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Wu JW, Chen WT, Huang CG, Chen YC, Hsu CW, Chien RN, Chang ML. Rheumatoid factor levels indicate cryoglobulinemia severity in hepatitis B e antigen-negative hepatitis B virus carriers: a 7-year prospective cohort study. Hepatol Int 2025; 19:118-130. [PMID: 39699792 DOI: 10.1007/s12072-024-10761-8] [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: 09/11/2024] [Accepted: 11/23/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND The phenotype of cryoglobulinemia in hepatitis B virus (HBV) carriers remains elusive. METHODS A 7-year prospective cohort of 648 hepatitis B e antigen (HBeAg)-negative Taiwanese HBV carriers [males: 344 (53%)] was conducted. RESULTS Among 648, 189 (29.2%) had cryoglobulinemia, and 26 (4.0%) had cryoglobulinemic syndrome (CS). More females; higher levels of rheumatoid factor (RF), immunoglobulin M (IgM) and fibrosis-4 indices; higher proportions of proteinuria, hematuria and hepatocellular carcinoma; and lower levels of quantitative HBsAg, C3, C4 and eGFR were noted in patients with than in those without cryoglobulinemia. The associations were RF levels with cryoglobulinemia (cutoff > 12.55 IU/mL), and RF levels and baseline autoimmune diseases with CS. CS patients, symptomless cryoglobulinemia patients and patients without cryoglobulinemia had the highest, moderate, and lowest RF levels, respectively. A greater percentage of mixed cryoglobulins [IgG (2 +), IgM (2 +) and IgA (1 +)] was noted in cryoglobulinemia patients with than in those without CS (11.5% vs. 0.81%, p = 0.002). Among the 7 CS patients treated with nucleos(t)ide analogues (Nucs), cryoglobulinemia disappeared in 3 and symptoms improved in 5 during therapy. The CS prevalence was highest (6%) in patients with a baseline age of 31-40 years. Among the 26 CS patients, 23 (88.5%), 20 (76.9%), and 16 (61.5%) had peripheral neuropathy, articular and skin involvement, respectively. The cumulative incidences of major outcomes and mortality did not differ between patients with and without cryoglobulinemia. CONCLUSIONS The prevalence rates of cryoglobulinemia and CS in HBeAg-negative HBV carriers were 29.2% and 4.0%, respectively. RF levels correlate with cryoglobulinemia severity. Mixed cryoglobulins of IgG (2 +), IgM (2 +) and IgA (1 +) are likely linked to CS, which might be alleviated by Nucs in some patients. The impact of cryoglobulinemia on long-term outcomes might be negligible.
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Affiliation(s)
- Jen-Wei Wu
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Guei Huang
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Chang Chen
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chao-Wei Hsu
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan.
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Dumolard L, Hilleret MN, Costentin C, Mercey-Ressejac M, Sturm N, Gerster T, Decaens T, Jouvin-Marche E, Marche PN, Macek Jilkova Z. Differences in the intrahepatic expression of immune checkpoint molecules on T cells and natural killer cells in chronic HBV patients. Front Immunol 2025; 15:1489770. [PMID: 39882238 PMCID: PMC11774737 DOI: 10.3389/fimmu.2024.1489770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Background Patients with chronic hepatitis B virus (HBV) infection are characterized by impaired immune response that fails to eliminate HBV. Immune checkpoint molecules (ICMs) control the amplitude of the activation and function of immune cells, which makes them the key regulators of immune response. Methods We performed a multiparametric flow cytometry analysis of ICMs and determined their expression on intrahepatic lymphocyte subsets in untreated and treated patients with HBV in comparison with non-pathological liver tissue. Results The liver of untreated HBV patients exhibited a high accumulation of PD-1+CD8+ T cells, while the frequencies of 4-1BB+ T cells, 4-1BB+ natural killer (NK) cells, and TIM-3+CD8+ T cells were the highest in the chronic hepatitis phase. Our findings showed that the HBeAg status is linked to a distinct immune phenotype of intrahepatic CD8+ T cells and NK cells characterized by high expression of ICMs, particularly 4-1BB. Importantly, antiviral treatment partially restored the normal expression of ICMs. Finally, we described important differences in ICM expression between intrahepatic and circulating NK cells in HBV patients. Conclusions Our study shows clear differences in the intrahepatic expression of ICMs on NK cells and T cells in chronic HBV patients depending on their clinical stage.
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Affiliation(s)
- Lucile Dumolard
- Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
| | - Marie-Noelle Hilleret
- Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Service d’hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, La Tronche, France
| | - Charlotte Costentin
- Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Service d’hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, La Tronche, France
| | - Marion Mercey-Ressejac
- Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Service d’hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, La Tronche, France
| | - Nathalie Sturm
- Service d’anatomie et de cytologie pathologiques, CHU Grenoble Alpes, Grenoble, France
- Translational Research in Autoimmunity and Inflammation Group (TRAIG), Translational Innovation in Medicine and Complexity (TIMC), University Grenoble-Alpes, CNRS Unité mixte de recherche (UMR) 5525, La Tronche, France
| | - Theophile Gerster
- Service d’hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, La Tronche, France
| | - Thomas Decaens
- Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Service d’hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, La Tronche, France
| | - Evelyne Jouvin-Marche
- Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
| | - Patrice N. Marche
- Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
| | - Zuzana Macek Jilkova
- Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Service d’hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, La Tronche, France
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Hsu WF, Chen CF, Lai HC, Su WP, Wang HW, Chen SH, Huang GT, Peng CY. Trajectories and Decline of Serum Hepatitis B Surface Antigen Predict Outcomes in Patients With Chronic Hepatitis B. Open Forum Infect Dis 2024; 11:ofae699. [PMID: 39679354 PMCID: PMC11639628 DOI: 10.1093/ofid/ofae699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 11/25/2024] [Indexed: 12/17/2024] Open
Abstract
Background The kinetics of serum hepatitis B surface antigen (HBsAg) levels during long-term nucleos(t)ide analogue (NA) therapy remains unclear. We delineated the kinetics of HBsAg and analyzed its association with long-term treatment outcomes. Methods We enrolled 912 treatment-naïve patients with chronic hepatitis B (CHB) who had received NA therapy for >12 months and analyzed the kinetic patterns through group-based trajectory models (GBTMs). Results The median treatment duration for the entire cohort was 60.3 months. GBTMs revealed 4 patterns in patients achieving HBsAg loss (groups 1-4) in the study population and in patients achieving HBsAg <100 IU/mL among those with HBeAg-negative CHB with baseline HBsAg ≥100 IU/mL (groups A-D). Patients in groups 1 and A had the highest rates of HBsAg loss (22.2%, 6/27) and of achieving HBsAg <100 IU/mL (47.5%, 56/118), respectively. HBsAg <40 IU/mL and <400 IU/mL at 12 months of treatment predicted group 1 and group A membership among all patients and those with HBeAg-negative CHB, respectively. Multivariable Cox regression analysis identified HBsAg trajectory group (group 1 vs groups 3 and 4: hazard ratio [HR], 179.46; P < .001; group 2 vs groups 3 and 4: HR, 24.34; P < .001) and HBsAg decline (HR, 82.14; P < .001) as independent predictors of both HBsAg loss and achieving HBsAg <100 IU/mL. Conclusions Serum HBsAg trajectories and decline can predict HBsAg loss and the achievement of HBsAg <100 IU/mL in patients with CHB receiving long-term NA therapy.
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Affiliation(s)
- Wei-Fan Hsu
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Chuen-Fei Chen
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wen-Pang Su
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hung-Wei Wang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Sheng-Hung Chen
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Guan-Tarn Huang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
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Abdelhamed W, El-Kassas M. Hepatitis B virus as a risk factor for hepatocellular carcinoma: There is still much work to do. LIVER RESEARCH (BEIJING, CHINA) 2024; 8:83-90. [PMID: 39959873 PMCID: PMC11771266 DOI: 10.1016/j.livres.2024.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/23/2024] [Accepted: 05/30/2024] [Indexed: 04/03/2025]
Abstract
Hepatitis B virus (HBV) infection is a significant health problem that can result in progression to liver cirrhosis, decompensation, and the development of hepatocellular carcinoma (HCC). On a country level, the prevalence of chronic HBV infection varies between 0.1% and 35.0%, depending on the locality and the population being investigated. One-third of all liver cancer fatalities worldwide are attributable to HBV. The adoption of standard birth-dose immunization exerted the most significant impact on the decline of HBV prevalence. HCC incidence ranges from 0.01% to 1.40% in noncirrhotic patients and from 0.9% to 5.4% annually, in the settings of liver cirrhosis. Although antiviral therapy significantly reduces the risk of developing HBV-related HCC, studies have demonstrated that the risk persists, and that HCC screening is still essential. This review discusses the complex relationship between HBV infection and HCC, recent epidemiological data, different aspects of clinical disease characteristics, and the impact of antiviral therapy in this context.
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Affiliation(s)
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Jeng WJ, Chien RN, Liaw YF. Reply: Halting antiviral therapy in patients with cirrhosis and chronic hepatitis B: A dangerous game? Hepatology 2024; 79:E134-E135. [PMID: 38150032 DOI: 10.1097/hep.0000000000000737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 11/29/2023] [Indexed: 12/28/2023]
Affiliation(s)
- Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
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Liu YC, Jeng WJ, Peng CW, Chien RN, Liaw YF. Higher end-of-treatment HBsAg levels is associated with later onset but not severe relapse in HBeAg-negative chronic hepatitis B patients stopping antivirals. Aliment Pharmacol Ther 2024; 59:762-773. [PMID: 38234285 DOI: 10.1111/apt.17880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/22/2023] [Accepted: 01/05/2024] [Indexed: 01/19/2024]
Abstract
BACKGROUND Quantitative hepatitis B surface antigen (qHBsAg) level at end-of-treatment (EOT) predict clinical relapse (CR) after nucleos(t)ide analogues (Nuc) in chronic hepatitis B(CHB) patients. It is unclear if higher EOT qHBsAg leads to earlier onset or more severe off-Nuc CR. AIM This large cohort study investigates the association between EOT qHBsAg and CR onset/severity. METHODS This study enrolled HBeAg-negative CHB patients who had achieved undetectable HBV DNA for over 1 year after receiving Nuc therapy before discontinuation. The EOT qHBsAg level was categorised into three groups: <100, 100-999, ≥1000 IU/mL. The study assessed the predictability of qHBsAg levels for CR, and analysed and compared the incidence, time to onset and severity of CR among these three groups. RESULTS Patients with higher EOT qHBsAg showed a higher incidence of CR (≥1000, 100-999, <100 IU/mL: 73%, 65%, and 38%, p < 0.01) but a later onset of CR (median time to CR: 35, 33 and 27 weeks, p < 0.01). The predictabilities of EOT qHBsAg for CR were greater in patients aged <50-year-old or with genotype C than in those aged ≥50-year-old or with genotype B. There's no correlation between EOT qHBsAg level and ALT folds at CR (Pearson correlation coefficient: r = -0.03, p = 0.35). EOT qHBsAg was neither a predictor for severe hepatitis flare nor a predictor for hepatic decompensation. CONCLUSIONS Predictability using EOT qHBsAg levels for CR differed in subgroups of age and genotypes. Higher EOT qHBsAg levels correlate with higher incidence but later onset of CR. No correlation between EOT qHBsAg and relapse severity was observed.
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Affiliation(s)
- Yen-Chun Liu
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chien-Wei Peng
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan
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Mohareb AM, Kouamé MG, Nouaman M, Kim AY, Larmarange J, Neilan AM, Lacombe K, Freedberg KA, Boyd A, Coffie P, Hyle EP. What does the scale-up of long-acting HIV pre-exposure prophylaxis mean for the global hepatitis B epidemic? J Int AIDS Soc 2024; 27:e26218. [PMID: 38444112 PMCID: PMC10935702 DOI: 10.1002/jia2.26218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 01/29/2024] [Indexed: 03/07/2024] Open
Abstract
INTRODUCTION The HIV and hepatitis B virus (HBV) epidemics are interconnected with shared routes of transmission and specific antiviral drugs that are effective against both viruses. Nearly, 300 million people around the world live with chronic HBV, many of whom are from priority populations who could benefit from HIV prevention services. Oral pre-exposure prophylaxis (PrEP) for HIV has implications in the prevention and treatment of HBV infection, but many people at increased risk of HIV acquisition may instead prefer long-acting formulations of PrEP, which are currently not active against HBV. DISCUSSION People at increased risk for HIV acquisition may also be at risk for or already be living with HBV infection. Oral PrEP with tenofovir is effective in preventing both HIV and HBV, and tenofovir is also the recommended treatment for chronic HBV infection. Although implementation of oral PrEP has been challenging in sub-Saharan Africa, investments in its scale-up could secondarily reduce the clinical impact of HBV. Long-acting PrEP, including injectable medicines and implantable rings, may overcome some of the implementation challenges associated with oral PrEP, such as daily pill burden, adherence challenges and stigma; however, current formulations of long-acting PrEP do not have activity against HBV replication. Ideally, PrEP programmes would offer both oral and long-acting formulations with HBV screening to optimize HIV prevention services and HBV prevention and care, when appropriate. People who are not immune to HBV would benefit from being vaccinated against HBV before initiating long-acting PrEP. People who remain non-immune to HBV despite vaccination may benefit from being offered oral, tenofovir-based PrEP given its potential for HBV PrEP. People using PrEP and living with HBV who are not linked to dedicated HBV care would also benefit from laboratory monitoring at PrEP sites to ensure safety when using and after stopping tenofovir. PrEP programmes are ideal venues to offer HBV screening, HBV vaccination for people who are non-immune and treatment with tenofovir-based PrEP for people with indications for HBV therapy. CONCLUSIONS Long-acting PrEP holds promise for reducing HIV incidence, but its implications for the HBV epidemic, particularly in sub-Saharan Africa, should not be overlooked.
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Affiliation(s)
- Amir M. Mohareb
- Medical Practice Evaluation CenterMassachusetts General HospitalBostonMassachusettsUSA
- Division of Infectious DiseasesMassachusetts General HospitalBostonMassachusettsUSA
- Harvard University Center for AIDS ResearchBostonMassachusettsUSA
| | - Menan Gérard Kouamé
- Département de Santé PubliqueUFR d'Odonto‐stomatologieUniversité Félix Houphouët BoignyAbidjanCôte d'Ivoire
| | - Marcellin Nouaman
- Département de Santé PubliqueUFR d'Odonto‐stomatologieUniversité Félix Houphouët BoignyAbidjanCôte d'Ivoire
| | - Arthur Y. Kim
- Division of Infectious DiseasesMassachusetts General HospitalBostonMassachusettsUSA
- Harvard University Center for AIDS ResearchBostonMassachusettsUSA
| | - Joseph Larmarange
- Centre Population et DéveloppementUniversité Paris Cité, IRD, InsermParisFrance
| | - Anne M. Neilan
- Medical Practice Evaluation CenterMassachusetts General HospitalBostonMassachusettsUSA
- Division of Infectious DiseasesMassachusetts General HospitalBostonMassachusettsUSA
- Harvard University Center for AIDS ResearchBostonMassachusettsUSA
- Division of General Academic PediatricsDepartment of PediatricsMassachusetts General HospitalBostonMassachusettsUSA
| | - Karine Lacombe
- Sorbonne Université, IPLESPParisFrance
- Department of Infectious DiseasesSt. Antoine Hospital, AP‐HPParisFrance
| | - Kenneth A. Freedberg
- Medical Practice Evaluation CenterMassachusetts General HospitalBostonMassachusettsUSA
- Division of Infectious DiseasesMassachusetts General HospitalBostonMassachusettsUSA
- Harvard University Center for AIDS ResearchBostonMassachusettsUSA
- Department of General Internal MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | - Anders Boyd
- Stichting HIV MonitoringAmsterdamthe Netherlands
- Department of Infectious DiseasesPublic Health Service of AmsterdamAmsterdamthe Netherlands
- Amsterdam UMC, Infectious DiseasesAmsterdamthe Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious DiseasesAmsterdamthe Netherlands
| | - Patrick Coffie
- Département de Santé PubliqueUFR d'Odonto‐stomatologieUniversité Félix Houphouët BoignyAbidjanCôte d'Ivoire
- Département de Dermatologie et InfectiologieUniversité Félix Houphouët‐BoignyAbidjanCôte d'Ivoire
| | - Emily P. Hyle
- Medical Practice Evaluation CenterMassachusetts General HospitalBostonMassachusettsUSA
- Division of Infectious DiseasesMassachusetts General HospitalBostonMassachusettsUSA
- Harvard University Center for AIDS ResearchBostonMassachusettsUSA
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Jeng WJ, Chien RN, Chen YC, Lin CL, Wu CY, Liu YC, Peng CW, Su CW, Hsu CE, Liaw YF. Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis. Hepatology 2024; 79:690-703. [PMID: 37625144 DOI: 10.1097/hep.0000000000000575] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND AND AIMS Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Chih-Lang Lin
- College of Medicine, Chang Gung University, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Keelung Branch, Taiwan
| | - Chia-Ying Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Cheng-Er Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
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Liaw YF. When to Stop Antiviral Therapy in HBeAg-Negative Patients with Chronic Hepatitis B? CURRENT HEPATOLOGY REPORTS 2024; 23:221-226. [DOI: 10.1007/s11901-024-00663-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/16/2024] [Indexed: 01/03/2025]
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10
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Hsu CE, Liaw YF. Hepatitis B Surface Antigen Kinetics After Tenofovir Withdrawal in Chronic Hepatitis B. Am J Gastroenterol 2024; 119:389-390. [PMID: 38305791 DOI: 10.14309/ajg.0000000000002470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Affiliation(s)
- Cheng-Er Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Kou B, Zhang Z, Han X, Zhou Z, Xu Z, Zhou X, Shen F, Zhou Y, Tian X, Yang G, Young JAT, Qiu H, Ottaviani G, Mayweg A, Zhu W, Shen HC, Liu H, Hu T. Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus. J Med Chem 2023; 66:14116-14132. [PMID: 37801325 DOI: 10.1021/acs.jmedchem.3c01145] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos(t)ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.
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Affiliation(s)
- Buyu Kou
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Zhisen Zhang
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Xingchun Han
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Zheng Zhou
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Lead Discovery, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Zhiheng Xu
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Lead Discovery, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Xue Zhou
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Fang Shen
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Yuan Zhou
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Xiaojun Tian
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Guang Yang
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - John A T Young
- Roche Innovation Center Basel, Roche Pharma Research and Early Development, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Hongxia Qiu
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Pharmaceutical Sciences, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Giorgio Ottaviani
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Pharmaceutical Sciences, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Alexander Mayweg
- Roche Innovation Center Basel, Roche Pharma Research and Early Development, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Wei Zhu
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Hong C Shen
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Haixia Liu
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Taishan Hu
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
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Hsu YC, Tseng CH, Kao JH. Safety considerations for withdrawal of nucleos(t)ide analogues in patients with chronic hepatitis B: First, do no harm. Clin Mol Hepatol 2023; 29:869-890. [PMID: 36916171 PMCID: PMC10577354 DOI: 10.3350/cmh.2022.0420] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/19/2023] [Accepted: 03/13/2023] [Indexed: 03/16/2023] Open
Abstract
Nucleos(t)ide analogues (NA) are widely used to treat hepatitis B virus (HBV) infection, but they cannot eradicate the virus and treatment duration can be lifelong if the endpoint is set at seroclearance of the hepatitis B surface antigen (HBsAg). As an alternative strategy, finite NA therapy without the prerequisite of HBsAg seroclearance has been proposed to allow treatment cessation in patients with sustained undetectable HBV viremia for two to three years. However, reactivation of viral replication almost always follows NA withdrawal. Whereas HBV reactivation might facilitate HBsAg seroclearance in some, it could lead to serious acute flare-ups in a certain proportion of patients. Occurrence and consequences of NA withdrawal flares are complicated with various factors involving the virus, host, and treatment. Accurate risk prediction for severe flares following NA cessation is essential to ensure patient safety. The risks of life-threatening flares in patients who discontinued NA according to the stopping rules of current guidelines or local reimbursement policies have recently been quantitatively estimated in large-scale studies, which also provided empirical evidence to help identify vulnerable patients at risk of devastating outcomes. Moreover, risk predictors were further explored and validated to hopefully aid in patient selection and management. In this narrative review with a focus on patient safety, we summarize and discuss current literature on the incidence of severe flares following NA cessation, risk stratification for candidate selection, rules of posttreatment monitoring, and indications for treatment resumption. We also share our thoughts on the limitations of existing knowledge and suggestions for future research.
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Affiliation(s)
- Yao-Chun Hsu
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Hao Tseng
- School of Medicine College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, E-Da Cancer Hospital, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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13
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Loglio A, Viganò M. Stopping nucleos(t)ide analogues treatment in non-cirrhotic HBeAg-negative patients: Yes, we can! Dig Liver Dis 2023; 55:1221-1222. [PMID: 37419725 DOI: 10.1016/j.dld.2023.06.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 06/26/2023] [Accepted: 06/30/2023] [Indexed: 07/09/2023]
Affiliation(s)
- Alessandro Loglio
- Gastroenterology, Hepatology and Transplantation Division, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Mauro Viganò
- Gastroenterology, Hepatology and Transplantation Division, ASST Papa Giovanni XXIII, Bergamo, Italy.
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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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15
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Schlaak JF. Current Therapy of Chronic Viral Hepatitis B, C and D. J Pers Med 2023; 13:964. [PMID: 37373953 DOI: 10.3390/jpm13060964] [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: 03/25/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The majority of chronic viral hepatitis cases are induced via infection with the hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). These patients are at increased risk for progressive liver disease leading to cirrhosis as well as hepatocellular carcinoma (HCC). HBV infection is well controlled by the currently available nucleosides as well as nucleotides, and the development of cirrhosis can be prevented. Additionally, it has been shown that HBV-induced liver fibrosis can regress during successful antiviral treatment; however, a "functional cure", i.e., loss of HBsAg, is a rare event when these drugs are used. Therefore, novel therapeutic strategies are aiming at the selective suppression of HBsAg levels in combination with immunostimulation. The development of directly acting antivirals (DAAs) has revolutionized HCV therapy, as almost all patients can be cured via this treatment. Additionally, DAA therapy has few, if any, side effects, and is generally well tolerated by patients. HDV remains the most challenging type of chronic viral hepatitis. Although novel therapeutic options have recently been approved, response rates are still less favorable compared to HBV and HCV. This review discusses current and future options for the treatment of chronic HBV, HCV, and HDV infection.
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Affiliation(s)
- Jörg F Schlaak
- Department of Internal Medicine, Ameos Hospital Oberhausen, Wilhelmstr. 34, 46145 Oberhausen, Germany
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16
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Wu Z(E, Xu D, Hu PJH, Huang TS. A hierarchical multilabel graph attention network method to predict the deterioration paths of chronic hepatitis B patients. J Am Med Inform Assoc 2023; 30:846-858. [PMID: 36794643 PMCID: PMC10114116 DOI: 10.1093/jamia/ocad008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/26/2022] [Accepted: 01/25/2023] [Indexed: 02/17/2023] Open
Abstract
OBJECTIVE Estimating the deterioration paths of chronic hepatitis B (CHB) patients is critical for physicians' decisions and patient management. A novel, hierarchical multilabel graph attention-based method aims to predict patient deterioration paths more effectively. Applied to a CHB patient data set, it offers strong predictive utilities and clinical value. MATERIALS AND METHODS The proposed method incorporates patients' responses to medications, diagnosis event sequences, and outcome dependencies to estimate deterioration paths. From the electronic health records maintained by a major healthcare organization in Taiwan, we collect clinical data about 177 959 patients diagnosed with hepatitis B virus infection. We use this sample to evaluate the proposed method's predictive efficacy relative to 9 existing methods, as measured by precision, recall, F-measure, and area under the curve (AUC). RESULTS We use 20% of the sample as holdouts to test each method's prediction performance. The results indicate that our method consistently and significantly outperforms all benchmark methods. It attains the highest AUC, with a 4.8% improvement over the best-performing benchmark, as well as 20.9% and 11.4% improvements in precision and F-measures, respectively. The comparative results demonstrate that our method is more effective for predicting CHB patients' deterioration paths than existing predictive methods. DISCUSSION AND CONCLUSION The proposed method underscores the value of patient-medication interactions, temporal sequential patterns of distinct diagnosis, and patient outcome dependencies for capturing dynamics that underpin patient deterioration over time. Its efficacious estimates grant physicians a more holistic view of patient progressions and can enhance their clinical decision-making and patient management.
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Affiliation(s)
- Zejian (Eric) Wu
- Department of Operations and Information Systems, David Eccles School of Business, University of Utah, Salt Lake City, Utah, USA
| | - Da Xu
- Department of Information Systems, College of Business, California State University Long Beach, Long Beach, California, USA
| | - Paul Jen-Hwa Hu
- Department of Operations and Information Systems, David Eccles School of Business, University of Utah, Salt Lake City, Utah, USA
| | - Ting-Shuo Huang
- Department of General Surgery, Keelung Chang Gung Memorial Hospital, Keelung City, Taiwan
- Department of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung City, Taiwan
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17
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Emerging Therapies for Chronic Hepatitis B and the Potential for a Functional Cure. Drugs 2023; 83:367-388. [PMID: 36906663 DOI: 10.1007/s40265-023-01843-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2023] [Indexed: 03/13/2023]
Abstract
Worldwide, an estimated 296 million people are living with chronic hepatitis B virus (HBV) infection, with a significant risk of morbidity and mortality. Current therapy with pegylated interferon (Peg-IFN) and indefinite or finite therapy with nucleoside/nucleotide analogues (Nucs) are effective in HBV suppression, hepatitis resolution, and prevention of disease progression. However, few achieve hepatitis B surface antigen (HBsAg) loss (functional cure), and relapse often occurs after the end of therapy (EOT) because these agents have no direct effect on durable template: covalently closed circular DNA (cccDNA) and integrated HBV DNA. Hepatitis B surface antigen loss rate increases slightly by adding or switching to Peg-IFN in Nuc-treated patients and this loss rate greatly increases up to 39% in 5 years with finite Nuc therapy with currently available Nuc(s). For this, great effort has been made to develop novel direct-acting antivirals (DAAs) and immunomodulators. Among the DAAs, entry inhibitors and capsid assembly modulators have little effect on reducing HBsAg levels; small interfering RNA, antisense oligonucleotides, and nucleic acid polymers in combination with Peg-IFN and Nuc may reduce HBsAg levels significantly, even a rate of HBsAg loss sustained for > 24 weeks after EOT up to 40%. Novel immunomodulators, including T-cell receptor agonists, check-point inhibitors, therapeutic vaccines, and monoclonal antibodies may restore HBV-specific T-cell response but not sustained HBsAg loss. The safety issues and the durability of HBsAg loss warrant further investigation. Combining agents of different classes has the potential to enhance HBsAg loss. Compounds directly targeting cccDNA would be more effective but are still in the early stage of development. More effort is required to achieve this goal.
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Peng CW, Jeng WJ, Yang HI, Liu YC, Chien RN, Liaw YF. A switch from tenofovir to entecavir prior to hepatitis B treatment cessation is associated with a reduced risk of off-therapy relapse: An observational study. J Gastroenterol Hepatol 2022; 37:2164-2172. [PMID: 35869752 DOI: 10.1111/jgh.15966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM In HBeAg negative chronic hepatitis B (CHB) patients, clinical relapse (CR) occurs more frequently, much earlier and often more severely after stopping tenofovir (TDF) and other nucleos(t)ide analogues (Nucs) than after stopping entecavir (ETV). It is unknown whether off-Nuc hepatitis flare can be alleviated by switching from one Nuc to another. METHODS HBeAg-negative CHB patients who had stopped Nuc according to the APASL stopping rule and had been followed-up for > 48 weeks after Nuc cessation were recruited. Patients were classified as four groups: ETV monotherapy (mono-ETV), TDF monotherapy (mono-TDF), switched to ETV (switch-ETV), and switched to TDF (switch-TDF). Both switch groups had switched to the replacement Nuc > 12 weeks prior to end of therapy. Propensity score matching (PSM) was performed to minimize confounders among groups. Cox regression analysis was used to identify risks factors for off-Nuc CR and flares. RESULTS A total of 1309 patients (1022 mono-ETV, 219 mono-TDF, 40 switch-ETV and 28 switch-TDF) were enrolled. The median time to CR was 39, 13, 38 and 14 weeks in mono-ETV, mono-TDF, switch-ETV and switch-TDF respectively (P < 0.001). After PSM, the mono-ETV (adjusted HR: 0.39, P < 0.001) and switch-ETV patients (adjusted HR: 0.41, P = 0.003) had both significantly later occurrence and lower rates of CR and flare. CONCLUSION In summary, the incidence and timing of CR was determined by ETV or TDF in the last 3 months prior to end of treatment. Patients treated with non-ETV-Nuc switched to ETV > 12 weeks before end of the original Nuc therapy may reduce/defer CR.
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Affiliation(s)
- Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hwai-I Yang
- Genomic Research Center, Academia Sinica, Taipei, Taiwan
| | - Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan
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Liaw YF. Perspectives on current controversial issues in the management of chronic HBV infection. J Gastroenterol 2022; 57:828-837. [PMID: 36053366 DOI: 10.1007/s00535-022-01918-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/18/2022] [Indexed: 02/04/2023]
Abstract
Clinical and basic research in the past decades has achieved consensus in the understanding of chronic hepatitis B virus (HBV) infection and the management of chronic hepatitis B and HBV-cirrhosis. However, debatable challenges to the existing consensus in the concept and/or definitions have emerged. These include (1). alanine aminotransferase upper limit of normal: traditional laboratory-defined vs fixed; (2). nomenclature for phases of chronic HBV infection: classical vs EASL proposal; (3). indication of antiviral therapy: to treat patients vs to treat HBV; (4). finite vs indefinite long-term antiviral therapy: A. finite therapy in HBV-cirrhosis; B. retreatment decision: biochemical markers vs HBsAg/ALT kinetics. The pros and cons of these controversial issues were reviewed, assessed, and discussed in depth based on relevant lines of scientific evidence, intended to clarify or solve these controversial issues.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199, Tung Hwa North Road, Taipei, 105, Taiwan.
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20
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Liaw YF. Hepatitis B flare: the good, the bad and the ugly. Expert Rev Gastroenterol Hepatol 2022; 16:1043-1051. [PMID: 36476208 DOI: 10.1080/17474124.2022.2156338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hepatitis B flare, defined as an event of abrupt ALT elevation to >5x ULN, is a frequent episode during the natural course or during/after antiviral therapy of chronic HBV infection, in both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B or liver cirrhosis. AREAS COVERED The definition, pathogenesis, clinical presentation, and management of hepatitis B flares in the published literature were reviewed. Hepatitis B flares have been considered as a result of the robust immune response of the patient to an upsurging HBV/HBV-antigen(s). 'Host-dominating flares,' reflect effective immune response, may resolve with ALT normalization and decline of HBV/ antigen(s). Contradictorily, 'virus-dominating flares,' reflect ineffective immune response, are usually followed by persistent/intermittent hepatitis and may even develop hepatic decompensation/failure. EXPERT OPINION Not all hepatitis B flares require antiviral therapy, and close observation with combined HBsAg/ALT kinetics along the ascending ALT during hepatitis flare may differentiate hepatitis flares for an appropriate treatment/retreatment decision. More studies are needed to verify this proposal. Further immunologic studies using multiple samples during hepatitis B flare are important to clarify the precise underlying mechanisms as the basis for further improvement in the management of hepatitis flare.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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21
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Zhu M, Wang H, Lou T, Xiong P, Zhang J, Li L, Sun Y, Wu Y. Current treatment of chronic hepatitis B: Clinical aspects and future directions. Front Microbiol 2022; 13:975584. [PMID: 36160238 PMCID: PMC9493448 DOI: 10.3389/fmicb.2022.975584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/26/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients’ health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases (2018 AASLD guidelines) (AASLD, 2018), European Association for the Study of the Liver (2017 EASL guidelines) (EASL, 2017), and Asian-Pacific Association for the Study of the Liver (2015 APASL guidelines) (APASL, 2015) also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: (1) Who should be treated in the general population according to the guidelines; (2) Treatment of specific populations infected with HBV; (3) Controversial issues in clinical practice; (4) Perspective.
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Affiliation(s)
- Minmin Zhu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Hui Wang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Tao Lou
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Pian Xiong
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Jiebing Zhang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Lele Li
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Yuchao Sun
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
| | - Yingping Wu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
- *Correspondence: Yingping Wu,
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22
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Chang ML, Chien RN, Liaw YF. Evidence-Based Management of Oral Nucleos(t)ide Analogue Withdrawal in Virally Suppressed Patients with Chronic HBV Infection. CURRENT HEPATOLOGY REPORTS 2022; 21:52-58. [DOI: 10.1007/s11901-022-00587-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/02/2025]
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23
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Liu YC, Jeng WJ, Peng CW, Chien RN, Liaw YF. The Role of Off-Therapy Viral Kinetics in the Timing and Severity of Flares in Hepatitis B e Antigen-Negative Patients. Clin Gastroenterol Hepatol 2022; 21:1533-1541.e11. [PMID: 36038130 DOI: 10.1016/j.cgh.2022.08.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatitis B flare occurs earlier and is more severe in patients stopping tenofovir (TDF) compared with entecavir (ETV). This study investigated relationship between hepatitis B virus (HBV) kinetics, onset timing, and the severity of flares. METHODS Hepatitis B e antigen-negative chronic hepatitis B patients who developed off-ETV or off-TDF hepatitis flare were recruited. Their HBV kinetics and the severity of flares were compared between patients with early (<6 months) and late (between 6 and 24 months) flares. Propensity score matching was performed at 1:1 adjusting for age, sex, cirrhosis, and end-of-treatment (EOT) hepatitis B surface antigen between off-ETV and off-TDF flares. RESULTS After propensity score matching, 76% and 15% of each 107 off-TDF and off-ETV patients, respectively, developed early flare. A much steeper HBV DNA upsurge (ΔHBV DNA/month) was observed in off-TDF than off-ETV flares (2.12 vs 0.73 log10 IU/mL; P < .01). Greater ΔHBV DNA/month correlated with earlier timing and higher peak alanine aminotransferase levels of flares. ΔHBV DNA/month ≥2.5 log10 IU/mL was an independent factor for severe off-TDF flare, and ≥1 log10 IU/mL was a predictor for severe off-ETV flares. CONCLUSIONS Greater HBV DNA upsurge rate (ΔHBV DNA/month) ≥1 log10 IU/mL is a key factor for an earlier onset and more severe flare. More frequent ΔHBV DNA/month ≥1 log10 IU/mL in off-TDF than off-ETV flares may explain why off-TDF flare mostly occurred early and was more severe. More stringent monitoring in those with ΔHBV DNA/month ≥1 log10 IU/mL at flare, especially ≥2.5 log10 IU/mL in early off-TDF flares, is important for timely retreatment to prevent decompensation.
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Affiliation(s)
- Yen-Chun Liu
- College of Medicine, Chang Gung University, Taipei, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Chien-Wei Peng
- College of Medicine, Chang Gung University, Taipei, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Taiwan.
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24
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Risks and benefits of oral HIV pre-exposure prophylaxis for people with chronic hepatitis B. THE LANCET HIV 2022; 9:e585-e594. [PMID: 35817068 PMCID: PMC9339532 DOI: 10.1016/s2352-3018(22)00123-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/18/2022] [Accepted: 04/20/2022] [Indexed: 12/20/2022]
Abstract
Individuals with chronic hepatitis B virus (HBV) infection who are at substantial risk of HIV acquisition benefit from pre-exposure prophylaxis (PrEP) with tenofovir-based antiviral therapy. Considering that tenofovir potently inhibits HBV, providing PrEP to individuals with HBV effectively results in treatment of their HBV infection. However, some clinicians might be hesitant to initiate PrEP in people with chronic HBV due to unknown risks of HBV reactivation, hepatitis, and acute liver failure during periods of antiviral cessation. Unfortunately, these knowledge gaps affect scale up of PrEP among people with chronic HBV. Emerging data regarding the risks and benefits of antiviral cessation in people with chronic HBV suggest that PrEP can be safely initiated despite the risks of non-adherence or discontinuation. People with chronic HBV who stop PrEP should be closely monitored for HBV reactivation and hepatitis flares after antiviral cessation.
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Finite versus Indefinite Nucleos(t)ide Analogue Therapy of Patients with Chronic Hepatitis B Exhibiting Negative HBsAg Levels after Treatment. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6069781. [PMID: 35872855 PMCID: PMC9307367 DOI: 10.1155/2022/6069781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 11/17/2022]
Abstract
Aim To determine whether a decrease in HBsAg to <0.05 IU/mL could be a criterion for cessation of finite nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). Methods This was a retrospective analysis of 6715 patients with CHB between January 1998 and May 2016. Patients were followed up every 12–24 weeks. Among 104 patients achieving HBsAg levels < 0.05 IU/mL, 71 were eligible for inclusion in the analysis: 31 received finite NUC therapy, and 40 received indefinite NUC therapy. In the finite therapy group, 9 patients received no NUC consolidation therapy, 6 received short-term (<1 year) consolidation, and 16 received long-term (>1 year) consolidation. The outcome measures were alanine aminotransferase (ALT), total bilirubin, albumin, hepatitis B virus DNA, and HBsAg levels. Results Baseline parameters and characteristics at the time when HBsAg levels had fallen to <0.05 IU/mL were similar between the finite and indefinite therapy groups. No patients experienced viral breakthrough/relapse during a median follow-up of 120 weeks. There were little or no differences in long-term outcomes between the finite and indefinite therapy groups and between the short-term and long-term consolidation groups. Conclusions Discontinuation of NUCs may be acceptable in patients whose HBsAg levels fall to <0.05 IU/mL. Consolidation therapy lasting <1 year appears adequate to prevent poor long-term prognosis.
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Broquetas T, Carrión JA. Current Perspectives on Nucleos(t)ide Analogue Therapy for the Long-Term Treatment of Hepatitis B Virus. Hepat Med 2022; 14:87-100. [PMID: 35936810 PMCID: PMC9346298 DOI: 10.2147/hmer.s291976] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/12/2022] [Indexed: 01/27/2023] Open
Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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27
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Liaw YF, Jeng WJ, Chien RN. Hepatocellular carcinoma and HBsAg loss after cessation of antiviral therapy. Liver Int 2022; 42:945-946. [PMID: 35129291 DOI: 10.1111/liv.15179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 02/13/2023]
Affiliation(s)
- Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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28
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Kaewdech A, Assawasuwannakit S, Sripongpun P, Chamroonkul N, Tangkijvanich P, Piratvisuth T. Clinical Utility of SCALE-B to Predict Hepatitis B Virus Relapse, Hepatitis B Surface Antigen Loss After Antiviral Cessation in Asian Patients After 2-Year Follow-up. Front Med (Lausanne) 2022; 9:859430. [PMID: 35402452 PMCID: PMC8987127 DOI: 10.3389/fmed.2022.859430] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/14/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Discontinuation of antiviral therapy in chronic hepatitis B (CHB) patients leads to a higher hepatitis B surface antigen (HBsAg) loss; yet, clinical relapse (CR) may occur. SCALE-B score was developed to predict off-treatment CR; however, validation of SCALE-B beyond a 48-week follow-up is rare. We studied whether SCALE-B and hepatitis B virus ribonucleic acid (HBV RNA) could predict outcomes in CHB patients after a 2-year follow-up. METHODS A total of 92 Thai CHB patients who stopped antiviral treatment were followed up; baseline characteristics, quantitative hepatitis B surface antigen (qHBsAg), hepatitis B core-related antigen (HBcrAg), and HBV RNA were collected at the time of discontinuation, and SCALE-B scores were calculated. Patients were followed up every 12 weeks for 48 weeks, and then, the intervals were upon primary doctors. Follow-up data regarding virological relapse (VR), CR, and HBsAg loss were obtained. RESULTS The median follow-up duration was 142 weeks; the cumulative incidences of VR, CR, and HBsAg loss were 65.2, 33.7, and 7.6%, respectively. After 48 weeks, VR and CR plateaued, but HBsAg loss increased from 2.2 to 7.6%. According to the SCALE-B strata, VR, CR, and HBsAg loss were significantly different. The highest stratum (≥ 320) was associated with higher VR, CR, and lesser HBsAg loss when compared to the lowest stratum, with adjusted hazard ratios of 5.0 (95% CIs: 1.8-14.4), 10.44 (95% CIs: 1.4-79.1), and 0.04 (95% CIs: 0.004-0.43), respectively. CONCLUSION At a median follow-up of 2.5 years after discontinuing therapy, HBsAg loss in Thai patients was found to increase over time. SCALE-B is a valuable tool for predicting CR, VR, and HBsAg loss; HBV RNA is not significantly associated with long-term outcomes. CLINICAL TRIAL REGISTRATION [www.ClinicalTrials.gov], identifier [TCTR20180316007].
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Affiliation(s)
- Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Suraphon Assawasuwannakit
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
- Department of Medicine, Panyananthaphikkhu Chonprathan Medical Center, Srinakharinwirot University, Nonthaburi, Thailand
| | - Pimsiri Sripongpun
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Naichaya Chamroonkul
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Pisit Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
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Liaw YF, Chien RN. Finite nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B: From an "option" to an "active recommendation". Kaohsiung J Med Sci 2022; 38:295-301. [PMID: 35262284 DOI: 10.1002/kjm2.12518] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 12/12/2022] Open
Abstract
Nucleos(t)ide analogue (Nuc) including entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide may suppress hepatitis B virus (HBV) DNA profoundly but have no direct action on covalently closed circular DNA, which is a very stable template for HBV production. Therefore, decades of long-term Nuc therapy are required to maintain HBV suppression and to achieve hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative patients. However, there are concerns including financial burden, adherence, and willingness for indefinite long-term Nuc therapy. Patients lost to follow-up and hence not monitored may risk severe relapse that may deteriorate to hepatic decompensation or even hepatic failure. Cessation of Nuc therapy in HBeAg-negative patients was initially considered in early 2000s. Earlier findings in Asian patients that finite Nuc therapy over 2-3 years is feasible and safe have founded Asian-Pacific Association for the Study of Liver stopping rule since 2008. Subsequent studies have confirmed the feasibility and safety of the strategy of finite Nuc therapy, which has finally been accepted as "an option" by American and European liver associations since 2016. More recent large studies since 2018 have further confirmed the pivotal finding of greatly increased HBsAg loss rate (~5-year 39%) after stopping Nuc therapy. With the high HBsAg loss rate as the main justification, the paradigm shift from indefinite long-term therapy to finite Nuc therapy in HBeAg-negative patients has been changing from an "option" to an "active recommendation" aiming to achieve HBsAg loss. More studies are needed to fine-tuning the strategy, including research for the optimal duration of consolidation therapy, timing to stop, and to start retreatment.
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Affiliation(s)
- Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
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30
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Liu YC, Jeng WJ, Peng CW, Chien RN, Liaw YF. Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies. Liver Int 2022; 42:551-560. [PMID: 34936719 DOI: 10.1111/liv.15140] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 11/23/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Clinical relapse occurs much earlier and more frequently in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients after stopping tenofovir (TDF) therapy than those off-entecavir (ETV). Clinical relapse may subside or progress to hepatitis flare which poses a safety concern. This study compared the incidence, timing and severity of hepatitis flares after stopping TDF and ETV. METHODS HBeAg-negative CHB patients who had stopped ETV or TDF were included in the study. Off-therapy hepatitis flare patterns were compared between off-ETV and off-TDF patients before and after propensity score matching (PSM). RESULTS The off-therapy hepatitis flares occurred more frequently (2-year: 58% vs 38%, P < .001) and much earlier (12 vs. 38 weeks, P < .001) in TDF group, with higher alanine aminotransferase (ALT) levels (after PSM: 536 vs. 419 U/L, P = .020) and two times rate of hepatic decompensation (4.0% vs. 2.1%, P = .322). The cirrhotic status [aHR: 20.531 (2.645-159.365), P = .004] and off-TDF [aHR: 5.530 (1.728-17.694), P = .004] were two independent predictors for hepatic decompensation. CONCLUSIONS Hepatitis flare occurred more frequently, earlier, and more severe in off-TDF than off-ETV patients. More stringent off-therapy monitoring within 6 months off-TDF is mandatory whereas more attention is needed after 6 months off-ETV.
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Affiliation(s)
- Yen-Chun Liu
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chien-Wei Peng
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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31
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Hirode G, Choi HSJ, Chen CH, Su TH, Seto WK, Van Hees S, Papatheodoridi M, Lens S, Wong G, Brakenhoff SM, Chien RN, Feld J, Sonneveld MJ, Chan HLY, Forns X, Papatheodoridis GV, Vanwolleghem T, Yuen MF, Hsu YC, Kao JH, Cornberg M, Hansen BE, Jeng WJ, Janssen HLA. Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study). Gastroenterology 2022; 162:757-771.e4. [PMID: 34762906 DOI: 10.1053/j.gastro.2021.11.002] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). METHODS This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)-negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. RESULTS Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7-16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1-38.7; P < .001). At 48 months of follow-up, Whites with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. CONCLUSIONS The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.
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Affiliation(s)
- Grishma Hirode
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada
| | | | - Tung-Hung Su
- National Taiwan University Hospital, Taipei, Taiwan
| | - Wai-Kay Seto
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Stijn Van Hees
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | | | - Sabela Lens
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Grace Wong
- The Chinese University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Sylvia M Brakenhoff
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Jordan Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Henry L Y Chan
- The Chinese University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Xavier Forns
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | | | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Yao-Chun Hsu
- E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | | | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany Centre for Individualized Infection Medicine, Hannover, Germany
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada.
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Current Trend in Antiviral Therapy for Chronic Hepatitis B. Viruses 2022; 14:v14020434. [PMID: 35216027 PMCID: PMC8877417 DOI: 10.3390/v14020434] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.
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Chang ML, Liaw YF. Hepatitis B Flare in Hepatitis B e Antigen-Negative Patients: A Complicated Cascade of Innate and Adaptive Immune Responses. Int J Mol Sci 2022; 23:ijms23031552. [PMID: 35163476 PMCID: PMC8836007 DOI: 10.3390/ijms23031552] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/19/2022] [Accepted: 01/26/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a dynamic process involving interactions among HBV, hepatocytes, and the host immune system. The natural course of chronic hepatitis B (CHB) is divided into four chronological phases, including the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases. During HBV flare, alanine aminotransferase (ALT) levels abruptly rise to >5× the upper limit of normal; this is thought to occur due to the immune response against an upsurge in serum HBV DNA and antigen levels. Hepatitis flares may occur spontaneously, during or after antiviral therapy, or upon immunosuppression or chemotherapy in both HBeAg-positive and HBeAg-negative patients. The clinical spectrum of HBV flares varies from asymptomatic to hepatic decompensation or failure. HBeAg seroconversion with ≥ 1 year of consolidation therapy is accepted as an endpoint of oral antiviral therapy in HBeAg-positive patients, but recommendations for treating HBeAg-negative patients differ. Thus, the management of HBeAg-negative patients has attracted increasing interest. In the current review, we summarize various types of HBV flares and the associated complex cascade of innate and adaptive immune responses, with a focus on HBeAg-negative CHB patients. Hopefully, this review will provide insight into immunopathogenesis to improve the management of HBV flares in HBeAg-negative CHB patients.
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Affiliation(s)
- Ming-Ling Chang
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
- Division of Hepatology, Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
- Correspondence: ; Tel.: +886-3-3281200 (ext. 8107); Fax: +886-3-3272236
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
- Division of Hepatology, Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
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Jeng WJ, Chien RN, Liaw YF. Disputing issues in the paradigm change to finite antiviral therapy in HBeAg-negative patients. J Hepatol 2021; 75:1498-1499. [PMID: 34214616 DOI: 10.1016/j.jhep.2021.06.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/15/2021] [Accepted: 06/21/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan; College of Medicine, Chang Gung University, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan; College of Medicine, Chang Gung University, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan; College of Medicine, Chang Gung University, Taiwan.
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35
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Lai CY, Yang SS, Lee SW, Tsai HJ, Lee TY. Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation. J Clin Med 2021; 10:4883. [PMID: 34768403 PMCID: PMC8584579 DOI: 10.3390/jcm10214883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Chronic hepatitis B (CHB) with severe acute exacerbation (SAE) is an urgent problem requiring nucleos(t)ide analogue (NA) therapy. We aim to evaluate the clinical relapse (CR) risk after discontinuing NA in patients with prior SAE. METHODS In this retrospective cohort study, CHB patients who discontinued NA therapy were screened between October, 2003 and January, 2019. A total of 78 non-cirrhotic patients who had received NA therapy for CHB with SAE, i.e., bilirubin ≥ 2 mg/dL and/or prothrombin time prolongation ≥3 s, (SAE group) were matched 1:2 with 156 controls without SAE (non-SAE group) by means of propensity scores (age, gender, NA categories, NA therapy duration, and HBeAg status). RESULTS The 5-year cumulative incidences of severe CR, i.e., ALT > 10X ULN, (42.78%, 95% CI: 27.84-57.73% vs. 25.42%, 95% CI: 16.26-34.58%; p = 0.045) and SAE recurrence (25.91%, 95% CI: 10.91-40.91% vs. 1.04%, 95% CI: 0-3.07%; p < 0.001) were significantly higher in the SAE group. Prior SAE history (HR 1.79, 95% CI: 1.04-3.06) was an independent factor for severe CR. The 5-year cumulative incidence of HBsAg seroclearance was significantly higher in the SAE group than that in the non-SAE group (16.82%, 95% CI: 2.34-31.30% vs. 6.02%, 95% CI: 0-13.23%; p = 0.049). CONCLUSIONS Even though it creates a greater chance of HBsAg seroclearance, NA therapy cessation may result in a high risk of severe CR in non-cirrhotic CHB patients with prior SAE.
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Affiliation(s)
- Chia-Yeh Lai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan
| | - Shou-Wu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Hsin-Ju Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
| | - Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
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36
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Jeng WJ, Liu YC, Peng CW, Chien RN, Liaw YF. Highly significant differences in HBsAg kinetics among patients with two types of hepatitis B flare, with and without retreatment. J Antimicrob Chemother 2021; 77:205-212. [PMID: 34618028 DOI: 10.1093/jac/dkab360] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 09/02/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Off-therapy hepatitis flare may be detrimental or, conversely, facilitate hepatitis B surface antigen (HBsAg) decline. Retreatment decisions are crucial. METHODS HBsAg was quantified before and during flares, at peak/retreatment start and at Months 6 and 12 in 336 entecavir/tenofovir-retreated and 105 non-retreated hepatitis B e antigen (HBeAg)-negative patients. Increasing HBsAg during ALT flare defined a 'virus-dominating flare' and decreasing HBsAg a 'host-dominating flare'. RESULTS Two hundred and eighty-eight retreated patients with a virus-dominating flare showed greater 1 year HBsAg decline (-1.0 versus -0.01 log10 IU/mL; P < 0.0001), more frequent rapid decline (69.8% versus 8.3%; P < 0001) and higher 3 year incidence of HBsAg < 100 IU/mL (32% versus 12%; P = 0.026) than 48 patients with a host-dominating flare, of whom 16 (33.3%) showed 3.8-fold (2 to 52-fold) HBsAg rebound on retreatment (versus 2/288; P < 0.0001). Compared with non-retreated controls, 1 year HBsAg decline was greater (-1.0 versus -0.47 log10 IU/mL; P < 0.0001) and faster (69.8% versus 42.5%; P < 0.0001) in patients with a virus-dominating flare, whereas 1 year HBsAg decline (-0.01 versus -0.16 log10 IU/mL) and 3 year HBsAg loss rate (0% versus 21%; P = 0.009) were lower in patients with a host-dominating flare. CONCLUSIONS Entecavir/tenofovir retreatment effectively decreases HBsAg level in patients with a virus-dominating flare but is ineffective/worse in patients with a host-dominating flare. These results support the use of combined HBsAg/ALT kinetics for the decision to retreat patients with a virus-dominating flare and withhold retreatment for patients with a host-dominating flare.
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Affiliation(s)
- Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Yen-Chun Liu
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Chien-Wei Peng
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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37
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Kaewdech A, Sripongpun P. Challenges in the discontinuation of chronic hepatitis B antiviral agents. World J Hepatol 2021; 13:1042-1057. [PMID: 34630873 PMCID: PMC8473499 DOI: 10.4254/wjh.v13.i9.1042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/07/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
Long-term antiviral treatment of chronic hepatitis B patients has been proven to be beneficial in reducing liver-related complications. However, lengthy periods of daily administration of medication have some inevitable drawbacks, including decreased medication adherence, increased cost of treatment, and possible long-term side effects. Currently, discontinuation of antiviral agent has become the strategy of interest to many hepatologists, as it might alleviate the aforementioned drawbacks and increase the probability of achieving functional cure. This review focuses on the current evidence of the outcomes following stopping antiviral treatment and the factors associated with subsequent hepatitis B virus relapse, hepatitis B surface antigen clearance, and unmet needs.
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Affiliation(s)
- Apichat Kaewdech
- Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand
| | - Pimsiri Sripongpun
- Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand.
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38
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Zuccaro V, Asperges E, Colaneri M, Marvulli LN, Bruno R. HBV and HDV: New Treatments on the Horizon. J Clin Med 2021; 10:jcm10184054. [PMID: 34575165 PMCID: PMC8471459 DOI: 10.3390/jcm10184054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/06/2021] [Accepted: 09/06/2021] [Indexed: 12/23/2022] Open
Abstract
Despite the accumulating knowledge, chronic hepatitis B (CHB) and HDV infection represent a global health problem, and there are still several critical issues, which frequently remain uncovered. In this paper, we provided an overview of the current therapeutic options and summarized the investigational therapies in the pipeline. Furthermore, we discussed some critical issues such as a “functional cure” approach, the futility of long-term NA therapy and the relevance of understanding drug actions and safety of antivirals, especially in special populations.
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Affiliation(s)
- Valentina Zuccaro
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
- Correspondence: ; Tel.: +39-0382502660
| | - Erika Asperges
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
| | - Marta Colaneri
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
| | - Lea Nadia Marvulli
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
- Dipartimento di Scienze Clinico-Chirurgiche, Diagnostiche e Pediatriche–Università di Pavia, 27100 Pavia, Italy
| | - Raffaele Bruno
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
- Dipartimento di Scienze Clinico-Chirurgiche, Diagnostiche e Pediatriche–Università di Pavia, 27100 Pavia, Italy
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39
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Medas R, Liberal R, Macedo G. Discontinuation of antiviral therapy in chronic hepatitis B patients. World J Clin Cases 2021; 9:6979-6986. [PMID: 34540953 PMCID: PMC8409197 DOI: 10.12998/wjcc.v9.i24.6979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/29/2021] [Accepted: 07/02/2021] [Indexed: 02/06/2023] Open
Abstract
Nucleos(t)ide analogs (NUC) are the first-line therapy for patients with chronic hepatitis B (CHB) recommended by most current guidelines. NUC therapy decreases progression of liver disease, reduces the risk of liver-related complications, and improves the quality of life of patients with CHB. Although indefinite or long-term NUC therapy is usually recommended, this strategy raises several concerns, such as side-effects, adherence, costs, and patient willingness to stop therapy. Recent data showed the feasibility, efficacy, and safety of stopping antiviral therapy in carefully selected CHB patients, leading to its incorporation in international guidelines. Patients who discontinue NUC have a higher likelihood of hepatitis B surface antigen (HBsAg) loss compared to patients who continue on therapy. Recommendations pertaining endpoints allowing safety discontinuation of NUC therapy differ among international guidelines. For hepatitis B e antigen (HBeAg)-positive patients, durable HBeAg seroconversion is considered an acceptable treatment endpoint. For HBeAg-negative patients, some guidelines propose undetectability hepatitis B virus DNA for at least 2 or 3 years, while others consider HBsAg loss as the only acceptable endpoint. CHB patients who stop therapy should remain under strict clinical and laboratorial follow-up protocols to detect and manage relapses in a timely manner. No reliable predictor of relapse has been consistently identified to date, although quantitative HBsAg has been increasingly studied as a reliable biomarker to predict safe NUC discontinuation.
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Affiliation(s)
- Renato Medas
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
| | - Rodrigo Liberal
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
| | - Guilherme Macedo
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
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40
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Huang PY, Wang JH, Hung CH, Lu SN, Hu TH, Chen CH. The role of hepatitis B virus core-related antigen in predicting hepatitis B virus relapse after cessation of entecavir in hepatitis B e antigen-negative patients. J Viral Hepat 2021; 28:1141-1149. [PMID: 33932245 DOI: 10.1111/jvh.13528] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/12/2021] [Accepted: 04/17/2021] [Indexed: 12/29/2022]
Abstract
This study investigated the ability of hepatitis B core-related antigen (HBcrAg) to predict hepatitis B virus (HBV) relapse in HBeAg-negative patients after cessation of entecavir therapy. A total of 301 HBeAg-negative patients without cirrhosis who had stopped entecavir therapy for at least 12 months were recruited. All patients fulfilled the stopping criteria proposed by the APASL 2012 guidelines. The five-year cumulative rates of virological relapse, clinical relapse and HBsAg loss were 71.6%, 57.3% and 18.7%, respectively. Serum HBsAg at end of treatment (EOT) was an independent predictor of virological relapse, clinical relapse and HBsAg loss; an EOT HBsAg of 150 IU/ml was the optimal cut-off value. The 5-year virological relapse rates for patients with <150 and ≥150 IU/ml HBsAg at EOT were 43.3% and 82.2% (p < 0.001), clinical relapse rates were 32.3% and 66.3% (p < 0.001), and HBsAg loss rates were 46.1% and 5.2% (p < 0.001), respectively. A baseline HBcrAg of 4 IU/ml was the optimal cut-off value for predicting HBV relapse. Among patients with an EOT HBsAg <150 IU/ml, the five-year virological relapse rates for patients with baseline HBcrAg levels ≤4 and >4 log U/ml were 27.9% and 59.1% (p = 0.006) and the clinical relapse rates were 18% and 48.1% (p = 0.014), respectively. EOT HBcrAg was not a significant predictor of virological or clinical relapse after cessation of entecavir. In conclusion, the combination of an EOT HBsAg of 150 IU/ml and baseline HBcrAg of 4 log U/ml can effectively predict the risk of HBV relapse after stopping entecavir therapy.
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Affiliation(s)
- Pao-Yuan Huang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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41
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Abstract
Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.
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Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan
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42
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APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients. Hepatol Int 2021; 15:833-851. [PMID: 34297329 DOI: 10.1007/s12072-021-10223-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is currently incurable. Long-term treatment with potent and safe nucleos(t)ide analogs (NAs) can reduce hepatocellular carcinoma (HCC) and cirrhosis-related complications through profound viral suppression. However, indefinite therapy raises several crucial issues with pros and cons. Because seroclearance of hepatitis B surface (HBsAg) as functional cure is not easily achievable, a finite therapy including sequential 48-week pegylated interferon therapy may provide an opportunity to facilitate HBsAg seroclearance by the rejuvenation of exhausted immune cells. However, the cost of stopping NA is the high incidence of virological relapse and surge of alanine aminotransferase (ALT) levels, which may increase the risk of adverse outcomes (e.g., decompensation, fibrosis progression, HCC, or liver-related mortality). So far, the APASL criteria to stop NA treatment is undetectable HBV DNA levels with normalization of ALT; however, this criterion for cessation of treatment is associated with various incidence rates of virological/clinical relapse and more than 40% of NA-stoppers eventually receive retreatment. A very intensive follow-up strategy and identification of low-risk patients for virological/clinical relapse by different biomarkers are the keys to stop the NA treatment safely. Recent studies suggested that decreasing HBsAg level at the end-of-treatment to < 100-200 IU/mL seems to be a useful marker for deciding when to discontinue NAs therapy. In addition, several viral and host factors have been reviewed for their potential roles in predicting clinical relapse. Finally, the APASL guidance has proposed rules to stop NA and the subsequent follow-up strategy to achieve a better prognosis after stopping NA. In general, for both HBeAg-positive and HBeAg-negative patients who have stopped treatment, these measurements should be done every 1-3 months at the minimum until 12 months.
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43
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Boyd A, Dezanet LNC, Lacombe K. Functional Cure of Hepatitis B Virus Infection in Individuals With HIV-Coinfection: A Literature Review. Viruses 2021; 13:1341. [PMID: 34372547 PMCID: PMC8309973 DOI: 10.3390/v13071341] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022] Open
Abstract
In individuals infected with hepatitis B virus (HBV), the loss of hepatitis B surface antigen (HBsAg) is the ultimate therapeutic goal, which defines "functional cure." For individuals living with human immunodeficiency virus (HIV), functional cure occurs roughly 2 per 100 person-years during potent anti-HBV containing antiretroviral therapy. Although this rate may be higher than expected in treated HBV mono-infected individuals, rates of functional cure widely vary between studies (0.6-10.5 per 100 person-years). Similar to HBV mono-infection, the phase of HBV infection, HBV (sub-)genotypes and hepatitis B "e" Ag-negative variants are associated with functional cure in treated HIV-HBV co-infection. In specifically HIV-HBV co-infected individuals, strong increases in CD4+ T cell counts after treatment initiation have also been linked to functional cure, yet this finding is inconsistent across studies. Several markers directly or indirectly reflecting HBV activity are being developed to predict functional cure, such as quantification of HBsAg, hepatitis B core-related antigen, HBsAg protein composition, anti-hepatitis B core antibodies and interferon-gamma-inducible protein 10. Few have been assessed during treatment in HIV-HBV co-infected individuals and none have been validated to predict functional cure. Novel therapeutics for HBV cure are essential for individuals with HIV-HBV co-infection and need to be separately evaluated in this population.
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Affiliation(s)
- Anders Boyd
- Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, 1018 WT Amsterdam, The Netherlands
- Stichting HIV Monitoring, 1105 BD Amsterdam, The Netherlands
| | - Lorenza N. C. Dezanet
- Institut Pierre Louis d’Épidémiologie et de Santé Publique, INSERM, IPLESP, Sorbonne Université, 75012 Paris, France; (L.N.C.D.); (K.L.)
| | - Karine Lacombe
- Institut Pierre Louis d’Épidémiologie et de Santé Publique, INSERM, IPLESP, Sorbonne Université, 75012 Paris, France; (L.N.C.D.); (K.L.)
- APHP, Hôpital Saint-Antoine, Service de Maladies Infectieuses et Tropicales, 75012 Paris, France
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44
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Peng CW, Jeng WJ. The main reasons for finite Nuc therapy in HBeAg-negative chronic hepatitis B patients. Hepatol Int 2021; 15:527-528. [PMID: 33904110 DOI: 10.1007/s12072-021-10168-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 02/22/2021] [Indexed: 11/28/2022]
Affiliation(s)
- Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Branch, Taiwan, 199, Tung Hwa North Road, Taipei, 105, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Branch, Taiwan, 199, Tung Hwa North Road, Taipei, 105, Taiwan. .,College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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45
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Cheng HR, Yang HC, Lin SR, Yang TY, Lin YY, Su TH, Tseng TC, Liu CJ, Kao JH. Combined viral quasispecies diversity and hepatitis B core-related antigen predict off-nucleos(t)ide analog durability in HBeAg-negative patients. Hepatol Int 2021; 15:582-592. [PMID: 33886088 DOI: 10.1007/s12072-021-10186-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/31/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Viral quasispecies dynamics between pre- and post-nucleos(t)ide analog (NA) therapy remains unclear. AIM This study aimed to investigate the HBV quasispecies evolution and its relationship with durability of off-therapy responses in HBeAg-negative chronic hepatitis B (CHB) patients who stopped NA therapy. METHODS Fifty-four HBeAg-negative CHB patients who stopped NAs, including 19 virological controllers (VC) who maintained serum HBV DNA < 2000 IU/mL beyond 1-year off-therapy, and 35 virological relapsers (VR) experiencing virological relapse within 1-year off-therapy were recruited. Viral quasispecies was analyzed by deep sequencing. Hepatitis B core-related antigen (HBcrAg) and HBsAg were also measured. RESULTS VC had significantly higher baseline viral quasispecies diversity of the precore/core gene, measured by nucleotide diversity, than VR. Low baseline viral nucleotide diversity (< 0.01) and high HBcrAg (≧ 2.0 KU/mL), but not HBsAg, at end of treatment (EOT) were significantly associated with higher risk of 1-year virological relapse (hazard ratio [HR] 6.09 and 3.31, respectively). Combination of low baseline viral nucleotide diversity and high HBcrAg at EOT could identify patients at high risk (HR 15.82). Further analysis of the evolution of HBV whole genome showed that HBV nucleotide diversity negatively correlated with serum HBV DNA levels. Notably, the viral quasispecies diversity between pre- and post-NA treatment remained relatively unchanged. CONCLUSION Higher baseline HBV quasispecies diversity associates with more durable off-therapy viral suppression in HBeAg-negative CHB patients. Combination of baseline viral nucleotide diversity and HBcrAg at EOT can identify patients at high risk for virological relapse after stopping NAs.
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Affiliation(s)
- Huei-Ru Cheng
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan
| | - Hung-Chih Yang
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Su-Ru Lin
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan
| | - Ta-Yu Yang
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan.
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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46
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Liaw YF. Hepatitis B Flare After Cessation of Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B: To Retreat or Not to Retreat. Hepatology 2021; 73:843-852. [PMID: 32810321 DOI: 10.1002/hep.31525] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/14/2020] [Accepted: 08/03/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Yun-Fan Liaw
- Liver Research UnitChang Gung Memorial HospitalChang Gung University College of MedicineTaipeiTaiwan
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Su T, Kao J. Withdrawal of Nucleos(t)ide Analogues in Hepatitis B e Antigen-Negative Patients: An Asian Perspective. Clin Liver Dis (Hoboken) 2021; 16:244-248. [PMID: 33489096 PMCID: PMC7805293 DOI: 10.1002/cld.950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/22/2020] [Accepted: 03/06/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Tung‐Hung Su
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan,Department of Internal MedicineNational Taiwan University College of MedicineTaipeiTaiwan,Hepatitis Research CenterNational Taiwan University HospitalTaipeiTaiwan
| | - Jia‐Horng Kao
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan,Department of Internal MedicineNational Taiwan University College of MedicineTaipeiTaiwan,Hepatitis Research CenterNational Taiwan University HospitalTaipeiTaiwan,Graduate Institute of Clinical MedicineNational Taiwan University College of MedicineTaipeiTaiwan,Department of Medical ResearchNational Taiwan University HospitalTaipeiTaiwan
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Manolakopoulos S, Kranidioti H, Kourikou A, Deutsch MM, Triantos C, Tsolias C, Manesis EK, Mathou N, Alexopoulou A, Hadziyannis E, Papatheodoridis G. Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues. Liver Int 2021; 41:48-57. [PMID: 33373114 DOI: 10.1111/liv.14654] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 08/11/2020] [Accepted: 08/24/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Discontinuation of nucleos(t)ide analogues (NA) remains a debatable issue in HBeAg-negative chronic hepatitis B (CHB). This study aimed to address the outcome of HBeAg-negative CHB patients who discontinued NA therapy. METHODS This prospective study included 57 non-cirrhotic HBeAg-negative Caucasian CHB patients who discontinued NA therapy after median virological remission of 6 years. All patients had regular blood tests. Virological relapse was defined as HBV DNA > 2000 IU/mL or >20 000 IU/mL and biochemical relapse as ALT > ULN (40 IU/mL) or >2xULN. All patients with retreatment predefined criteria restarted entecavir or tenofovir. RESULTS Of the 57 patients, 29 remained without retreatment after median follow-up of 65 months (range: 36-87) following treatment discontinuation. At 3, 6, 12, 24, 36 and 48 months, cumulative rates of retreatment were 16%, 20%, 32%, 35%, 46% and 50%, while the proportion of patients with HBV DNA < 2000 IU/mL and ALT < ULN were 73%, 60%, 52%, 52%, 47% and 37% respectively. All patients had virological and biochemical response after retreatment. No patient developed liver failure, hepatocellular carcinoma or death. Cumulative rates of HBsAg loss were 2%, 4%, 7%, 10% and 20% at 3, 6, 12, 24 and 36 months. HBsAg levels < 100 IU/mL at the end of NA treatment could predict HBsAg loss (P = .001). CONCLUSIONS Our study supports that NA therapy can be safely stopped in non-cirrhotic patients with HBeAg-negative CHB. Over a median follow-up of more than 5 years, half of the patients remained without retreatment with a substantial proportion of them achieving functional cure.
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Affiliation(s)
- Spilios Manolakopoulos
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Academic Department of Gastroenterology, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Hariklia Kranidioti
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Kourikou
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Melanie-Maria Deutsch
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Athens, Greece
| | - Chrysostomos Tsolias
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Athens, Greece
| | | | - Nicoletta Mathou
- Department of Gastroenterology, "Konstantopoulio-Patission" General Hospital, Nea Ionia, Athens, Greece
| | - Alexandra Alexopoulou
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Emilia Hadziyannis
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George Papatheodoridis
- Academic Department of Gastroenterology, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Shih C, Wu SY, Chou SF, Yuan TTT. Virion Secretion of Hepatitis B Virus Naturally Occurring Core Antigen Variants. Cells 2020; 10:cells10010043. [PMID: 33396864 PMCID: PMC7823318 DOI: 10.3390/cells10010043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/21/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023] Open
Abstract
In natural infection, hepatitis B virus (HBV) core protein (HBc) accumulates frequent mutations. The most frequent HBc variant in chronic hepatitis B patients is mutant 97L, changing from an isoleucine or phenylalanine to a leucine (L) at HBc amino acid 97. One dogma in the HBV research field is that wild type HBV secretes predominantly virions containing mature double-stranded DNA genomes. Immature genomes, containing single-stranded RNA or DNA, do not get efficiently secreted until reaching genome maturity. Interestingly, HBc variant 97L does not follow this dogma in virion secretion. Instead, it exhibits an immature secretion phenotype, which preferentially secretes virions containing immature genomes. Other aberrant behaviors in virion secretion were also observed in different naturally occurring HBc variants. A hydrophobic pocket around amino acid 97 was identified by bioinformatics, genetic analysis, and cryo-EM. We postulated that this hydrophobic pocket could mediate the transduction of the genome maturation signal for envelopment from the capsid interior to its surface. Virion morphogenesis must involve interactions between HBc, envelope proteins (HBsAg) and host factors, such as components of ESCRT (endosomal sorting complex required for transport). Immature secretion can be offset by compensatory mutations, occurring at other positions in HBc or HBsAg. Recently, we demonstrated in mice that the persistence of intrahepatic HBV DNA is related to virion secretion regulated by HBV genome maturity. HBV virion secretion could be an antiviral drug target.
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Affiliation(s)
- Chiaho Shih
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
- Correspondence: (C.S.); (T.-T.T.Y.)
| | - Szu-Yao Wu
- Chimera Bioscience Inc., No. 18 Siyuan St., Zhongzheng Dist., Taipei 10087, Taiwan;
| | - Shu-Fan Chou
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA;
| | - Ta-Tung Thomas Yuan
- TFBS Bioscience, Inc. 3F, No. 103, Ln 169, Kangning St., Xizhi Dist., New Taipei City 221, Taiwan
- Correspondence: (C.S.); (T.-T.T.Y.)
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50
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Liaw YF, Jeng WJ. Benefit of stopping finite nucleos(t)ide analogues therapy in chronic hepatitis B patients. Gut 2020; 69:1898-1899. [PMID: 31784470 DOI: 10.1136/gutjnl-2019-320341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 11/26/2019] [Accepted: 11/26/2019] [Indexed: 01/05/2023]
Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Wen-Juei Jeng
- Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Cente, Taipei, Taiwan
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