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Maung ST, Decharatanachart P, Chaiteerakij R. Hepatitis B Surface Antigen Seroclearance Rate After Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B-A Systematic Review and Meta-Analysis. J Gastroenterol Hepatol 2025; 40:1079-1104. [PMID: 40041970 DOI: 10.1111/jgh.16920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 05/11/2025]
Abstract
AIM To identify factors influencing HBsAg seroclearance rates after stopping nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB). METHODS We conducted a comprehensive literature search in databases from inception to July 2024. Subgroup analyses and meta-regression were performed to determine factors associated with HBsAg seroclearance, including ethnicity, HBV genotype, NA therapy duration, end-of-treatment (EOT) qHBsAg levels, HBeAg status, cirrhosis status, and follow-up duration. RESULTS The meta-analysis included 62 studies (n = 9867) with a pooled HBsAg seroclearance rate of 10% (95%CI: 8%-12%, I2 = 92%) after NA cessation. HBeAg-negative patients showed significantly higher rates than HBeAg-positive patients (11% vs. 5%, p = 0.030). Subgroup analysis revealed higher seroclearance with follow-up of >5 years (18%, p = 0.004), showing significantly higher rates were observed in studies with longer follow-up periods. Caucasians showed a higher rate (12%) than Asians (9%, p = 0.067). Studies adhering to AASLD, EASL, or APASL stopping rules showed no significant differences in rates. Patients with EOT qHBsAg ≤2.0 log IU/mL had higher rates (23%) than those with >2.0 log IU/mL (11%). Re-treated patients had lower seroclearance (6%) compared to those not re-treated (17%, p = 0.178). Meta-regression identified ethnicity, HBeAg status, and follow-up duration as significant contributors to heterogeneity. Egger's test showed no evidence of publication bias (p = 0.1928). CONCLUSION Our meta-analysis highlights the role of ethnicity, EOT qHBsAg levels, HBeAg-status, and follow-up duration in determining HBsAg seroclearance rates. These findings stress the need for personalized NA discontinuation strategies and further research on HBV genotypes and biomarkers to improve treatment outcomes and predict seroclearance more accurately.
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Affiliation(s)
- Soe Thiha Maung
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Ma Har Myaing Hospital, Yangon, Myanmar
| | - Pakanat Decharatanachart
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Division of Academic Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Li S, Shi L, Huang C, Li M, Meng T, Wang H, Zhao X, Xu X, You H, Jia J, Kong Y. Impact of hepatitis B surface antigen quantification on achieving a functional cure in patients with chronic hepatitis B: A systematic review and meta-analysis. Ann Hepatol 2025:101921. [PMID: 40316220 DOI: 10.1016/j.aohep.2025.101921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 03/17/2025] [Accepted: 03/25/2025] [Indexed: 05/04/2025]
Abstract
INTRODUCTION AND OBJECTIVES Baseline hepatitis B surface antigen (HBsAg) levels are associated with the likelihood of achieving HBsAg loss which defines the functional cure. However, optimal HBsAg cut-offs for predicting HBsAg loss have not been systematically investigated." Therefore, in this systematic review and meta-analysis, we evaluated the impact of baseline levels of HBsAg on achieving a functional cure in patients with chronic hepatitis B (CHB). MATERIALS AND METHODS We searched PubMed, Embase, and Cochrane Library up to December 31, 2023, to identify studies comparing combination therapy with nucleos(t)ide analogues (NAs) and conventional/pegylated interferon (IFN) versus monotherapy. We pooled the proportion of HBsAg loss among studies stratified by different 75th percentile of baseline HBsAg levels and other clinical characteristics. RESULTS We included 24 studies with 3446 participants. At the end of treatment, studies recruiting patients with 75th percentile of baseline HBsAg below 500 and 1000 IU/mL had the highest proportions of HBsAg loss in the combination group, reaching 14 % (95 % CI: 9-21 %) and 17 % (95 % CI: 10-24 %), respectively. One-year IFN-NAs combination treatment achieved a higher proportion of HBsAg loss (9 %, 95 % CI: 6-12 %) than six-month IFN-NAs treatment (1 %, 95 % CI: 0-2 %). Patients with normal alanine transaminase (ALT) had higher HBsAg loss (11 %, 95 % CI: 6-17 %) than those with elevated ALT (4 %, 95 % CI: 2-7 %). Meta-regression indicated a positive association between male percentage in studies and HBsAg loss. CONCLUSIONS The optimal baseline HBsAg thresholds would be 500-1000 IU/mL, which represents high-response subpopulation for achieving functional cure with currently available therapy.
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Affiliation(s)
- Shun Li
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Lichen Shi
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, China.
| | - Cheng Huang
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, China.
| | - Min Li
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Tongtong Meng
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Hao Wang
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Xinyu Zhao
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Xiaoqian Xu
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Hong You
- National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Jidong Jia
- Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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Mahajan A, Kharawala S, Desai S, Kendrick S, Das J, Gielen V. Association of Hepatitis B Surface Antigen Levels With Long-Term Complications in Chronic Hepatitis B Virus Infection: A Systematic Literature Review. J Viral Hepat 2024; 31:746-759. [PMID: 39150061 DOI: 10.1111/jvh.13988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 07/09/2024] [Accepted: 07/17/2024] [Indexed: 08/17/2024]
Abstract
Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.
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Affiliation(s)
| | | | | | | | - Joyeta Das
- Research and Development, GSK, Brentford, Middlesex, UK
| | - Vera Gielen
- Research and Development, GSK, Brentford, Middlesex, UK
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Wang CW, Huang CF, Yeh ML, Liang PC, Jang TY, Wei YJ, Hsu PY, Hsieh MY, Lin YH, Huang JF, Dai CY, Chuang WL, Yu ML. Assessment of hepatitis B virus relapse in cancer patients receiving chemotherapy with prophylactic nucleos(t)ide analogues: Implications for overall mortality. Liver Int 2024; 44:2592-2604. [PMID: 38984849 DOI: 10.1111/liv.16030] [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: 02/16/2024] [Revised: 05/24/2024] [Accepted: 06/26/2024] [Indexed: 07/11/2024]
Abstract
BACKGROUND AND AIMS We aimed to explore the risk factors associated with virological and clinical relapse, as well as their impact on overall mortality, in hepatitis B virus (HBV)-infected patients receiving nucleos(t)ide analogues (NUCs) therapy prior to chemotherapy initiation. METHODS From 2010 to 2020, we conducted a prospective cohort study involving patients with HBV infection undergoing cytotoxic chemotherapy. We utilized the Kaplan-Meier method and Cox proportional hazard regression models to assess risk factors. RESULTS We observed that TDF or TAF (HR: 2.16, 95% CI 1.06-4.41; p = .034), anthracycline (HR: 1.73, 95% CI 1.10-2.73; p = .018), baseline HBV DNA (HR: 1.55, 95% CI 1.33-1.81; p < .001) and end-of-treatment HBsAg titre >100 IU/mL (HR: 7.81, 95% CI 1.94-31.51; p = .004) were associated with increased risk of virological relapse. Additionally, TDF or TAF (HR: 4.91, 95% CI 1.45-16.64; p = .011), baseline HBV DNA (HR: 1.48, 95% CI 1.10-1.99; p = .009) and end-of-treatment HBsAg titre >100 IU/mL (HR: 6.09, 95% CI .95-38.87; p = .056) were associated with increased risk of clinical relapse. Furthermore, we found that virological relapse (HR: 3.32, 95% CI 1.33-8.32; p = .010) and clinical relapse (HR: 3.59, 95% CI 1.47-8.80; p = .005) significantly correlated with all-cause mortality in HBV patients receiving cytotoxic chemotherapy with prophylactic NUCs therapy. CONCLUSIONS The risk of virological and clinical relapse was linked to baseline HBV DNA, end-of-treatment HBsAg levels and TDF or TAF for prophylaxis; additionally, experiencing relapse heightens the risk of all-cause mortality. Further research is warranted to explore potential strategies for preventing virological and clinical relapse in high-risk patients.
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Affiliation(s)
- Chih-Wen Wang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tyng-Yuan Jang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Ju Wei
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Yao Hsu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
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Leowattana W, Leowattana P, Leowattana T. Quantitative hepatitis B core antibody and quantitative hepatitis B surface antigen: Novel viral biomarkers for chronic hepatitis B management. World J Hepatol 2024; 16:550-565. [PMID: 38689745 PMCID: PMC11056893 DOI: 10.4254/wjh.v16.i4.550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/03/2024] [Accepted: 03/12/2024] [Indexed: 04/24/2024] Open
Abstract
The management of hepatitis B virus (HBV) infection now involves regular and appropriate monitoring of viral activity, disease progression, and treatment response. Traditional HBV infection biomarkers are limited in their ability to predict clinical outcomes or therapeutic effectiveness. Quantitation of HBV core antibodies (qAnti-HBc) is a novel non-invasive biomarker that may help with a variety of diagnostic issues. It was shown to correlate strongly with infection stages, hepatic inflammation and fibrosis, chronic infection exacerbations, and the presence of occult infection. Furthermore, qAnti-HBc levels were shown to be predictive of spontaneous or treatment-induced HBeAg and HBsAg seroclearance, relapse after medication termination, re-infection following liver transplantation, and viral reactivation in the presence of immunosuppression. qAnti-HBc, on the other hand, cannot be relied on as a single diagnostic test to address all problems, and its diagnostic and prognostic potential may be greatly increased when paired with qHBsAg. Commercial qAnti-HBc diagnostic kits are currently not widely available. Because many methodologies are only semi-quantitative, comparing data from various studies and defining universal cut-off values remains difficult. This review focuses on the clinical utility of qAnti-HBc and qHBsAg in chronic hepatitis B management.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand.
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
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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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Huang CW, Yang CT, Su PY, Chen YY, Huang SP, Yen HH. Long-Term Hepatitis B Surface Antigen Profile and Seroclearance Following Antiviral Treatment: A Single-Center, Real-World Cohort Study. Biomedicines 2023; 11:2966. [PMID: 38001966 PMCID: PMC10669103 DOI: 10.3390/biomedicines11112966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/04/2023] [Accepted: 11/01/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatitis B surface antigen (HBsAg) seroclearance, an indicator of recovery from hepatitis B virus (HBV) infection, is uncommon in long-term nucleos(t)ide analog (NUC) therapy. We compared the incidence of HBsAg seroclearance in patients with and without NUC discontinuation to identify predictors of HBsAg seroclearance. This retrospective study enrolled adult patients with a chronic HBV infection followed for ≥12 months after NUC discontinuation (finite group) and those treated with NUCs for >3 years (non-finite group). Demographic, clinical, and laboratory data were analyzed. The study cohort included 978 patients, including 509 and 469 patients in the finite and non-finite groups, respectively. Cumulative HBsAg seroclearance incidence was significantly higher in the finite group than in the non-finite group (p = 0.006). The 5- and 10-year cumulative HBsAg seroclearance incidence were 6.6% and 18.9% in the finite group and 3% and 14.6% in the non-finite group, respectively. The likelihood of HBsAg seroclearance was higher in those with end of treatment (EOT) HBsAg levels of <100 IU/mL and in those without clinical relapse (CR). The cumulative 3-year CR incidence was 16.8%. The incidence of liver decompensation and hepatocellular carcinoma were 4.1 and 0.4 per 1000 person-years, respectively. The hepatocellular carcinoma incidence did not significantly differ between the finite and non-finite groups (p = 0.941). In conclusion, higher HBsAg seroclearance incidence in patients receiving finite therapy, and the increased likelihood of HBsAg seroclearance in those with EOT HBsAg levels of <100 IU/mL and in those without CR should be considered during decision-making of treatment options.
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Affiliation(s)
- Chih-Wen Huang
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
| | - Chen-Ta Yang
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Pei-Yuan Su
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Yang-Yuan Chen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Siou-Ping Huang
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
| | - Hsu-Heng Yen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
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Gane EJ, Kim W, Lim TH, Tangkijvanich P, Yoon JH, Sievert W, Sukeepaisarnjaroen W, Thompson AJ, Pavlovic V, Surujbally B, Wat C, Brown BD, Achneck HE, Yuen MF. First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection. J Hepatol 2023; 79:1139-1149. [PMID: 37524230 DOI: 10.1016/j.jhep.2023.07.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 06/12/2023] [Accepted: 07/09/2023] [Indexed: 08/02/2023]
Abstract
BACKGROUND & AIMS RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). METHODS This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg (n = 6) or placebo (n = 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n = 4 in each cohort) or placebo (n = 6). RESULTS RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. CONCLUSIONS These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. CLINICAL TRIAL NUMBER ClinicalTrials.gov NCT03772249. IMPACT AND IMPLICATIONS Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians.
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Affiliation(s)
- Edward J Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital and University of Auckland, Auckland, New Zealand
| | - Won Kim
- Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
| | | | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| | | | | | | | | | | | | | - Cynthia Wat
- Roche Products, Welwyn Garden City, United Kingdom
| | - Bob D Brown
- Dicerna Pharmaceuticals Inc., a Novo Nordisk Company, Lexington, Massachusetts, United States
| | - Hardean E Achneck
- Dicerna Pharmaceuticals Inc., a Novo Nordisk Company, Lexington, Massachusetts, United States
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
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9
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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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10
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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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11
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Xie Y, Li M, Ou X, Zheng S, Gao Y, Xu X, Yang Y, Ma A, Li J, Nan Y, Zheng H, Liu J, Wei L, Feng B. Lower end of treatment HBsAg and HBcrAg were associated with HBsAg loss after nucleos(t)ide analog cessation. BMC Gastroenterol 2023; 23:224. [PMID: 37386460 PMCID: PMC10308768 DOI: 10.1186/s12876-023-02852-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Since hepatitis B surface antigen (HBsAg) loss is rarely achieved with nucleos(t)ide analog (NA) treatment, most patients require life-long NA treatment. Previous studies have shown that some patients remain virologically responsive even after NA cessation. However, there is still controversy surrounding whether NA discontinuation increases the HBsAg loss rate. Therefore, this study aimed to assess the cumulative rate of HBsAg loss and identify the predictors of HBsAg loss after NA discontinuation. METHODS This multicenter prospective study included HBV e antigen (HBeAg)-positive patients without cirrhosis from 12 hospitals in China who met the inclusion criteria. The enrolled patients stopped NA and were followed up with clinical and laboratory assessments every 3 months for 24 months after NA cessation or until clinical relapse (CR) occurred. RESULTS Overall, 158 patients were classified into two groups. Group A included patients with HBsAg positivity at NA cessation (n = 139), and Group B included patients with HBsAg negativity at NA cessation (n = 19). In Group A, the 12-month and 24-month cumulative rates of HBsAg loss were4.3%and 9.4%, respectively. End of treatment (EOT) HBsAg (hazard ratio (HR) = 0.152, P < 0.001) and EOT hepatitis B core-related antigen (HBcrAg) (HR = 0.257, P = 0.001) were associated with HBsAg loss. The areas under the receiver operating characteristic curves for EOT HBsAg and HBcrAg levels were 0.952 (P < 0.001) and 0.765 (P < 0.001), respectively. Patients with EOT HBsAg ≤ 135 IU/mL (59.2% vs. 1.3%, P < 0.001) or HBcrAg ≤ 3.6 logU/mL (17% vs. 5.4%, P = 0.027) had a higher 24-month cumulative HBsAg loss rate. In Group B, none of the patients experienced virological relapse after NA cessation. Only 1 (5.3%) patient had HBsAg reversion. CONCLUSIONS EOT HBsAg ≤ 135 IU/mL or HBcrAg ≤ 3.6 logU/mL can be used to identify patients with a higher likelihood of HBsAg loss after NA cessation. Patients with HBsAg negativity after NA cessation have favorable clinical outcomes, and HBsAg loss was durable in most cases.
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Affiliation(s)
- Yandi Xie
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China
| | - Minghui Li
- Department of Hepatology Division, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Sujun Zheng
- Complicated Liver Diseases and Artificial Liver Treatment and Training Center, Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment and Research, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Yinjie Gao
- Department of Infectious Diseases, The Fifth Medical Center, General Hospital of PLA, Beijing, 100039, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Ying Yang
- Department of Infectious Diseases, The Second Hospital of Xingtai, Xingtai, Hebei, 054001, China
| | - Anlin Ma
- Department of Infectious Disease, Friendship Hospital, Beijing, 100029, China
| | - Jia Li
- Department of Liver Disease, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China
| | - Huanwei Zheng
- Department of Liver Disease, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, 050021, China
| | - Juan Liu
- Research Center for Technologies in Nucleic Acid-Based Diagnostics, Changsha, Hunan, 410205, China
| | - Lai Wei
- Department of Hepatopancreatobiliary Disease, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Bo Feng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China.
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12
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Ruta S, Grecu L, Iacob D, Cernescu C, Sultana C. HIV-HBV Coinfection-Current Challenges for Virologic Monitoring. Biomedicines 2023; 11:1306. [PMID: 37238976 PMCID: PMC10215721 DOI: 10.3390/biomedicines11051306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
HIV-HBV coinfected patients have higher rates of liver-related morbidity, hospitalizations, and mortality compared to HBV or HIV mono-infected ones. Clinical studies have shown an accelerated progression of liver fibrosis and an increased incidence of HCC, resulting from the combined action of HBV replication, immune-mediated hepatocytolysis, and HIV-induced immunosuppression and immunosenescence. Antiviral therapy based on dually active antiretrovirals is highly efficient, but late initiation, global disparities in accessibility, suboptimal regimens, and adherence issues may limit its impact on the development of end-stage liver disease. In this paper, we review the mechanisms of liver injuries in HIV-HBV coinfected patients and the novel biomarkers that can be used for treatment monitoring in HIV-HBV coinfected persons: markers that assess viral suppression, markers for liver fibrosis evaluation, and predictors of oncogenesis.
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Affiliation(s)
- Simona Ruta
- Virology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Laura Grecu
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Diana Iacob
- Department for the Prevention and Control of Healthcare Associated Infections, Emergency University Hospital, 050098 Bucharest, Romania;
| | | | - Camelia Sultana
- Virology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
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13
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Kostyushev D, Kostyusheva A, Brezgin S, Ponomareva N, Zakirova NF, Egorshina A, Yanvarev DV, Bayurova E, Sudina A, Goptar I, Nikiforova A, Dunaeva E, Lisitsa T, Abramov I, Frolova A, Lukashev A, Gordeychuk I, Zamyatnin AA, Ivanov A, Chulanov V. Depleting hepatitis B virus relaxed circular DNA is necessary for resolution of infection by CRISPR-Cas9. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 31:482-493. [PMID: 36865089 PMCID: PMC9972396 DOI: 10.1016/j.omtn.2023.02.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 02/01/2023] [Indexed: 02/05/2023]
Abstract
CRISPR-Cas9 systems can directly target the hepatitis B virus (HBV) major genomic form, covalently closed circular DNA (cccDNA), for decay and demonstrate remarkable anti-HBV activity. Here, we demonstrate that CRISPR-Cas9-mediated inactivation of HBV cccDNA, frequently regarded as the "holy grail" of viral persistence, is not sufficient for curing infection. Instead, HBV replication rapidly rebounds because of de novo formation of HBV cccDNA from its precursor, HBV relaxed circular DNA (rcDNA). However, depleting HBV rcDNA before CRISPR-Cas9 ribonucleoprotein (RNP) delivery prevents viral rebound and promotes resolution of HBV infection. These findings provide the groundwork for developing approaches for a virological cure of HBV infection by a single dose of short-lived CRISPR-Cas9 RNPs. Blocking cccDNA replenishment and re-establishment from rcDNA conversion is critical for completely clearing the virus from infected cells by site-specific nucleases. The latter can be achieved by widely used reverse transcriptase inhibitors.
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Affiliation(s)
- Dmitry Kostyushev
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119991, Russia
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, Sochi 354340, Russia
| | - Anastasiya Kostyusheva
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119991, Russia
| | - Sergey Brezgin
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119991, Russia
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, Sochi 354340, Russia
| | - Natalia Ponomareva
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119991, Russia
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, Sochi 354340, Russia
- Department of Pharmaceutical and Toxicological Chemistry, Sechenov First Moscow State Medical University, Moscow 119146, Russia
| | - Natalia F. Zakirova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow 119991, Russia
| | - Aleksandra Egorshina
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119991, Russia
| | - Dmitry V. Yanvarev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow 119991, Russia
| | - Ekaterina Bayurova
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 108819, Russia
| | - Anna Sudina
- Federal State Budgetary Institution Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological Agency, Moscow 119435, Russia
| | - Irina Goptar
- Izmerov Research Institute of Occupational Health, Moscow 105275, Russia
| | | | - Elena Dunaeva
- Central Research Institute of Epidemiology, Moscow 111123, Russia
| | - Tatiana Lisitsa
- Federal State Budgetary Institution Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological Agency, Moscow 119435, Russia
| | - Ivan Abramov
- Federal State Budgetary Institution Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological Agency, Moscow 119435, Russia
| | - Anastasiia Frolova
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Alexander Lukashev
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119991, Russia
| | - Ilya Gordeychuk
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 108819, Russia
- Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow 127994, Russia
| | - Andrey A. Zamyatnin
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, Sochi 354340, Russia
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow 119991, Russia
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Alexander Ivanov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow 119991, Russia
| | - Vladimir Chulanov
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, Sochi 354340, Russia
- Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow 127994, Russia
- Department of Infectious Diseases, Sechenov First Moscow State Medical University, Moscow 119146, Russia
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia
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14
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Yao Y, Zhang J, Li X, Zao X, Cao X, Chen G, Ye Y. Systematic review: Clinical outcomes of discontinuation of oral antivirals in hepatitis B-related liver cirrhosis. Front Public Health 2022; 10:1037527. [PMID: 36407996 PMCID: PMC9670108 DOI: 10.3389/fpubh.2022.1037527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Background Discontinuation of Nucleos(t)ide analogs (NAs) remains one of the most controversial topics in the management of hepatitis B-related liver cirrhosis. However, clinical outcomes after NAs discontinuation have not been studied. Aim The aim of this systematic review is to evaluate existing data on clinical outcomes of NAs withdrawal in chronic hepatitis B (CHB) patients with cirrhosis. Methods A literature search (until May 2022) was performed in order to identify all published studies including hepatitis B-related cirrhotic patients who discontinued NAs in virological remission with off-therapy follow-up >12 months. Results Nineteen studies with 1,287 hepatitis B-related cirrhotic patients were included. Most cirrhotic patients were compensated and achieved complete virological suppression when they stopped the antiviral therapy. The pooled proportions of virological relapse and clinical relapse after NAs discontinuation in cirrhotic patients were 55.23 (95% CI: 40.33-69.67) and 43.56% (95% CI: 26.13-61.85), respectively. HBsAg loss was observed in 56 of 500 (pooled proportion = 13.68%, 95% CI: 5.82-24.18) cirrhotic patients. And the pooled proportions of HCC development, hepatic decompensation and overall mortality were 8.76 (95% CI: 2.25-18.95), 3.63 (95% CI: 1.31-7.03), and 0.85% (95% CI: 0.35-1.57), respectively, after NAs discontinuation in cirrhotic patients. Conclusion In hepatitis B-related compensated cirrhosis, who have achieved complete virological suppression, discontinuation of oral antivirals still carries a high relapse rate, but the incidence of adverse events is generally low and controlled during follow-up of at least 12 months. Of attention is that discontinuation of NAs can achieve a high rate of HBsAg seroclearance. This study may be helpful in the management of NAs in cirrhotic patients. Systematic review registration http://www.crd.york.ac.uk/PROSPERO, identifier: CRD42020170103.
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Affiliation(s)
- Yuhao Yao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- First School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaxin Zhang
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoke Li
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaobin Zao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xu Cao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Yong'an Ye
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
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15
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Lok J, Dusheiko G, Carey I, Agarwal K. Review article: novel biomarkers in hepatitis B infection. Aliment Pharmacol Ther 2022; 56:760-776. [PMID: 35770458 DOI: 10.1111/apt.17105] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Chronic hepatitis B remains a global health problem with an estimated 296 million people affected worldwide. Individuals are at risk of serious complications such as cirrhosis and hepatocellular carcinoma and accurately predicting these clinical endpoints has proven difficult. However, several viral biomarkers have recently been developed, including quantitative HBV surface antigen (qHBsAg), hepatitis B RNA (HBV RNA) and core-related antigen (HBcrAg), and shown promise in a range of clinical settings. AIMS To critically appraise these novel biomarkers, exploring their potential uses, availability of assays and areas for future development. METHODS We performed a literature search of PubMed, identifying articles published in the field of hepatitis B biomarkers between 2010 and 2022. RESULTS Novel biomarkers such as HBcrAg, HBV RNA and qHBsAg may be useful in predicting treatment outcomes, stratifying the risk of future complications and estimating off-treatment viral reactivation. Furthermore, HBV RNA and HBcrAg titres may accurately reflect cccDNA transcriptional activity, and this is particularly informative in the context of nucleoside analogue therapy. On a cautionary note, most studies have been performed in Caucasian or Asian populations, and methods for detecting HBV RNA lack standardisation. CONCLUSION Novel viral biomarkers have the potential to provide additional insights into the natural history of infection and allow a more bespoke, cost-effective framework of care. However, access remains limited, and further efforts are needed to validate their use in ethnically diverse populations, confirm predictive cut-off values, and establish their role in the era of novel antiviral therapies.
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Affiliation(s)
- James Lok
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
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16
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Upadhyay P, Lal BB, Sood V, Khanna R, Gupta E, Rastogi A, Alam S. Incidence and Predictors of Relapse After Stopping Antiviral Therapy in Pediatric Chronic Hepatitis B. Pediatr Infect Dis J 2022; 41:714-719. [PMID: 35703278 DOI: 10.1097/inf.0000000000003602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND There are no definite end-points for stopping therapy in pediatric chronic hepatitis B (CHB). The study objective was to evaluate the incidence of relapse after stopping antiviral therapy and to identify its predictors. METHODS All hepatitis B surface antigen (HBsAg) positive children presenting to our hospital, who had been on antivirals for at least 2 years with undetectable hepatitis B virus-deoxyribonucleic acid (HBV-DNA) and normal alanine aminotransferase (ALT) on 3 consecutive occasions over last 12 months were included. Antivirals were stopped if liver biopsy showed histological activity index <5 and fibrosis (Ishak) <3. Virological relapse was defined as the elevation of HBV-DNA (>2000 IU/mL) and biochemical relapse as a rise in ALT levels to >2 times the upper limit of normal. Those having biochemical relapse were started on pegylated interferon alpha-2b-based sequential therapy. RESULTS Of the 114 children with CHB screened, 31 HBsAg-positive children fulfilled inclusion criteria and antivirals were stopped in them. Virological and biochemical relapse was seen in 12 (38.7%) and 5 (16.1%) children within 12 months of stopping antiviral treatment. On Cox regression, hepatitis B e antigen (HBeAg) positive status at the time of stopping antiviral therapy (HR: 6.208, 95% CI: 1.630-23.638) and longer time taken for HBV-DNA to become undetectable while on antivirals (HR: 1.027, 95% CI: 1.000-1.055) were the independent predictors of relapse. CONCLUSION Discontinuation of antiviral treatment in children with CHB resulted in relapse in one-third of the patients. Relapse was frequent in those who were HBeAg-positive at the time of stopping therapy and in those who required longer therapy for HBV-DNA to become undetectable.
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Affiliation(s)
- Piyush Upadhyay
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant Bihari Lal
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajeev Khanna
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ekta Gupta
- Department of Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Seema Alam
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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17
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Hall SAL, Vogrin S, Wawryk O, Burns GS, Visvanathan K, Sundararajan V, Thompson A. Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis. Gut 2022; 71:1629-1641. [PMID: 34493592 DOI: 10.1136/gutjnl-2020-323979] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 08/25/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Sustained virological suppression and hepatitis B surface antigen (HBsAg) loss have been described after nucleot(s)ide analogue (NA) discontinuation for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We performed a meta-analysis of the clinical outcomes after NA discontinuation for HBeAg-negative CHB. METHODS Studies involving NA cessation in HBeAg-negative CHB individuals with a median follow-up of ≥12 months were included. Participants were HBeAg-negative at the time of NA initiation. Random effects meta-analyses were performed for the following clinical outcomes: (1) virological relapse (VR) at 6 and 12 months; (2) clinical relapse (CR) at 6 and 12 months and (3) HBsAg loss. Effect of other variables was estimated using subgroup analysis and meta-regression. Studies including patients stopping entecavir (ETV) and/or tenofovir disoproxil fumarate (TDF) were considered separately to studies including patients stopping older generation NA. RESULTS N=37 studies met inclusion criteria. Cumulative incidence of VR and CR after stopping ETV/TDF was 44% and 17% at 6 months and 63% and 35% at 12 months. Similar relapse rates were observed after stopping older NAs. Among patients stopping ETV/TDF, TDF cessation was associated with increased CR rates at 6 months versus ETV. There was an association between follow-up ≥4 years and HBsAg loss rates when stopping older NAs. Hepatic decompensation and hepatocellular carcinoma were rare but occurred more frequently in studies including cirrhotic individuals. CONCLUSION VR is common after NA discontinuation, however, CR was only seen in one-third of patients at 12 months. Stopping NA therapy can be followed by HBsAg clearance, and rates are higher with longer follow-up.
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Affiliation(s)
| | - Sara Vogrin
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Olivia Wawryk
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Gareth S Burns
- Gastroenterology Department, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
| | - Kumar Visvanathan
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.,Infectious Diseases Department, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
| | - Vijaya Sundararajan
- Department of Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Alexander Thompson
- Gastroenterology Department, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
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Fang HW, Yen YH, Hung CH, Wang JH, Hu TH, Lu SN, Chen CH. Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir. Dig Dis Sci 2022; 67:3402-3411. [PMID: 34241753 DOI: 10.1007/s10620-021-07128-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/20/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The predictors of persistent virological suppression after clinical relapse remain unclear. AIMS To investigate the predictors of retreatment or persistent virological suppression after clinical relapse in chronic hepatitis B (CHB) patients who discontinued entecavir or tenofovir disoproxil fumarate (TDF). METHODS A total of 243 hepatitis B e antigen-negative CHB patients without cirrhosis who experienced clinical relapse after entecavir or TDF cessation were enrolled. RESULTS Of the 243 CHB patients, 192 received retreatment and 51 did not receive retreatment after clinical relapse. Of the 51 patients without retreatment, 23 achieved persistent virological suppression (persistent HBV DNA < 2000 IU/mL at least 2 years) and 10 experienced hepatitis B surface antigen (HBsAg) loss. The Cox regression analysis showed that short consolidation duration, short duration of the first clinical relapse from the end of treatment (EOT), and high bilirubin and HBV DNA levels at the first clinical relapse were independent predictors of retreatment. Long duration of the first clinical relapse from the EOT and low HBsAg levels at the first clinical relapse were independent factors of patients with persistent virological suppression. The rates of persistent virological suppression at the first clinical relapse among patients with HBsAg < 100 and ≥ 100 IU/mL were 44.4% (12/27) and 5.1% (11/216) (P < 0.001), respectively. Baseline HBsAg levels and no retreatment requirement were independent factors associated with HBsAg loss. CONCLUSIONS The HBsAg of 100 IU/mL at the first clinical relapse could predict persistent virological suppression after clinical relapse in patients who discontinued entecavir or TDF therapy.
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Affiliation(s)
- Hsin-Wei Fang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.
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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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20
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Hall SAL, Burns GS, Anagnostou D, Vogrin S, Sundararajan V, Ratnam D, Levy MT, Lubel JS, Nicoll AJ, Strasser SI, Sievert W, Desmond PV, Ngu MC, Angus P, Sinclair M, Meredith C, Matthews G, Revill PA, Jackson K, Littlejohn M, Bowden DS, Locarnini SA, Visvanathan K, Thompson AJ. Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels. Aliment Pharmacol Ther 2022; 56:310-320. [PMID: 35521992 DOI: 10.1111/apt.16968] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/06/2022] [Accepted: 04/28/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND AIMS Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss. METHODS We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNA RESULTS In total, 110 patients [62% entecavir (ETV); 28% tenofovir (TDF), 10% other] were enrolled. Median age was 56 years, 57% were male, 85% were Asian, median baseline HBsAg level was 705 (214-2325) IU/ml. Virological reactivation occurred in 109/110 patients, median time to detection was 8 (4-12) weeks, and occurred earlier after stopping TDF versus ETV (median 4 vs. 12 weeks p < 0.001). At week 96, 77 (70%) remained off-treatment, 65 (59%) had ALT <2× ULN, 31 (28%) patients were in disease remission with HBVDNA <2000 IU/ml plus ALT <2× ULN and 7 (6%) patients had lost HBsAg. Baseline HBsAg ≤10 IU/ml was associated with HBsAg loss (6/9 vs. 1/101 p < 0.001). ALT >5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues. CONCLUSION Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT <2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.
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Affiliation(s)
- Samuel A L Hall
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Gareth S Burns
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Despina Anagnostou
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
| | - Sara Vogrin
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Vijaya Sundararajan
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
- The Department of Public Health, La Trobe University, Melbourne, Australia
| | - Dilip Ratnam
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Australia
- Monash University, Melbourne, Australia
| | - Miriam T Levy
- Gastroenterology Department of Liverpool Hospital, Sydney, Australia
| | - John S Lubel
- Department of Gastroenterology, Alfred Health, Melbourne, Australia
- Central Clinical School, Monash University, The Alfred Centre, Melbourne, Australia
| | - Amanda J Nicoll
- Gastroenterology Department of Eastern Health, Melbourne, Australia
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
- University of Sydney, Sydney, Australia
| | - William Sievert
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Australia
- Monash University, Melbourne, Australia
| | - Paul V Desmond
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
| | - Meng C Ngu
- Gastroenterology Department of Concord Repatriation General Hospital, Sydney, Australia
| | - Peter Angus
- Department of Gastroenterology & Hepatology, Austin Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - Marie Sinclair
- Department of Gastroenterology & Hepatology, Austin Health, Melbourne, Australia
| | | | - Gail Matthews
- Department of infectious Disease, St Vincent's Hospital Sydney, Sydney, Australia
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - D Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Stephen A Locarnini
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Kumar Visvanathan
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Alexander J Thompson
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
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Hawkins C, Kang M, Bhattacharya D, Cloherty G, Kuhns M, Matining R, Thio C, Samaneka W, Chinula L, Mulinda N, Badal-Faesen S, Sugandhavesa P, Lama J, Gaseitsiwe S, Holzmayer V, Anderson M, Murphy R, Peters M. Hepatitis B surface antigen and hepatitis B RNA changes in HIV/hepatitis B virus co-infected participants receiving hepatitis B virus-active antiretroviral therapy. AIDS 2022; 36:975-984. [PMID: 35165216 PMCID: PMC9167724 DOI: 10.1097/qad.0000000000003193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION With advances in hepatitis B virus (HBV) therapies, there is a need to identify serum biomarkers that assess the HBV covalently closed circular DNA (cccDNA) reservoir and predict functional cure in HIV/HBV co-infection. METHODS In this retrospective study, combining samples from HIV/HBV co-infected participants enrolled in two ACTG interventional trials, proportions achieving HBsAg less than 0.05 log10 IU/ml and HBV RNA less than log10 1.65 U/ml or not detected (LLoQ/NEG) in response to DUAL [tenofovir TDF+emtricitabine (FTC)] vs. MONO [FTC or lamivudine (3TC)] HBV-active ART, were measured. Predictors of qHBsAg less than 0.05 log10 IU/ml were evaluated in logistic regression models. RESULTS There were 88 participants [58% women, median age 34; 47 on DUAL vs. 41 on MONO HBV-active ART]. Twenty-one percent achieved HBsAg less than 0.05 log10 IU/ml (30% DUAL vs. 10% MONO). Time to HBsAg less than 0.05 log10 IU/ml was lower (P = 0.02) and the odds of achieving HBsAg less than 0.05 log10 IU/ml were higher (P = 0.07) in DUAL participants. HBV RNA became less than LLoQ/NEG in 47% (DUAL 60% vs. MONO 33%). qHBsAg less than 3 log10 IU/ml was the strongest predictor of HBsAg less than 0.05 log10 IU/ml. CONCLUSION This study supports current recommendations of TDF-based DUAL-HBV active ART for initial use in HIV/HBV co-infection. HBV RNA could be a useful marker of treatment response in HIV/HBV co-infected patients on HBV-active ART.
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Affiliation(s)
- Claudia Hawkins
- Department of Medicine, Feinberg School of Medicine, Northwestern University CRS, Chicago, Illinois
| | - Minhee Kang
- Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Debika Bhattacharya
- David Geffen School of Medicine, Division of Infectious Diseases, University of California, Los Angeles (UCLA), California
| | - Gavin Cloherty
- Infectious Diseases Research, Abbott, Abbott Park, Illinois
| | - Mary Kuhns
- Infectious Diseases Research, Abbott, Abbott Park, Illinois
| | - Roy Matining
- Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Chloe Thio
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Lameck Chinula
- UNC Project Malawi CRS, UNC Department of Obstetrics and Gynecology's Division of Global Women's Health, Chapel Hill, North Carolina, USA
| | | | - Sharlaa Badal-Faesen
- Clinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | | | - Javier Lama
- Asociacion Civil Impacta Salud y Educacion, Lima, Peru, and Botswana Harvard School of Public Health AIDS Initiative Partnership, Botswana
| | - Simani Gaseitsiwe
- Clinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Vera Holzmayer
- Infectious Diseases Research, Abbott, Abbott Park, Illinois
| | - Mark Anderson
- Infectious Diseases Research, Abbott, Abbott Park, Illinois
| | - Robert Murphy
- Department of Medicine, Feinberg School of Medicine, Northwestern University CRS, Chicago, Illinois
| | - Marion Peters
- Department of Medicine, Feinberg School of Medicine, Northwestern University CRS, Chicago, Illinois
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22
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Tseng TN, Kuo YH, Hu TH, Hung CH, Wang JH, Lu SN, Chen CH. Kinetics in HBsAg after Stopping Entecavir or Tenofovir in Patients with Virological Relapse but Not Clinical Relapse. Viruses 2022; 14:v14061189. [PMID: 35746660 PMCID: PMC9227936 DOI: 10.3390/v14061189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/23/2022] [Accepted: 05/26/2022] [Indexed: 12/07/2022] Open
Abstract
This study investigated the kinetics in HBsAg and the HBsAg loss rate after entecavir or tenofovir disoproxil fumarate (TDF) cessation in patients with chronic hepatitis B (CHB) who achieved virological suppression after virological relapse without clinical relapse. A total 504 HBeAg-negative, non-cirrhotic patients who previously received entecavir or TDF with post-treatment and who were followed up for at least 30 months were included. Of the 504 patients, 128 achieved sustained virological suppression (Group I), and 81 experienced virological relapse without clinical relapse. Of the 81 patients, 52 had intermittent or persistent HBV DNA > 2000 IU/mL (Group II), and 29 achieved persistent virological suppression (HBV DNA < 2000 IU/mL) for at least 1.5 years (Group III) after virological relapse. A generalized estimating equations analysis showed that Groups I and III experienced larger off-treatment HBsAg declines than Group II (both, p < 0.001). The post-treatment HBsAg declines of Group I and Group III were similar (p = 0.414). A multivariate analysis showed that there were no differences in the HBsAg change and HBsAg decline (p = 0.920 and 0.886, respectively) or HBsAg loss rate (p = 0.192) between Group I and Group III. The patients who achieved persistent viral suppression after HBV relapse without clinical relapse have a similar decline in HBsAg and the HBsAg loss rate as the sustained responders.
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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Luo M, Zhou B, Hou J, Jiang D. Biomarkers for predicting nucleos(t)ide analogs discontinuation and hepatitis B virus recurrence after drug withdrawal in chronic hepatitis B patients. Hepatol Res 2022; 52:337-351. [PMID: 35089634 DOI: 10.1111/hepr.13749] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/22/2021] [Accepted: 01/20/2022] [Indexed: 12/11/2022]
Abstract
AIM To summarize HBV-related biomarkers predicting nucleos(t)ide analogs (NAs) discontinuation and hepatitis B virus (HBV) recurrence after drug withdrawal in chronic hepatitis B (CHB) patients, providing references for clinical medication, so as to manage CHB patients more scientifically. METHODS Related pieces of literature were retrieved in PubMed and the results were sorted out. We then analyzed and summarized these articles. RESULTS We found that HBV related biomarkers maybe could predict NAs withdrawal safely and the possibility of relapse after treatment cessation, including hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV DNA, HBV RNA, pregenomic-RNA (pgRNA), hepatitis B core-related antigen (HBcrAg), hepatitis B core antibody (anti-HBc), and models containing several indicators for predicting the effectiveness of treatment. CONCLUSIONS HBV DNA, HBV RNA, pgRNA, HBcrAg, anti-HBc, as well as the prediction models formed by several biomarkers could predict the safe discontinuation of NAs before HBsAg loss and recurrence.
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Affiliation(s)
- Mengqi Luo
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deke Jiang
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Wang CR, Zhong GC, Chen ZW, Hu P. A Nomogram for Predicting Non-Rebound in HBV-Infected Pregnant Women With Mother-to-Child Transmission Prevention. Front Med (Lausanne) 2021; 8:746759. [PMID: 34805216 PMCID: PMC8596549 DOI: 10.3389/fmed.2021.746759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 09/24/2021] [Indexed: 11/15/2022] Open
Abstract
Background: Current guidelines recommend that pregnancies with mother-to-child transmission (MTCT) prevention can cease antiviral treatment after delivery. We aimed to develop a nomogram for predicting non-rebound in HBV-infected pregnant women with MTCT prevention after post-partum nucleos(t)ide analogs (NAs) withdrawal based on parameters before treatment cessation. Methods: Pregnant women receiving antiviral therapy for MTCT prevention and who withdrew from taking NAs after delivery were included in this study. We used the least absolute shrinkage and selection operator (LASSO) logistics and a two-way stepwise regression to select prognostic factors for the risk model, and the concordance index (C-index) was used to assess its discrimination. Internal validation was performed through bootstrapping. Results: Of 92 included patients, 16 and 76 experienced non-rebound and virologic rebound within 48 weeks of post-partum NAs cessation, respectively. Platelet to lymphocyte ratio (PLR) at 34 ± 2 weeks of gestation, a reduction in hepatitis B surface antigen (HBsAg) from baseline to 34 ± 2 weeks of gestation, and hepatitis B virus (HBV) DNA declining from baseline to the end of treatment (EOT) were entered into the final risk model. Its C-index was 0.91 (95% CI, 0.82–0.99), and it reached as high as 0.88 after bootstrapping validation. The decision curve and decision tree were further developed to facilitate the application of this model. Conclusions: We developed a nomogram for predicting non-rebound in pregnant women with MTCT prevention after the withdrawal of antiviral agents, which facilitates physicians in making appropriate treatment recommendations.
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Affiliation(s)
- Chun-Rui Wang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Guo-Chao Zhong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Wei Chen
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Gara N, Tana MM, Kattapuram M, Auh S, Sullivan L, Fryzek N, Walter M, Umarova R, Zhao X, Cloherty G, Doo E, Heller T, Liang TJ, Ghany MG. Prospective Study of Withdrawal of Antiviral Therapy in Patients with Chronic Hepatitis B after Prolonged Virological Response. Hepatol Commun 2021; 5:1888-1900. [PMID: 34558806 PMCID: PMC8557321 DOI: 10.1002/hep4.1761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/17/2021] [Accepted: 04/25/2021] [Indexed: 01/05/2023] Open
Abstract
Nucleoside analogue (NA) therapy for chronic hepatitis B (CHB) is associated with improved clinical outcomes, but usually requires long-term use. Whether treatment can be safely withdrawn and the factors associated with post-withdrawal outcome are not well defined. To assess long-term outcomes after stopping antiviral therapy, patients with hepatitis B e antigen (HBeAg)-negative CHB who had received antiviral therapy for 4 or more years with hepatitis B virus (HBV) DNA (≤100 IU/mL) were prospectively withdrawn from antiviral therapy and monitored monthly for the initial 6 months and every 3 months thereafter. Those with clinical relapse were retreated according to severity of relapse. Fifteen patients were withdrawn from lamivudine (4), adefovir (5), or a combination of the two (6) after a mean treatment duration of 8.4 years. The mean age was 45 years, 13 were male, and 8 were initially HBeAg-positive before treatment. After a mean follow-up of 6.6 years, outcomes differed by pretreatment HBeAg status. All patients who were HBeAg+ before treatment experienced virological relapse (8 of 8); 6 of 8 experienced clinical relapse; 4 of 8 had ALT flares; 5 of 8 required re-initiation of treatment, one of whom cleared hepatitis B surface antigen (HBsAg); and 3 of 8 remained off treatment, one of whom cleared HBsAg. In contrast, 4 of 7 patients who were HBeAg-negative before treatment experienced virological relapse, 3 of 7 experienced clinical relapse, and 1 of 7 had an alanine aminotransferase (ALT) flare. None restarted treatment, and 4 of 7 cleared HBsAg. Low pre-withdrawal HBsAg level was predictive of HBsAg loss. Conclusion: NA therapy can be safely withdrawn with long-term remission and high rates of HBsAg loss in most HBeAg-negative patients without cirrhosis. Patients who were initially HBeAg+ should not be withdrawn from treatment, because clinical relapse was frequent and often severe.
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Affiliation(s)
- Naveen Gara
- Gastroenterology & Liver InstituteEscondidoCAUSA
| | - Michele M Tana
- University of California San Francisco School of MedicineSan FranciscoCAUSA
| | - Meera Kattapuram
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Sungyoung Auh
- Clinical CoreNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Lauren Sullivan
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Nancy Fryzek
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Mary Walter
- Clinical CoreNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Regina Umarova
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Xiongce Zhao
- Office of the DirectorNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | | | - Edward Doo
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Theo Heller
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - T Jake Liang
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Marc G Ghany
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
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van Bömmel F, Berg T. Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B. Hepatol Commun 2021; 5:1632-1648. [PMID: 34558833 PMCID: PMC8485892 DOI: 10.1002/hep4.1708] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Systematic discontinuation of long-term treatment with nucleos(t)ide analogues (NAs) is one strategy to increase functional cure rates in patients with chronic hepatitis B e antigen (HBeAg)-negative hepatitis B. Currently, available study results are heterogeneous; however, long-term hepatitis B surface antigen (HBsAg) loss rates of up to 20% have been reported in prospective trials. This review proposes criteria that can be used when considering NA discontinuation in patients with chronic hepatitis B virus (HBV). Discontinuing NA treatment frequently results in a virologic and biochemical relapse that runs through different phases: the lag phase, reactivation phase, and consolidation phase. The HBV-DNA flares observed during the reactivation phase are often transient and most likely represent a trigger for inducing a long-term immune control by specific CD8+ T cells, and therefore do not need immediate interventions but close follow-up evaluation. Low HBsAg levels at the time of treatment cessation predict a positive long-term response to NA discontinuation associated with a higher likelihood of HBsAg clearance. Other host and viral biomarkers are currently under evaluation that may prove to be helpful to further characterize the population that may benefit most from the finite NA treatment concept. Potential harmful biochemical flares during the reactivation phase need to be identified early and can be effectively terminated by reintroducing NA treatment. Hepatic decompensation represents a risk to patients with cirrhosis undergoing NA discontinuation. Therefore, the finite NA approach should only be considered after excluding advanced fibrosis and cirrhosis and if a close follow-up of the patient and supervision by an experienced physician can be guaranteed. Conclusion: For selected patients, NA discontinuation has become a powerful tool to achieve control over HBeAg-negative HBV infections. Its significant effect represents a challenge to novel treatment approaches, but it may also serve as their enhancer.
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Affiliation(s)
- Florian van Bömmel
- Division of HepatologyDepartment of Medicine IILeipzig University Medical CenterLeipzigGermany
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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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Song DS, Jang JW, Yoo SH, Kwon JH, Nam SW, Bae SH, Choi JY, Yoon SK. Improving the Prediction of Relapse After Nucleos(t)ide Analogue Discontinuation in Patients With Chronic Hepatitis B. Clin Infect Dis 2021; 73:e892-e903. [PMID: 33417679 DOI: 10.1093/cid/ciab007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Current guidelines recommend rules for stopping nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB), but off-therapy relapse is still high. This study aimed to identify predictors of off-therapy relapse and improve existing stopping rules. METHODS This retrospective study included 488 patients with CHB (262 hepatitis B e antigen [HBeAg]-positive and 226 HBeAg-negative) who discontinued NAs. Posttreatment relapse was investigated. RESULTS During the median follow-up period of 73.3 months, the cumulative 5-year and 10-year virologic relapse (VR) rates were 73.5% and 76.1%, respectively. In HBeAg-positive patients, end-of-therapy hepatitis B surface antigen (HBsAg) levels (hazard ratio [HR], 1.93 [95% confidence interval {CI}, 1.42-2.61]) and consolidation duration ≥2 years (HR, 0.31 [95% CI: .17-.58]) were independent predictors of VR. Consolidation ≥2 years and low HBsAg levels (≤560 IU/mL) significantly lowered VR rates. In HBeAg-negative patients, only the HBsAg level (HR, 1.61 [95% CI: 1.24-2.11]) was independently predictive of VR. Cirrhosis was significantly associated with higher VR rates in HBeAg-negative patients with low HBsAg levels (≤800 IU/mL). Combining end-of-therapy HBsAg levels with current stopping rules or consolidation duration further reduced off-therapy relapse, with 2-year VR rates of approximately 15%-25% in HBeAg-positive patients and 35% in HBeAg-negative patients. CONCLUSIONS End-of-therapy HBsAg levels, consolidation duration, and cirrhosis are key determinants of off-therapy relapse. Together with low HBsAg levels, extended consolidation therapy for ≥2 years should be ensured, and cirrhotic patients should continue NAs even if low HBsAg levels are achieved. A combination of these parameters will help identify individuals at low risk of relapse and significantly improve the predictive ability of the existing stopping rules.
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Affiliation(s)
- Do Seon Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sun Hong Yoo
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soon Woo Nam
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
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30
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Berg T, Lampertico P. The times they are a-changing - A refined proposal for finite HBV nucleos(t)ide analogue therapy. J Hepatol 2021; 75:474-480. [PMID: 33957187 DOI: 10.1016/j.jhep.2021.04.040] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/09/2021] [Accepted: 04/26/2021] [Indexed: 12/11/2022]
Abstract
Although discontinuation of nucleos(t)ide analogue (NA) treatment before HBsAg loss is part of all current HBV treatment guidelines for HBeAg-positive patients who achieve HBeAg seroconversion, a treatment endpoint known to be associated with silencing of HBV transcriptional activity and restoration of HBV-specific immune control, whether it is even appropriate to consider NA discontinuation before HBsAg loss in the HBeAg-negative phase remains highly controversial. Despite the growing evidence that a relevant, albeit small, proportion of patients with HBeAg-negative disease can be cured by stopping NA treatment, the fear of discontinuation-associated relapse and the uncertainty of how to predict off-therapy response and monitor patients after discontinuation have generated scepticism and subsequently led to low implementation of this concept in the clinic. In this article, we propose a concept in which NA discontinuation-associated relapse is an integral part of the stop-to-cure approach and ultimately the trigger for achieving HBsAg loss. However, the relapse in this sense becomes functionally effective only if HBV-specific immune reinvigoration and silencing of HBV transcriptional activity have been achieved during the NA treatment period. The probability of functional cure and the severity of post-discontinuation flares depend on the underlying baseline transcriptional activity of HBV when NA therapy was started, as well as the duration of NA treatment, both factors that should be considered as we move towards individualised approaches to HBV cure.
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Affiliation(s)
- Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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31
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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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32
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Gao L, Hu Y, Shi X, Li X, Zhang D, Ren H. 48 weeks outcome after cessation of nucleos(t)ide analogue therapy in chronic hepatitis B patients. Ann Hepatol 2021; 19:329-334. [PMID: 31884016 DOI: 10.1016/j.aohep.2019.10.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/22/2019] [Accepted: 10/01/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVE The aim of the present study was to investigate the significance of serum HBsAg levels in treatment cessation of nucleoside analogues (NAs) in patients with chronic hepatitis B (CHB) infection. METHODS In 158 CHB patients with long-term NAs treatment, 74 patients were in HBeAg negative and had a HBsAg level <1500IU/mL, 36 of whom were informed and consented to cease NAs. HBsAg, HBV DNA and liver function were examined in the 1st, 3rd, 6th, 9th and 12th month after treatment cessation. RESULTS The sustained response rate was 88.89% (32/36) within one year after NAs cessation. Sub-group analysis was based on HBsAg levels of patients with NAs cessation, there was no relapse case in 11 patients whose HBsAg <50IU/mL, and the negative predictive value (NPV) was 100%. Seroconversion of HBsAg occurred in 3 patients. 2 patients from 21 cases whose HBsAg was between 50IU/mL and 1000IU/mL relapsed. 2 of 4 patients whose in HBsAg >1000IU/mL relapsed. HBsAg of patients with a sustained response decreased slowly. In contrast, HBsAg levels increased gradually in relapsed patients, and the increase of HBsAg was precedent to relapses of HBV DNA and ALT. Multivariate analysis suggested that only HBsAg level showed a close correlation with HBV DNA relapses. ROC curve analysis suggested that the increase of HBsAg level in the 3rd and 6th month after NAs cessation had a great predictive value for relapses. CONCLUSION Monitoring of base line HBsAg level can predict outcomes of NAs cessation in HBeAg-negative chronic hepatitis B. HBsAg <50IU/mL has higher predictive values of better sustained responses in HBeAg-negative CHB patients.
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Affiliation(s)
- Li Gao
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
| | - Yue Hu
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
| | - Xiaofeng Shi
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China.
| | - Xin Li
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
| | - Dazhi Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
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García-López M, Lens S, Pallett LJ, Testoni B, Rodríguez-Tajes S, Mariño Z, Bartres C, García-Pras E, Leonel T, Perpiñán E, Lozano JJ, Rodríguez-Frías F, Koutsoudakis G, Zoulim F, Maini MK, Forns X, Pérez-Del-Pulgar S. Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients. J Hepatol 2021; 74:1064-1074. [PMID: 33278456 PMCID: PMC8062913 DOI: 10.1016/j.jhep.2020.11.043] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 10/28/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Factors associated with a successful outcome upon nucleos(t)ide analogue (NA) treatment withdrawal in HBeAg-negative chronic hepatitis B (CHB) patients have yet to be clarified. The objective of this study was to analyse the HBV-specific T cell response, in parallel with peripheral and intrahepatic viral parameters, in patients undergoing NA discontinuation. METHODS Twenty-seven patients without cirrhosis with HBeAg-negative CHB with complete viral suppression (>3 years) were studied prospectively. Intrahepatic HBV-DNA (iHBV-DNA), intrahepatic HBV-RNA (iHBV-RNA), and covalently closed circular DNA (cccDNA) were quantified at baseline. Additionally, serum markers (HBV-DNA, HBsAg, HBV core-related antigen [HBcrAg] and HBV-RNA) and HBV-specific T cell responses were analysed at baseline and longitudinally throughout follow-up. RESULTS After a median follow-up of 34 months, 22/27 patients (82%) remained off-therapy, of whom 8 patients (30% of the total cohort) lost HBsAg. Baseline HBsAg significantly correlated with iHBV-DNA and iHBV-RNA, and these parameters were lower in patients who lost HBsAg. All patients had similar levels of detectable cccDNA regardless of their clinical outcome. Patients achieving functional cure had baseline HBsAg levels ≤1,000 IU/ml. Similarly, an increased frequency of functional HBV-specific CD8+ T cells at baseline was associated with sustained viral control off treatment. These HBV-specific T cell responses persisted, but did not increase, after treatment withdrawal. A similar, but not statistically significant trend, was observed for HBV-specific CD4+ T cell responses. CONCLUSIONS Decreased cccDNA transcription and low HBsAg levels are associated with HBsAg loss upon NA discontinuation in patients with HBeAg-negative CHB. The presence of functional HBV-specific T cells at baseline are associated with a successful outcome after treatment withdrawal. LAY SUMMARY Nucleos(t)ide analogue therapy can be discontinued in a high proportion of chronic hepatitis B patients without cirrhosis. The strength of HBV-specific immune T cell responses may contribute to successful viral control after antiviral treatment interruption. Our comprehensive study provides in-depth data on virological and immunological factors than can help guide individualised therapy in patients with chronic hepatitis B.
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Affiliation(s)
- Mireia García-López
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Laura J Pallett
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| | - Barbara Testoni
- INSERM U1052-Cancer Research Center of Lyon (CRCL), University of Lyon, UMR_S1052, CRCL, Lyon, France
| | - Sergio Rodríguez-Tajes
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Concepción Bartres
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Ester García-Pras
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Thais Leonel
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Elena Perpiñán
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | | | - Francisco Rodríguez-Frías
- Liver Pathology Unit, Department of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, CIBERehd, Barcelona, Spain
| | - George Koutsoudakis
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Fabien Zoulim
- INSERM U1052-Cancer Research Center of Lyon (CRCL), University of Lyon, UMR_S1052, CRCL, Lyon, France
| | - Mala K Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| | - Xavier Forns
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
| | - Sofía Pérez-Del-Pulgar
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
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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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35
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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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Liu H, Wan Z, She L, Zhu Y, Cai Z, Wu B, Zhuang Q, Ke P, Wu X, Li Z, Huang X. Inflammation Pharmacological Reaction and YMDD Mutational Patterns in Lamivudine Therapeutics Hepatitis B Virus. Front Pharmacol 2021; 12:648170. [PMID: 33935748 PMCID: PMC8081950 DOI: 10.3389/fphar.2021.648170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/19/2021] [Indexed: 02/05/2023] Open
Abstract
Background/Aims: Emergence of tyrosine-methionine-aspartate-aspartate (YMDD) motif in reverse transcriptase is a serious problem in chronic hepatitis B(CHB) patients after Lamivudine (LAM) therapy. However, the relationship between inflammation pharmacological reaction and YMDD mutational patterns of CHB has not been well-characterized. The aim of this study was to investigate the inflammation pharmacological reaction and different YMDD mutants patterns of CHB patients. Methods: We investigated the inflammation pharmacological reaction and YMDD mutational patterns through biochemical, serological and virological detection among 83 CHB patients, including 25 YMDD mutants, 25 under detection, and 33 control patients without YMDD mutants. Results: Prevalence of YMDD mutation patterns is different. Among 25 YMDD mutants patients, YIDD was the dominant mutation (72%), followed YVDD (16%) and the hybrid YIDD + YVDD (12%). The time course during the YMDD mutations was also different. 52.4% patients developed the mutation less than 12 months after the LAM therapy. Serum hepatitis B virus (HBV) DNA level in patients with YMDD mutants were significantly higher than that in control and negative groups. Serum HbsAg and HbeAg in patients with YMDD mutants were also higher than those in control and negative groups, despite no significant difference was found forserum HbeAb. ALT and AST levels were also significantly higher in mutants group. Conclusions: Illuminating inflammation pharmacological reaction and YMDD mutational patterns of CHB during pathological process may have implications for future therapy in YMDD mutation patients. This may have impact on the choice of treatment strategies for lamivudine-resistant HBV.
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Affiliation(s)
- Hongcan Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Hongcan Liu, ; Zhuo Li, ; Xianzhang Huang,
| | - Zemin Wan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lanhui She
- Department of Infectious Diseases, Guangzhou Women and Children’s Medical Center, Guangzhou, China
| | - Yajuan Zhu
- Department of Ultrasound, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhiliang Cai
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Wu
- Genetic Testing Lab, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qizhen Zhuang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peifeng Ke
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinzhong Wu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhuo Li
- Genetic Testing Lab, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Hongcan Liu, ; Zhuo Li, ; Xianzhang Huang,
| | - Xianzhang Huang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Hongcan Liu, ; Zhuo Li, ; Xianzhang Huang,
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Ridruejo E. Editorial: biomarkers in HBV and prediction of treatment response. Aliment Pharmacol Ther 2021; 53:332-333. [PMID: 33368512 DOI: 10.1111/apt.16171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
LINKED CONTENT
This article is linked to Lim et al papers. To view these articles, visit https://doi.org/10.1111/apt.16149 and https://doi.org/10.1111/apt.16226
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Affiliation(s)
- Ezequiel Ridruejo
- Hepatology Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas, CEMIC, Ciudad Autónoma de Buenos Aires, Argentina
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Pilar, Argentina
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Wübbolding M, Lopez Alfonso JC, Lin CY, Binder S, Falk C, Debarry J, Gineste P, Kraft ARM, Chien RN, Maasoumy B, Wedemeyer H, Jeng WJ, Meyer Hermann M, Cornberg M, Höner Zu Siederdissen C. Pilot Study Using Machine Learning to Identify Immune Profiles for the Prediction of Early Virological Relapse After Stopping Nucleos(t)ide Analogues in HBeAg-Negative CHB. Hepatol Commun 2021; 5:97-111. [PMID: 33437904 PMCID: PMC7789842 DOI: 10.1002/hep4.1626] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 09/01/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022] Open
Abstract
Treatment with nucleos(t)ide analogues (NAs) may be stopped after 1-3 years of hepatitis B virus DNA suppression in hepatitis B e antigen (HBeAg)-negative patients according to Asian Pacific Association for the Study of Liver and European Association for the Study of Liver guidelines. However, virological relapse (VR) occurs in most patients. We aimed to analyze soluble immune markers (SIMs) and use machine learning to identify SIM combinations as predictor for early VR after NA discontinuation. A validation cohort was used to verify the predictive power of the SIM combination. In a post hoc analysis of a prospective, multicenter therapeutic vaccination trial (ABX-203, NCT02249988), hepatitis B surface antigen, hepatitis B core antigen, and 47 SIMs were repeatedly determined before NA was stopped. Forty-three HBeAg-negative patients were included. To detect the highest predictive constellation of host and viral markers, a supervised machine learning approach was used. Data were validated in a different cohort of 49 patients treated with entecavir. VR (hepatitis B virus DNA ≥ 2,000 IU/mL) occurred in 27 patients. The predictive value for VR of single SIMs at the time of NA stop was best for interleukin (IL)-2, IL-17, and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5) with a maximum area under the curve of 0.65. Hepatitis B core antigen had a higher predictive power than hepatitis B surface antigen but lower than the SIMs. A supervised machine-learning algorithm allowed a remarkable improvement of early relapse prediction in patients treated with entecavir. The combination of IL-2, monokine induced by interferon γ (MIG)/chemokine (C-C motif) ligand 9 (CCL9), RANTES/CCL5, stem cell factor (SCF), and TNF-related apoptosis-inducing ligand (TRAIL) was reliable in predicting VR (0.89; 95% confidence interval: 0.5-1.0) and showed viable results in the validation cohort (0.63; 0.1-0.99). Host immune markers such as SIMs appear to be underestimated in guiding treatment cessation in HBeAg-negative patients. Machine learning can help find predictive SIM patterns that allow a precise identification of patients particularly suitable for NA cessation.
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Affiliation(s)
- Maximilian Wübbolding
- Department of Gastroenterology, Hepatology, and EndocrinologyHannover Medical SchoolHannoverGermany.,Centre for Individualised Infection Medicinea joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany.,German Center for Infection ResearchPartner-Site Hannover-BraunschweigHannoverGermany
| | - Juan Carlos Lopez Alfonso
- Centre for Individualised Infection Medicinea joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany.,Department of Systems Immunology and Braunschweig Integrated Centre of Systems BiologyHelmholtz Centre for Infection ResearchBraunschweigGermany
| | - Chun-Yen Lin
- Department of Gastroenterology and HepatologyChang Gung Memorial HospitalLinkou branchTaoyuanTaiwan.,College of MedicineChang Gung UniversityTaipeiTaiwan
| | - Sebastian Binder
- Centre for Individualised Infection Medicinea joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany.,Department of Systems Immunology and Braunschweig Integrated Centre of Systems BiologyHelmholtz Centre for Infection ResearchBraunschweigGermany
| | - Christine Falk
- Institute of Transplantation ImmunologyHannover Medical SchoolHannoverGermany
| | - Jennifer Debarry
- Centre for Individualised Infection Medicinea joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany.,TWINCOREa joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany
| | | | - Anke R M Kraft
- Department of Gastroenterology, Hepatology, and EndocrinologyHannover Medical SchoolHannoverGermany.,Centre for Individualised Infection Medicinea joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany.,German Center for Infection ResearchPartner-Site Hannover-BraunschweigHannoverGermany
| | - Rong-Nan Chien
- Department of Gastroenterology and HepatologyChang Gung Memorial HospitalLinkou branchTaoyuanTaiwan.,College of MedicineChang Gung UniversityTaipeiTaiwan.,Liver Research UnitChang Gung Memorial HospitalLinkouTaiwan
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, and EndocrinologyHannover Medical SchoolHannoverGermany.,German Center for Infection ResearchPartner-Site Hannover-BraunschweigHannoverGermany
| | - Wen-Juei Jeng
- Department of Gastroenterology and HepatologyChang Gung Memorial HospitalLinkou branchTaoyuanTaiwan.,College of MedicineChang Gung UniversityTaipeiTaiwan
| | - Michael Meyer Hermann
- Centre for Individualised Infection Medicinea joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany.,Department of Systems Immunology and Braunschweig Integrated Centre of Systems BiologyHelmholtz Centre for Infection ResearchBraunschweigGermany.,Institute for Biochemistry, Biotechnology and BioinformaticsTechnische Universität BraunschweigBraunschweigGermany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, and EndocrinologyHannover Medical SchoolHannoverGermany.,Centre for Individualised Infection Medicinea joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany.,German Center for Infection ResearchPartner-Site Hannover-BraunschweigHannoverGermany.,TWINCOREa joint venture of Helmholtz Centre for Infection Research and Hannover Medical SchoolHannoverGermany
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Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B. Antiviral Res 2020; 185:104992. [PMID: 33279523 DOI: 10.1016/j.antiviral.2020.104992] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
Long-term treatment with nucleos(t)ide analogs (NAs) is the current first line therapy for patients with chronic hepatitis B (CHB), recommended by most of the current guidelines. NAs prevent disease progression, liver failure, decrease the risk of hepatocellular carcinoma (HCC), and have favorable safety profiles. However, low rates of on-therapy functional cure (hepatitis B surface antigen [HBsAg] loss), which is regarded as the optimal end point, prevent many patients from stopping NA therapy with the need for a lifelong treatment. The higher likelihood of HBsAg loss associated with stopping as compared to continuing NAs has got a lot of attention recently. Recommendations regarding endpoints allowing for safely stopping NA therapy differ between international guidelines. Whereas in HBeAg-positive patients, HBeAg seroconversion with at least one year of consolidation therapy is an acceptable endpoint of treatment, the recommendations for HBeAg-negative ones differ. Some guidelines propose ≥3 years of HBV DNA undetectability to stop NA while others regard HBsAg loss as the only acceptable endpoint. Stopping NA can lead to substantial rates of virologic relapses and consequent ALT flares in some cases. Moreover, no reliable predictor(s) of post-NA relapses have been identified so far. Quantitative HBsAg is becoming an increasingly promising marker to predict safe NA cessation. On the other hand, investigating the role of the immune system in mediating sustained virologic responses after NA withdrawal is needed to suggest immunological biomarkers to safely stop NA. In this article, we will review relevant literature regarding NA stopping strategy and discuss promising viral and immunological biomarkers to predict antiviral responses and thus to help identify patients who are more likely to achieve HBsAg seroclearance.
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Chiu SM, Kuo YH, Wang JH, Hung CH, Hu TH, Lu SN, Chen CH. Associations of HBV Genotype B vs C Infection With Relapse After Cessation of Entecavir or Tenofovir Therapy. Clin Gastroenterol Hepatol 2020; 18:2989-2997.e3. [PMID: 32353534 DOI: 10.1016/j.cgh.2020.04.048] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/26/2020] [Accepted: 04/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We compared rates of relapse of hepatitis B virus (HBV) infection between patients with HBV genotype B vs genotype C infection after cessation of entecavir or tenofovir disoproxil fumarate (TDF) therapy. All patients included in the study were HB e antigen (HBeAg)-negative. METHODS We performed a retrospective study of 460 HBeAg-negative patients without cirrhosis in Taiwan who had stopped entecavir or TDF treatment for at least 12 months; data were collected from 2007 through 2016. All patients fulfilled the stopping criteria proposed by the APASL 2012 guidelines. Patients were evaluated every 1-3 months during the first 6 months after stopping therapy and then every 3 months until their last hospital visit; HB surface antigen (HBsAg) was measured in serum samples collected before treatment, after 12 months of treatment, and at the end of treatment. Virologic relapse was defined as a serum level of HBV DNA >2000 IU/mL after the cessation of treatment; clinical relapse was defined as increase in alanine aminotransferase more than 2-fold the upper limit of normal (40 U/L) and level of HBV DNA >2000 IU/mL after stopping treatment. RESULTS Significantly higher proportions of patients with HBV genotype B infection had virologic and clinical relapse and retreatment than patients with HBV genotype C infection, among all patients and among patients matched by propensity sore. Patients who discontinued TDF therapy had significantly higher rates and earlier times of virologic and clinical relapse than patients who discontinued entecavir therapy, among all patients and propensity score-matched patients. Multivariate analysis showed that TDF therapy, old age, HBV genotype B, and higher end of treatment HBsAg level were independently associated with virologic and clinical relapse. Five-year rates of virologic and clinical relapse were low (19.2% and 15.4%, respectively) in patients with a combination of end of treatment level of HBsAg of 100 IU/mL or less and HBV genotype C infection. Rates of off-therapy HBsAg loss, development of hepatocellular carcinoma, and hepatic decompensation did not differ significantly between patients with HBV genotypes B vs C infection or between the entecavir vs TDF groups. CONCLUSIONS Higher proportions of HBeAg-negative patients with HBV genotype B infection have virologic and clinical relapse and retreatment than patients with HBV genotype C infection, after cessation of entecavir or TDF therapy.
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Affiliation(s)
- Shao-Ming Chiu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yuan-Hung Kuo
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Chiyai Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Chiyai Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
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Broquetas T, Garcia-Retortillo M, Micó M, Canillas L, Puigvehí M, Cañete N, Coll S, Viu A, Hernandez JJ, Bessa X, Carrión JA. Hepatitis B surface antigen and hepatitis B core-related antigen kinetics after adding pegylated-interferon to nucleos(t)ids analogues in hepatitis B e antigen-negative patients. World J Hepatol 2020; 12:1076-1088. [PMID: 33312431 PMCID: PMC7701972 DOI: 10.4254/wjh.v12.i11.1076] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/23/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues (NAs) rarely achieve hepatitis B surface antigen (HBsAg) loss.
AIM To evaluate if the addition of pegylated interferon (Peg-IFN) could decrease HBsAg and hepatitis B core-related antigen (HBcrAg) levels and increase HBsAg loss rate in patients under NAs therapy.
METHODS Prospective, non-randomized, open-label trial evaluating the combination of Peg-IFN 180 µg/week plus NAs during forty-eight weeks vs NAs in monotherapy. Hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients of a tertiary hospital, under NAs therapy for at least 2 years and with undetectable viral load, were eligible. Patients with hepatitis C virus, hepatitis D virus or human immunodeficiency virus co-infection and liver transplanted patients were excluded. HBsAg and HBcrAg levels (log10 U/mL) were measured at baseline and during ninety-six weeks. HBsAg loss rate was evaluated in both groups. Adverse events were recorded in both groups. The kinetic of HBsAg for each treatment group was evaluated from baseline to weeks 24 and 48 by the slope of the HBsAg decline (log10 IU/mL/week) using a linear regression model.
RESULTS Sixty-five patients were enrolled, 61% receiving tenofovir and 33% entecavir. Thirty-six (55%) were included in Peg-IFN-NA group and 29 (44%) in NA group. After matching by age and treatment duration, baseline HBsAg levels were comparable between groups (3.1 vs 3.2) (P = 0.25). HBsAg levels at weeks 24, 48 and 96 declined in Peg-IFN-NA group (-0.26, -0.40 and -0.44) and remained stable in NA group (-0.10, -0.10 and -0.10) (P < 0.05). The slope of HBsAg decline in Peg-IFN-NA group (-0.02) was higher than in NA group (-0.00) (P = 0.015). HBcrAg levels did not change. Eight (22%) patients discontinued Peg-IFN due to adverse events. The HBsAg loss was achieved in 3 (8.3%) patients of the Peg-IFN-NA group and 0 (0%) of the NA group.
CONCLUSION The addition of Peg-IFN to NAs caused a greater and faster decrease of HBsAg levels compared to NA therapy. Side effects of Peg-IFN can limit its use in clinical practice.
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Affiliation(s)
- Teresa Broquetas
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Montserrat Garcia-Retortillo
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Miquel Micó
- Laboratori de Referencia de Catalunya, El Prat de Llobregat, Barcelona 08820, Spain
| | - Lidia Canillas
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
| | - Marc Puigvehí
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Nuria Cañete
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Susana Coll
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Ana Viu
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
| | - Juan Jose Hernandez
- Laboratori de Referencia de Catalunya, El Prat de Llobregat, Barcelona 08820, Spain
| | - Xavier Bessa
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - José A Carrión
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
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Incidence and Factors Associated With HBV Relapse After Cessation of Entecavir or Tenofovir in Patients With HBsAg Below 100 IU/mL. Clin Gastroenterol Hepatol 2020; 18:2803-2812.e2. [PMID: 32360818 DOI: 10.1016/j.cgh.2020.04.037] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 04/02/2020] [Accepted: 04/10/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We investigated the incidence and factors associated with relapse of hepatitis B virus (HBV) infection in patients with levels of HB surface antigen (HBsAg) less than 100 IU/mL after cessation of entecavir or tenofovir disoproxil fumarate (TDF) treatment. METHODS We collected data from patients with chronic HBV infection without cirrhosis treated with entecavir from 2007 through 2015 or TDF from 2011 through 2016 in Taiwan. We identified 135 patients with levels of HBsAg less than 100 IU/mL at the end of treatment (79 entecavir and 56 TDF) and collected data from them for a median of 87 weeks (interquartile range, 48-161 wk) for use as the development set. We collected data from 108 patients from separate medical centers in Taiwan, followed up for a median of 126 weeks (interquartile range, 61-214 wk), and used these as the validation group. Post-treatment virologic relapse was defined as a serum HBV DNA level greater than 2000 IU/mL, and clinical relapse was defined as an alanine aminotransferase level greater than 80 U/L and a HBV DNA level greater than 2000 IU/mL. RESULTS In the development group, the 5-year incidences of virologic relapse, clinical relapse, and HBsAg loss were 40.9%, 32.5%, and 47%, respectively. The baseline HBV DNA and end-of-treatment levels of HBsAg were associated independently with relapse. In the development group, 17.3% of patients with end-of-treatment HBsAg levels less than 40 IU/mL had a virologic relapse within 5 years, whereas 67.6% of patients with a HBsAg level of 40 IU/mL or more had a virologic relapse within 5 years (P < .001); proportions of patients with clinical relapses were 10.2% (HBsAg <40 IU/mL) and 57.6% (HBsAg ≥40 IU/mL; P < .001). In the validation groups, for patients with end-of-treatment HBsAg levels less than 40 IU/mL or 40 IU/mL or more, the rates of virologic relapse at 5 years were 31.1% and 80.5% (P < .001), and rates of clinical relapse were 14.2% and 50.3% (P < .001), respectively. Rates of virologic and clinical relapse within 5 years were low (<10%) in patients with a combination of end-of-treatment HBsAg level less than 40 IU/mL and baseline HBV DNA level less than 5 × 104 IU/mL, or baseline hepatitis B core-related antigen level less than 4 log U/mL in the development group. CONCLUSIONS An end-of-treatment HBsAg level of 40 IU/mL or less is optimal for stopping nucleos(t)ide analog therapy. Waiting to stop therapy until patients have a combination of baseline HBV DNA level of 5 × 104 IU/mL or hepatitis B core-related antigen of 4 log U/mL and end-of-treatment HBsAg level of 40 IU/mL might reduce the risk of HBV relapse.
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The evolution and clinical impact of hepatitis B virus genome diversity. Nat Rev Gastroenterol Hepatol 2020; 17:618-634. [PMID: 32467580 DOI: 10.1038/s41575-020-0296-6] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2020] [Indexed: 02/06/2023]
Abstract
The global burden of hepatitis B virus (HBV) is enormous, with 257 million persons chronically infected, resulting in more than 880,000 deaths per year worldwide. HBV exists as nine different genotypes, which differ in disease progression, natural history and response to therapy. HBV is an ancient virus, with the latest reports greatly expanding the host range of the Hepadnaviridae (to include fish and reptiles) and casting new light on the origins and evolution of this viral family. Although there is an effective preventive vaccine, there is no cure for chronic hepatitis B, largely owing to the persistence of a viral minichromosome that is not targeted by current therapies. HBV persistence is also facilitated through aberrant host immune responses, possibly due to the diverse intra-host viral populations that can respond to host-mounted and therapeutic selection pressures. This Review summarizes current knowledge on the influence of HBV diversity on disease progression and treatment response and the potential effect on new HBV therapies in the pipeline. The mechanisms by which HBV diversity can occur both within the individual host and at a population level are also discussed.
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Liu Y, Xue J, Liao W, Yan H, Liang X. Serum HBV RNA Dynamic and Drug Withdrawal Predictor Value in Patients With Chronic HBV Infection on Long-term Nucleos(t)ide Analogue (NA) Therapy. J Clin Gastroenterol 2020; 54:e73-e82. [PMID: 32604147 PMCID: PMC7458089 DOI: 10.1097/mcg.0000000000001376] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/10/2020] [Indexed: 02/07/2023]
Abstract
AIMS This study aimed to investigate the dynamic pattern of serum hepatitis B virus (HBV) RNA in chronic hepatitis B (CHB) patients on long-term nucleos(t)ide analogue (NA) therapy and evaluate predictor value of end-of-treatment (EOT) serum HBV RNA status on drug-withdrawal durability. METHODS We carried out a real-life cohort study of 326 CHB patients on NA treatment between February 12, 2016 and February 21, 2018. Thirty of these patients discontinued NA treatment after enrollment, and were included in 2-year off-therapy follow-up. Serum HBV RNA levels were determined using the RNA simultaneous amplification testing method. RESULTS Both serum HBV RNA and DNA levels declined significantly in long-term antiviral progress. When the treatment duration was longer than 3 years, the undetectable rates of HBV RNA and DNA were 55.10% and 97.0%, respectively. The serum HBV RNA-negative rate was 39.5%. The cumulative 2-year off-therapy viral and clinical relapse rate was 40.56%; 95% confidence interval (95% CI), 21.51-59.61 and 31.31%; 95% CI, 11.32-51.29 in all patients, respectively. Patients with EOT hepatitis B surface antigen (HBsAg)≤1000 IU/mL plus HBV RNA negativity had a relatively lower cumulative 2-year off-therapy viral relapse rate (23.01%; 95% CI, 0.17-45.99). EOT HBsAg≤1000 IU/mL plus HBV RNA negativity showed obvious superiority for the EOT HBsAg≤1000 IU/mL single in drug withdrawal durability prediction, with better specificity (18.18% vs. 72.73%, P=0.03), and the positive predictive value and negative predictive value were 76.92% and 47.06%, respectively. CONCLUSIONS In the long-term antiviral process, both serum HBV RNA and DNA levels declined significantly. EOT serum HBV RNA negativity was not an independent drug withdrawal marker, but can complement the HBsAg titer to monitor drug withdrawal in CHB patients on long-term NA therapy.
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Affiliation(s)
| | | | - Wei Liao
- Departments of Infectious Diseases
| | - Hongli Yan
- Reproductive Medicine Center, Changhai Hospital, Second Military Medical University, Shanghai, China
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Yim HJ, Kim JH, Park JY, Yoon EL, Park H, Kwon JH, Sinn DH, Lee SH, Lee JH, Lee HW. Comparison of clinical practice guidelines for the management of chronic hepatitis B: When to start, when to change, and when to stop. Clin Mol Hepatol 2020; 26:411-429. [PMID: 32854458 PMCID: PMC7641563 DOI: 10.3350/cmh.2020.0049] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/21/2020] [Indexed: 02/06/2023] Open
Abstract
Clinical practice guidelines are important for guiding the management of specific diseases by medical practitioners, trainees, and nurses. In some cases, the guidelines are utilized as a reference for health policymakers in controlling diseases with a large public impact. With this in mind, practice guidelines for the management of chronic hepatitis B (CHB) have been developed in the United States, Europe, and Asian-Pacific regions to suggest the best-fit recommendations for each social and medical circumstance. Recently, the Korean Association for the Study of the Liver published a revised version of its clinical practice guidelines for the management of CHB. The guidelines included updated information based on newly available antiviral agents, the most recent opinion on the initiation and cessation of treatment, and updates for the management of drug resistance, partial virological response, and side effects. Additionally, CHB management in specific situations was comprehensively revised. This review compares the similarities and differences among the various practice guidelines to identify unmet needs and improve future recommendations.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Eileen L Yoon
- Department of Internal Medicine, Inje University College of Medicine, Seoul, Korea
| | - Hana Park
- Department of Health Medicine, Asan Medical Center, Seoul, Korea
| | - Jung Hyun Kwon
- Department of Internal Medicine, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Dong Hyun Sinn
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Chonan, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Hall S, Howell J, Visvanathan K, Thompson A. The Yin and the Yang of Treatment for Chronic Hepatitis B-When to Start, When to Stop Nucleos(t)ide Analogue Therapy. Viruses 2020; 12:v12090934. [PMID: 32854335 PMCID: PMC7552074 DOI: 10.3390/v12090934] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022] Open
Abstract
Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed "treat-all" strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of "stopping" NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the "treat-all" strategy, as well as the "stop" strategy, and how they may both have a role in the management of patients with chronic hepatitis B.
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Affiliation(s)
- Samuel Hall
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
- Correspondence:
| | - Jessica Howell
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
| | - Kumar Visvanathan
- Infectious Diseases Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia;
| | - Alexander Thompson
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
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Hepatitis B surface antigen seroclearance: Immune mechanisms, clinical impact, importance for drug development. J Hepatol 2020; 73:409-422. [PMID: 32333923 DOI: 10.1016/j.jhep.2020.04.013] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 04/03/2020] [Accepted: 04/07/2020] [Indexed: 12/16/2022]
Abstract
HBsAg seroclearance occurs rarely in the natural history of chronic hepatitis B (CHB) infection and is associated with improved clinical outcomes. Many factors are associated with HBsAg seroconversion, including immune and viral factors. However, the immune mechanisms associated with HBsAg seroclearance are still difficult to elucidate. HBsAg seroclearance is the ideal aim of HBV treatment. Unfortunately, this goal is rarely achieved with current treatments. Understanding the mechanisms of HBsAg loss appears to be important for the development of curative HBV treatments. While studies from animal models give insights into the potential immune mechanisms and interactions occurring between the immune system and HBsAg, they do not recapitulate all features of CHB in humans and are subject to variability due to their complexity. In this article, we review recent studies on these immune factors, focusing on their influence on CHB progression and HBsAg seroconversion. These data provide new insights for the development of therapeutic approaches to partially restore the anti-HBV immune response. Targeting HBsAg will ideally relieve the immunosuppressive effects on the immune system and help to restore anti-HBV immune responses.
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Wang CH, Chang KK, Lin RC, Kuo MJ, Yang CC, Tseng YT. Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study. Medicine (Baltimore) 2020; 99:e19907. [PMID: 32358357 PMCID: PMC7440314 DOI: 10.1097/md.0000000000019907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
There has been no clear consensus on the optimal consolidation periods following HBeAg seroconversion (SC) in HBeAg-positive chronic hepatitis B (CHB) patients. Our study aimed to prospectively compare relapse rates between 12 months' and 18 months' consolidation periods to see whether or not there is beneficial durability of tenofovir disoproxil fumarate (TDF) therapy with longer consolidation periods.We enrolled a total of 137 HBeAg-positive Asian CHB patients treated with TDF monotherapy. Forty-six patients achieved HBeAg SC. Then, they were randomly assigned to consolidation period of either 12 months (group A) or 18 months (group B). After stopping TDF therapy, all patients were followed up for 12 months.Thirteen patients (56.5%) relapsed in group A and 12 patients (52.2%) relapsed in group B after 12 months' follow-up (P = .958). Pretreatment HBsAg level is the only significant predictor for off-therapy recurrence by univariate analysis (P = .024). Baseline HBeAg >1000 S/CO in group B patients were significantly less likely to relapse than those of group A (P = .046). Baseline alanine aminotransferase (ALT) >133 U/L could significantly predict occurrence of HBeAg SC (P = .008; 95% CI: 0.545-0.763; AUC: 0.654).Overall, a prolonged consolidation period has no positive effect on TDF therapy on sustained viral suppression in HBeAg-positive Asian CHB patients. However, a prolonged consolidation period was beneficial to patients with high baseline semi-quantitative HBeAg levels in terms of off-treatment durability. Baseline ALT > 133 U/L could significantly predict the occurrence of HBeAg SC.
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Affiliation(s)
- Chun-Hsiang Wang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Kuo-Kuan Chang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Ruey-Chang Lin
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Ming-Jeng Kuo
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Chi-Chieh Yang
- Department of Hepatogastroenterology, Show Chwan Memorial Hospital, Changhua
| | - Yuan-Tsung Tseng
- Committee of Medical Research, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
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Hadziyannis E, Hadziyannis S. Current practice and contrasting views on discontinuation of nucleos(t)ide analog therapy in chronic hepatitis B. Expert Rev Gastroenterol Hepatol 2020; 14:243-251. [PMID: 32162562 DOI: 10.1080/17474124.2020.1738219] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Long-term, even indefinite treatment with nucleos(t)ide analogs (NAs) is the current first-line therapy for patients with chronic hepatitis B (CHB), regardless of its histological stage. Guidelines and recommendations on duration and endpoints of NA therapy in CHB are not identical and change over time.Areas covered: The authors review NA discontinuation approaches and views with an emphasis on HBeAg-negative patients based on published studies relevant to the topic, stressing on whether or not the optimal endpoint of HBsAg loss is practically achievable.Expert opinion: Discontinuation of NA therapy in HBeAg-negative noncirrhotic patients has to be considered after long-term effective treatment with controlled liver disease activity, undetectable viremia, and significant decline in serum HBsAg titers. Close post-treatment monitoring is required for early intervention in cases of severe clinical relapse. Immediate retreatment hampers the favorable outcome of HBsAg clearance (functional cure) and should be avoided in transient ALT flares. Predictors of such relapses are still under investigation and include viral and patient factors. For HBeAg-positive noncirrhotic patients, there is wide acceptance of the endpoint of HBeAg seroconversion, after a long consolidation period.
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Affiliation(s)
- Emilia Hadziyannis
- Second Academic Department of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Stephanos Hadziyannis
- Second Academic Department of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
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Lai CL, Wong DKH, Wong GTY, Seto WK, Fung J, Yuen MF. Rebound of HBV DNA after cessation of nucleos/tide analogues in chronic hepatitis B patients with undetectable covalently closed. JHEP Rep 2020; 2:100112. [PMID: 32462119 PMCID: PMC7242874 DOI: 10.1016/j.jhepr.2020.100112] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 03/09/2020] [Accepted: 03/14/2020] [Indexed: 02/08/2023] Open
Abstract
Background & Aims Nucleos(t)ide analogues (NUCs) effectively suppress serum HBV DNA. Previously, we have identified 21 patients with undetectable covalently closed circular DNA (cccDNA) upon long-term NUC therapy. This study investigated the effect of NUC withdrawal in patients with undetectable cccDNA. Methods Nineteen patients on long term NUCs (median 13.4 years) were recruited: 13 were randomized to discontinue NUCs; 6 to continue taking NUCs. All had undetectable cccDNA at the time of last liver biopsy (median time 2.9 years prior to randomization). Serum HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), liver biochemistry, and serum HBV RNA were monitored. Results At the time of randomization, all patients had undetectable serum HBV DNA and HBV RNA. Twelve of the 13 patients had HBV DNA rebound to 100 IU/ml within 20 weeks of NUC discontinuation. The thirteenth patient had HBV DNA rebound at week 70. Three patients experienced biochemical flares after re-treatment which subsequently resolved. There was no significant association between the time of HBV DNA rebound and baseline HBsAg, HBcrAg and alanine aminotransferase, duration of treatment, and age at which treatment was stopped (all p >0.05). At the time of HBV DNA rebound, HBV DNA levels correlated with HBcrAg levels (p = 0.003), but not with HBsAg levels (p = 0.262). Conclusions In patients with undetectable intrahepatic cccDNA, virologic rebound still occurred after NUC cessation. At the rebound of HBV DNA, the kinetics of HBsAg production were independent of those of viral DNA replication. Additional studies are required to determine the factors that may predict virologic rebound and when NUCs can be discontinued in HBsAg-positive patients with chronic hepatitis B. Lay summary It has been shown that following long-term nucleos(t)ide analogue treatment for chronic hepatitis B, some patients have undetectable levels of viral DNA in their livers. We tested the results of withdrawing nucleos(t)ide analogue treatment in these patients and found that viral relapse could occur in patients with undetectable viral DNA. Further research is required to determine whether nucleos(t)ide analogue treatment can be discontinued in specific patients with chronic hepatitis B.
Patients on long-term nucleos(t)ide analogue treatment with undetectable HBV DNA may have undetectable cccDNA. Stopping treatment for patients with undetectable cccDNA resulted in rebound of serum HBV DNA, mostly within 20 weeks. There is no association between time of HBV DNA rebound and other viral markers, including HBsAg titers and HBcrAg. Even in patients with undetectable cccDNA in liver biopsies, virologic relapse can still occur.
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Key Words
- ALT, alanine aminotransferase
- CHB, chronic hepatitis B
- Chronic hepatitis B
- ETV, entecavir
- HBcrAg, hepatitis B core-related antigen
- HBeAg, hepatitis B e antigen
- HBsAg, hepatitis B surface antigen
- LdT, telbivudine
- NUCs, nucleos(t)ide analogues
- TDF, tenofovir disoproxil fumarate
- ULN, upper limit of normal
- anti-HBe, antibody to HBeAg
- antiviral therapy
- cccDNA, covalently closed circular DNA
- hepatitis B virus DNA rebound
- stopping therapy
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Affiliation(s)
- Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Gerald Tsz-Yau Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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