study were similar in the 2 groups (25.1 ± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects (AEs) (53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively (P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment (€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001).
CONCLUSION TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.
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Affiliation(s)
- Manuel Rodríguez
- Division of Gastroenterology and Hepatology. Hospital Universitario Central de Asturias, Oviedo 33011, Spain
| | - Juan Manuel Pascasio
- Unit for the Clinical Management of Digestive Diseases, IBIS, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain and CIBERehd
| | - Enrique Fraga
- Liver Transplantation and Hepatology Unit, Gastroenterology Service, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
| | - Javier Fuentes
- Digestive Medicine Service, Hospital Universitario Miguel Servet, Zaragoza 50009, Spain
| | - Martín Prieto
- Hepatology Unit, Digestive Medicine Service, Hospital Universitari i Politècnic La Fe, Valencia 46026, Spain and CIBERehd
| | | | - José Luis Calleja
- Liver Unit, Hospital Universitario Puerta de Hierro de Majadahonda, Universidad Autónoma de Madrid, Madrid 28049, Spain
| | - Esther Molina
- Digestive Medicine Service, Hospital Clínico de Santiago de Compostela, La Coruña 15706, Spain
| | | | - María Ángeles Blanco
- Digestive Medicine Service, Hospital General Universitario Gregorio Marañón, Madrid 28007, España
| | - Javier Salmerón
- Digestive Medicine Unit, Complejo Hospitalario de Granada, Granada 18014, Spain
| | - María Lucía Bonet
- Digestive Medicine Service, Hospital Universitario Son Espases, Palma de Mallorca 07120, Spain
| | - José Antonio Pons
- Hepatology Unit, IMIB Hospital Universitario Virgen de la Arrixaca, Murcia 30120, Spain
| | - José Manuel González
- Digestive Medicine Service, Hospital Clínico Universitario de Valladolid, Valladolid 47003, Spain
| | | | - Francisco Jorquera
- Division of Gastroenterology and Hepatology, Complejo Asistencial Universitario de León, León 24001, Spain CIBERehd and IBIOMED León
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Lim YS, Lee YS, Gwak GY, Byun KS, Kim YJ, Choi J, An J, Lee HC, Yoo BC, Kwon SY. Monotherapy with tenofovir disoproxil fumarate for multiple drug-resistant chronic hepatitis B: 3-year trial. Hepatology 2017; 66:772-783. [PMID: 28370419 DOI: 10.1002/hep.29187] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Revised: 03/05/2017] [Accepted: 03/23/2017] [Indexed: 12/15/2022]
Abstract
UNLABELLED Combination therapy has been recommended for the treatment of patients harboring multiple drug-resistant hepatitis B virus (HBV). However, we recently demonstrated that monotherapy with tenofovir disoproxil fumarate (TDF) for 48 weeks displayed noninferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with HBV resistant to multiple drugs, including ETV and adefovir. Nonetheless, whether prolonged TDF monotherapy would be safe and increase the virologic response rate in these patients was unclear. Among 192 patients with HBV-resistance mutations to ETV and/or adefovir, who were randomized to receive TDF monotherapy (n = 95) or TDF/ETV combination therapy (n = 97) for 48 weeks, 189 agreed to continue TDF monotherapy (TDF-TDF group) or to switch to TDF monotherapy (TDF/ETV-TDF group) and 180 (93.8%) completed the 144-week study. Serum HBV DNA <15 IU/mL at week 48, the primary efficacy endpoint, was achieved in 66.3% in the TDF-TDF group and 68.0% in the TDF/ETV-TDF group (P = 0.80). At week 144, the proportion with HBV DNA <15 IU/mL increased to 74.5%, which was significantly higher compared with that at week 48 (P = 0.03), without a significant difference between groups (P = 0.46). By on-treatment analysis, a total of 79.4% had HBV DNA <15 IU/mL at week 144. Transient virologic breakthrough occurred in 6 patients, which was due to poor drug adherence. At week 144, 19 patients who had HBV DNA levels >60 IU/mL qualified for genotypic resistance analysis, and 6 retained some of their baseline resistance mutations of HBV. No patients developed additional resistance mutations throughout the study period. CONCLUSION TDF monotherapy was efficacious and safe for up to 144 weeks, providing an increasing rate of virologic response in heavily pretreated patients with multidrug-resistant HBV. (Hepatology 2017;66:772-783).
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Affiliation(s)
- Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jihyun An
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Byung Chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
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Lampertico P, Agarwal K, Berg T, Buti M, Janssen HL, Papatheodoridis G, Zoulim F, Tacke F. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017; 67:370-398. [PMID: 28427875 DOI: 10.1016/j.jhep.2017.03.021] [Citation(s) in RCA: 3724] [Impact Index Per Article: 465.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 03/23/2017] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2,000IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother to child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa treatment can also be considered in mild to moderate chronic hepatitis B patients. Combination therapies are not generally recommended. All patients should be monitored for risk of disease progression and HCC. Treated patients should be monitored for therapy response and adherence. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.
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Grossi G, Viganò M, Loglio A, Lampertico P. Hepatitis B virus long-term impact of antiviral therapy nucleot(s)ide analogues (NUCs). Liver Int 2017; 37 Suppl 1:45-51. [PMID: 28052621 DOI: 10.1111/liv.13291] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 10/25/2016] [Indexed: 02/13/2023]
Abstract
The goal of antiviral therapy is to improve the quality of life and survival of patients with chronic hepatitis B (CHB) by halting the progression to cirrhosis, end-stage liver disease or hepatocellular carcinoma (HCC), thus preventing anticipated liver-related death. Oral administration of potent and less resistance-prone nucleot(s)ide analogues (NUCs), such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF) has become the most popular treatment strategy worldwide because of their excellent efficacy and safety profile as well as easy management confirmed in both registration trials and in clinical practice studies. Long-term administration of ETV or TDF suppresses HBV replication in >95% of patients, resulting in biochemical remission, histological improvement including the regression of cirrhosis and prevention or reversal of clinical decompensation but not the development of HCC, particularly in patients with cirrhosis. Moreover, NUCs can be administered to all patients including those with severe liver disease, the elderly and in those who do not respond, are unwilling to take or have contraindications to interferon. The need for long-term, perhaps indefinite, treatment is the main limitation of NUCs therapy with the associated costs, unknown long-term safety and the low rates of hepatitis B surface antigen (HBsAg) seroclearance, which is still the best stopping rule for NUCs-treated patients with cirrhosis.
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Affiliation(s)
- Glenda Grossi
- "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Mauro Viganò
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - Alessandro Loglio
- "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Pietro Lampertico
- "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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Song BC. Switch to tenofovir-based therapy or to continue adefovir-based therapy in CHB patients with suboptimal response to adefovir-based combination? Clin Mol Hepatol 2016; 22:439-442. [PMID: 28081595 PMCID: PMC5266348 DOI: 10.3350/cmh.2016.0108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 12/01/2016] [Indexed: 11/16/2022] Open
Affiliation(s)
- Byung-Cheol Song
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
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