|
1
|
Wang CH, Chang KK, Lin RC, Kuo MJ, Yang CC, Tseng YT. Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study. Medicine (Baltimore) 2020; 99:e19907. [PMID: 32358357 PMCID: PMC7440314 DOI: 10.1097/md.0000000000019907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
There has been no clear consensus on the optimal consolidation periods following HBeAg seroconversion (SC) in HBeAg-positive chronic hepatitis B (CHB) patients. Our study aimed to prospectively compare relapse rates between 12 months' and 18 months' consolidation periods to see whether or not there is beneficial durability of tenofovir disoproxil fumarate (TDF) therapy with longer consolidation periods.We enrolled a total of 137 HBeAg-positive Asian CHB patients treated with TDF monotherapy. Forty-six patients achieved HBeAg SC. Then, they were randomly assigned to consolidation period of either 12 months (group A) or 18 months (group B). After stopping TDF therapy, all patients were followed up for 12 months.Thirteen patients (56.5%) relapsed in group A and 12 patients (52.2%) relapsed in group B after 12 months' follow-up (P = .958). Pretreatment HBsAg level is the only significant predictor for off-therapy recurrence by univariate analysis (P = .024). Baseline HBeAg >1000 S/CO in group B patients were significantly less likely to relapse than those of group A (P = .046). Baseline alanine aminotransferase (ALT) >133 U/L could significantly predict occurrence of HBeAg SC (P = .008; 95% CI: 0.545-0.763; AUC: 0.654).Overall, a prolonged consolidation period has no positive effect on TDF therapy on sustained viral suppression in HBeAg-positive Asian CHB patients. However, a prolonged consolidation period was beneficial to patients with high baseline semi-quantitative HBeAg levels in terms of off-treatment durability. Baseline ALT > 133 U/L could significantly predict the occurrence of HBeAg SC.
Collapse
Affiliation(s)
- Chun-Hsiang Wang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Kuo-Kuan Chang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Ruey-Chang Lin
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Ming-Jeng Kuo
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Chi-Chieh Yang
- Department of Hepatogastroenterology, Show Chwan Memorial Hospital, Changhua
| | - Yuan-Tsung Tseng
- Committee of Medical Research, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
| |
Collapse
|
|
2
|
Jun BG, Lee SH, Kim HS, Kim SG, Kim YS, Kim BS, Jeong SW, Jang JY, Kim YD, Cheon GJ. Predictive Factors for Sustained Remission after Discontinuation of Antiviral Therapy in Patients with HBeAg-positive Chronic Hepatitis B. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 67:28-34. [PMID: 26809629 DOI: 10.4166/kjg.2016.67.1.28] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS The optimal timing for discontinuing oral antiviral therapy in patients with HBeAg-positive chronic hepatitis B (CHB) is unclear. The aim of our study was to investigate sustained remission after stopping antiviral therapy in patients with HBeAg-positive CHB. METHODS We analyzed the medical records of 58 patients who were HBeAg-positive and had discontinued antiviral therapy. Antiviral therapy was discontinued after HBeAg seroconversion and HBV DNA negativity for 6-12 months with consolidation therapy. Virologic relapse was defined as an increase in serum HBV DNA >2,000 IU/mL. RESULTS No difference was observed between the virologic non-relapse and virologic relapse groups in baseline HBV DNA level (p=0.441) or duration of seroconversion (p=0.070). Time-to-undetectable HBV DNA during treatment was shorter in the virologic non-relapse group (29 patients) compared to the relapse group (29 patients) (4.9±2.6 vs. 13.2±12.7 months; p<0.01). Cumulative relapse rates were 12.7 in month 3, 32.7 in month 6, 47.3 in month 12, and 52.7% in month 18. We determined by multivariate analysis that the consolidation period (≥18 months, p=0.020) and early virologic response (HBV DNA <20 IU/mL) at six months during antiviral therapy (p=0.017) were significant predictors for sustained remission. CONCLUSIONS A consolidation period of at least 18 months and early virological response at six months during antiviral therapy were associated with sustained remission in patients with HBeAg-positive CHB after treatment.
Collapse
Affiliation(s)
- Baek Gyu Jun
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Boo Sung Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Young Don Kim
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| |
Collapse
|
|
3
|
Man Cho S, Choe BH. Treatment strategies according to genotype for chronic hepatitis B in children. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:336. [PMID: 27761440 DOI: 10.21037/atm.2016.09.06] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
This review article was requested by editor-in-chief of this journal as 'pediatric CHB treatment' for the upcoming special issue. The main objective of chronic hepatitis B (CHB) treatment is diminishing the risk of complications related to chronic liver disease. In Asia, there are already some reports about hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infected children. The key points of treatment in children with CHB infections are selection of which patients to treat and conformation of the optimal therapy time that would reduce viral resistance. The choice of therapy is determined by the district (Western/Eastern), HBV genotype, medical accessibility, and economic state of the country. Newly developed nucleos(t)ide analogues (NAs) are potent in children with CHB. However, to improve therapeutic efficacy, physicians are recommended to follow treatment guidelines and determine the specific genotype in the CHB patient. In this article, the treatment of pediatric CHB is reviewed according to differences in genotype.
Collapse
Affiliation(s)
- Seung Man Cho
- Department of Pediatrics, Dongguk University School of Medicine, Gyeongju, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| |
Collapse
|
|
4
|
Jung KS, Park JY, Chon YE, Kim HS, Kang W, Kim BK, Kim SU, Kim DY, Han KH, Ahn SH. Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients. J Gastroenterol 2016; 51:830-9. [PMID: 26687058 DOI: 10.1007/s00535-015-1153-1] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 11/27/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Little is known about stopping rules of nucelos(t)ide analog (NA) treatment for chronic hepatitis B (CHB). METHODS A total of 113 consecutive patients with CHB (45 HBeAg-positive and 68 HBeAg-negative CHB patients), who met the cessation criteria of NA treatment as per the Asian-Pacific Association for the Study of the Liver (APASL) guideline, were enrolled in this prospective cohort study. The primary endpoint was to evaluate virological relapse (VR) rate within 1 year, which was defined as reappearance of hepatitis B virus (HBV)-DNA > 2000 IU/mL after cessation of NA treatment. In this cohort, entecavir was used in 81 (71.7 %) and lamivudine in 32 (28.3 %) patients. RESULTS Within 1 year after NA treatment, VR occurred in 26 (57.8 %) HBeAg-positive patients and in 37 (54.4 %) HBeAg-negative patients. In univariate and subsequent multivariate analysis, age > 40 years [odds ratio (OR) 10.959; 95 % confidence interval (CI) 2.211-54.320; P = 0.003) and a pre-treatment HBV DNA level >2000,000 IU/mL (OR 9.285; 95 % CI 1.545-55.795; P = 0.036) were identified as independent risk factors for VR in HBeAg-positive patients, and age > 40 years (OR 6.690; 95 % CI 1.314-34.057; P = 0.022) and an end-of-treatment HBcrAg level >3.7 log IU/mL (OR 3.751; 95 % CI 1.187-11.856; P = 0.024) were identified in HBeAg-negative patients. During follow up, neither hepatic decompensation nor hepatocellular carcinoma (HCC) occurred, and HBV DNA suppression was achieved in all patients who received antiviral re-treatment. CONCLUSION Our data suggested that the APASL stopping rule could be applied if a candidate was properly selected using individual risk factors. However, regular monitoring should be performed after cessation of NA treatment and long-term outcomes need to be evaluated further.
Collapse
Affiliation(s)
- Kyu Sik Jung
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Young Eun Chon
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Hyon-Suk Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Wonseok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
- Brain Korea 21 Project of Medical Science, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea.
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
- Liver Cirrhosis Clinical Research Center, Seoul, Korea.
- Brain Korea 21 Project of Medical Science, Seoul, Korea.
| |
Collapse
|
|
5
|
Yao CC, Lee CM, Hung CH, Wang JH, Hu TH, Lu SN, Changchien CS, Hsu MC, Chen CH. Combining age and HBsAg level predicts post-treatment durability of nucleos(t)ide analogue-induced HBeAg seroconversion. J Gastroenterol Hepatol 2015; 30:918-24. [PMID: 25532588 DOI: 10.1111/jgh.12874] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/01/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Previous studies have indicated that lamivudine-induced hepatitis B e antigen (HBeAg) seroconversion may not be durable in the Asian population. We investigated the useful predictors of post-treatment hepatitis B virus (HBV) relapse in patients with nucleos(t)ide analogue (NA)-induced HBeAg loss/seroconversion. METHODS A total of 157 non-cirrhotic patients with NA-induced HBeAg loss/seroconversion (78, lamivudine; 68, entecavir; 11, telbivudine) were retrospectively analyzed. All patients had at least 12 months of post-treatment follow-up and consolidation therapy duration. RESULTS The cumulative rate of post-treatment HBV relapse at 5 years was 57.1%. Multivariate analysis revealed that age and baseline hepatitis B surface antigen (HBsAg) levels independently predicted post-treatment HBV relapse. The post-treatment HBV relapse rate was significantly higher in patients aged > 40 years than in those < 40 years (P < 0.001). A baseline HBsAg level of 2000 IU/mL was the optimal cut-off value for predicting post-treatment HBV relapse (P = 0.002). The post-treatment HBV relapse risk further increased with the presence of both risk factors (age ≥ 40 years and baseline HBsAg level ≥ 2000 IU/mL; P < 0.001). A prolonged consolidation therapy period of ≥ 18 or 24 months had no positive effect on sustained viral suppression. There was no significant difference in post-treatment HBV relapse rates between patients with lamivudine- and entecavir-induced HBeAg loss/seroconversion during the off-treatment follow-up (P = 0.31). CONCLUSION The combination of an age of 40 years and a baseline HBsAg level of 2000 IU/mL was a useful marker for predicting post-treatment HBV relapse in patients with NA-induced HBeAg loss/seroconversion.
Collapse
Affiliation(s)
- Chih-Chien Yao
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Thio CL, Hawkins C. Hepatitis B Virus and Hepatitis Delta Virus. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1815-1839.e7. [DOI: 10.1016/b978-1-4557-4801-3.00148-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
7
|
Ridruejo E, Marciano S, Galdame O, Reggiardo MV, Muñoz AE, Adrover R, Cocozzella D, Fernandez N, Estepo C, Mendizábal M, Romero GA, Levi D, Schroder T, Paz S, Fainboim H, Mandó OG, Gadano AC, Silva MO. Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir. J Viral Hepat 2014; 21:590-6. [PMID: 24188363 DOI: 10.1111/jvh.12200] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 09/21/2013] [Indexed: 01/03/2023]
Abstract
Registration studies show entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg-positive and HBeAg-negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty-nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log10 IU/mL. Ninety-two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti-HBe positive; 14% became HBsAg negative and 13% anti-HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off-treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off-treatment, 3 of them showed HBeAg reversion and 4 lost anti-HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.
Collapse
Affiliation(s)
- E Ridruejo
- Hepatology Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno 'CEMIC', Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina; Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Provincia de Buenos Aires, Pilar, Argentina
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Kwon JH, Jang JW, Choi JY, Park CH, Yoo SH, Bae SH, Yoon SK. Should lamivudine monotherapy be stopped or continued in patients infected with hepatitis B with favorable responses after more than 5 years of treatment? J Med Virol 2013; 85:34-42. [PMID: 23154874 DOI: 10.1002/jmv.23421] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Regarding the limited evidence for determining the optimal duration of antiviral treatment for hepatitis B, the long-term outcome of patients with favorable responses to over 5 years of lamivudine monotherapy was investigated. Two hundred seventy-one patients who had received lamivudine for at least 5 years were enrolled. Ultimately, 72 patients without YMDD mutations and showing hepatitis B virus (HBV) DNA levels <2.5 pg/ml after 5 years of treatment were analyzed. Mean treatment duration with lamivudine was 9.1 ± 2.6 years. During the treatment, HBeAg and HBsAg loss/seroconversion rates were 95 and 6.9%, respectively. Decompensation and hepatocellular carcinoma (HCC) developed in 2.8 and 6.9% of patients, respectively. Old age and cirrhosis were risk factors for HCC development. Finally, 11.1% of patients developed YMDD mutations after 8.3 ± 2.4 years of treatment. There was no hepatic decompensation among the patients who developed delayed YMDD mutations. Sixteen patients who achieved a complete response stopped lamivudine and four patients showed relapses 10.3 ± 8.5 months after stopping lamivudine. Relapsed patients had more cirrhotic livers and higher rates of HBeAg positivity at 5 years than patients who maintained complete response. The present study suggests that patients who do not develop YMDD mutations over 5 years of treatment with lamivudine may continue lamivudine monotherapy until the loss of HBsAg. However, even for the patients showing favorable response over 5 years of treatment, those in older ages, with cirrhosis or who show poor HBeAg responses should be on careful monitoring to detect the development of viral mutations, relapse and even HCC.
Collapse
Affiliation(s)
- Jung Hyun Kwon
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | | | | | | | | | | | | |
Collapse
|
|
9
|
Kim SS, Lee D, Lee MH, Cheong JY, Cho SW. Association of on-treatment serum hepatitis B surface antigen level with sustained virological response to nucleos(t)ide analog in patients with hepatitis B e-antigen positive chronic hepatitis B. Hepatol Res 2013; 43:219-27. [PMID: 22835015 DOI: 10.1111/j.1872-034x.2012.01065.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM This study evaluated the on-treatment serum hepatitis B surface antigen (HBsAg) level during nucleos(t)ide analog (NUC) therapy and the correlation with off-treatment sustained virological response (SVR). METHODS Fifty-one consecutive patients with hepatitis B e-antigen (HBeAg) positive chronic hepatitis B who achieved HBeAg loss/seroconversion after NUC therapy and completed 12 months or more of additional therapy were included. Serum HBsAg and hepatitis B virus (HBV) DNA levels were determined at baseline, 3, 6, 9 and 12 months, and at the end of treatment. SVR was defined as HBV DNA levels of less than 10 000 copies/mL until 6 or 12 months off-treatment without reappearance of HBeAg. RESULTS Twenty-two (43.1%) and 13 (25.5%) patients maintained SVR at 6 and 12 months off-treatment, respectively. In univariate analyses, a decline of HBsAg of 0.5 log(10) IU/mL or less at 6 months (P = 0.006) and 12 months (P = 0.013), the mean change in HBsAg level at 6 months (P = 0.024), and lamivudine or entecavir treatment (P = 0.019) were significant predictive factors for SVR at 6 months off-treatment. A decline of HBsAg of 0.5 log(10) IU/mL or less at 6 months and lamivudine or entecavir treatment were independent factors on multivariate analyses (odds ratio [OR], 16.67; 95% confidence interval [CI], 1.86-142.86 [P = 0.012]; and OR, 14.83; 95% CI, 1.18-185.73 [P = 0.036]; respectively). CONCLUSION On-treatment serum HBsAg level predicted early off-treatment SVR to NUC therapy in patients infected with genotype C.
Collapse
Affiliation(s)
- Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | | | | | | | | |
Collapse
|
|
10
|
Song MJ, Song DS, Kim HY, Yoo SH, Bae SH, Choi JY, Yoon SK, Paik YH, Lee JS, Lee HW, Kim HJ. Durability of viral response after off-treatment in HBeAg positive chronic hepatitis B. World J Gastroenterol 2012; 18:6277-6283. [PMID: 23180949 PMCID: PMC3501777 DOI: 10.3748/wjg.v18.i43.6277] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the durability in hepatitis B e antigen (HBeAg) positive chronic hepatitis B patients who discontinued antiviral treatment.
METHODS: A total of 48 HBeAg positive chronic hepatitis B patients who were administered nucleoside analogues and maintained virological response for ≥ 6 mo [hepatitis B virus (HBV) DNA < 300 copies/mL and HBeAg seroconversion] before cessation of treatment were enrolled between February 2007 and January 2010. The criteria for the cessation of the antiviral treatment were defined as follows: (1) achievement of virological response; and (2) duration of consolidation therapy (≥ 6 mo). After treatment cessation, the patients were followed up at 3-6 mo intervals. The primary endpoint was serologic and virologic recurrence rates after withdrawal of antiviral treatment. Serologic recurrence was defined as reappearance of HBeAg positivity after HBeAg seroconversion. Virologic recurrence was defined as an increase in HBV-DNA level > 104 copies/mL after HBeAg seroconversion with previously undetectable HBV-DNA level.
RESULTS: During the median follow-up period of 18.2 mo (range: 5.1-47.5 mo) after cessation of antiviral treatment, the cumulative serological recurrence rate was 15 % at 12 mo. The median duration between the cessation of antiviral treatment and serologic recurrence was 7.2 mo (range: 1.2-10.9 mo). Of the 48 patients with HBeAg positive chronic hepatitis, 20 (41.6%) showed virological recurrence. The cumulative virologic recurrence rates at 12 mo after discontinuing the antiviral agent were 41%. The median duration between off-treatment and virologic recurrence was 7.6 mo (range: 4.3-27.1 mo). The mean age of the virological recurrence group was older than that of the non-recurrence group (46.7 ± 12.1 years vs 38.8 ± 12.7 years, respectively; P = 0.022). Age (> 40 years) and the duration of consolidation treatment (≥ 15 mo) were significant predictive factors for offtreatment durability in the multivariate analysis [P = 0.049, relative risk (RR) 0.31, 95% CI (0.096-0.998) and P = 0.005, RR 11.29, 95% CI (2.054-65.12), respectively]. Patients with age (≤ 40 years) who received consolidation treatment (≥ 15 mo) significantly showed durability in HBeAg positive chronic hepatitis B patients (P = 0.014). These results suggest that additional treatment for more than 15 mo after HBeAg seroconversion in patients who are ≤ 40 years old may be beneficial in providing a sustained virological response.
CONCLUSION: Our data suggest that HBeAg seroconversion is an imperfect end point in antiviral treatment. Long-term consolidation treatment (≥ 15 mo) in younger patients is important for producing better prognosis in HBeAg positive chronic hepatitis B.
Collapse
|
|
11
|
He J, Bowen JM, Xie F, Goeree R. Cost-effectiveness analysis of antiviral treatments for HBeAg-positive chronic hepatitis B in Canada. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2012; 15:894-906. [PMID: 22999140 DOI: 10.1016/j.jval.2012.06.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 05/15/2012] [Accepted: 06/13/2012] [Indexed: 06/01/2023]
Abstract
OBJECTIVE To conduct a cost-effectiveness analysis of currently available nucleos(t)ide antiviral treatments (lamivudine, telbivudine, entecavir, and tenofovir) for chronic hepatitis B in Canada. METHODS Markov modeling was used to project the lifetime health benefits and costs associated with the antiviral treatments. The hypothetical patient population was hepatitis B e antigen-positive chronic hepatitis B-infected patients aged 34 years. Quality-adjusted life-years were used as a measure of effectiveness. Long-term cumulative incidence of liver complications was also projected. Treatment effectiveness data were derived from the literature; meta-analysis was conducted when there was a large variance in reported effectiveness data. Costs were obtained from a cost analysis of treating chronic hepatitis B-related complications in Canada. Stochastic parameter uncertainty was examined in probabilistic sensitivity analysis by using second-order Monte Carlo simulation. Alternative modeling assumptions were assessed in scenario analysis. One-way sensitivity analysis was used to explore each parameter's impact on the uncertainty of the results. RESULTS In the base-case analysis, telbivudine was dominated by entecavir and tenofovir. Tenofovir strictly dominated lamivudine, telbivudine, and entecavir. Over the 72-year period of the model, the expected life expectancy (undiscounted) of lamivudine, telbivudine, entecavir, and tenofovir was 35.71, 36.94, 37.65, and 37.99 years, respectively. Tenofovir had the highest expected quality-adjusted life-years at 11.86 (discounted) in all comparisons. Scenario and sensitivity analyses proved the robustness of the base-case results. The projected 10-year cumulative incidence of cirrhosis and hepatocellular carcinoma was 11.40% and 3.05%, respectively, for tenofovir, which is significantly lower than that for lamivudine. CONCLUSION Tenofovir generated the best results compared with all other therapies under evaluation.
Collapse
Affiliation(s)
- Jing He
- Canadian Institute for Health Information, Toronto, ON, Canada.
| | | | | | | |
Collapse
|
|
12
|
Kim SS, Cheong JY, Cho SW. Current Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B. Gut Liver 2011; 5:278-87. [PMID: 21927654 PMCID: PMC3166666 DOI: 10.5009/gnl.2011.5.3.278] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Accepted: 05/13/2011] [Indexed: 12/12/2022] Open
Abstract
Although the prevalence of chronic hepatitis B has decreased considerably in recent years due to widespread use of the hepatitis B virus (HBV) vaccine, its prevalence still remains high in adults, and this can place a significant burden on health care in areas with endemic HBV. Since the introduction of nucleos(t)ide analogues (NUCs), there has been marked improvement in the care of patients with chronic hepatitis B, resulting in increased survival. However, the emergence of drug resistance in patients treated with NUCs is a major concern. The number of multi-drug resistant patients is increasing, and many patients may not respond to the currently available drugs. In this review, we describe the current status of NUC therapy for antiviral-naïve and -resistant patients.
Collapse
Affiliation(s)
- Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | | | | |
Collapse
|
|
13
|
Abstract
BACKGROUND AND AIMS Different definitions of virologic relapse (VR) are being used. One way of defining VR is "reappearance of HBV DNA in the serum," while another definition is an "increase in HBV DNA level greater than 1 log in two determinations at least 4 weeks apart." The aim of this study was to see the effectiveness of these two definitions METHODS Forty-five HBeAg-positive chronic hepatitis B patients with a virologic response [negative PCR (<12 IU/ml)] who had discontinued therapy were analyzed retrospectively for VR, HBeAg reversion and biochemical flare. RESULTS HBV DNA reappeared in the serum (≥12 IU/ml) of all 45 patients (100%). An increase in HBV DNA level greater than 1 log in two determinations at least 4 weeks apart was identified in 20 of 25 patients (80%). Biochemical flare and HBeAg reversion were observed in 18 (40%) and 14 (31%) patients, respectively. Peak off-therapy HBV DNA level was significantly associated with biochemical flare (r=0.758, P<0.001) and HBeAg reversion (r=0.645, P<0.001). Two patients with high initial off-therapy HBV DNA levels (≥4.0 log(10) IU/ml) were reassessed at 4 weeks, and both experienced a biochemical flare and HBeAg reversion. Two patients had an increase in HBV DNA level greater than 1 log at a very low level (1 log to 2 or 3 log), but did not experience biochemical flare or HBeAg reversion during follow-up. CONCLUSIONS Reappearance of HBV DNA was universal when sensitive HBV DNA assay was used. Waiting 4 weeks to confirm VR may be harmful for patients with a high HBV DNA level, and was ineffective to indicate re-therapy for patients with increase in HBV DNA at a very low level. There is a need for improved and standardized definitions of VR.
Collapse
|
|
14
|
Lee HS, Yoo BC, Lee KS, Kim JH, Um SH, Ryu SH, Lee YS, Kim YS, Yoo K, Han JY, Hwang JS, Kim TH, Yang JM, Lee HJ, Chon CY, Cho M, Han BH, Hwang SG, Byun KS, Chung YH, Cho SH, Koh KC, Kim BI, Kim HC, Paik SW, Lee MS, Yoo HW, Han CJ. Clevudine-induced viral response, associated with continued reduction of HBsAg titer, was durable after the withdrawal of therapy. J Gastroenterol 2011; 46:410-4. [PMID: 21181212 DOI: 10.1007/s00535-010-0354-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Accepted: 11/13/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND This study was conducted to evaluate the durability of clevudine-induced viral response after the withdrawal of treatment. METHODS Patients who showed a complete response [alanine aminotransferase (ALT) normalization and hepatitis B virus (HBV) DNA <4,700 copies/mL for hepatitis B envelope antigen (HBeAg)-negative patients; ALT normalization, HBV DNA <4,700 copies/mL, and HBeAg seroconversion for HBeAg-positive patients] in the previous clevudine phase III trials were followed for an additional 96 weeks without any treatment for hepatitis B. RESULTS Of the 63 patients in the study cohort, 73% and 35% of the patients had HBV DNA <141,500 and <4,700 copies/mL, respectively, and 75% of the patients had normal ALT at the end of follow-up. HBeAg seroconversion was maintained in 81% of the patients and hepatitis B surface antigen (HBsAg) loss occurred in 3 patients. Continued HBsAg titer decrease (-0.5 log IU/mL) was observed in the sustained viral responders, suggesting the reduction of covalently closed circular DNA in hepatocytes. CONCLUSIONS The clevudine-induced viral response was durable in the majority of patients for 2 years after the withdrawal of treatment.
Collapse
Affiliation(s)
- Hyo-Suk Lee
- Seoul National University Hospital, Seoul, Korea
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Abstract
The goal of hepatitis B treatment is to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma. Ideally, clinical studies should demonstrate that hepatitis B therapies can prevent liver-related complications; however, these clinical endpoints evolve over years or decades. Therefore, clinical trials have relied on intermediate endpoints to evaluate the efficacy of treatment and to determine when treatment can be stopped. Intermediate endpoints that have been used include biochemical, histological, virological, and serological endpoints. This review will discuss the validity of these intermediate endpoints as surrogates of clinical endpoints, and the rates at which these intermediate endpoints can be achieved with currently available therapies.
Collapse
Affiliation(s)
- W Chotiyaputta
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA
| | | |
Collapse
|
|
16
|
Hepatitis B e antigen seroconversion: a critical event in chronic hepatitis B virus infection. Dig Dis Sci 2010; 55:2727-34. [PMID: 20238245 DOI: 10.1007/s10620-010-1179-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2009] [Accepted: 02/22/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND Replication of hepatitis B virus (HBV) is the primary driver of disease progression and clinical outcomes in patients with chronic hepatitis B (CHB), but other factors, such as hepatitis B e antigen (HBeAg) status, also influence disease course. The importance of HBeAg seroconversion is underscored by current CHB treatment guidelines that recommend limiting the duration of antiviral therapy in HBeAg-positive patients who achieve seroconversion. AIMS A 2-day meeting of leading hepatologists with extensive experience managing patients with CHB in the Asia-Pacific region was held with the overall goals of reviewing and evaluating (1) available data on the relationship between HBeAg seroconversion and clinical outcomes for patients with HBeAg-positive CHB, and (2) the ways in which seroconversion should influence patient management. CONCLUSIONS It was agreed that HBeAg seroconversion is an important serologic end point for patients with CHB and that achieving this goal should be an important consideration in treatment selection. Patients with HBeAg-positive CHB should consider pegylated interferon if they are aged < 40 years (especially women), have lower HBV DNA levels, can afford this treatment, and have a lifestyle that would support adherence to injection therapy. Alternatively, nucleos(t)ide analogs are recommended in patients with alanine aminotransferase levels ≥ 2 × the upper limit of normal, HBV DNA levels < 9 log(10) IU/ml, and compensated CHB. Entecavir, telbivudine, and tenofovir may be used as first-line therapy; they can be administered as a finite therapeutic course in HBeAg-positive patients who seroconvert. Telbivudine and tenofovir should be considered in women of child-bearing potential.
Collapse
|
|
17
|
Almasio PL, Cammà C, Di Marco V, Craxì A. Hepatitis B: Prognosis and Treatment. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 2010:448-464. [DOI: 10.1002/9781444314403.ch27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
18
|
Reijnders JGP, Perquin MJ, Zhang N, Hansen BE, Janssen HLA. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology 2010; 139:491-8. [PMID: 20381492 DOI: 10.1053/j.gastro.2010.03.059] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2009] [Revised: 03/16/2010] [Accepted: 03/24/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Inconsistencies in results and guideline recommendations regarding the durability of nucleos(t)ide analogue-induced hepatitis B e antigen (HBeAg) seroconversion require clarification. We studied the long-term durability of nucleos(t)ide analogue-induced HBeAg seroconversion in patients with chronic hepatitis B virus (HBV) infection. METHODS We performed a single-center cohort study of 132 HBeAg-positive patients who had received nucleos(t)ide analogue therapy. RESULTS During a median treatment duration of 26 months (range, 16-43 mo), HBeAg seroconversion occurred in 46 of 132 subjects (35%). Forty-two subjects (91%) had follow-up evaluation after HBeAg seroconversion. During a median follow-up period of 59 months (range, 28-103 mo) after HBeAg seroconversion, 13 of 42 patients (31%) showed a durable remission (defined as HBeAg negative and HBV-DNA level<10,000 copies/mL). Overall, 33 of 42 subjects (79%) continued therapy after HBeAg seroconversion; of these, 22 (67%) showed serologic and/or virologic recurrence. Nine of 42 subjects (21%) discontinued therapy after HBeAg seroconversion and at least 6 months of consolidation therapy. Only 2 patients showed a durable response in the absence of therapy. Disease recurrence in patients who continued therapy after HBeAg seroconversion was preceded by the development of resistance (80% of these patients); resistance only occurred in subjects given lamivudine monotherapy. In contrast, recurrence after treatment discontinuation or noncompliance was observed in all patients given nucleos(t)ide analogues. CONCLUSIONS Induction of HBeAg seroconversion by nucleos(t)ide analogues is temporary in most patients with chronic HBV infection. Long-term continuation of nucleos(t)ide analogue treatment, irrespective of the occurrence of HBeAg seroconversion, appears to be necessary.
Collapse
Affiliation(s)
- Jurriën G P Reijnders
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | | | | | | | | |
Collapse
|
|
19
|
Wang L, Liu F, Liu YD, Li XY, Wang JB, Zhang ZH, Wang YZ. Stringent cessation criterion results in better durability of lamivudine treatment: a prospective clinical study in hepatitis B e antigen-positive chronic hepatitis B patients. J Viral Hepat 2010; 17:298-304. [PMID: 19758278 DOI: 10.1111/j.1365-2893.2009.01178.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The cessation criteria for lamivudine treatment vary in published articles and their results are contradictory, especially factors predicting relapse. To clarify these contradictions, this long-term follow-up study of 125 Chinese hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients was designed with stringent cessation criterion. All patients received lamivudine and achieved HBeAg seroconversion (group A, n = 82) or loss (group B, n = 43) with undetectable hepatitis B virus (HBV) DNA by PCR assay during the treatment. Lamivudine was withdrawn >or=6 months after HBeAg seroconversion/loss occurred. The median treatment durations were 24 (12-54) months and 36 (18-89) months in group A and group B, respectively. Patients were followed up for median 24 (2-84) months. The cumulative relapse (defined as serum HBV DNA >or=10(4) copies/mL) rates in the two groups at months 12, 24, 36 and 48 were 23.4%vs 35.0%, 25.0%vs 37.7%, 25.0%vs 41.1% and 29.4%vs 41.1%, respectively (log-rank test, P = 0.119). For patients whose total treatment duration >or=18 months in group A, the cumulative relapse rates at months 12, 24, 36 and 48 were 18.3%, 20.1%, 20.1% and 25.1%, which was significantly lower than those with a shorter duration (log-rank test, P = 0.002). The mean age and median total duration were statistically different between relapsers and nonrelapsers in group A (33.9 +/- 13.6 vs 23.1 +/- 11.0 years, P < 0.001 and 24 vs 26 months, P = 0.003). Cox regression revealed that age was the only predictive factor for relapse (RR, 1.069; 95% CI, 1.032-1.106, P < 0.001). Patients aged <30 years relapsed less frequently in 5 years (12.3%vs 53.5%, P = 0.001). In conclusion, for patients who maintained HBeAg seroconversion for >or=6 months and total duration for >or=18 months, lamivudine withdrawal is a reasonable option. Prolonged treatment may be required for patients aged greater than 30 years to reduce relapse.
Collapse
Affiliation(s)
- L Wang
- Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Shandong University, Jinan, China.
| | | | | | | | | | | | | |
Collapse
|
|
20
|
Lau GKK. Current treatments for patients with HBeAg-positive chronic hepatitis B virus infection: a comparison focusing on HBeAg seroconversion. Liver Int 2010; 30:512-20. [PMID: 20102511 DOI: 10.1111/j.1478-3231.2009.02198.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
HBeAg seroconversion, in association with undetectable levels of hepatitis B virus DNA as determined by polymerase chain reaction, is an important goal in the treatment of patients with HBeAg-positive chronic hepatitis B (CHB). Achievement of sustained HBeAg seroconversion at an early age (<40 years) is associated with a reduced incidence of hepatic complications, increased rates of HBsAg loss and seroconversion and improved survival rates, whether the seroconversion is spontaneous or treatment induced. Patients with HBeAg-positive CHB who achieve sustained HBeAg seroconversion and complete 6-12 months of consolidation therapy are eligible for stopping therapy. In randomized clinical studies involving patients with HBeAg-positive CHB, treatment with pegylated interferon (PegIFN)-alpha is associated with higher and more durable HBeAg seroconversion rates than are lamivudine and adefovir. More recently, newer generation oral nucleos(t)ide analogs (NAs) have become available. These include entecavir, telbivudine and tenofovir, and they demonstrate superior antiviral potency and efficacy. This review examines the importance of HBeAg seroconversion as an end point for therapy in the treatment of patients with HBeAg-positive CHB, and examines the rates and durability of HBeAg seroconversion with PegIFN and oral NA therapy. The mechanisms for enhanced HBeAg seroconversion rates with new-generation NAs are also discussed.
Collapse
Affiliation(s)
- George K K Lau
- Clinical Trial Center, LKS Faculty of Medicine, The University of Hong Kong, Humanity and Health GI and Liver Clinic, Hong Kong, SAR.
| |
Collapse
|
|
21
|
Kuo YH, Chen CH, Wang JH, Hung CH, Tseng PL, Lu SN, Changchien CS, Lee CM. Extended lamivudine consolidation therapy in hepatitis B e antigen-positive chronic hepatitis B patients improves sustained hepatitis B e antigen seroconversion. Scand J Gastroenterol 2010; 45:75-81. [PMID: 20030580 DOI: 10.3109/00365520903394550] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Longer lamivudine (LAM) consolidation therapy after hepatitis B e antigen (HBeAg) seroconversion has been demonstrated to reduce the cumulative relapse rate. However, the optimal interval of LAM consolidation therapy remains controversial. We evaluated the post-treatment durability of LAM-induced HBeAg seroconversion and the length of LAM consolidation therapy required to maintain sustained HBeAg seroconversion. MATERIAL AND METHODS This retrospective study included 401 naive HBeAg-positive chronic hepatitis B patients who were treated with LAM 100 mg daily for at least 24 weeks (range 24-258 weeks). Among them, 124 patients who achieved a complete response (HBeAg seroconversion, alanine aminotransferase normalization, hepatitis B virus DNA < 200 copies/ml) at the end of LAM therapy were followed up for at least 48 weeks (range 48-350 weeks). RESULTS Of the 124 complete responders, 42 (33.87%) achieved a sustained response (persistent response >or= 48 weeks). However, the cumulative relapse rates at 48 and 96 weeks post-treatment were 54.03% and 68.4%, respectively. Multivariate analysis revealed pretreatment age <or= 34 years [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.40-3.62; p < 0.001] and LAM consolidation therapy >or= 48 weeks (HR 2.44; 95% CI 1.35-4.40; p = 0.003) to be independent factors for predicting a sustained response. CONCLUSIONS LAM-induced HBeAg seroconversion is not durable in Taiwan. However, a duration of LAM consolidation therapy > 48 weeks may be favorable for maintaining durable HBeAg seroconversion.
Collapse
Affiliation(s)
- Yuan-Hung Kuo
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Niao-Sung, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Lee HW, Lee HJ, Hwang JS, Sohn JH, Jang JY, Han KJ, Park JY, Kim DY, Ahn SH, Paik YH, Lee CK, Lee KS, Chon CY, Han KH. Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B. Hepatology 2010; 51:415-21. [PMID: 19902424 DOI: 10.1002/hep.23323] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED The reported durability of virologic response after successful lamivudine monotherapy is variable, and the question remains as to whether virologic responses can be maintained over an extended follow-up period. The aim of this study was to investigate posttreatment durability, the optimal duration of additional treatment after HBeAg clearance or seroconversion, and determinants for sustained virologic response (SVR) following lamivudine monotherapy in patients with HBeAg-positive chronic hepatitis B (CHB). From January 1999 to August 2004, 178 Korean patients with HBeAg-positive CHB were treated with lamivudine and achieved complete responses, defined as a loss of serum HBeAg and hepatitis B virus DNA, and alanine aminotransferase normalization. The mean duration of lamivudine monotherapy was 26 months (range, 12-77). SVR was maintained in 138 patients (77.5%). Host and viral factors were compared between 138 patients with SVR and 40 patients whose response was not sustained. The cumulative relapse rates increased from 15.9% at 1 year to 30.2% at 5 years, with a mean time to relapse after cessation of lamivudine of 12 months (range, 7-42). Most relapses occurred within 2 years after discontinuation of lamivudine (33/40, 82.5%). On multivariate analysis, age <or=40 years and additional treatment for more than 12 months after HBeAg clearance or seroconversion were independent factors for SVR. CONCLUSION The lamivudine-induced virologic response was durable in patients under 40 years old and those receiving lamivudine for more than 12 months after HBeAg clearance or seroconversion. Age and additional treatment were major predictive factors for SVR.
Collapse
Affiliation(s)
- Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Luo J, Li J, Chen RL, Nie L, Huang J, Liu ZW, Luo L, Yan XJ. Autologus dendritic cell vaccine for chronic hepatitis B carriers: a pilot, open label, clinical trial in human volunteers. Vaccine 2010; 28:2497-504. [PMID: 20117267 DOI: 10.1016/j.vaccine.2010.01.038] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2009] [Revised: 12/23/2009] [Accepted: 01/17/2010] [Indexed: 01/07/2023]
Abstract
Antigen-presenting autologous dendritic cells (ADCs), primed with antigen, have been used in immunotherapy. We evaluated ADCs for treatment of chronic hepatitis B (CHB). ADCs were administered to 380 CHB patients. Virological, biochemical, and serological responses were evaluated in each patient over the course of 48 weeks. Undetectable levels of HBV DNA were reported in 46.36% of patients negative for the hepatitis B "e" antigen (HBeAg) and 3.13% HBeAg-positive patients. Normalization of alanine aminotransferase levels occurred in both HBeAg-positive (P=0.007) and HBeAg-negative (P=0.003) patients. It appears that ADC vaccination effectively reconstructed the immunity and elicited virological, serological, and biochemical improvements in some patients with chronic HBV. No side effects were observed.
Collapse
Affiliation(s)
- Jin Luo
- Institute of Genetic Diagnosis, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, Shaanxi, China
| | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Lampertico P, Aghemo A, Viganò M, Colombo M. HBV and HCV therapy. Viruses 2009; 1:484-509. [PMID: 21994557 PMCID: PMC3185503 DOI: 10.3390/v1030484] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Revised: 10/08/2009] [Accepted: 10/19/2009] [Indexed: 02/06/2023] Open
Abstract
One year of interferon therapy inhibits HBV replication in one third of the patients whereas long-term administration of oral nucleos(t)ide analogues is efficient in most of them, as long as early treatment adaptation in patients with partial virological response and resistance is provided. Following the demonstration of a more potent antiviral effect in terms of sustained virological response (SVR) rates, Pegylated-IFN coupled with Ribavirin has become the standard treatment for chronic hepatitis C, with nearly 65% of all treated patients achieving a SVR. Long-term suppression of HBV and eradication of HCV would halt the progression of chronic hepatitis to cirrhosis, hepatocellular carcinoma and liver decompensation.
Collapse
Affiliation(s)
- Pietro Lampertico
- “A.M. Migliavacca” Center for Liver Disease, First Gastroenterology Unit, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
| | - Alessio Aghemo
- “A.M. Migliavacca” Center for Liver Disease, First Gastroenterology Unit, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
| | - Mauro Viganò
- “A.M. Migliavacca” Center for Liver Disease, First Gastroenterology Unit, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
| | - Massimo Colombo
- “A.M. Migliavacca” Center for Liver Disease, First Gastroenterology Unit, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
| |
Collapse
|
|
25
|
Maimone S, Calvaruso V, Pleguezuelo M, Squadrito G, Amaddeo G, Jacobs M, Khanna P, Raimondo G, Dusheiko G. An evaluation of transient elastography in the discrimination of HBeAg-negative disease from inactive hepatitis B carriers. J Viral Hepat 2009; 16:769-74. [PMID: 19709363 DOI: 10.1111/j.1365-2893.2009.01120.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver biopsy is frequently required in HBeAg-negative disease to determine the stage of fibrosis. It can be difficult to distinguish cohorts with undetectable HBeAg who may have varying degrees of fibrosis due to different stages of disease. We have assessed the utility of transient elastography (TE) to evaluate differences in HBeAg-negative patients. A total of 220 HBsAg-positive individuals were studied: 125 (group 1) had an inactive HBsAg carrier state and 95 (group 2) were HBeAg-negative, anti-HBe-positive patients with persistently or intermittent elevation of alanine aminotransferase (ALT) and/or HBV DNA >10(5) copies/mL. Mean stiffness was 4.83 +/- 1.2 kPa in group 1 vs 8.53 +/- 6 kPa in group 2 (P < 0.001); statistically significant differences were also found between AST/ULN ALT/ULN ratios, HBV DNA in group 1 vs group 2, respectively (P < 0.001). In the multivariate analysis, the only variable independently associated with the stage of fibrosis was the stiffness. This study shows that mean hepatic stiffness by elastography is significantly lower in patients with inactive hepatitis B compared to those with HBeAg-negative disease. The procedure is a useful adjunct to diagnosis to confirm a clinical pattern of disease, and for more selective use of liver biopsy before considering antiviral therapy.
Collapse
Affiliation(s)
- S Maimone
- Centre for Hepatology, Royal Free Hospital and University College School of Medicine, London, UK
| | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Song BC, Cui XJ, Cho YK, Choi EK, Hyun S, Song HJ, Kim HU. New scoring system for predicting relapse after lamivudine-induced hepatitis B e-antigen loss in chronic hepatitis B patients. Hepatol Res 2009; 39:1064-71. [PMID: 19619252 DOI: 10.1111/j.1872-034x.2009.00560.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM In endemic areas of hepatitis B virus (HBV) infection, lamivudine-induced hepatitis B e-antigen (HBeAg) loss is not durable. We developed a scoring system to predict the relapse after lamivudine-induced HBeAg loss. METHODS Of 93 HBeAg-positive chronic hepatitis B patients receiving lamivudine therapy, we studied the 30 patients who achieved HBeAg loss. Qualitative polymerase chain reaction assays for HBV DNA were performed after HBeAg loss; if results were negative on two consecutive occasions, lamivudine treatment was stopped. Serum HBV DNA levels at the time of HBeAg loss were determined using stored serum by the Cobas Amplicor HBV Monitor Kit. RESULTS Cumulative relapse rates were 44%, 55.8% and 59.8%, after 1, 2 and 5 years, respectively. Univariate analysis showed that the risk factors for relapse were age (>/= 30 years), HBV DNA level (>/= 60 IU/mL) at the time of HBeAg loss and liver cirrhosis. Independent risk factors for relapse were age (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.2-17.6) and serum HBV DNA level at the time of HBeAg loss (OR, 5.1; 95% CI, 1.3-21.6). We developed a scoring system based on these independent risk factors. No relapse was observed for patients with a risk score of 0. For patients with a risk score of 1, the relapse rates were 41%, 49% and 56% at 1, 2 and 5 years, respectively. All patients with a risk score of 2 relapsed (P = 0.01). CONCLUSION Our new scoring system may be useful for predicting relapses in patients with lamivudine-induced HBeAg loss. Treatment strategies should be individualized according to risk score.
Collapse
Affiliation(s)
- Byung-Cheol Song
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Fung J, Lai CL, Tanaka Y, Mizokami M, Yuen J, Wong DKH, Yuen MF. The duration of lamivudine therapy for chronic hepatitis B: cessation vs. continuation of treatment after HBeAg seroconversion. Am J Gastroenterol 2009; 104:1940-6; quiz 1947. [PMID: 19455108 DOI: 10.1038/ajg.2009.200] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The aim of this study was to compare the virological and biochemical relapse rates in Asian chronic hepatitis B patients with lamivudine-induced hepatitis B e antigen (HBeAg) seroconversion, between those who stopped therapy after HBeAg seroconversion and those who continued to receive lamivudine. METHODS All patients with lamivudine-induced HBeAg seroconversion were included. Patients who stopped lamivudine after HBeAg seroconversion (n=22) were compared with 79 patients who continued to receive lamivudine (n=79). Demographic, virological, and biochemical parameters were recorded at baseline, and throughout the duration of follow-up. RESULTS In patients who stopped lamivudine, the median follow-up after stopping lamivudine was 20 months. Of these patients, 14 (64%) had virological rebound, with a cumulative incidence of 82% at 4 years. There was no significant difference in number of flares between patients with normal alanine aminotransferase (ALT) and undetectable hepatitis B virus (HBV) DNA at the time of stopping lamivudine compared with that in patients with either abnormal ALT, detectable HBV DNA, or both (P=0.73). The cumulative incidence of HBeAg seroreversion and ALT flares at 5 years after stopping lamivudine was 9 and 44%, respectively. Of the 79 patients who continued with lamivudine, 62 (78%) had undetectable HBV DNA at the time of last follow-up, whereas no patients had undetectable HBV DNA after stopping lamivudine (P<0.001). The cumulative incidence of ALT flares at 5 years was 16% (P<0.001 compared with those who stopped taking lamivudine). After a median treatment duration of 79 months, lamivudine-resistant mutations occurred in eight patients (10%). CONCLUSIONS In Asian HBeAg-positive patients, continuing with lamivudine after achieving HBeAg seroconversion was associated with a higher proportion of undetectable HBV DNA and a lower number of ALT flares, when compared with those with cessation of lamivudine. In patients who achieved HBeAg seroconversion with lamivudine, the resistance rate was not high when treatment was continued after HBeAg seroconversion.
Collapse
Affiliation(s)
- James Fung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Kim JH, Lee SJ, Joo MK, Kim CH, Choi JH, Jung YK, Yim HJ, Yeon JE, Park JJ, Kim JS, Bak YT, Byun KS. Durability of antiviral response in HBeAg-positive chronic hepatitis B patients who maintained virologic response for one year after lamivudine discontinuation. Dig Dis Sci 2009; 54:1572-7. [PMID: 18975080 DOI: 10.1007/s10620-008-0508-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2008] [Accepted: 08/22/2008] [Indexed: 12/13/2022]
Abstract
The purpose of this study is to determine the long-term relapse rate and associated risk factors in HBeAg-positive chronic hepatitis B (CHB) patients who had maintained virologic response (VR) for 1 year after lamivudine (LMV) discontinuation. We enrolled 55 treatment-naive HBeAg-positive CHB patients who achieved and maintained VR until 1 year after LMV discontinuation. Delayed relapse was defined as an elevation of HBV DNA after sustained VR for 1 year. During follow-up, 16 of 55 patients (29%) showed delayed relapse. Beginning 1 year after LMV discontinuation, the cumulative rates of relapse after 2 and 4 years were 29 and 44%, respectively. In multivariate analysis, age (P = 0.029) and >2,000 copies/ml HBV DNA 3 months after LMV discontinuation (P = 0.047) were significant predictors of delayed relapse. Delayed relapse is not infrequent, even in patients who maintain VR for 1 year after LMV discontinuation. Therefore, LMV maintenance therapy might be considered in HBeAg-positive CHB patients who achieve VR.
Collapse
Affiliation(s)
- Ji Hoon Kim
- Department of Internal Medicine, Guro Hospital, Korea University College of Medicine, 97, Guro-Dong Gil, Guro-Dong, Guro-Ku, Seoul, 152-703, South Korea
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Wu IC, Shiffman ML, Tong MJ, Marcellin P, Mondou E, Frederick D, Snow-Lampart A, Sorbel J, Rousseau F, Chang TT. Sustained hepatitis B e antigen seroconversion in patients with chronic hepatitis B after adefovir dipivoxil treatment: analysis of precore and basal core promoter mutants. Clin Infect Dis 2008; 47:1305-1311. [PMID: 18840078 DOI: 10.1086/592570] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND This study evaluated the persistence of hepatitis B e antigen (HBeAg) seroconversion (which is considered to be an important therapeutic end point) after adefovir dipivoxil treatment. METHODS Forty-five patients who experienced confirmed HBeAg seroconversion and had a serum hepatitis B virus DNA level < 10(5) copies/mL while receiving 10 mg of adefovir dipivoxil in a prior study were enrolled in the present study. At the time of the last dose of adefovir dipivoxil (baseline), the median age of the patients was 35 years, 64% were male, 73% were Asian, 27% were white, the median alanine aminotransferase level was 25 IU/L, and the median serum hepatitis B virus DNA level was 3.0 log copies/mL. The median follow-up time was 150 weeks (range, 13-252 weeks). RESULTS Forty-one patients maintained sustained seroconversion at the last 2 assessments, and 4 experienced seroreversion at weeks 12 (3 patients) and 16 (1 patient) of follow-up. Approximately 50% of patients had a hepatitis B virus DNA level < 1000 copies/mL at the last visit of the study period. Of 13 patients who were viremic and had available samples at the last visit, 11 had basal core promoter and/or precore mutations. Notably, 8 of these 11 patients had basal core promoter and/or precore mutations before adefovir dipivoxil therapy despite being HBeAg positive. The median duration of adefovir dipivoxil treatment was shorter before seroconversion (48 vs. 108 weeks; P = .03) and longer after seroconversion (41 vs. 22 weeks; P = .02) for patients who experienced sustained seroconversion, compared with the patients who experienced seroreversion. CONCLUSIONS Prolonged adefovir dipivoxil therapy after HBeAg seroconversion appeared to increase the likelihood of sustained HBeAg seroconversion. Most patients who experienced HBeAg seroconversion and had viremia had precore and/or basal core promoter mutants, which usually existed before initiation of adefovir dipivoxil therapy.
Collapse
Affiliation(s)
- I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Enomoto M, Tamori A, Kohmoto MT, Hayashi T, Morikawa H, Jomura H, Sakaguchi H, Habu D, Kawada N, Shiomi S, Nishiguchi S. Optimal duration of additional therapy after biochemical and virological responses to lamivudine in patients with HBeAg-negative chronic hepatitis B: a randomized trial. Hepatol Res 2008; 38:954-9. [PMID: 18498358 DOI: 10.1111/j.1872-034x.2008.00378.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIM The endpoint of treatment with nucleoside analogs remains unclear for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We report the results of a randomized trial to determine the optimal duration of additional therapy after response to lamivudine in HBeAg-negative patients. METHODS Twenty-two patients with HBeAg-negative chronic hepatitis B who exhibited biochemical and virological responses to lamivudine were enrolled. When patients responded to treatment, they were randomly assigned to receive 12 more months of therapy (Group A, 11 patients) or 24 more months of therapy (Group B, 11 patients). RESULTS The baseline characteristics of the patients were similar in the two groups. Biochemical and virological responses were obtained in all patients within 6 months. Drug resistance developed in one patient in Group A during month 7 of additional therapy, and in five patients in Group B from months 13-23 of additional therapy. Ten patients in Group A and six in Group B completed the protocol and were included in analysis. Eight of the 10 patients in Group A experienced relapse between months 2 and 14 after the discontinuation of therapy, while three of the six patients in Group B experienced relapse between months 2 and 24. There was no difference in cumulative relapse rate between the groups (P = 0.275). CONCLUSION Additional therapy with lamivudine for longer than 12 months after biochemical and virological responses in patients with HBeAg-negative chronic hepatitis B could increase the risk of drug resistance, but did not reduce the rate of relapse.
Collapse
Affiliation(s)
- Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University Medical School, Osaka, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Kumar M, Sarin SK. Pharmacology, clinical efficacy and safety of lamivudine in hepatitis B virus infection. Expert Rev Gastroenterol Hepatol 2008; 2:465-95. [PMID: 19072396 DOI: 10.1586/17474124.2.4.465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Lamivudine was the first nucleoside analog for the treatment of chronic hepatitis B (CHB). It is well-tolerated and induces a decrease in serum HBV DNA levels associated with normalization of serum alanine aminotransferase levels. However, a sustained response with hepatitis B 'e' antigen to anti-hepatitis B e seroconversion is obtained in a smaller proportion of patients and hepatitis B surface antigen loss is exceptional. The response is maintained during therapy, and needs to be continued indefinitely in the majority of patients since withdrawal of treatment is generally followed by a rapid reappearance of the virus. However, mutations can be induced in long-term treatment.
Collapse
Affiliation(s)
- Manoj Kumar
- Department of Gastroenterology, Academic Block, GB Pant Hospital, New Delhi-110002, India.
| | | |
Collapse
|
|
32
|
Carosi G, Rizzetto M. Treatment of chronic hepatitis B: recommendations from an Italian workshop. Dig Liver Dis 2008; 40:603-17. [PMID: 18499540 DOI: 10.1016/j.dld.2008.03.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2008] [Revised: 03/03/2008] [Accepted: 03/04/2008] [Indexed: 12/11/2022]
Abstract
The changing scenario of hepatitis B virus therapy has encouraged the organisation of a workshop, endorsed by three Italian scientific societies, aimed at defining the current recommendations for hepatitis B virus treatment. Liver histology and stage of disease remain fundamental for treatment decisions; interferon and nucleoside/nucleotide analogues-based therapy represent different strategies for different phases of the hepatitis B virus disease. The recommendations defined: new and lower cut-off of hepatitis B virus-DNA for eligibility to therapy according to disease stage, how to optimise the use of nucleoside/nucleotide analogues and to individualise the monitoring of response and what to do with treatment failures. Specific recommendations have also been given for cirrhosis patients, those immune suppressed and co-infected with HIV and other hepatitis viruses.
Collapse
Affiliation(s)
- G Carosi
- Department of Infectious and Tropical Diseases, University of Brescia, AO Spedali Civili, Brescia, Italy.
| | | |
Collapse
|
|
33
|
Bronowicki JP, Nani A, Barraud H, Cadranel JF. [Is it possible to stop nucleos(t)ide analogue based therapy in chronic hepatitis B?]. ACTA ACUST UNITED AC 2008; 32:S50-5. [PMID: 18662610 DOI: 10.1016/s0399-8320(08)73265-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Nucleos(t)ide analogues are very efficient in the treatment of chronic hepatitis B. In the HBe antigen positive patients, the HBe seroconversion rates range from 12 to 22% after one year of treatment. When HBe seroconversion occure, it is possible to stop the treatment with analogue but only in non cirrhotic patients. If the treatment with analogue is continued for at least 6 months after confirmed HBeAg seroconversion, the HBe seroconversion is durable in 70-90% of patients. The follow up should be done during years. Stopping the treatment is more problematic in HBe antigen negative patients. A virological relapse occur in 44 to 80% of cases and a biochemical relapse occur in 30 to 70% of cases. Stopping the treatment with an analogue in this population should be considered only in a prospective study with careful monitoring and with a long term follow up.
Collapse
Affiliation(s)
- J-P Bronowicki
- Hépato-gastroentérologie, INSERM 724, CHU de Nancy, 54500 Vandoeuvre-les-Nancy, France.
| | | | | | | |
Collapse
|
|
34
|
Combination therapy of lamivudine and adefovir in Japanese patients with chronic hepatitis B. Hepatol Int 2008; 2:361-9. [PMID: 19669266 PMCID: PMC2716896 DOI: 10.1007/s12072-008-9081-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2007] [Accepted: 04/27/2008] [Indexed: 12/22/2022]
Abstract
PURPOSE This study aimed to clarify the long-term efficacy of the lamivudine treatment in Japanese patients with chronic hepatitis B either with or without lamivudine resistance or with or without adefovir add-on treatment. METHODS We followed 110 patients who received lamivudine for more than 12 months, including 67 hepatitis B e antigen (HBeAg)-positive and 43 HBeAg-negative patients. RESULTS The median follow-up after the onset of lamivudine was 48 (range = 12-86) months. In all the patients with or without lamivudine resistance, the level of alanine aminotransferase (ALT) normalization decreased from 70.0% at 1 year to 36.4% at 5 years and the loss of serum HBV DNA level decreased from 72.7% at 1 year to 31.8% at 5 years. Sixty patients (54.6%) developed a lamivudine-resistant mutation, and this occurrence was more frequently observed in those who were HBeAg-positive (P < 0.01), those with a low level of ALT (P < 0.05), and those with a high level of serum HBV DNA (P < 0.01). Thirty-six of 60 patients received adefovir in addition to lamivudine to treat breakthrough hepatitis. A Cox proportional hazards model analysis revealed the level of baseline HBV DNA to be the best predictive factor for the virus recrudescence (risk ratio = 0.466, 95% confidence interval [CI]: 0.246-0.842, P = 0.011) and the breakthrough hepatitis (risk ratio = 0.444, 95% CI: 0.218-0.879, P = 0.019). We carefully monitored the efficacy of this treatment both in patients who received adefovir and in those who did not since the beginning of the lamivudine treatment. The normalization level of ALT was 61.4% at 5 years and the loss of serum HBV DNA was 61.4% at 5 years since lamivudine was started. A histologic improvement was observed in patients with ALT levels less than two times the upper limit of normal at the time of a second liver biopsy. CONCLUSIONS Although the efficacy of lamivudine is limited because of breakthrough hepatitis, adefovir was used as a salvage treatment of patients with lamivudine-resistant chronic hepatitis B. In addition, lamivudine was used for the treatment of Japanese patients with chronic hepatitis B with or without lamivudine resistance, and was found to be useful regarding the long-term virologic and biochemical responses.
Collapse
|
|
35
|
Chan HLY, Wong VWS, Chim AML, Wong GLH, Chan HY, Sung JJY. Treatment of Patients with Chronic Hepatitis B who have Failed Previous Antiviral Treatment with Pegylated Interferon α2a (40 kDa; PEGASYS®). Antivir Ther 2008. [DOI: 10.1177/135965350801300406] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Background Although nucleot(s)ide analogues can effectively suppress hepatitis B virus (HBV) replication, many patients experience relapse of hepatitis after cessation of treatment. We aimed to investigate the efficacy of pegylated interferon α2a (PEG-IFN-α2a) in these difficult-to-treat patients. Methods Chronic hepatitis B patients who have received antiviral drugs for ≥12 months and stopped for ≥6 months were treated by 48-week PEG-IFN-α2a. Virological response was defined as HBV DNA <10,000 copies/ml and hepatitis B e antigen (HBeAg) seroconversion (for HBeAg-positive patients). Results A total of 40 patients, 29 HBeAg-positive and 11 HBeAg-negative, with median log10 HBV DNA 7.3 copies/ml and alanine aminotransferase 110 IU/ml were studied. The last antiviral treatment was given for 92 +61 weeks and stopped for 176 +88 weeks. At the end of treatment, 22 (12 HBeAg-positive and 10 HBeAg-negative; 55%) patients had virological response and 16 (7 HBeAg-positive and 9 HBeAg-negative; 40%) patients had undetectable HBV DNA (<100 copies/ml). At 24 weeks post-treatment, 14 (8 HBeAg-positive and 6 HBeAg-negative; 35%) patients had virological response and 9 (5 HBeAg-positive and 4 HBeAg-negative; 23%) patients had undetectable HBV DNA. Two (5%) patients had lost hepatitis B surface antigen. HBV DNA levels at week 24 best predicted sustained virological response (area under curve 0.76, 95% confidence interval 0.60–0.92, P=0.007). At HBV DNA cutoffs of 3 logs and 5 logs at week 24, the sensitivity/specificity for sustained virological response were 50%/85% and 86%/62%, respectively. Conclusions PEG-IFN-α2a was effective in the treatment of chronic hepatitis B patients who have failed previous antiviral treatment.
Collapse
Affiliation(s)
- Henry L-Y Chan
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent W-S Wong
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Angel M-L Chim
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace L-H Wong
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hoi-Yun Chan
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Joseph J-Y Sung
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| |
Collapse
|
|
36
|
Wong VWS, Wong GLH, Tsang SWC, Hui AY, Chim AML, Yiu KKL, Chan HY, Chan FKL, Sung JJY, Chan HLY. Long-Term follow-up of Lamivudine Treatment in Patients with Severe Acute Exacerbation of Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B. Antivir Ther 2008. [DOI: 10.1177/135965350801300407] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown. Methods Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospectively recruited from 1999 to 2004 and treated with lamivudine. All patients had alanine amino-transferase (ALT) and serum bilirubin levels 10x and 3x above the upper limit of normal, respectively. HBeAg-positive patients without severe acute exacerbation served as controls. Results Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine for a median of 2.8 (range 1.0–7.1) years and 3.8 (range 3.5–8.4) years, respectively. Compared with controls, patients with severe acute exacerbation had higher HBeAg seroconversion rates (78% versus 52%; P=0.02) and lower risk of virological breakthrough. However, 33% of patients with severe acute exacerbation still developed lamivudine resistance and virological breakthrough by year 5. HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough. All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response. Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for ≥6 months, 11 (73%) had virological relapse at a median of 1.4 (0.2-3.9) years. ALT increased beyond 10x the upper limit of normal in six (38%) patients who stopped lamivudine and two (7%) patients on maintained lamivudine treatment ( P=0.02). Conclusion Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine, virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion. Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine.
Collapse
Affiliation(s)
- Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| | | | - Alex Yui Hui
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| | - Angel Mei-Ling Chim
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| | - Karen Kar-Lum Yiu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| | - Hoi-Yun Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| | - Francis Ka-Leung Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| | - Joseph Jao-Yiu Sung
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR
| |
Collapse
|
|
37
|
Piratvisuth T, Lau G, Chao YC, Jin R, Chutaputti A, Zhang QB, Tanwandee T, Button P, Popescu M. Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Hepatol Int 2008; 2:102-10. [PMID: 19669285 PMCID: PMC2716864 DOI: 10.1007/s12072-007-9022-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2007] [Revised: 08/05/2007] [Accepted: 08/07/2007] [Indexed: 12/21/2022]
Abstract
PURPOSE The 2 reported trials investigated the effectiveness of treatment with peginterferon alfa-2a in Asian patients with chronic hepatitis B (CHB). METHODS Patients with HBeAg-positive (n = 708) or HBeAg-negative (n = 332) CHB were enrolled in 2 randomized, double blind, placebo-controlled studies. Patients received peginterferon alfa-2a 180 mug once weekly, peginterferon plus lamivudine 100 mg per day, or lamivudine alone for 48 weeks. Patients were followed up at 6 and 12 months posttreatment. RESULTS Peginterferon alfa-2a provided significantly higher rates of HBeAg seroconversion (31%) in HBeAg-positive patients than did lamivudine (19%, P = 0.005) 6 months posttreatment, irrespective of genotype. Of these, 83% achieving seroconversion during treatment or early posttreatment sustained their response at 12 months posttreatment. In patients who seroconverted, 69% maintained HBV DNA suppression at <10,000 copies/ml and alanine aminotrasferase (ALT) normalization. In HBeAg-negative patients, peginterferon produced a significantly higher combined response of HBV DNA at <20,000 copies/ml and ALT normalization (45%) than lamivudine (31%, P = 0.032), irrespective of genotype. Almost 80% of these patients sustained their response at 12 months posttreatment. CONCLUSIONS In conclusion, a finite course of peginterferon alfa-2a provides significant and sustained treatment benefit in Asian CHB patients, who have traditionally been regarded as difficult to treat.
Collapse
Affiliation(s)
- Teerha Piratvisuth
- Department of Internal Medicine, NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital , Prince of Songkla University, Hat Yai, Songkla, 90110, Thailand,
| | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. THE LANCET. INFECTIOUS DISEASES 2007; 8:167-78. [PMID: 18053766 DOI: 10.1016/s1473-3099(07)70264-5] [Citation(s) in RCA: 153] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Currently available options for the treatment of chronic hepatitis B virus (HBV) infection include standard and pegylated interferon alfa and four oral antiviral agents (lamivudine, adefovir, entecavir, and telbivudine). These treatment strategies are either therapies of finite duration that aim to achieve sustained off-therapy responses, or long-term treatments that aim to maintain on-therapy remission. Pegylated interferon alfa may offer higher sustained off-therapy responses after 1 year, but most patients do not respond. Oral antivirals are the only candidates for long-term treatment of patients with chronic HBV infection. Viral suppression has favourable effects on patients' outcome and modifies the natural history of the disease. Viral resistance is the main drawback of long-term antiviral therapy. Lamivudine monotherapy is associated with higher resistance (year 1, 10-27%; year 2, 37-48%; year 4, 60-65%) than adefovir (year 1, 0%; year 2, 3%; year 5, 29%) or telbivudine (year 1, 3-4%; year 2, 9-22%). Entecavir resistance is rare in naive individuals (year 4, <1%), but increases over time in lamivudine-resistant patients (year 4, 43%). The best strategy for long-term therapy in chronic HBV infection has yet to be established.
Collapse
|
|
39
|
Abstract
Four oral antiviral agents have been approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B: lamivudine, adefovir, entecavir, and telbivudine. This article reviews the durability of response, dose regimen, predictors of response, safety, and problems with resistance of these four agents and of promising agents currently in phase III clinical trials for the treatment of patients who have hepatitis B e antigen-positive and -negative chronic hepatitis B.
Collapse
Affiliation(s)
- Albert D Min
- Division of Digestive Diseases, Beth Israel Medical Center, First Avenue at 16th Street, New York, NY 10003, USA
| | | |
Collapse
|
|
40
|
Lin CL, Liao LY, Liu CJ, Yu MW, Chen PJ, Lai MY, Chen DS, Kao JH. Hepatitis B viral factors in HBeAg-negative carriers with persistently normal serum alanine aminotransferase levels. Hepatology 2007; 45:1193-8. [PMID: 17464993 DOI: 10.1002/hep.21585] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
UNLABELLED Chronic hepatitis B patients with high-normal serum ALT (levels of 0.5-1x upper limit of normal) are still at risk of liver disease progression. We thus investigated the correlation between serum ALT level and hepatitis B viral factors in HBeAg-negative carriers with persistently normal serum ALT level (PNALT). Baseline clinical and virological features of 414 HBeAg-negative carriers, including 176 (42.5%) with low-normal ALT (levels of less than 0.5x upper limit of normal) and 238 (57.5%) with high-normal ALT, were compared. Compared with HBV carriers with low-normal ALT, those with high-normal ALT were older (41 vs. 37 years, P<0.001) and had a greater frequency of serum HBV DNA level>10(4) copies/ml (63.4% vs. 47.5%, P<0.001) as well as a higher prevalence of basal core promoter T1762/A1764 mutant (36.5% vs. 24.2%, P=0.01). Multivariate analysis showed that factors associated with a high-normal serum ALT level included male sex [odds ratio (OR), 1.82; 95% confidence interval (CI), 1.10-3.01, P=0.019], increasing age (OR, <30 years: 1, reference; 30-39 years: 2.43, 95% CI, 1.18-5.03, P=0.016; 40-49 years: 4.22, 95% CI, 1.99-8.93, P<0.001; >or=50 years: 4.06, 95% CI, 1.69-9.78, P=0.002) and serum HBV DNA level>10(4) copies/ml (OR, 1.83; 95% CI, 1.07-3.13, P=0.027). CONCLUSION HBeAg-negative patients with persistently normal ALT are not a homogenous group, and those with high-normal ALT share some of the characteristics that have been associated with adverse long-term outcomes.
Collapse
Affiliation(s)
- Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai branch, Taipei City Hospital, and Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Affiliation(s)
- Anna S F Lok
- Division of Gastroenterology, University of Michigan Medical Center, 3912 Taubman Center, Box 0362, Ann Arbor, MI 48109-0362, USA.
| | | |
Collapse
|
|
42
|
Abstract
The available evidence on interferon-alpha (IFN) treatment for chronic hepatitis B is sufficient to conclude that in patients with HBeAg positive chronic hepatitis, standard IFN therapy significantly improves clearance of HBeAg (number needed to treat [NNT] = 4), loss of HBV-DNA (NNT = 4) and clearance of HBsAg (NNT = 18). HBeAg positive patients with normal or slightly raised ALT should be treated only if there is histological evidence of progressive disease. In patients with HBeAg negative chronic hepatitis, less than 20% of subjects who have achieved an end-of-treatment virological response after a course of standard IFN maintain a sustained virological response in the long-term. IFN treatment could help to delay or prevent disease decompensation and liver-related deaths but further large studies are needed. Lamivudine is effective at reducing, and sometimes clearing, HBV replication in heavily immunosuppressed patients and can be safely administered to patients with advanced liver disease. Lamivudine should be continued over an undefined extended period of time, with a switch from lamivudine to adefovir if there is an HBV-DNA breakthrough under therapy. Adefovir, excluding cost, is preferable to lamivudine as a first-choice because there is less chance of inducing resistance. The long-term benefit of lamivudine and adefovir and the role of combinations is under investigation.
Collapse
Affiliation(s)
- Antonio Craxì
- Clinica Medica I, Cattedra di Gastroenterologia, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.
| | | | | |
Collapse
|
|
43
|
Jang JW, Bae SH, Choi JY, Kim CW, Han NI, Han JY, Choi SW, Yoon SK, Chung KW, Sun HS. Early virological response predicts outcome during extended lamivudine retreatment in patients with chronic hepatitis B who relapsed after initial HBeAg responses. J Gastroenterol Hepatol 2006; 21:384-91. [PMID: 16509863 DOI: 10.1111/j.1440-1746.2005.04035.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Studies from hepatitis B virus endemic areas have shown less durable lamivudine-induced responses and have raised issues about the management of a post-treatment relapse. METHODS From January 2000 to June 2004, all 51 patients (43 HBeAg-positive and eight HBeAg-negative) were retreated with lamivudine for at least 12 months. All had a post-treatment relapse after HBeAg responses (HBeAg loss/seroconversion) during the first therapy. RESULTS During retreatment, HBeAg seroconversion occurred more frequently in those patients with HBeAg seroconversion than in those with HBeAg loss alone during prior lamivudine therapy (P = 0.001). On multivariate analysis, prior HBeAg seroconversion and early virological response (EVR) (< or = 2 months of retreatment) independently predicted HBeAg seroconversion (P = 0.012 and P = 0.004, respectively). With regard to virological breakthrough, only the time to virological response (> 2 months of retreatment) remained significant (P = 0.048). Among the HBeAg-negative patients, virological breakthrough occurred in only one patient with a late virological response. CONCLUSIONS EVR is a major predictor in determining a favorable response to lamivudine retreatment. Our observations suggest that lamivudine retreatment will provide more therapeutic gains in those patients with a prior HBeAg seroconversion than in those with HBeAg loss alone.
Collapse
Affiliation(s)
- Jeong Won Jang
- Department of Internal Medicine and WHO Collaborating Center on Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Byun KS, Kwon OS, Kim JH, Yim HJ, Chang YJ, Kim JY, Yeon JE, Park JJ, Kim JS, Bak YT, Lee CH. Factors related to post-treatment relapse in chronic hepatitis B patients who lost HBeAg after lamivudine therapy. J Gastroenterol Hepatol 2005; 20:1838-42. [PMID: 16336441 DOI: 10.1111/j.1440-1746.2005.03952.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM It is uncertain if a patient's lamivudine response after HBeAg loss is durable. In Korean chronic hepatitis B patients, the relapse rate is high after termination of lamivudine therapy for patients with HBeAg loss. We evaluated the factors related to relapse in chronic hepatitis B patients with HBeAg loss after lamivudine therapy. METHODS A total of 132 chronic hepatitis B patients, who initially had HBeAg and did not have decompensated features, were analyzed in this study. These patients lost the HBeAg after lamivudine therapy and then their therapy was stopped. Post-treatment serum alanine aminotransferase (ALT), HBeAg, anti-HBe and hepatitis B virus (HBV) DNA were monitored until relapse. RESULTS Seventy-five patients relapsed (cumulative relapse rate: 56% at 6 months). Upon univariate analysis, the factors of age, serum total bilirubin, presence of anti-HBe after HBeAg loss, and the duration of additional lamivudine therapy after HBeAg loss were associated with relapse. Upon multivariate analysis, older age, a higher serum total bilirubin and the shorter duration of additional lamivudine therapy were significant risk factors for relapse. Patterns of relapse were the re-elevation of ALT, re-emergence of HBV DNA (69 patients) and reappearance of HBeAg (55 patients). CONCLUSIONS To prevent relapse in patients with chronic hepatitis B infection after lamivudine therapy, age and serum bilirubin level of patients as well as a prolonged duration of additional lamivudine therapy should be considered.
Collapse
Affiliation(s)
- Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Abstract
BACKGROUND Infection with the hepatitis B virus (HBV) affects two billion people worldwide, and an estimated 400 million people are chronically infected. Currently, FDA-approved regimens for the treatment of chronic HBV include interferon-alpha2b, peginterferon-alpha2a, lamivudine, adefovir dipivoxil, and recently, entecavir. OBJECTIVE The purpose of this review is to evaluate the pharmacokinetic and pharmacodynamic properties, and the clinical efficacy and safety of entecavir in the treatment of nucleoside-naĩve and nucleoside-resistant HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). SEARCH METHODOLOGY: Computerized searches of PubMed and International Pharmaceutical Abstracts from 1985 to July 10, 2005, were performed with the search headings: entecavir, BMS-200475, and chronic hepatitis B. FINDINGS Entecavir, a new deoxyguanosine analog, represents a third agent within the nucleoside/nucleotide HBV polymerase inhibitor class with distinct advantages over lamivudine and adefovir dipivoxil: it has a three-step mechanism of action, is the most potent inhibitor of HBV DNA polymerase, is not associated with any major adverse effects, and has a limited potential for resistance. In phase II and III clinical trials, entecavir was found to be superior to lamivudine for all primary endpoints evaluated in both nucleoside-naïve and lamivudine-resistant patients. Entecavir was effective in both HBeAg-positive and HBeAg-negative nucleoside-naïve patients. At this time, optimal duration of entecavir therapy is unknown. CONCLUSION Entecavir represents a new first- or second-line treatment option for patients chronically infected with HBV. Long-term efficacy and safety studies as well as studies of entecavir in combination with interferon products or other nucleoside/nucleotide analogs are eagerly awaited.
Collapse
Affiliation(s)
- Anastasia Rivkin
- Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA.
| |
Collapse
|
|
46
|
Yoon SK, Jang JW, Kim CW, Bae SH, Choi JY, Choi SW, Lee YS, Lee CD, Chung KW, Sun HS, Kim BS. Long-term results of lamivudine monotherapy in Korean patients with HBeAg-positive chronic hepatitis B: response and relapse rates, and factors related to durability of HBeAg seroconversion. Intervirology 2005; 48:341-9. [PMID: 16024938 DOI: 10.1159/000086061] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2004] [Accepted: 11/22/2004] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE The aim of this study was to evaluate retrospectively the long-term effects of lamivudine in 461 Korean patients with chronic hepatitis B who were treated for more than 12 months. METHODS The annual rates of virological response and breakthrough were examined and the predictive factors for post-treatment relapse in 114 patients who achieved hepatitis B e antigen (HBeAg) loss or seroconversion after lamivudine therapy were also analyzed. RESULTS During follow-up, the rates of HBeAg seroconversion after 1, 2, 3, 4 and 5 years of treatment were 22.9, 33.2, 47.6, 54.2 and 58.8%, respectively, while those for virological breakthrough at 1, 2, 3 and 4 years were 8.2, 41.7, 55.7 and 64.8%, respectively. Ninety-five patients (20.6%) had HBeAg seroconversion and 19 (4.1%) showed HBeAg loss alone with disappearance of hepatitis B virus DNA in serum. Seroconversion was higher with prolonged treatment in patients who had elevated serum alanine aminotransferase. The cumulative relapse rates in the seroconversion group were 52.0 and 55.7% 1 and 2 years after treatment, respectively. Age and the duration of additional treatment were significant predictive factors for post-treatment relapse. Patients aged </=40 who had additional treatment for >12 months after seroconversion had the lowest relapse rate (p < 0.001). CONCLUSIONS These results suggest that additional treatment for over 12 months after HBeAg seroconversion in younger patients may produce a better long-term outcome.
Collapse
Affiliation(s)
- Seung Kew Yoon
- Department of Internal Medicine and WHO Collaborating Center for Reference and Research on Viral Hepatitis, College of Medicine, Catholic University of Korea, Seoul, South Korea.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Shin JW, Park NH, Park JH, Park JH, Jeong ID, Bang SJ, Joo KR, Kim DH. Efficacy of lamivudine re-treatment for relapsed patients after an initial lamivudine therapy in HBeAg-positive chronic hepatitis B. J Viral Hepat 2005; 12:393-7. [PMID: 15985010 DOI: 10.1111/j.1365-2893.2005.00606.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
The efficacy of lamivudine re-treatment in chronic hepatitis B (CHB) patients who relapse after HBeAg seroconversion with lamivudine has not been investigated. The aim of this study was to evaluate the efficacy of lamivudine re-treatment in relapsed patients. Among 192 patients who had achieved HBeAg seroconversion with lamivudine at a dose of 100 mg/day, 121 patients discontinued lamivudine. Relapse occurred in 49 patients (40.5%). Thirty-three relapsed patients received lamivudine re-treatment for at least 6 months. The mean duration of lamivudine re-treatment was 16 months and the follow-up period was 8.9 months. HBeAg seroconversion was achieved in 23 patients (69.7%). The cumulative HBeAg seroconversion rates at 5, 9, and 12 months were 60, 64, and 67%, respectively. The mean time to HBeAg seroconversion in lamivudine re-treatment was shorter than that in the initial therapy (4.7 months vs. 9.7 months). Viral breakthrough occurred in six (18.2%) patients. All patients with viral breakthrough were accompanied by elevation of serum alanine aminotransferase (ALT) levels. Among 15 patients who discontinued lamivudine re-treatment after HBeAg seroconversion, relapse occurred in six patients (40%). All relapses occurred within 9 months after the discontinuation of lamivudine re-treatment. In conclusion, lamivudine re-treatment in relapsed patients after initial lamivudine therapy had a higher response rate and shorter duration to HBeAg seroconversion than during the initial therapy. However, HBeAg seroconversion induced by lamivudine re-treatment was not durable.
Collapse
Affiliation(s)
- J W Shin
- Division of Gastroenterology, Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Sung JJY, Wong ML, Bowden S, Liew CT, Hui AY, Wong VWS, Leung NWY, Locarnini S, Chan HLY. Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy. Gastroenterology 2005; 128:1890-7. [PMID: 15940624 DOI: 10.1053/j.gastro.2005.03.009] [Citation(s) in RCA: 183] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS This study aimed to determine whether intrahepatic hepatitis B virus (HBV) covalently closed circular (ccc) DNA and total HBV DNA levels at the end of therapy would predict sustained response to therapy. METHODS Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients receiving either lamivudine monotherapy or combination of peginterferon and lamivudine had liver biopsy at the end of 1 year therapy and were followed for 52 more weeks after cessation of therapy. Serum HBV DNA, intrahepatic HBV ccc DNA, and total HBV DNA levels were determined. RESULTS Forty-seven patients, including 34 males and 13 females, were studied. Twenty-seven patients received combination therapy, and 20 patients received lamivudine monotherapy. Twenty-nine patients had end-of-treatment virologic response, and 15 patients had sustained response 52 weeks after therapy. At the end of treatment, log serum HBV DNA levels correlated well with log intrahepatic HBV cccDNA and log intrahepatic total HBV DNA levels. Log intrahepatic cccDNA and log intrahepatic total DNA levels were significantly lower among patients with sustained virologic response. The adjusted odds ratio for log cccDNA was 5.3 (95% CI: 1.5-18.2, P = .009) and, for log intrahepatic HBV DNA, was 4.4 (95% CI: 1.3-14.7, P = .015) to predict sustained virologic response. Using log cccDNA at -0.80 copies/genome equivalent as cutoff, the sensitivity, specificity, and positive and negative predictive values and accuracy of predicting sustained virologic response were 73%, 78%, 56%, 86%, and 77% respectively. CONCLUSIONS Intrahepatic HBV cccDNA and intrahepatic total HBV DNA levels at the end of therapy are superior to serum HBV DNA as surrogates of sustained virologic response.
Collapse
Affiliation(s)
- Joseph J Y Sung
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Liu CJ, Huang WL, Chen PJ, Lai MY, Kao JH, Chen DS. End-of-treatment virologic response does not predict relapse after lamivudine treatment for chronic hepatitis B. World J Gastroenterol 2004; 10:3574-8. [PMID: 15534909 PMCID: PMC4611995 DOI: 10.3748/wjg.v10.i24.3574] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Attaining hepatitis B e antigen (HBeAg) seroconversion during lamivudine treatment is associated with fewer relapses in HBeAg-positive patients. In HBeAg-negative patients, predictors for post-treatment relapse remain largely unknown. We therefore studied whether end-of-treatment virologic response correlated with relapse after lamivudine treatment.
METHODS: We prospectively analyzed 12 HBeAg-negative patients and 14 HBeAg-positive patients with chronic hepatitis B, who received at least 9 mo of lamivudine treatment and were followed up for 12 mo post-treatment. Relapse of hepatitis B activity was defined by an elevation of serum ALT level above twice the upper limit of normal as well as reappearance of serum HBV DNA by the branched DNA assay or HBeAg during the follow-up period. The serum viral loads during and at the end of treatment were further determined by a quantitative real-time polymerase chain reaction assay.
RESULTS: Relapse occurred in 6 (50.0%) HBeAg-negative patients within 12 mo post-treatment. Two relapsers had end-of-treatment serum viral load < 1000 copies/mL, the proportion was not significantly different from that in the 6 non-relapsers (33.3% vs 16.7%; P = 1.00). Hepatitis B virus (HBV) DNA levels did not correlate with post-treatment relapse in HBeAg-positive patients either. However, genotype C patients tended to have a lower relapse rate than genotype B patients (14.3% vs 57.9%, P = 0.08).
CONCLUSION: Our results suggest that end-of-treatment virologic response cannot predict post-treatment relapse in patients with HBeAg-negative or -positive chronic hepatitis B. The impact of HBV genotype on the response to lamivudine treatment awaits further studies.
Collapse
Affiliation(s)
- Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, China
| | | | | | | | | | | |
Collapse
|
|
50
|
Abstract
During the past decade, major breakthroughs have been achieved in treatment of chronic hepatitis B. Currently, three therapeutic agents are approved for chronic hepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. In patients with HBeAgpositive chronic hepatitis B, all of these drugs achieve HBeAg loss (24-33%) and anti-HBe seroconversion (12-30%) rates that are superior to those observed in untreated controls. Interferon-alpha has several drawbacks, such as the parenteral administration and the development of frequent and potentially serious side effects. Lamivudine is a safe drug with rare and generally mild side effects. Lamivudine induces an initial virological remission in 70-90% of patients, but only 30-40% of patients remain in remission after the third year due to progressively increasing viral resistance. The main advantage of adefovir dipivoxil is the rare emergence of resistance, which has been identified in less than 2% of patients at 2 yr of treatment. Adefovir is also effective against lamivudine-resistant strains. This review will focus on the natural history and recently gained knowledge on the treatment of chronic hepatitis B.
Collapse
Affiliation(s)
- Young-Suk Lim
- Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea
| | - Dong Jin Suh
- Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea
| |
Collapse
|