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Campos-Valdez M, Castro-García MA, Ramos-Márquez ME, Gurrola-Díaz CM, Salazar-Montes AM, Sánchez-Orozco LV. An Update on Viral Hepatitis B and C in Mexico: Advances and Pitfalls in Eradication Strategies. Microorganisms 2024; 12:1368. [PMID: 39065136 PMCID: PMC11279215 DOI: 10.3390/microorganisms12071368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/30/2024] [Accepted: 06/30/2024] [Indexed: 07/28/2024] Open
Abstract
In Mexico, hepatitis B and C infections are a significant burden on the health system. The aim of this narrative review was to analyze the state of the art on hepatitis B and C in Mexico by searching and studying available data in academic articles and government reports and statements on epidemiology, prevention, treatment, and elimination strategies undertaken by the Mexican government. Even where the government has implemented a hepatitis B vaccination strategy to reduce its incidence, a very low proportion of people complete the vaccination schedule. Regarding hepatitis C, there is a National Elimination Program that emphasizes the importance of screening, diagnosis, and treatment focused on the population at risk. With the implementation of this program, more than a million fast tests have been carried out and the positive cases have been verified by viral load. Infected patients are tested to determine liver function, fibrosis stage, and coinfection with HBV and/or HIV. Patients without cirrhosis and/or coinfections are treated in first-level care centers, while those with cirrhosis and/or comorbidities are referred to specialists. The possibility of hepatitis C eradication in Mexico seems more likely than eradication of hepatitis B; however, major challenges remain to be overcome to reach both infections' elimination.
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Affiliation(s)
| | | | | | | | | | - Laura Verónica Sánchez-Orozco
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada 950, Independencia Oriente, Puerta 7, Edificio Q Segundo Nivel, Guadalajara 44340, Jalisco, Mexico (M.A.C.-G.)
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Aliasi-Sinai L, Worthington T, Lange M, Kushner T. Maternal-to-Child Transmission of Hepatitis B Virus and Hepatitis Delta Virus. Clin Liver Dis 2023; 27:917-935. [PMID: 37778777 DOI: 10.1016/j.cld.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Maternal-to-child transmission of hepatitis B virus (HBV) and hepatitis delta virus (HDV) can lead to the risk of progressive liver disease in infants, but fortunately effective interventions exist to decrease transmission. Counseling on the risk of maternal-to-child transmission, care pathways to decrease transmission, and the implications of HBV and HDV on pregnancy outcomes are the key components of caring for pregnant people living with HBV and HDV.
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Affiliation(s)
| | - Theresa Worthington
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Marcia Lange
- Icahn School of Medicine at Mount Sinai, New York, USA
| | - Tatyana Kushner
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA.
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Woo HY, Heo J, Tak WY, Lee HJ, Chung WJ, Park JG, Park SY, Park YJ, Lee YR, Hwang JS, Kweon YO. Effect of switching from nucleos(t)ide maintenance therapy to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomized trial. PLoS One 2022; 17:e0270716. [PMID: 35867702 PMCID: PMC9307167 DOI: 10.1371/journal.pone.0270716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 06/14/2022] [Indexed: 11/22/2022] Open
Abstract
AIMS Induction of a durable viral response is difficult to achieve in patients with chronic hepatitis B (CHB), even from long-term use of a nucleos(t)ide analogue (NA). This study investigated whether switching to peginterferon (PegIFN) alfa-2a after long-term NA therapy induced a durable viral response. METHODS Patients with hepatitis B e antigen (HBeAg)-positive CHB who received any NA for at least 72 weeks and had a low level of HBV DNA (≤100 IU/mL) were randomized (1:1) to receive PegIFN alfa-2a (180 μg/week) or NA for 48 weeks. The primary endpoint was change in the hepatitis B surface antigen (HBsAg) titer during antiviral therapy. RESULTS We randomized 149 CHB patients to the two groups. Compared to baseline, the HBsAg levels in both groups were not lower at week 12, but were lower after 24, 36, and 48 weeks (all p<0.001). The maximal HBsAg decline in the PegIFN alfa-2a group was at week 36 (0.50±0.88 log10 IU/mL), and this decline was smaller in the NA group (0.08±0.46 log10 IU/mL). The percentage of patients with HBeAg seroconversion at week 48 was also greater in the PegIFN alfa-2a group (15/75 [20.0%] vs. 5/74 [6.8%], p = 0.018). Multivariable analysis indicated the PegIFN alfa-2a group had a greater change in HBeAg seroconversion at week 48 (p = 0.027). Patients had relatively good tolerance to PegIFN alfa-2a therapy. CONCLUSIONS CHB patients who switched to PegIFN alfa-2a for 48 weeks had a significantly lower HBsAg titer and increased HBeAg seroconversion relative to those who remained on NA therapy. TRIAL REGISTRATION (ClinicalTrials.gov; NCT01769833).
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Affiliation(s)
- Hyun Young Woo
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Won Young Tak
- Department of Internal Medicine, College of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Woo Jin Chung
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Jung Gil Park
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, College of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Young Joo Park
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Yu Rim Lee
- Department of Internal Medicine, College of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Jae Seok Hwang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Young Oh Kweon
- Department of Internal Medicine, College of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
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Charatcharoenwitthaya P, Kaewdech A, Piratvisuth T. Controversies in Treating Chronic HBV: The Role of PEG-interferon-alfa. Clin Liver Dis 2021; 25:741-762. [PMID: 34593151 DOI: 10.1016/j.cld.2021.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pegylated interferon-alpha therapy is one of the first-line chronic hepatitis B treatment. Finite treatment duration, absence of drug resistance, delayed response, and higher hepatitis B surface antigen loss than nucleos(t)ides analog therapy are the advantages of pegylated interferon-alpha treatment. Common side effects and subcutaneous injections requirement limit its use. Identifying patients likely to respond to pegylated interferon-alpha and optimizing treatment is reasonable. Motivating patients to complete the 48-week treatment is necessary. Treatment is stopped or switched to other treatment strategies in patients with stopping rule criteria. Combination therapy with nucleos(t)ides analog may improve response, but remains controversial.
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Affiliation(s)
- Phunchai Charatcharoenwitthaya
- Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Wang-Lang Road, Bangkok 10700, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand; NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand.
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Post G, Howell J, Sow A, Ndow G, Chemin I, Lo G, Cessay A, Cohen D, Njie R, Toure S, Diop M, Sombie R, Nana J, Leroy V, Lacombe K, Bojang L, Tacke F, Toure-Kane C, Ka M, Mendy M, Mboup S, Thursz M, Shimakawa Y, Ingiliz P, Lemoine M. Clinical utility of quantifying hepatitis B surface antigen in African patients with chronic hepatitis B. J Viral Hepat 2021; 28:1003-1010. [PMID: 33749097 DOI: 10.1111/jvh.13499] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 03/11/2021] [Indexed: 12/20/2022]
Abstract
The clinical utility of quantifying hepatitis B surface antigen (qHBsAg) levels in African subjects with chronic hepatitis B virus (HBV) infection has been poorly documented. From a multicentre cohort of 944 HBV-infected African patients, we aimed to assess whether qHBsAg alone can accurately identify i) those in a HBeAg-negative chronic HBV infection phase at low risk of liver disease progression and ii) those in need of antiviral therapy according to the 2017 EASL guidelines. We analysed 770 HBV mono-infected treatment-naïve patients, mainly males (61%) from West Africa (92%), median age 35 years (IQR: 30-44), median HBV DNA: 95.6 IU/ml (10.0-1,300.0), median qHBsAg 5,498 IU/ml (1,171-13,000) and HBeAg-pos 38 (5%). A total of 464/770 (60.2%) patients were classified as HBeAg-negative chronic infection (median age 36 years (31-46), median ALT 23 IU/l (18-28), median HBV-DNA 33.5 IU/ml (3.8-154.1), median LSM 4.8 kPa (4.1-5.8)) and qHBsAg levels had poor accuracy to identify these subjects with an AUROC at 0.58 (95%CI: 0.54-0.62), sensitivity 55.0% and specificity 55.6%; 118/770 (15.3%) patients were eligible for treatment according to the 2017 EASL criteria. qHBsAg correlated poorly with HBV DNA and had poor accuracy to select patients for antiviral therapy with an AUROC at 0.54 (0.49-0.60), sensitivity 46.6% and specificity 46.9%. In African treatment-naïve HBV-infected subjects, the clinical utility of qHBsAg to identify subjects in HBeAg-negative infection phase or subjects eligible for antiviral therapy seems futile. Whether qHBsAg levels can be used as a predictor of long-term liver complications in Africa needs to be further investigated.
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Affiliation(s)
- Gerrit Post
- Department of Gastroenterology and Hepatology, Charité University Medical Center, Berlin, Germany
- Center for Infectiology, Berlin, Germany
| | - Jess Howell
- Disease Elimination, Burnet Institute, Department of Gastroenterology, St. Vincent's Hospital, Department of Epidemiology and Preventive Medicine, Monash University Melbourne, Victoria, Australia
| | - Amina Sow
- Laboratoire de Bactériologie & Virologie, CHNU Dalal Jamm Guediawaye, IRESSEF Diamnoadio Dakar, Senegal
| | - Gibril Ndow
- Medical Research Council the Gambia unit (MRCG, London School of Hygiene and Tropical Medicine, Viral hepatitis Unit, Fajara, The Gambia
| | - Isabelle Chemin
- INSERM U1052, CNRS 5286, Univ Lyon, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Gora Lo
- Laboratoire de Bactériologie & Virologie, CHNU Dalal Jamm Guediawaye, IRESSEF Diamnoadio Dakar, Senegal
| | - Amie Cessay
- Medical Research Council the Gambia unit (MRCG, London School of Hygiene and Tropical Medicine, Viral hepatitis Unit, Fajara, The Gambia
| | - Damien Cohen
- INSERM U1052, CNRS 5286, Univ Lyon, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Ramou Njie
- International Agency for Research on Cancer (IARC, Lyon, France
| | - Souleymane Toure
- Unite de Formation et de Recherche (UFR) des sciences de la santé de l'Universite de Thies, Senegal
| | - Madoky Diop
- Unite de Formation et de Recherche (UFR) des sciences de la santé de l'Universite de Thies, Senegal
| | - Roger Sombie
- Service d'hépatogastro-entérologie, Centre Hospitalier Universitaire Yalgado Ouédraogo, Université Joseph Ki-Zerbo, Ouagadougou, Burkina Faso
| | - Jean Nana
- Department of Hepatology & Gastroenterology, Université Grenoble Alpes, Grenoble, France
| | - Vincent Leroy
- Department of Hepatology & Gastroenterology, Université Grenoble Alpes, Grenoble, France
| | - Karine Lacombe
- Department of infectious diseases and tropical medicine, hôpital Saint-Antoine, SorbonneUniversité, Inserm IPLESP, APHP, Sorbonne, France
| | - Lamin Bojang
- Medical Research Council the Gambia unit (MRCG, London School of Hygiene and Tropical Medicine, Viral hepatitis Unit, Fajara, The Gambia
| | - Frank Tacke
- Department of Gastroenterology and Hepatology, Charité University Medical Center, Berlin, Germany
| | - Coumba Toure-Kane
- Laboratoire de Bactériologie & Virologie, CHNU Dalal Jamm Guediawaye, IRESSEF Diamnoadio Dakar, Senegal
| | - Mourtalla Ka
- Unite de Formation et de Recherche (UFR) des sciences de la santé de l'Universite de Thies, Senegal
| | - Maimuna Mendy
- International Agency for Research on Cancer (IARC, Lyon, France
| | - Souleymane Mboup
- Laboratoire de Bactériologie & Virologie, CHNU Dalal Jamm Guediawaye, IRESSEF Diamnoadio Dakar, Senegal
| | - Mark Thursz
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Hepatology Section, Imperial College London, St Mary's campus, London, UK
| | - Yusuke Shimakawa
- Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
| | - Patrick Ingiliz
- Department of Gastroenterology and Hepatology, Charité University Medical Center, Berlin, Germany
- Center for Infectiology, Berlin, Germany
| | - Maud Lemoine
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Hepatology Section, Imperial College London, St Mary's campus, London, UK
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Kang L, Pian Y, Gao Z, Hu J, Nie J. The influence of hepatitis B virus infection in pregnant women. Health Care Women Int 2021; 42:251-260. [PMID: 33724163 DOI: 10.1080/07399332.2021.1883024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We carried out the investigation to evaluate hepatitis B virus (HBV) infection status and the influence of HBV infection in pregnant women in Tianjin of China. We founded that the prevalence of HBsAg was 3.77% (69/1829). 88.57% (1620/1829) pregnant women conducted HBsAg screening in last pregnancy. Spontaneous abortion and premature delivery did not show significant differences between HBV infected and uninfected pregnant women. But ALT and AST levels were significantly higher in infected women. And 56.65% of participants (997/1760) were anti-HBs positive. In conclusion, HBsAg prevalence was moderate in pregnant women in this region, which was consistent with the total population in western Pacific regions. And HBV infection did not influence spontaneous abortion and premature delivery. But the HBsAg screening was conducted mostly in the last pregnancy. Early screening and intervention were suggested in pregnant women within countries of moderately endemic regions.
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Affiliation(s)
- Lina Kang
- Department of Clinical Laboratory, Tianjin Binhai New Area Dagang Hospital, Tianjin, China
| | - Yaya Pian
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhenxiang Gao
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jihong Hu
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jingjing Nie
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
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He Z, Chen J, Wang J, Xu L, Zhou Z, Chen M, Zhang Y, Shi M. Expression of hepatitis B surface antigen in liver tissues can serve as a predictor of prognosis for hepatitis B virus-related hepatocellular carcinoma patients after liver resection. Eur J Gastroenterol Hepatol 2021; 33:76-82. [PMID: 32049678 PMCID: PMC7704243 DOI: 10.1097/meg.0000000000001698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 12/19/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatitis B surface antigen (HBsAg) is a detectable index after hepatitis B virus (HBV) infection, which is a risk factor of hepatocellular carcinoma (HCC). However, few studies have focused on the expression of HBsAg in HCC patients' liver tissues. This study aimed to explore the potential utility of using HBsAg protein expression in normal liver tissues as a prognostic factor for HCC patients who underwent liver resection. STUDY DESIGN The study enrolled 100 HCC patients with seropositivity for HBsAg. The liver tissues were collected, and tissue microarrays were constructed. The expression of HBsAg in liver tissues were measured by immunohistochemistry (IHC). Relevant clinical data and follow-up records were collected for analysis. RESULTS HBsAg expressions was detected in 29 patients (positive group) and was unable to be detected in the remaining 71 patients (negative group). The patients in the positive group had higher HBV DNA levels (P < 0.05) than the patients in the negative group. The overall survival (OS) rate of the positive group was worse than the OS rate of the negative group (P = 0.013). The OS rates after resection at 1 and 2 years in negative group were 90.1% and 85.7%, respectively, while the value in the positive group were 79.3% and 65.5%, respectively. Multivariate analysis showed that HBsAg expression in liver tissues, ascites and alpha-fetoprotein levels were independent factors influencing OS. Similarly, after propensity score matching (PSM), the OS was worse in the positive group than in the negative group, and HBsAg expression could also serve as a predictor for OS (P = 0.039). The OS rates after resection and PSM at 1 and 2 years were 93.2% and 85.9% in the negative group, while the value in the positive group were 79.3% and 65.5%. CONCLUSION As determined according to grouping based on immunohistochemistry staining results for HBsAg, this study indicated that HBsAg expression in liver tissues could predict the OS of HBV-related HCC patients after liver resection.
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Affiliation(s)
- Ziming He
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Jinbin Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Juncheng Wang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Li Xu
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zhongguo Zhou
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Minshan Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Yaojun Zhang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Mude Shi
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center
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Chen YC, Jeng WJ, Hsu CW, Lin CY. Impact of hepatic steatosis on treatment response in nuclesos(t)ide analogue-treated HBeAg-positive chronic hepatitis B: a retrospective study. BMC Gastroenterol 2020; 20:146. [PMID: 32397963 PMCID: PMC7216492 DOI: 10.1186/s12876-020-01289-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 04/30/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The impact of hepatic steatosis (HS) on treatment response following nucleos(t)ide analogue (NA) treatment for chronic hepatitis B (CHB) patients has not been clearly elucidated. We aimed to investigate the difference in HBeAg seroclearance between NA-treated HBeAg-positive CHB patients with and without HS. METHODS We retrospectively recruited HBeAg-positive CHB patients receiving liver biopsy and NA monotherapy. The baseline clinical characteristics and cumulative incidence of HBeAg seroclearance were compared between patients with and without HS and age/gender-matched subgroup analysis was performed. RESULTS A total of 196 patients were enrolled from 2003 April to 2016 October. The mean age was 39.6 ± 11.2 years, 142 (72.4%) were males and 94 (48%) had histological evidence of HS. Median treatment duration and follow-up period were 24.3 months and 54.9 months, respectively. HBeAg seroclearance was achieved in 56/102 (54.9%) and 54/94 (57.4%) patients with and without HS, respectively (p = 0.830). The 5-year cumulative incidence of HBeAg seroclearance in patients with and without HS was 62.8 and 67.7% in overall population (p = 0.398) and 62.4 and 66.9% in age/gender-matched subgroups (p = 0.395), respectively. The rate of HBeAg seroclearance was comparable between patients with or without HS in different NA monotherapy (all p > 0.05). CONCLUSIONS HS had no significant impact on HBeAg seroclearance in HBeAg-positive CHB patients with NA monotherapy during long-term follow-up.
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Affiliation(s)
- Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, and University, Linkou, No 5, Fu Hsing Street, Guishan Dist, Taoyuan City, 33302, Taiwan, Republic of China. .,College of Medicine, Chang Gung University, No.259, Wen Hua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan, Republic of China.
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, and University, Linkou, No 5, Fu Hsing Street, Guishan Dist, Taoyuan City, 33302, Taiwan, Republic of China.,College of Medicine, Chang Gung University, No.259, Wen Hua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan, Republic of China
| | - Chao-Wei Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, and University, Linkou, No 5, Fu Hsing Street, Guishan Dist, Taoyuan City, 33302, Taiwan, Republic of China.,College of Medicine, Chang Gung University, No.259, Wen Hua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan, Republic of China
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, and University, Linkou, No 5, Fu Hsing Street, Guishan Dist, Taoyuan City, 33302, Taiwan, Republic of China.,College of Medicine, Chang Gung University, No.259, Wen Hua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan, Republic of China
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Effect of nucleos(t)ide analogue on serum HBsAg level in chronic hepatitis B patients: A 3-years study. Biomed Pharmacother 2019; 122:109698. [PMID: 31918272 DOI: 10.1016/j.biopha.2019.109698] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/18/2019] [Accepted: 11/24/2019] [Indexed: 12/27/2022] Open
Abstract
AIM We aim to explore the effects of nucleos(t)ide analogues (NUCs) on the changes of HBsAg in chronic hepatitis B (CHB) patients. METHODS A total of 264 CHB patients were enrolled in our study. All of them were treated with NUCs for at least three years. Quantification of HBsAg levels were measured by Elecsys HBsAg II. RESULTS Although HBsAg levels were significantly higher in HBeAg seropositive CHB patients at baseline than in HBeAg seronegative CHB patients (3.84 ± 0.82 vs 3.21 ± 0.59 IU/mL), HBsAg levels declined more rapidly in the HBeAg seropositive group (P < 0.001). In HBeAg-positive CHB patients, HBsAg level in the telbivudine (LDT)-treated group was 3.68 ± 0.56 IU/mL after 52-week of treatment, which was significantly higher than that in lamivudine (LAM)-treated group (P = 0.009). Multivariable analyses showed that baseline HBV DNA viral load (OR = 0.75, P = 0.018), baseline ALT level (OR = 0.99, P = 0.015), and baseline HBsAg level (OR = 0.188, P < 0.001) were independent factors that affected HBsAg decline in HBeAg seropositive CHB patients. For HBeAg seronegative CHB patients, the average of serum HBsAg levels in LAM-, LdT-, adefovir (ADV)-, and entecavir (ETV)-treated groups at baseline, 52 weeks, 104 weeks, and 156 weeks were similar. Multivariable analyses showed that only baseline HBV DNA level (OR = 0.56, P = 0.020) and baseline HBsAg level (OR = 0.57, P = 0.012) were independent factors that affected HBsAg decline in HBeAg seronegative patients with CHB. Baseline HBV DNA level (OR = 0.72, P = 0.010) and baseline HBsAg level (OR = 0.19, P < 0.001) were independent factors that affected all CHB patients. CONCLUSIONS CHB Patients who had received NUCs antiviral treatment showed a slow but significant decrease in serum HBsAg level. Long-term monitoring and continuous antiviral treatment are necessary, especially for those patients with risk factors associated with HBsAg decline.
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Clinical utility of HBV surface antigen quantification in HBV e antigen-negative chronic HBV infection. Nat Rev Gastroenterol Hepatol 2019; 16:631-641. [PMID: 31477873 DOI: 10.1038/s41575-019-0197-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2019] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a serious problem owing to its worldwide distribution and potential adverse sequelae that include cirrhosis and/or hepatocellular carcinoma. Current antiviral therapies have much improved outcomes, but few patients achieve the ultimate goal of hepatitis B surface antigen (HBsAg) loss (functional cure). As hepatitis B e antigen (HBeAg)-negative chronic HBV infection is the final phase prior to HBsAg loss, the management of patients in this phase together with quantification of HBsAg has attracted increasing clinical and research interest. This Review integrates the findings from research in HBsAg kinetics and discusses how they might inform our understanding and management of HBeAg-negative chronic HBV infection. Studies have shown that HBsAg levels are highly predictive of the presence of inactive HBV infection and that serial changes in HBsAg levels might predict HBsAg loss within 1-3 years. Data also suggest that quantitative HBsAg monitoring is important during hepatitis flare and antiviral therapy, especially in the timing of the decision to stop therapy and to start off-therapy retreatment. These findings have shed new light on the natural course of HBV infection and might lead to optimization of the management of HBeAg-negative chronic HBV infection and contribute to the paradigm shift from indefinite to finite therapy for patients with HBV infection.
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He L, Su M, Ou G, Wang L, Deng J, Zhuang H, Xiang K, Li T. The modulation of HBsAg level by sI126T is affected by additional amino acid substitutions in the S region of HBV. INFECTION GENETICS AND EVOLUTION 2019; 75:104006. [PMID: 31442597 DOI: 10.1016/j.meegid.2019.104006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/12/2019] [Accepted: 08/15/2019] [Indexed: 11/17/2022]
Abstract
The hepatitis B surface antigen (HBsAg) is a vital serum marker for hepatitis B virus (HBV) infection. Amino acid (AA) substitutions in small hepatitis B surface protein (SHBs) are known to affect HBsAg level. However, how the genetic backbones of SHBs sequences would affect the roles of a specific AA substitution on HBsAg level remains unclear. In this study, we found that sI126 had a very high substitution detection rate of 17.54% (40/228) in untreated chronic hepatitis B cohort with subgenotype C2 HBV infection. Among different substitution types at sI126, the sI126T (N = 28) was found to be associated with significantly lower serum HBsAg level. Clone sequencing revealed that sI126T-harboring SHBs sequences had varied genetic backbones with zero to nine additional AA substitutions. Thus, we constructed 24 HBsAg expression plasmids harboring sI126T without (plasmid 1, P1) or with (P2-P24) additional AA substitution(s) and studied them in the HepG2 cells. The HBsAg levels were determined by both ELISA and Western blot. In vitro experiments showed that P1 significantly reduced HBsAg level and its secretion (p < .05), however, P2-P24 showed various extracellular and intracellular HBsAg levels. No significant differences were detected among the HBsAg mRNA levels of nine representative mutant plasmids. Our findings suggest that the modulation of HBsAg level by sI126T is affected by additional AA substitution(s) in the S region of HBV. The effects of AA combination substitutions in SHBs sequences on HBsAg levels are worthwhile for more attentions in terms of HBV biology and its clinical application.
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Affiliation(s)
- Lingyuan He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Xueyuan Road 38, Haidian District, Beijing 100191, China
| | - Mingze Su
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Xueyuan Road 38, Haidian District, Beijing 100191, China
| | - Guomin Ou
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Xueyuan Road 38, Haidian District, Beijing 100191, China
| | - Luwei Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Xueyuan Road 38, Haidian District, Beijing 100191, China
| | - Juan Deng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Xueyuan Road 38, Haidian District, Beijing 100191, China
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Xueyuan Road 38, Haidian District, Beijing 100191, China
| | - Kuanhui Xiang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Xueyuan Road 38, Haidian District, Beijing 100191, China.
| | - Tong Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Xueyuan Road 38, Haidian District, Beijing 100191, China.
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12
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Lai MW, Hsu CW, Lin CL, Chien RN, Lin WR, Chang CS, Liang KH, Yeh CT. Multiple doses of hepatitis B recombinant vaccine for chronic hepatitis B patients with low surface antigen levels: a pilot study. Hepatol Int 2018; 12:456-464. [PMID: 30088198 DOI: 10.1007/s12072-018-9890-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 07/21/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Seroclearance of hepatitis B surface antigen (HBsAg) has been rarely achieved in the treatment of chronic hepatitis B (CHB) patients. We administered HBsAg-based recombinant vaccine in patients with low HBsAg concentrations. METHODS Twenty hepatitis B e antigen-negative patients, with HBsAg < 1000 IU/ml, were enrolled. Vaccines were administered every 8 weeks for 48 weeks (seven doses). HBsAg levels and anti-HBs were assayed longitudinally until 48 weeks post-vaccination. HLA genotyping and cDNA microarray were performed to search for response predictors. RESULTS Nineteen patients completed the study. At the end of vaccination, HBsAg declined significantly (Δ = - 0.27 ± 0.49 log IU/ml, p = 0.0005). The annual decline rate was significantly greater than that of an age-, gender-, and baseline HBsAg-matched control group (Δ = - 0.18 ± 0.46 versus + 0.11 ± 0.42 log IU/ml/year; p = 0.0229). Two patients achieved HBsAg seroclearance. Fourteen had significant HBsAg decline (Δ = - 0.64 ± 0.88 log IU/ml). No significant adverse events occurred during the trial. cDNA microarray identified the top up- and down-regulated genes in responders as HLA-DQ and HLA-DMB, respectively. HLA genotyping identified HLA-DQB1*04, HLA-DRB1*04, and HLA-B*40 as predictors for non-response (p = 0.0499, 0.0152, and 0.0314, respectively). CONCLUSIONS In low-level HBsAg CHB patients, serial HBsAg-based vaccinations were safe, resulting in significant HBsAg decline. HLA gene expression and genotypes played a role in vaccine responsiveness (ClinicalTrials.gov Identifier: NCT01817725).
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Affiliation(s)
- Ming-Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chao-Wei Hsu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Rong-Nan Chien
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Wey-Ran Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chi-Sheng Chang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
| | - Kung-Hao Liang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
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13
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Cho H, Ahn H, Lee DH, Lee JH, Jung YJ, Chang Y, Nam JY, Cho YY, Lee DH, Cho EJ, Yu SJ, Lee JM, Kim YJ, Yoon JH. Entecavir and tenofovir reduce hepatitis B virus-related hepatocellular carcinoma recurrence more effectively than other antivirals. J Viral Hepat 2018; 25:707-717. [PMID: 29316069 DOI: 10.1111/jvh.12855] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 11/13/2017] [Indexed: 12/15/2022]
Abstract
Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high-potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low-potency NAs after curative treatment of hepatitis B virus (HBV)-related HCC. This study included 607 consecutive HBV-related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low-potency NA; n = 90) and group C (high-potency NA; n = 256). The primary end-point was recurrence-free survival (RFS). During the duration of follow-up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log-rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time-dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.
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Affiliation(s)
- H Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - H Ahn
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - J-H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Jung
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Y Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J Y Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y Y Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D H Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - E J Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - S J Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J M Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J-H Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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14
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Jeng WJ, Chen YC, Liaw YF. Great and rapid HBsAg decline in patients with on-treatment hepatitis flare in early phase of potent antiviral therapy. J Viral Hepat 2018; 25:421-428. [PMID: 29193573 DOI: 10.1111/jvh.12833] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 10/13/2017] [Indexed: 12/11/2022]
Abstract
HBsAg decline during nucleos(t)ide analogue therapy in chronic hepatitis B with lower pretherapy ALT is usually small and slow. This study aimed to investigate why ~10% of such patients showed "rapid HBsAg decline" ≥0.5 log10 IU/mL by month 6 of therapy. Patients with persistent pretherapy ALT <5X ULN who had qHBsAg at baseline, months 6 and 12 of entecavir or tenofovir therapy were studied. "On-treatment ALT elevation" was defined as >10% increase above baseline to >2X ULN during first 6 months of therapy. Of the 256 patients treated, 51 experienced transient "on-treatment ALT elevation" [group A], including 30 (11.7%) with ALT elevation to 2-5X ULN [group A-1] and 21 (8.2%) flared to >5X ULN [group A-2]. The magnitude of qHBsAg decline and rate of "rapid HBsAg decline" by month 6 was significantly greater and more frequent in group A (-0.446 vs -0.042 log10 IU/mL; 45.1 vs 8.8%, respectively, P = 0.000) than in the remaining 205 patients without on-treatment ALT elevation (group B), being greatest in patients with hepatitis flare (group A-2: -0.559 log10 IU/mL and 57.1%, respectively). In patients with therapy ≥2 years, patients with "on-treatment ALT elevation" also showed significantly greater annual HBsAg decline, more frequent to <100 IU/mL and 4 times higher HBsAg seroclearance rate. "On-treatment ALT elevation," especially flare >5X ULN, during entecavir therapy or tenofovir therapy may enhance/accelerate HBsAg decline, suggesting the effect of immune restoration upon potent viral suppression.
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Affiliation(s)
- W-J Jeng
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Y-C Chen
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Y-F Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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15
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Balsitis S, Gali V, Mason PJ, Chaniewski S, Levine SM, Wichroski MJ, Feulner M, Song Y, Granaldi K, Loy JK, Thompson CM, Lesniak JA, Brockus C, Kishnani N, Menne S, Cockett MI, Iyer R, Mason SW, Tenney DJ. Safety and efficacy of anti-PD-L1 therapy in the woodchuck model of HBV infection. PLoS One 2018; 13:e0190058. [PMID: 29444087 PMCID: PMC5812555 DOI: 10.1371/journal.pone.0190058] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 12/07/2017] [Indexed: 02/06/2023] Open
Abstract
Immune clearance of Hepatitis B virus (HBV) is characterized by broad and robust antiviral T cell responses, while virus-specific T cells in chronic hepatitis B (CHB) are rare and exhibit immune exhaustion that includes programmed-death-1 (PD-1) expression on virus-specific T cells. Thus, an immunotherapy able to expand and activate virus-specific T cells may have therapeutic benefit for CHB patients. Like HBV-infected patients, woodchucks infected with woodchuck hepatitis virus (WHV) can have increased hepatic expression of PD-1-ligand-1 (PD-L1), increased PD-1 on CD8+ T cells, and a limited number of virus-specific T cells with substantial individual variation in these parameters. We used woodchucks infected with WHV to assess the safety and efficacy of anti-PD-L1 monoclonal antibody therapy (αPD-L1) in a variety of WHV infection states. Experimentally-infected animals lacked PD-1 or PD-L1 upregulation compared to uninfected controls, and accordingly, αPD-L1 treatment in lab-infected animals had limited antiviral effects. In contrast, animals with naturally acquired WHV infections displayed elevated PD-1 and PD-L1. In these same animals, combination therapy with αPD-L1 and entecavir (ETV) improved control of viremia and antigenemia compared to ETV treatment alone, but with efficacy restricted to a minority of animals. Pre-treatment WHV surface antigen (sAg) level was identified as a statistically significant predictor of treatment response, while PD-1 expression on peripheral CD8+ T cells, T cell production of interferon gamma (IFN-γ) upon in vitro antigen stimulation (WHV ELISPOT), and circulating levels of liver enzymes were not. To further assess the safety of this strategy, αPD-L1 was tested in acute WHV infection to model the risk of liver damage when the extent of hepatic infection and antiviral immune responses were expected to be the greatest. No significant increase in serum markers of hepatic injury was observed over those in infected, untreated control animals. These data support a positive benefit/risk assessment for blockade of the PD-1:PD-L1 pathway in CHB patients and may help to identify patient groups most likely to benefit from treatment. Furthermore, the efficacy of αPD-L1 in only a minority of animals, as observed here, suggests that additional agents may be needed to achieve a more robust and consistent response leading to full sAg loss and durable responses through anti-sAg antibody seroconversion.
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Affiliation(s)
- Scott Balsitis
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Volodymyr Gali
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Pamela J. Mason
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Susan Chaniewski
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Steven M. Levine
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Michael J. Wichroski
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Michael Feulner
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Yunling Song
- Discovery Toxicology, Bristol-Myers Squibb, Princeton, New Jersey, United States of America
| | - Karen Granaldi
- Discovery Toxicology, Bristol-Myers Squibb, Princeton, New Jersey, United States of America
| | - James K. Loy
- Discovery Toxicology, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Chris M. Thompson
- Immunotoxicology, Drug Safety Evaluation, Bristol-Myers Squibb, New Brunswick, New Jersey, United States of America
| | - Jacob A. Lesniak
- Immunotoxicology, Drug Safety Evaluation, Bristol-Myers Squibb, New Brunswick, New Jersey, United States of America
| | - Catherine Brockus
- Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, New Jersey, United States of America
| | - Narendra Kishnani
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey, United States of America
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown Univ. Medical Center, Washington, DC, United States of America
| | - Mark I. Cockett
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Renuka Iyer
- Liver and Pancreas Tumor Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America
| | - Stephen W. Mason
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
| | - Daniel J. Tenney
- Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America
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16
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Alidjinou EK, Michel C, Canva V, Ajana F, Hober D, Bocket L. Very slow decline of hepatitis B virus surface antigen and core related antigen in chronic hepatitis B patients successfully treated with nucleos(t)ide analogues. J Med Virol 2018; 90:989-993. [PMID: 29315722 DOI: 10.1002/jmv.25028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 12/28/2017] [Indexed: 01/24/2023]
Abstract
We investigated the decline of hepatitis B virus surface antigen (HBsAg) and core related antigen (HBcrAg) in chronic hepatitis B patients sussessfully treated with nucleos(t)ide analogues. In patients with plasma viral suppression, the baseline median levels of HBsAg and HBcrAg were 3.1 and 3.0 log U/mL, respectively. The levels in naïve patients were 4.2 and 3.6 log U/mL for HBsAg and HBcrAg, respectively. No significant decline was observed in patients with viral suppression within a year period. A low reduction was observed during the first months after treatment initiation, especially regarding HBcrAg. The dynamics of these antigens after viral suppression should be further investigated.
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Affiliation(s)
- Enagnon K Alidjinou
- Univ Lille, Faculté de Médecine, CHU Lille, Laboratoire de Virologie EA3610, Lille, France
| | - Charlotte Michel
- Univ Lille, Faculté de Médecine, CHU Lille, Laboratoire de Virologie EA3610, Lille, France
| | - Valérie Canva
- CHU de Lille, Service des Maladies de l'Appareil Digestif, Lille, France
| | - Faïza Ajana
- CH Dron, Service Universitaire des Maladies Infectieuses, Tourcoing, France
| | - Didier Hober
- Univ Lille, Faculté de Médecine, CHU Lille, Laboratoire de Virologie EA3610, Lille, France
| | - Laurence Bocket
- Univ Lille, Faculté de Médecine, CHU Lille, Laboratoire de Virologie EA3610, Lille, France
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Zhang L, Xie XY, Chen Y, Ge NL, Chen RX, Gan YH, Zhang BH, Wang YH, Ren ZG. Hepatitis B surface antigen predicts recurrence after radiofrequency ablation in patients with low hepatitis B virus loads. Medicine (Baltimore) 2017; 96:e9377. [PMID: 29384914 PMCID: PMC6392890 DOI: 10.1097/md.0000000000009377] [Citation(s) in RCA: 3] [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: 12/25/2022] Open
Abstract
Radiofrequency ablation (RFA) is a first-line option for the treatment of small liver cancers, but the recurrence remains a problem affecting long-term survival. Hepatitis B virus (HBV) activity is associated with the prognosis of hepatocellular carcinoma (HCC). We investigated the significance of hepatitis B surface antigen (HBsAg) in HCC recurrence after curative RFA treatment in HBV-related small HCC.We enrolled 404 HBV-related patients with small HCC (≤3 cm) who underwent curative RFA. We used univariate and multivariate analyses to investigate the baseline levels of HBsAg, in addition to other known risk factors for HCC recurrence, for association with HCC tumor recurrence after curative RFA.The overall 1-, 2-, and 3-year recurrence-free survival (RFS) rates were 75%, 50%, and 34%, respectively. The median recurrence-free time was 25 months. The level of HBsAg was an independent risk factor for recurrence in patients with lower HBV-DNA levels. In hepatitis Be antigen (HBeAg)-negative patients, the 1-, 2-, and 3-year RFS rates were 79%, 64%, and 44%, respectively, for that with low HBsAg levels, compared with 73%, 50%, and 37%, respectively, for that with high HBsAg levels (P = .039).HBsAg might serve as a valuable marker to evaluate the risk of HCC recurrence in HBeAg-negative patients with low HBV viral load.
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18
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Osiowy C, Coffin C, Andonov A. Review of Laboratory Tests used in Monitoring Hepatitis B Response to Pegylated Interferon and Nucleos(t)ide Analog Therapy. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2016; 8:177-193. [PMID: 27547127 PMCID: PMC4969325 DOI: 10.1007/s40506-016-0080-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
There are only two currently approved classes of hepatitis B virus (HBV) antiviral agents, pegylated interferon (Peg-IFN), and nucleos(t)ide analogs (NAs) for chronic HBV infection. Although Peg-IFN is used for a finite 48-week duration and offers a greater chance of sustained off-treatment virological response, it is poorly tolerated and can only be offered to selected patients. The NAs are well tolerated but require prolonged therapy due to risk of relapse with treatment cessation. There is evolving data that novel virological assays (e.g., quantitative hepatitis B surface antigen, quantitative hepatitis B core antigen, quantitative antibody to core protein) in combination with hepatitis B genotype and more sensitive HBV DNA polymerase chain reaction (PCR) assays may be useful to predict response to IFN as well as off-treatment NA durability. Utilization of these clinical laboratory tests may be important given the development of novel anti-HBV therapies, hoping to achieve a cure for chronic hepatitis B infection.
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Affiliation(s)
- Carla Osiowy
- Bloodborne Pathogens and Hepatitis, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington St., Winnipeg, MB R3E 3R2 Canada
| | - Carla Coffin
- Liver Unit, Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, AB Canada
| | - Anton Andonov
- Bloodborne Pathogens and Hepatitis, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington St., Winnipeg, MB R3E 3R2 Canada
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19
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Jeng WJ, Chen YC, Chang ML, Liaw YF. α-Fetoprotein level-dependent early hepatitis B surface antigen decline during entecavir therapy in chronic hepatitis B with hepatitis flare. J Antimicrob Chemother 2016; 71:1601-8. [PMID: 26936920 DOI: 10.1093/jac/dkw019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 01/15/2016] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Hepatitis B surface antigen (HBsAg) reduction during nucleos(t)ide analogue therapy is related to ALT level. ALT reflects hepatocytolysis while α-fetoprotein (AFP) ≥100 ng/mL during hepatitis flare reflects more extensive hepatocytolysis (bridging hepatic necrosis). The impact of AFP levels on early HBsAg kinetics during entecavir therapy was investigated. METHODS HBsAg level was measured at baseline and months 6 and 12 of entecavir therapy in 149 chronic hepatitis B patients with hepatitis flare, defined as ALT ≥5× upper limit of normal (ULN), and 58 patients with ALT <5× ULN. RESULTS There was a significantly greater HBsAg reduction in an ALT (<5, 5-10, 10-20 and ≥20× ULN, P = 0.001) and AFP (<20, 20-99 and ≥100 ng/mL, P = 0.000) level-dependent manner. In hepatitis flares with a peak AFP level ≥20 ng/mL, the differences in HBsAg reduction across all ALT levels became non-significant. HBsAg reduction was greater in genotype B- than genotype C-infected patients with baseline ALT ≥20× ULN, but the difference became non-significant in those with peak AFP ≥100 ng/mL. Multivariate linear regression analysis showed that AFP level ≥100 ng/mL, baseline HBsAg level and genotype B were independent significant factors for greater HBsAg decline at month 6 of entecavir therapy. CONCLUSIONS During entecavir therapy, early HBsAg reduction increased in an AFP and ALT level-dependent manner, suggesting the impact of hepatocytolysis rather than nucleos(t)ide analogue per se. Notably, a higher AFP level during hepatitis flare, reflecting more extensive hepatic necrosis, was a more powerful factor than ALT and genotype for greater HBsAg decline.
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Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yi-Cheng Chen
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Ming-Ling Chang
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Chu X, Wu B, Fan H, Hou J, Hao J, Hu J, Wang B, Liu G, Li C, Meng S. PTD-fused p53 as a potential antiviral agent directly suppresses HBV transcription and expression. Antiviral Res 2016; 127:41-9. [PMID: 26784393 DOI: 10.1016/j.antiviral.2016.01.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 01/05/2016] [Accepted: 01/14/2016] [Indexed: 01/12/2023]
Abstract
In Hepatitis B virus (HBV) infection, the virus generates numerous viral mRNAs/proteins and viral loads, which plays a major role in driving T cell tolerance, viral persistence, and hepatocellular carcinoma. However, currently available anti-HBV agents have no direct effect on viral mRNA transcription and protein expression. In this study, we designed a recombinant fusion of p53 protein with the cell-penetrating peptide PTD (protein transduction domain of trans-activator of transcription), which mediated p53 internalization into hepatocytes. PTD-p53 effectively suppressed HBV transcription and antigen expression by interaction with viral enhancers. We further provide evidence that PTD-p53 counteracts the viral transcription feedback loop and effectively suppressed HBV production of viral mRNAs, as well as HBsAg, HBeAg, and HBcAg, both in vitro and in vivo. Our results thereby provide a basis for developing a new therapeutic approach against HBV infection.
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Affiliation(s)
- Xiaoyu Chu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China; School of Life Sciences, Anhui University, Hefei, PR China
| | - Bo Wu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China; School of Life Sciences, Anhui University, Hefei, PR China
| | - Hongxia Fan
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Junwei Hou
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Junli Hao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Jun Hu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Baozhong Wang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China; School of Life Sciences, Anhui University, Hefei, PR China
| | - Guangze Liu
- Transgenic Engineering Research Laboratory, Infectious Disease Center, 458th Hospital, Guangzhou, PR China.
| | - Changfei Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China.
| | - Songdong Meng
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China.
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Molecular Detection and Characterization of Hepatitis B Virus. Mol Microbiol 2016. [DOI: 10.1128/9781555819071.ch32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
INTRODUCTION The hepatitis B virus (HBV) causes chronic hepatitis B (CHB) in ∼350 million people worldwide who have an increased risk of end-stage liver disease and/or hepatocellular carcinoma. SOURCES OF DATA Several peer-reviewed papers featuring new approaches to anti-HBV management. Additionally, we also reviewed recent abstract presentations at international congresses. AREAS OF AGREEMENT There has been great progress in CHB therapy with the development of standard and pegylated interferon (i.e. PEG-IFN) as well as nucleos/tide analogs (NAs). IFN has both antiviral and immunomodulatory effects and through immune-mediated destruction of infected hepatocytes offers the possibility of finite therapy. However, this 'killing for a cure' antiviral strategy may not be tolerated in many, especially in cirrhotic patients. NAs inhibit viral reverse transcriptase, have few side effects and prevent liver disease progression, but cannot offer a cure as they have little effect on the resilient HBV covalently closed circular DNA (cccDNA) intermediate. Moreover, NAs such as tenofovir and entecavir offer a high genetic barrier to resistance, but are expensive and not readily available in many global regions. GROWING POINTS Despite significant treatment advances, there is increased recognition of the need for improved anti-HBV treatments, and new virologic tests for monitoring treatment response. AREAS OF CONTROVERSY The role of quantitative hepatitis B surface antigen, intrahepatic cccDNA levels and viral genotype in selecting treatment candidates and refining NA stopping rules. AREAS TIMELY FOR DEVELOPING NEW RESEARCH Potential new therapies include viral entry inhibitors, RNA interference technologies (i.e. RNAi) and small molecules that modulate cccDNA transcription, as well as novel immunomodulatory therapies to boost HBV-specific T cell responses. The ultimate goal of new tests and anti-HBV therapies is to reduce the burden and expense of life-long CHB treatment, as 'only diamonds are forever'.
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Affiliation(s)
- Carla S Coffin
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
| | - Samuel S Lee
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
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Suh SK, Song S, Oh HB, Hwang SH, Hah SS. Aptamer-based competitive binding assay for one-step quantitation of hepatitis B surface antigen. Analyst 2015; 139:4310-4. [PMID: 24987752 DOI: 10.1039/c4an00619d] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
An aptamer-based competitive binding assay for one-step (i.e. no requirement of pre-treatment) quantitation of target molecules of interest has been developed. This method has been successfully employed for the fast and sensitive detection of the surface antigen of the hepatitis B virus (HBsAg). The key features of our method include its low intrinsic background noise, low costs, high resolution, and high sensitivity, enabling the detection of as low as 1.25 mIU mL(-1), approximately 40-fold better than that of the most widely used Abbott Architect assay for HBsAg detection, without the tedious extraction and/or washing procedures. Moreover, this assay has better recovery and accuracy than that of conventional competitive binding assay or others for HBsAg quantitation.
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Affiliation(s)
- Sung-Kwan Suh
- Department of Chemistry and Research Institute for Basic Sciences, Kyung Hee University, Seoul 130-701, Korea.
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Sequential combination therapy with pegylated interferon leads to loss of hepatitis B surface antigen and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B patients receiving long-term entecavir treatment. Antimicrob Agents Chemother 2015; 59:4121-8. [PMID: 25941216 DOI: 10.1128/aac.00249-15] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 04/14/2015] [Indexed: 12/14/2022] Open
Abstract
Nucleos(t)ide analogues rarely result in a durable off-treatment response in chronic hepatitis B infection, whereas pegylated interferon (Peg-IFN) induces a long-lasting response only in a subset of patients. We assessed the effect of sequential combination therapy with Peg-IFN-α2a and entecavir in hepatitis B e antigen (HBeAg)-positive patients with prior long-term entecavir therapy and investigated the predictors of response to treatment. HBeAg-positive individuals who did not achieve HBeAg seroconversion during previous long-term entecavir therapy, receiving Peg-IFN-α2a added to ongoing entecavir therapy (sequential combination [S-C] therapy; n = 81) for 48 weeks or remaining on entecavir monotherapy (n = 116), were retrospectively included. A matched pair was created at a 1:1 ratio from each treatment group. The primary endpoint was HBeAg seroconversion at week 48. Subgroup analysis of response prediction was conducted for 81 patients with S-C therapy. More patients in the S-C therapy group achieved HBeAg seroconversion than those in the entecavir group (44% versus 6%; P < 0.0001). An HBeAg level of <200 signal-to-cutoff ratio (S/CO) at baseline was a strong predictor for higher HBeAg seroconversion than that achieved when HBeAg was ≥200 S/CO (64.2% versus 17.9%; P < 0.0001). Hepatitis B surface antigen (HBsAg) levels at baseline and the decrease in HBsAg levels predicted HBsAg loss in the S-C therapy group. The combination of baseline HBeAg of <200 S/CO and HBsAg of <1,000 IU/ml and an HBsAg decline at week 12 of ≥0.5 log10 IU/ml provided the highest rate of HBeAg seroconversion (92.31%) and HBsAg loss (83.3%) at week 48. Patients receiving sequential combination therapy have a higher rate of HBeAg seroconversion and are more likely to experience HBsAg clearance than do those continuing entecavir monotherapy. Sequential combination therapy can be guided by baseline HBsAg/HBeAg levels and on-treatment HBsAg dynamics.
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Hou JL, Gao ZL, Xie Q, Zhang JM, Sheng JF, Cheng J, Chen CW, Mao Q, Zhao W, Ren H, Tan DM, Niu JQ, Chen SJ, Pan C, Tang H, Wang H, Mao YM, Jia JD, Ning Q, Xu M, Wu SM, Li J, Zhang XX, Ji Y, Dong J, Li J. Tenofovir disoproxil fumarate vs adefovir dipivoxil in Chinese patients with chronic hepatitis B after 48 weeks: a randomized controlled trial. J Viral Hepat 2015; 22:85-93. [PMID: 25243325 DOI: 10.1111/jvh.12313] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) has demonstrated long-term efficacy and a high barrier to resistance in multiple chronic hepatitis B (CHB) populations outside of China. This study aimed to evaluate the efficacy and safety of TDF compared with adefovir dipivoxil (ADV) in Chinese patients with CHB during 48 weeks of treatment (ClinicalTrial.gov number, NCT01300234). A Phase 3, multicentred, randomized, double-blind, controlled trial compared the efficacy and safety of TDF with ADV in Chinese patients with CHB. The primary endpoint was the proportion of patients with HBV DNA <400 copies/mL in each treatment group at Week 48, using an unpooled Z-test for superiority. Secondary endpoints included viral suppression, serologic response, histological improvement, normalization of alanine aminotransferase (ALT) levels and the emergence of resistance mutations. A total of 509 patients, 202 hepatitis B e antigen (HBeAg)-positive and 307 HBeAg-negative, with HBV DNA ≥10(5) copies/mL received either TDF 300 mg od or ADV 10 mg od. At Week 48, TDF demonstrated superior viral suppression compared with ADV in both HBeAg-positive (76.7% vs 18.2%, P < 0.0001) and HBeAg-negative (96.8% vs 71.2%, P < 0.0001) patients. The majority of patients in both treatment arms achieved ALT normalization (>85%). No resistance to TDF was observed. The frequency of adverse events was comparable between treatment arms (TDF 3.9% vs ADV 4.8%). In this double-blind, randomized, clinical trial, TDF demonstrated superiority over ADV with respect to viral suppression in Chinese patients with CHB at 48 weeks of treatment and without the development of resistance.
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Affiliation(s)
- J L Hou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Guangzhou, China
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Hepatitis B inactive carriers: An overlooked population? GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2014. [DOI: 10.1016/j.jpge.2014.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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27
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Okuhara S, Umemura T, Joshita S, Shibata S, Kimura T, Morita S, Komatsu M, Matsumoto A, Yoshizawa K, Katsuyama Y, Ota M, Tanaka E. Serum levels of interleukin-22 and hepatitis B core-related antigen are associated with treatment response to entecavir therapy in chronic hepatitis B. Hepatol Res 2014; 44:E172-80. [PMID: 24308754 DOI: 10.1111/hepr.12287] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 11/28/2013] [Accepted: 12/02/2013] [Indexed: 02/08/2023]
Abstract
AIM We sought to clarify the associations between serum cytokines and chemokines, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and hepatitis B virus (HBV) DNA and response to entecavir therapy in chronic hepatitis B. METHODS We analyzed six cytokines (interleukin [IL]-2, IL-6, IL-10, IL-12p70, IL-21 and IL-22) and five chemokines (CCL2, CCL3, CXCL9, CXCL10 and CXCL11) before and at 6, 12 and 24 months during entecavir therapy in 48 chronic hepatitis B patients. Quantitative measurement of HBsAg, HBcrAg and HBV DNA was performed. A virological response (VR) was defined as serum HBV DNA of less than 2.1 log copies/mL by treatment month 24. RESULTS Thirty-nine patients (81%) achieved a VR. Serum IL-6 (P = 0.031), CXCL-9 (P = 0.002), and CXCL-10 (P = 0.001) were high in chronic HBV and correlated positively with transaminases and bilirubin. Before treatment, elevated IL-22 (P = 0.031) and lower HBsAg (P = 0.001) and HBcrAg (P < 0.001), but not HBV DNA, were associated with a favorable treatment outcome. In multivariate analysis, high IL-22 (hazard ratio = 13.67, P = 0.046) and low HBcrAg (hazard ratio = 10.88, P = 0.048) were independently associated with a VR. The levels of IL-22 (P < 0.001), HBsAg (P < 0.001), and HBcrAg (P < 0.001) all decreased from baseline to 24 months of treatment in virological responders. CONCLUSION Serum IL-22 and HBcrAg are predictive markers of a VR to entecavir therapy in patients with chronic hepatitis B.
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Affiliation(s)
- Sadahisa Okuhara
- Department of Medicine, Division of Hepatology and Gastroenterology, Matsumoto, Japan
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Larsson SB, Eilard A, Malmström S, Hannoun C, Dhillon AP, Norkrans G, Lindh M. HBsAg quantification for identification of liver disease in chronic hepatitis B virus carriers. Liver Int 2014; 34:e238-45. [PMID: 24118747 DOI: 10.1111/liv.12345] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 09/22/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Quantification of hepatitis B surface antigen (HBsAg) has been proposed as a useful diagnostic marker for clinical staging (identification of inactive carrier state) and prognosis of chronic hepatitis B virus (HBV) infection. The aim of this study was to investigate the correlation between HBsAg levels in serum and histological liver damage in patients with chronic infection. METHODS HBsAg levels in serum (by Abbott Architect) were related to HBV DNA, ALT and histological score (n=160) and covalently closed circular DNA (cccDNA) (n=84). RESULTS HBsAg levels correlated with cccDNA, serum HBV DNA, ALT and high inflammation scores (P<0.001). Among HBeAg-negative patients, an HBsAg level below 3.0 log10 IU/ml identified minimal liver damage (normal ALT and mild inflammation) with a predictive value of 92% (alone) or 96% (in combination with HBV DNA<4.0 log10 copies/ml), whereas an HBsAg level above 3.5 log10 IU/ml identified severe inflammation with a predictive value of 16% (alone) or 33% (in combination with HBV DNA>5.0 log10 copies/ml). CONCLUSIONS HBsAg levels reflect clinical stage and liver disease, and a combined quantification of HBsAg and HBV DNA may improve clinical staging.
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Affiliation(s)
- Simon B Larsson
- Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden
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29
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Chen GY, Zhu MF, Zheng DL, Bao YT, Wang J, Zhou X, Lou GQ. Baseline HBsAg predicts response to pegylated interferon-α2b in HBeAg-positive chronic hepatitis B patients. World J Gastroenterol 2014; 20:8195-8200. [PMID: 25009392 PMCID: PMC4081692 DOI: 10.3748/wjg.v20.i25.8195] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 01/16/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the predictive effect of baseline hepatitis B surface antigen (HBsAg) on response to pegylated interferon (PEG-IFN)-α2b in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.
METHODS: This retrospective analysis compared the treatment efficacy of PEG-IFN-α2b alone in 55 HBeAg-positive CHB patients with different baseline HBsAg levels. Serum HBV DNA load was measured at baseline, and at 12, 24 and 48 wk of therapy. Virological response was defined as HBV DNA < 1000 IU/mL. Serum HBsAg titers were quantitatively assayed at baseline, and at 12 and 24 wk.
RESULTS: Eighteen patients had baseline HBsAg > 20 000 IU/mL, 26 patients had 1500-20000 IU/mL, and 11 patients had < 1500 IU/mL. Three (16.7%), 11 (42.3%) and seven (63.6%) patients in each group achieved a virological response at week 48, with a significant difference between groups with baseline HBsAg levels > 20000 or < 20000 IU/mL (P = 0.02). Thirteen patients had an HBsAg decline > 0.5 log10 and 30 patients < 0.5 log10 at week 12; and 6 (46.2%) and 10 (33.3%) in each group achieved virological response at week 48, with no significant difference between the two groups (P = 0.502). Eighteen patients had an HBsAg decline > 1.0 log10 and 30 patients < 1.0 log10 at week 24, and 8 (44.4%) and 11 (36.7%) achieved a virological response at week 48, with no significant difference between the two groups (P = 0.762). None of the 16 patients with HBsAg > 20000 IU/mL at week 24 achieved a virological response at week 48.
CONCLUSION: Baseline HBsAg level in combination with HBV DNA may become an effective predictor for guiding optimal therapy with PEG-IFN-α2b against HBeAg-positive CHB.
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Yeon JE. [Clinical significance of hepatitis B surface antigen quantification in chronic hepatitis B]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2014; 63:335-40. [PMID: 24953609 DOI: 10.4166/kjg.2014.63.6.335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Since the discovery of HBsAg in the early 1960s, presence of HBsAg in serum has only served to diagnose hepatitis B. Recent development in the quantitative measurement of serum HBsAg has enabled us to improve our understanding on the management of chronic hepatitis B. The surface antigen (sAg) level is at its highest in immune tolerance phase and decreases to the lowest level in immune control/inactive phase when HBeAg is cleared from the serum. Combination of serum sAg titer less than 1,000 IU/mL and serum HBV DNA less than 2,000 IU/mL can identify true inactive carrier from e antigen (eAg) negative hepatitis with diagnostic accuracy of 95%. During the natural course of chronic hepatitis B, changes or absolute level of sAg less than certain level can predict spontaneous sero-clearance of HBsAg. Although the decline of sAg is very slow in interferon (IFN)/pegylated interferon (PEG-IFN) or oral nucleos(-t)ide treated patients, interferon based therapy results in a greater decrease of sAg level and sAg loss. Lack of any decline in sAg titer during PEG-IFN therapy could identify the group of patients who do not response to IFN/PEG-IFN therapy. With the aid of serum HBV DNA, quantitative measurement of serum HBsAg level can be used to optimize the management of chronic hepatitis B in our daily practice.
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Affiliation(s)
- Jong Eun Yeon
- Department of Internal Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 152-703, Korea
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Romero M, Madejón A, García-Samaniego J. ¿Es útil la cuantificación de los niveles del HBsAg en el control del paciente con infección crónica por el virus de la hepatitisB? GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:350-3. [DOI: 10.1016/j.gastrohep.2013.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 10/28/2013] [Indexed: 01/15/2023]
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Tan Z, Li M, Kuang X, Tang Y, Fan Y, Deng G, Wang Y, He D. Clinical implications of hepatitis B surface antigen quantitation in the natural history of chronic hepatitis B virus infection. J Clin Virol 2014; 59:228-234. [PMID: 24529415 DOI: 10.1016/j.jcv.2014.01.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 12/20/2013] [Accepted: 01/19/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND HBsAg quantitation may be useful for managing patients with hepatitis B virus (HBV) infection. OBJECTIVES We explored the clinical implications of HBsAg quantitation for patients with HBsAg levels >250IU/ml (Abbott Diagnostics). STUDY DESIGN Two hundred and thirty-three HBV-infected patients comprising 29 immune tolerance cases, 49 treatment-naïve HBeAg-positive chronic hepatitis B (CHB) cases, 91 inactive HBV carrier cases, and 64 treatment-naïve HBeAg-negative CHB cases were analyzed. HBsAg was quantified by the Architect HBsAg assay (Abbott Diagnostics) after a 1:500 automated dilution. RESULTS AND CONCLUSIONS HBsAg (log10IU/ml) was established for immune tolerance (4.50±0.43), HBeAg-positive CHB (4.17±0.66), inactive HBV carrier (3.32±0.44), and HBeAg-negative CHB (3.23±0.40); (p=4.92×10(-35)). No significant difference was observed between inactive HBV carrier and HBeAg-negative CHB (p=0.247). The proportions of HBsAg <2000IU/ml for inactive HBV carrier and HBeAg-negative CHB were 51.6% and 59.3%, respectively (p=0.341). Positive correlations between HBsAg and HBV DNA were observed for immune tolerance (p=1.23×10(-4)) and HBeAg-positive CHB (p=0.003), but not for HBeAg-negative CHB (p=0.432). A negative correlation between HBsAg and age was observed for immune tolerance (p=0.030), HBeAg-positive CHB (p=0.016), and inactive HBV carrier (p=0.001), but not in HBeAg-negative CHB (p=0.249). No significant differences between HBsAg and ALT for HBeAg-positive (p=0.338) or HBeAg-negative CHB (p=0.564) were observed. For patients with HBsAg quantitation >250IU/ml, HBsAg may reflect HBV DNA replication for HBeAg-positive cases. HBsAg is not a suitable marker for evaluating hepatitis activity and distinguishing between cases of HBeAg-negative CHB and inactive HBV carrier state.
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Affiliation(s)
- Zhaoxia Tan
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China; The Chongqing Key Laboratory for Research of Infectious Diseases, China
| | - Maoshi Li
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China; The Chongqing Key Laboratory for Research of Infectious Diseases, China
| | - Xuemei Kuang
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China; The Chongqing Key Laboratory for Research of Infectious Diseases, China
| | - Yu Tang
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China; The Chongqing Key Laboratory for Research of Infectious Diseases, China
| | - Yi Fan
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China; The Chongqing Key Laboratory for Research of Infectious Diseases, China
| | - Guohong Deng
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China; The Chongqing Key Laboratory for Research of Infectious Diseases, China
| | - Yuming Wang
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China; The Chongqing Key Laboratory for Research of Infectious Diseases, China
| | - Dengming He
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China; Liver Disease Diagnosis and Treatment Center, The 88th Hospital of Chinese PLA, China; The Chongqing Key Laboratory for Research of Infectious Diseases, China.
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Sohn W, Paik YH, Kim JM, Kwon CH, Joh JW, Cho JY, Gwak GY, Choi MS, Lee JH, Koh KC, Paik SW, Yoo BC. HBV DNA and HBsAg Levels as Risk Predictors of Early and Late Recurrence after Curative Resection of HBV-related Hepatocellular Carcinoma. Ann Surg Oncol 2014; 21:2429-35. [DOI: 10.1245/s10434-014-3621-x] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Indexed: 12/15/2022]
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Kawanaka M, Nishino K, Nakamura J, Oka T, Urata N, Goto D, Suehiro M, Kawamoto H, Kudo M, Yamada G. Quantitative Levels of Hepatitis B Virus DNA and Surface Antigen and the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Receiving Long-Term Nucleos(t)ide Analogue Therapy. Liver Cancer 2014; 3:41-52. [PMID: 24804176 PMCID: PMC3995398 DOI: 10.1159/000343857] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Serum levels of hepatitis B virus (HBV) DNA are an important predictor of the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV infection. However, little is known about whether high levels of hepatitis B surface antigen (HBsAg) increase the risk for HCC. METHODS We investigated 167 patients who were treated with nucleos(t)ide analogues (NA) for at least 2 years (median: 5.8 years, range: 2-13.1 years). Relationships between reduced levels of HBsAg and various factors were evaluated. In addition, we evaluated the usefulness of quantitative serum levels of HBV DNA and HBsAg as predictors of HCC development in patients receiving long-term NA therapy. RESULTS HCC developed in 9 of the 167 NA-treated patients. In the 9 patients with HCC, HBV DNA was undetectable (<2.1 log copies/mL), but HBsAg levels were ≥2000 C.O.I. in 7 patients. No maternal transmission, long NA treatment period, HBV DNA levels <3.0 log copies/mL, and reduced hepatitis B e antigen levels during the first 24 weeks of treatment were a significant factor of HBsAg levels <2000 C.O.I.. CONCLUSIONS Hepatocarcinogenesis was observed in patients with high HBsAg levels, despite the negative conversion of HBV DNA as a result of long-term NA therapy. Therefore, to suppress hepatocarcinogenesis, it is important to control not only HBV DNA levels but also HBsAg levels.
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Affiliation(s)
- Miwa Kawanaka
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Ken Nishino
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Jun Nakamura
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Takahito Oka
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Noriyo Urata
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Daisuke Goto
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Mitsuhiko Suehiro
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Hirofumi Kawamoto
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan
| | - Gotaro Yamada
- Department of General Internal Medicine 2, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
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Song IH, Kim SM, Choo YK. Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy. World J Gastroenterol 2013; 19:8867-8872. [PMID: 24379609 PMCID: PMC3870537 DOI: 10.3748/wjg.v19.i47.8867] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 10/23/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a grave primary liver cancer that has a limited therapeutic option because it is generally diagnosed later in an advanced stage due to its aggressive biologic behavior. The early detection of HCC has a great impact on the treatment efficacy and survival of patients at high risk for cancer. Potential host, environmental, and virus-related risk factors have been introduced. Hepatitis B virus (HBV) is a major cause of end-stage liver diseases such as liver cirrhosis or HCC in endemic areas, and its serologic or virologic status is considered an important risk factor. HCC risk prediction derived from the identification of major risk factors is necessary for providing adequate screening/surveillance strategies to high-risk individuals. Several risk prediction models for HBV-related HCC have been presented recently with simple, efficient, and readily available to use parameters applicable to average- or unknown-risk populations as well as high-risk individuals. Predictive scoring systems of risk estimation to assess HCC development can provide the way to an evidence-based clinical approach for cost- and effort-effective outcomes, capable of inducing a personalized surveillance program according to risk stratification. In this review, the concepts and perspectives of the risk prediction of HCC are discussed through the analysis of several risk prediction models of HBV-related HCC.
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Is HBsAg quantification ready, for prime time? Clin Res Hepatol Gastroenterol 2013; 37:559-63. [PMID: 23932705 DOI: 10.1016/j.clinre.2013.07.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Accepted: 07/01/2013] [Indexed: 02/04/2023]
Abstract
Despite the availability of an efficient hepatitis B vaccine, approximately 240 million individuals are chronically infected with hepatitis B virus worldwide. One-fourth of hepatitis B surface antigen (HBsAg)-positive patients will develop complications, such as cirrhosis or hepatocellular carcinoma, both major causes of liver-related deaths. Antiviral therapies, such as pegylated interferon alpha or nucleoside/nucleotide analogues, are effective in suppressing HBV DNA and reducing the subsequent risk of fibrosis progression, cirrhosis and hepatocellular carcinoma. HBsAg has proven to be a steady, reliable marker of chronic HBV carriage that can also be used to predict clinical outcomes. Three commercial enzyme immunoassays are now available for HBsAg quantification. A number of recent studies have shown clinical utility of HBsAg quantification in combination with HBV DNA levels to identify inactive carriers who need antiviral therapy and in interferon treated-patients in order to predict the virological response to pegylated interferon alpha.
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Lei X, Gao X, Yang J, Sun Y, Sai Y, You W, Yuan H. The genotype C could play a key role in hepatitis B virus associated nephritis among the northwest Chinese children. Eur J Intern Med 2013; 24:835-8. [PMID: 23988262 DOI: 10.1016/j.ejim.2013.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 06/04/2013] [Accepted: 07/16/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatitis B virus-associated glomerulonephritis (HBV-GN) is a kind of immune complex-induced glomerulonephritis. The present study was designed to determine whether Hepatitis B virus (HBV) genotype is associated with glomerulonephritis in north-west Chinese children. METHODS A total of 296 HBV-infected patients were enrolled in this study. The serum of patients was subjected to DNA extraction and the HBV genotypes were determined by PCR. RESULTS The results showed that genotype C (49%) was predominant within the subjects, compared to HBV/B (38.5%), B/C recombinant (7.4%) and none B/C (5.1%). The serum tests showed that the changes of Complement 3 (C3) and alanine amino transferase (ALT) levels in the genotype C patients were significantly greater than those in the genotype B patients. The frequency of genotype C in HBV-GN patients was higher than that in non HBV-GN patients (χ2 value=30.239, P<0.001). But, it was not associated with renal dysfunction. Furthermore, The genotype C was associated with high HBV-DNA load (82.9% vs 17.1%, P<0.001), which is seen more frequently in the HBV-GN children (86.3% vs 13.3%, P=0.004). CONCLUSIONS The genotype C may play a role in HBV-GN children, via favoring HBV replication.
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Affiliation(s)
- Xiaoyan Lei
- Pediatric Department, Gansu Provincial Hospital, Lanzhou City, 730000, China.
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Shouval D. Focus. J Hepatol 2013; 59:1151-2. [PMID: 24021425 DOI: 10.1016/j.jhep.2013.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 09/04/2013] [Indexed: 12/04/2022]
Affiliation(s)
- Daniel Shouval
- Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
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Jeng WJ, Sheen IS, Chen YC, Hsu CW, Chien RN, Chu CM, Liaw YF. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology 2013; 58:1888-96. [PMID: 23744454 DOI: 10.1002/hep.26549] [Citation(s) in RCA: 180] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Accepted: 05/22/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED The optimal duration of nucelos(t)ide analog (Nuc) treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B virus (HBV) infection is unknown. The Asian Pacific Association for the Study of the Liver (APASL) guidelines recommend that treatment can be discontinued if undetectable HBV-DNA has been documented on three occasions ≥ 6 months apart. This study aimed to test this stopping rule in HBeAg-negative chronic hepatitis B (CHB) patients treated with entecavir (ETV). Ninety-five patients (39 cirrhosis) were treated with ETV for a median of 721 (395-1,762) days before stopping therapy and were then monitored with serum HBV DNA and alanine aminotransferase (ALT) at least every 3 months. Within 1 year after stopping ETV therapy, "clinical relapse" (an episode of ALT elevation >2 × upper limit of normal plus HBV-DNA >2,000 IU/mL) occurred in 43 (45.3%) of the 95 patients. Of the 39 cirrhosis patients, 17 (43.6%) relapsed and one (2.6%) developed decompensation. The median duration until relapse was 230 days (74.4% >6 months). Logistic regression analysis showed that baseline HBV-DNA ≤ 2 × 10(5) IU/mL was the only significant independent factor for sustained response. The 1-year relapse rate was 29% in patients with a baseline HBV DNA ≤ 2 × 10(5) IU/mL versus 53% in those with HBV DNA >2 × 10(5) IU/mL (P = 0.027). For the latter, consolidation therapy >64 weeks reduced the relapse rate to 33.3% in patients without cirrhosis. CONCLUSION With an overall 1-year relapse rate of 45% and 29% in those with a baseline serum HBV DNA ≤ 2 × 10(5) IU/mL, the APASL stopping rule for HBeAg-negative CHB patients with proper off-therapy monitoring is adequate even in patients with cirrhosis. Consolidation therapy >64 weeks seems more appropriate for those with higher baseline HBV DNA.
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Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Linkou Medical Center, Chang Gung Memorial Hospital, Taipei, Taiwan; College of Medicine, Chang Gung University, Taipei, Taiwan
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Su CW, Wu CY, Hung HH, Wu CH, Sheen IJ, Wu JC. Differential roles of serum hepatitis B virus DNA and hepatitis B surface antigen level in predicting virological breakthrough in patients receiving lamivudine therapy. J Gastroenterol Hepatol 2013; 28:1849-58. [PMID: 23730852 DOI: 10.1111/jgh.12283] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/15/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM The role of serum hepatitis B surface antigen (HBsAg) level in determining virological breakthrough (VB) for patients with hepatitis B virus (HBV) infection receiving lamivudine remains unclear. The study aimed to evaluate the impact of serum HBsAg levels on VB among patients receiving lamivudine therapy, especially in a setting of low HBV viral load. METHODS Two hundred sixty-eight consecutive treatment-naïve patients who underwent lamivudine therapy for chronic hepatitis B were enrolled. Factors in terms of VB were analyzed by multivariate analysis. RESULTS After a median treatment duration of 67.1 weeks, 102 patients had VB. Multivariate analysis showed that positive hepatitis B e antigen (HBeAg) (hazard ratio 2.165, P = 0.026) and HBV DNA levels ≥ 2000 IU/mL after 6 months of lamivudine therapy (hazard ratio 5.236, P = 0.001) were independent risk factors predicting VB. The cumulative VB rates stratified by HBeAg-positive and -negative at 3 years were 44.7% and 26.3%, respectively. At 3 years, the cumulative VB rates stratified by the HBV DNA < 2000 and ≥ 2000 IU/mL after 6 months of therapy were 25.5% and 79.4%, respectively. For HBeAg-positive patients with serum HBV DNA < 2000 IU/mL after 6 months of therapy, baseline HBsAg levels ≥ 20,000 IU/mL was the only risk factor associated with VB. CONCLUSIONS For chronic hepatitis B patients treated with lamivudine, serum HBV DNA level > 2000 IU/mL after 6 months of therapy could predict subsequent VB. In patients with lower on-treatment viral load, baseline serum HBsAg level is associated with the emergence of VB, especially for those with serum positive HBeAg.
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Affiliation(s)
- Chien-Wei Su
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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Akuta N, Suzuki F, Kobayashi M, Hara T, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Saitoh S, Ikeda K, Kumada H. Correlation between hepatitis B virus surface antigen level and alpha-fetoprotein in patients free of hepatocellular carcinoma or severe hepatitis. J Med Virol 2013; 86:131-8. [PMID: 24123090 DOI: 10.1002/jmv.23790] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2013] [Indexed: 12/19/2022]
Abstract
Alfa-fetoprotein (AFP) is used as a marker of early hepatocarcinogenesis. However, the impact of hepatitis B virus surface antigen (HBsAg) on this relationship in patients with HBV infection is not clear. The present study evaluated the relation between HBsAg and AFP levels at the initial visit in 1,610 untreated HBV patients, free of hepatocellular carcinoma (HCC) or severe hepatitis. The cumulative rate of HCC was significantly lower in patients with a low AFP level (≤10 µg/L; below the upper limit of normal) than in those with a high AFP level (≥11 µg/L) at the initial visit. In patients with HBsAg levels more than 500 IU/ml, HBsAg levels correlated significantly and negatively with AFP levels, and significantly with platelet count. Multivariate analysis of data of patients with HBsAg more than 500 IU/ml identified HBsAg (<7,000 IU/ml), albumin (<3.9 g/dl), platelet count (<20.0 × 10(4) /mm(3)), gamma-glutamyl transpeptidase (≥50 IU/L), aspartate aminotransferase (≥34 IU/L), HBeAg (positive), and HBV core-related antigen (≥3.0 log U/ml) as determinants of a high AFP. Especially, in patients with HBsAg more than 500 IU/ml and low transaminase levels (below the upper limit of normal), HBsAg was identified as significant determinant of a high AFP. On the other hand, in patients with HBsAg less than 500 IU/ml, multivariate analysis identified albumin, gamma-glutamyl transpeptidase, and HBV core-related antigen as determinants of a high AFP. The results indicated that HBsAg level seems to affect, at least in part, the AFP levels, and that it can be used as a surrogate marker of early hepatocarcinogenesis.
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Affiliation(s)
- Norio Akuta
- Department of Hepatology and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
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Stene-Johansen K, Barlinn R. [Diagnosis of chronic hepatitis B infection]. TIDSSKRIFT FOR DEN NORSKE LEGEFORENING 2013; 133:1717-21. [PMID: 24005708 DOI: 10.4045/tidsskr.12.1206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
BACKGROUND Infection with the hepatitis B virus can lead to chronic liver inflammation with the risk of developing cirrhosis and cancer of the liver. Increased knowledge and improved treatment of chronic hepatitis B infection in recent years mean that virological tests are increasingly used to ascertain the course of illness, status and response to treatment by the individual patient. The purpose is therefore to provide an updated overview of available diagnostics. METHOD The article builds on a selection of original and review articles identified through a search in Medline, as well as experience of microbiological diagnostics from the national reference laboratory for the hepatitis virus in Norway. RESULTS Detection of virus proteins and antibodies to these, as well as virus quantification and characterisation, form an important part of the assessment of hepatitis B infection, including confirmation of the chronic phase of the illness. INTERPRETATION Proper diagnosis is based on a broad selection of different serological and virological markers. Genotype and certain mutations may affect the course of illness and the response to treatment. To prevent further transmission and offer effective treatment, it is important to identify chronic carriers, but also persons who have previously been infected with hepatitis B virus with risk of reactivation.
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Loggi E, Bihl FK, Cursaro C, Granieri C, Galli S, Brodosi L, Furlini G, Bernardi M, Brander C, Andreone P. Virus-specific immune response in HBeAg-negative chronic hepatitis B: relationship with clinical profile and HBsAg serum levels. PLoS One 2013; 8:e65327. [PMID: 23750252 PMCID: PMC3672146 DOI: 10.1371/journal.pone.0065327] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 04/24/2013] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND AIMS The immune impairment characterizing chronic hepatitis B (cHBV) infection is thought to be the consequence of persistent exposure to viral antigens. However, the immune correlates of different clinical stages of cHBV and their relation with different levels of HBsAg have not been investigated. The aim of the present study was to evaluate the relationship between HBV-specific T cells response and the degree of in vivo HBV control and HBsAg serum levels in HBeAg-HBeAb+ cHBV. METHODS Peripheral blood mononuclear cells from 42 patients with different clinical profiles (treatment-suppressed, inactive carriers and active hepatitis) of cHBV, 6 patients with resolved HBV infection and 10 HBV-uninfected individuals were tested with overlapping peptides spanning the entire HBV proteome. The frequency and magnitude of HBV-specific T cell responses was assessed by IFNγ ELISPOT assay. Serum HBsAg was quantified with a chemiluminescent immunoassay. RESULTS The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups. However, inactive carriers targeted preferentially the core region. In untreated patients, the breadth of the anti-core specific T cell response was inversely correlated with serum HBsAg concentrations as well as HBV-DNA and ALT levels and was significantly different in patients with HBsAg levels either above or below 1000 IU/mL. The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients. CONCLUSIONS Different clinical outcomes of cHBV infection are associated with the magnitude, breadth and specificity of the HBV-specific T cell response. Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.
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Affiliation(s)
- Elisabetta Loggi
- Department of Medical and Surgical Scinces, University of Bologna, Bologna, Italy
| | - Florian K. Bihl
- Gastroenterology Section, Ospedale Regionale di Bellinzona e Valli, Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Carmela Cursaro
- Department of Medical and Surgical Scinces, University of Bologna, Bologna, Italy
| | - Camilla Granieri
- Department of Medical and Surgical Scinces, University of Bologna, Bologna, Italy
| | - Silvia Galli
- Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Bologna, Italy
| | - Lucia Brodosi
- Department of Medical and Surgical Scinces, University of Bologna, Bologna, Italy
| | - Giuliano Furlini
- Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Bologna, Italy
| | - Mauro Bernardi
- Department of Medical and Surgical Scinces, University of Bologna, Bologna, Italy
| | - Christian Brander
- AIDS Research Institute IrsiCaixa - HIVACAT, Germans Trias i Pujol Hospital, Autonomous University Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Pietro Andreone
- Department of Medical and Surgical Scinces, University of Bologna, Bologna, Italy
- * E-mail:
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Zhou B, Liu M, Lv G, Zheng H, Wang Y, Sun J, Hou J. Quantification of hepatitis B surface antigen and E antigen: correlation between Elecsys and architect assays. J Viral Hepat 2013; 20:422-9. [PMID: 23647959 DOI: 10.1111/jvh.12044] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 10/29/2012] [Indexed: 12/20/2022]
Abstract
Quantification of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and their change model during treatment are emerging as a useful tool for assessing the outcome of hepatitis B virus (HBV) infection and predicting the efficacy of antiviral therapy. The aim of this study was to compare the performance of the Elecsys and Architect assays for HBsAg and HBeAg quantification. Quantification of HBsAg and HBeAg, determined by these two assays, were assessed in 1292 sera from patients with chronic hepatitis B(CHB). HBeAg quantification in serum was performed by calibrating the results through HBeAg Paul-Ehrlich international (PEI) reference standard. The HBV genotype was determined by direct sequencing and phylogenetic analysis. Of 1292 samples, the distribution of genotype was 514 (39.78%) genotype B, 776 (60.06%) genotype C, 2 (0.16%) genotype D. The results of HBsAg and HBeAg quantification between the Architect and Elecsys assays were significantly correlated (HBsAg: r = 0.939; HBeAg: r = 0.987), independent of HBV genotype and treatment phase. The mean differences between the two methods (the log10 [Elecsys] - the log10 [Architect]) were 0.075 log10 IU/mL and -0.149 log10 PE IU/mL in quantifying HBsAg and HBeAg, respectively. This study demonstrates a high correlation between the Elecsys and the Architect assays in quantifying HBsAg and HBeAg, regardless of HBV genotype. Both the two assays can be used to monitor the HBsAg and HBeAg levels in patients with chronic hepatitis B.
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Affiliation(s)
- B Zhou
- Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Martinot-Peignoux M, Carvalho-Filho R, Lapalus M, Netto-Cardoso ACF, Lada O, Batrla R, Krause F, Asselah T, Marcellin P. Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naïve, e antigen-positive patients. J Hepatol 2013; 58:1089-1095. [PMID: 23369792 DOI: 10.1016/j.jhep.2013.01.028] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 01/14/2013] [Accepted: 01/18/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Little is currently known about the association between serum HBsAg or HBV DNA levels and the severity of liver disease in chronic hepatitis B (CHB) patients. Therefore, we investigated these relationships in a large cohort of unselected, well-characterized, treatment-naïve CHB patients. METHODS CHB patients were assessed at the Hôpital Beaujon in Paris, France, between 2000 and 2008. Serum samples and liver biopsies were obtained on the same day. HBsAg, HBV DNA, and HBV genotype were investigated using commercial diagnostic assays and liver histology was scored using the METAVIR system. RESULTS 406 patients were included in this cross-sectional study. Serum HBsAg and HBV DNA levels in hepatitis B e antigen-positive (HBeAg[+]) patients showed strong correlation (r=0.44, p<0.0001), as did serum HBsAg levels and fibrosis severity (r=0.43, p<0.0001). HBeAg(+) patients with moderate to severe fibrosis exhibited significantly lower serum HBsAg and HBV DNA levels compared with patients with no or mild fibrosis. Modeling analysis suggested a serum HBsAg cut-off of 3.85 logIU/ml would provide a theoretical sensitivity of 100% (95% CI: 0-100), theoretical specificity of 86% (95% CI: 50-100), and a negative predictive value of 100% (95% CI: 67-100) in HBeAg(+) patients infected with HBV genotype B or C. CONCLUSIONS We found an association between low serum HBsAg levels and moderate to severe fibrosis in HBeAg(+) CHB patients. Furthermore, we described a serum HBsAg cut-off for the prediction of fibrosis severity in CHB patients infected with HBV genotype B or C.
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Affiliation(s)
- Michelle Martinot-Peignoux
- Centre de Recherche Biomédicale Bichat-Beaujon (CRB3), INSERM U-773 and Service d'Hépatologie Hôpital Beaujon APHP, Université Paris-Diderot, 92110 Clichy, France.
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Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky JM. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol 2013; 58:676-83. [PMID: 23219442 DOI: 10.1016/j.jhep.2012.11.039] [Citation(s) in RCA: 208] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 11/19/2012] [Accepted: 11/20/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Information regarding long-term HBsAg kinetics during treatment with nucleoside/nucleotide analogues is limited. The aim of the present study was to assess whether finite nucleoside/nucleotide analogue treatment duration could be envisaged during the patient's lifetime. METHODS Patients with chronic hepatitis B receiving different schedules of nucleoside/nucleotide analogues were followed for a median duration of 102 months, i.e., 8.5 years (interquartile range: 88-119 months). Long-term HBV DNA and HBsAg level kinetics were modeled in order to estimate time to clear HBsAg during therapy in patients with undetectable HBV DNA. RESULTS Antiviral therapy was associated with a slow but consistent reduction in the level of HBsAg in most of the patients. Three patterns of HBsAg level declines were identified: decline during both the detectable and undetectable HBV DNA phases; decline during the HBV DNA detectable period only; decline during the HBV DNA undetectable period only. The mean HBsAg titer at the time when HBV DNA became undetectable was 3.29 ± 0.49 Log₁₀ international units (IU)/ml, and the mean slope was -0.007 ± 0.007 Log₁₀ IU/month, i.e., an average decline of 0.084 Log₁₀ IU/year. The corresponding calculated median number of years needed to clear HBsAg was 52.2 years (interquartile range: 30.8-142.7). CONCLUSIONS This study, based on the very long-term follow-up of patients with chronic hepatitis B treated with potent nucleoside/nucleotide analogues, shows that HBsAg clearance is unlikely to occur during the patient's lifetime, even if HBV replication is well controlled. Thus, lifetime therapy is required in the vast majority of HBV-infected patients.
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Affiliation(s)
- Stéphane Chevaliez
- National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
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Block TM, Gish R, Guo H, Mehta A, Cuconati A, Thomas London W, Guo JT. Chronic hepatitis B: what should be the goal for new therapies? Antiviral Res 2013; 98:27-34. [PMID: 23391846 DOI: 10.1016/j.antiviral.2013.01.006] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 01/14/2013] [Accepted: 01/28/2013] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B can currently be medically managed with either pegylated interferon-alpha (pegIFN-α) or one of the five nucleos(t)ide analog Direct Acting Antivirals (DAAs) that inhibit the hepatitis B virus (HBV) DNA polymerase. While pegIFN-α is effective in approximately one-third of the treated patients, the polymerase inhibitors significantly reduce viral load in the vast majority of those treated. However, neither pegIFN-α nor nucleosi(t)de analogs are capable of reliably eliminating the virus and achieving a cure. Moreover, the interferons and polymerase inhibitors are recommended by US, European and Asian professional society practice guidelines for use in only a subset of those infected with HBV. This subset is the population with the greatest levels of circulating viral DNA and abnormal liver function. Although this is the population at the highest risk for cirrhosis and liver cancer, those who fall outside the treatment guidelines, with low levels of viral replication and normal serum ALTs, may also benefit from antiviral therapy. The questions are thus: are new classes of drugs needed to manage chronic hepatitis B? Is a cure possible? Is a cure even necessary? It is therefore important to define the meaning of a cure and determine what the goals of new therapies should be. In this article, we address those questions and propose two operational definitions of medically attainable cures. The first is a "functional cure" based on the clinical outcome, in which the patient's life expectancy becomes the same as that of an individual who has resolved his HBV infection without therapy. Because such an outcome cannot be measured over the short term, we also define an "apparent virological cure," based on the stable off-drug suppression of HBV viremia and antigenemia and the normalization of ALTs and other laboratory tests. We suggest that such a virological cure should be the goal of future therapeutics in all patients with chronic hepatitis B. The extent to which a virological cure predicts a functional cure will only be determined by long-term follow-up.
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Affiliation(s)
- Timothy M Block
- Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, USA.
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Bouthry E, Pivert A, Ducancelle A, Lunel-Fabiani F. Quantification de l’antigène HBs : intérêts et limites dans le suivi des patients infectés par le virus de l’hépatite B. IMMUNO-ANALYSE & BIOLOGIE SPÉCIALISÉE 2012; 27:332-338. [DOI: 10.1016/j.immbio.2012.07.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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49
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A novel multiplex real-time PCR assay for the concurrent detection of hepatitis A, B and C viruses in patients with acute hepatitis. PLoS One 2012; 7:e49106. [PMID: 23145085 PMCID: PMC3493491 DOI: 10.1371/journal.pone.0049106] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 10/04/2012] [Indexed: 12/16/2022] Open
Abstract
A novel multiplex real-time PCR assay for concurrent detection of hepatitis viruses was evaluated for its clinical performance in screening patients with acute hepatitis. A total of 648 serum samples were collected from patients with acute symptoms of hepatitis. Concurrent detection of nucleic acids of HAV, HBV and HCV was performed using the Magicplex™ HepaTrio Real-time Detection test. Serum nucleic acid levels of HBV and HCV were also quantified by the Cobas® AmpliPrep/Cobas® TaqMan® (CAP/CTM) HBV and HCV tests. Patients’ medical records were also reviewed. Concordance rates between the results from the HepaTrio and the CAP/CTM tests for the detection of HBV and HCV were 94.9% (k = 0.88) and 99.2% (k = 0.98), respectively. The cycle threshold values with the HepaTrio test were also correlated well with the levels of HBV DNA (r = −0.9230) and HCV RNA (r = −0.8458). The sensitivity and specificity of the HepaTrio test were 93.8% and 98.2%, respectively, for detecting HBV infection, and 99.1% and 100.0%, respectively, for HCV infection. For the HepaTrio test, 21 (3.2%) cases were positive for both HBV and HCV. Among the positive cases, 6 (0.9%) were true coinfections. This test also detected 18 (2.8%) HAV positives. The HepaTrio test demonstrated good clinical performance and produced results that agreed well with those of the CAP/CTM assays, especially for the detection of HCV. This assay was also able to detect HAV RNA from anti-HAV IgM-positive individuals. Therefore, this new multiplex PCR assay could be useful for the concurrent detection of the three hepatitis viruses.
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Orito E, Fujiwara K, Kanie H, Ban T, Yamada T, Hayashi K. Quantitation of HBsAg predicts response to entecavir therapy in HBV genotype C patients. World J Gastroenterol 2012; 18:5570-5575. [PMID: 23112549 PMCID: PMC3482643 DOI: 10.3748/wjg.v18.i39.5570] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 03/28/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To analysis the factors that predict the response to entecavir therapy in chronic hepatitis patients with hepatitis B virus (HBV) genotype C. METHODS Fifty patients [hepatitis B e antigen (HBeAg)-negative:HBeAg-positive = 26:24] with HBV genotype C, who received naïve entecavir therapy for > 2 years, were analyzed. Patients who showed HBV DNA levels ≥ 3.0 log viral copies/mL after 2 years of entecavir therapy were designated as slow-responders, while those that showed < 3.0 log copies/mL were termed rapid-responders. Quantitative hepatitis B surface antigen (HBsAg) levels (qHBsAg) were determined by the Architect HBsAg QT immunoassay. Hepatitis B core-related antigen was detected by enzyme immunoassay. Pre-C and Core promoter mutations were determined using by polymerase chain reaction (PCR). Drug-resistance mutations were detected by the PCR-Invader method. RESULTS At year 2, HBV DNA levels in all patients in the HBeAg-negative group were < 3.0 log copies/mL. In contrast, in the HBeAg-positive group, 41.7% were slow-responders, while 58.3% were rapid-responders. No entecavir-resistant mutants were detected in the slow-responders. When the pretreatment factors were compared between the slow- and rapid-responders; the median qHBsAg in the slow-responders was 4.57 log IU/mL, compared with 3.63 log IU/mL in the rapid-responders (P < 0.01). When the pretreatment factors predictive of HBV DNA-negative status at year 2 in all 50 patients were analyzed, HBeAg-negative status, low HBV DNA levels, and low qHBsAg levels were significant (P < 0.01). Multivariate analysis revealed that the low qHBsAg level was the most significant predictive factor (P = 0.03). CONCLUSION Quantitation of HBsAg could be a useful indicator to predict response to entecavir therapy.
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