|
1
|
Qian Z, Hu M, Wu H, Chen H, Liao G, Kang Z, Lin X, Peng J. The Efficacy of Antiviral Treatment for Chronic Hepatitis B Patients with Normal ALT Levels: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2022; 22. [DOI: 10.5812/hepatmon-129836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 10/03/2022] [Accepted: 10/06/2022] [Indexed: 01/04/2025]
Abstract
Context: When nucleos(t)ide analogues (NAs) were applied clinically to manage chronic hepatitis B virus infection, the prognosis of chronic hepatitis B (CHB) patients greatly improved. However, certain CHB patients with normal alanine aminotransferase (ALT) levels were not used to be considered as the population with the need for antiviral treatment. Objectives: This systematic review and meta-analysis collected and analyzed data from clinical trials to assess and compare the efficacy of antiviral treatment among patients with elevated and normal ALT levels. Methods: A systematic search was performed to gather studies published from 1990.01 to 2022.08 in PubMed and Web of Science databases. The quality of the literature was assessed, and 16 studies were included for further analysis. Basic information on included studies and study populations was collected. A meta-analysis was carried out to evaluate three major outcomes of viral response, hepatitis B envelope antigen (HBeAg) loss, and HBeAg seroconversion after NAs treatment based on data extracted from these studies. Odds ratios (ORs) with 95% confidence intervals (CIs) for all outcomes were calculated using fixed-effects models. Results: In the 16 relevant studies, 5,345 patients met the inclusion criteria, including 3,687 patients receiving NAs treatment. All patients were grouped into one with elevated ALT and another with normal ALT based on whether their pretreatment ALT levels > 1*upper limit of normal (ULN). For patients receiving lamivudine, the viral response showed no significant difference between the groups with elevated and normal ALT levels (pooled log OR: 0.51 [-0.23 - 1.26], P = 0.79); the pooled log OR for HBeAg loss was 1.19 (0.63 - 1.76, P = 0.03) and pooled log OR for HBeAg seroconversion was 2.19 (0.91 - 3.47, P = 0.40). For patients receiving first-line therapy with tenofovir disoproxil fumarate (TDF) and entecavir (ETV), the viral response showed no significant difference between the two groups: Pooled log OR (0.38 [-0.22 - 0.97], P = 0.10). The pooled log OR for HBeAg loss and HBeAg seroconversion was (-0.07 [-0.81 - 0.67], P = 0.68) and (0.40 [-0.84 - 1.63], P = 0.88), respectively. Conclusions: The efficacies of first-line therapy with TDF and ETV treatments were similar in groups with elevated and normal ALT levels for the outcomes of viral response and HBeAg loss. These findings may support further treatment of CHB patients with normal ALT levels.
Collapse
|
|
2
|
Ray G. Current Scenario of Hepatitis B and Its Treatment in India. J Clin Transl Hepatol 2017; 5:277-296. [PMID: 28936409 PMCID: PMC5606974 DOI: 10.14218/jcth.2017.00024] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 05/18/2017] [Accepted: 06/03/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B is a significant public health problem in India, yet disease awareness is very low among the general population. The disease is mostly acquired horizontally, but the role of vertical transmission should not be underestimated. In spite of the fact that the majority of cases are e negative disease, most patients present in the advanced stage and even with hepatocellular carcinoma, the leading cause of which is hepatitis B. High-risk groups (especially tribals) also harbour significant disease burden and have a high prevalence of occult infection, supporting the potential of unknowingly spreading the disease. Findings on the relation of genotypes with disease severity or drug action have been conflicting. Though recently, oral antivirals with high genetic barrier to resistance have shown good viral suppression in the long term, e and s seroconversion is poor and relapse is universal upon therapy discontinuation. As no cure is possible with the currently available therapy, the target is long-term viral suppression by prolonged administration of oral antivirals; unfortunately, this leads to poor treatment adherence, which along with the high cost of therapy results in disease progression and spread of infection. At present, therefore, emphasis should be put on health education of the general and high-risk populations, along with health care workers to increase knowledge on such preventive measures as avoiding unsafe injection practices, high-risk sex, performing unnecessary injection and blood transfusion and providing proper screening of blood products; these efforts should be combined with intensive screening and aggressive vaccination programs, especially in high-risk groups and areas of high endemicity. Vaccination strategies are still below par and logistics should be developed for wider coverage; in addition, further research should be carried out on the efficacy and mode of usage for different types of vaccine.
Collapse
Affiliation(s)
- Gautam Ray
- Gastroenterology Unit, Department of Medicine, B.R.Singh Hospital, Kolkata, India
| |
Collapse
|
|
3
|
Kim MN, Park JY, Ahn SH, Kim BK, Kim SU, Kim DY, Han KH. Durability of the virological response after lamivudine discontinuation in lamivudine-resistant patients with a complete virological response after lamivudine and adefovir combination therapy. J Med Virol 2016; 89:85-90. [PMID: 27357598 DOI: 10.1002/jmv.24616] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2016] [Indexed: 12/17/2022]
Abstract
We investigated the durability of virological response after lamivudine (LAM) discontinuation in LAM-resistant chronic hepatitis B (CHB) patients with complete virological response after LAM-adefovir (ADV) combination therapy. We enrolled 58 patients switched to ADV monotherapy with undetectable viral loads (<12 IU/ml) and normal alanine aminotransferase levels after ADV add-on combination treatment for at least 6 months in LAM-resistant CHB patients. Virologic relapse was defined as HBV DNA detection at more than 20 IU/ml by quantitative polymerase chain reaction determined on two consecutive measurements. During median 40.9 months of follow-up (range 11.5-79.0 months), seven (12.1%) patients experienced virological relapse. The cumulative rate of virological relapse at 3 and 5 years was 5.5% and 22.4%, respectively. Two patients had elevated alanine aminotransferase during virological relapse. These seven patients with virological relapse had undetectable HBV DNA after switching to tenofovir therapy. In our study, switching to ADV monotherapy resulted in sustained HBV DNA suppression in 87.9% of the patients during median 40.9 months follow-up. This adapting step-down strategy, switching from combination therapy to monotherapy in virologically suppressed CHB patients with stable liver disease, may reduce the cost burden and the risk of potentially harmful effects of combination therapy. J. Med. Virol. 89:85-90, 2017. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. .,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. .,Yonsei Liver Center, Yonsei University Health System, Seoul, Korea.
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Yonsei University Health System, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Yonsei University Health System, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Yonsei University Health System, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Yonsei University Health System, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Yonsei University Health System, Seoul, Korea
| |
Collapse
|
|
4
|
Jung YK, Yeon JE, Lee KG, Jung ES, Kim JH, Kim JH, Seo YS, Yim HJ, Um SH, Ryu HS, Byun KS. Virologic response is not durable after adefovir discontinuation in lamivudine-resistant chronic hepatitis B patients. THE KOREAN JOURNAL OF HEPATOLOGY 2012; 17:261-7. [PMID: 22310790 PMCID: PMC3304672 DOI: 10.3350/kjhep.2011.17.4.261] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Background/Aims We investigated the durability of the biochemical and virologic responses after adefovir (ADV) discontinuation in lamivudine-resistant (LMV-R) chronic hepatitis B (CHB) patients, and the outcomes of ADV discontinuation compared to that of ADV maintenance. Methods The indication for ADV treatment cessation was an undetectable level of hepatitis B virus (HBV) DNA documented on two occasions at least 6 months apart. All patients received additional ADV for at least 12 months after the confirmation of undetectable HBV DNA (Cobas TaqMan PCR assay, <70 copies/mL). Of 36 patients who had a sufficient ADV therapeutic effect, 19 discontinued ADV treatment, while the others maintained it. A virologic rebound was arbitrarily defined as the redetection of HBV DNA at a level higher than 105 copies/mL. Results In the ADV discontinuation group, ADV treatment and additional therapy were administered for medians of 33 months (range, 12-47 months) and 18 months, respectively. The patients were followed for a median of 12 months (range, 3-30 months) after ADV cessation. During that period, 18 of 19 patients (95%) experienced viral relapse. Viral rebound was observed in six patients (32%). However, 12 of 18 patients (67%) exhibited serum HBV DNA levels of less than 105 copies/mL. Biochemical relapses were observed in four of the six patients with viral rebound. In the ADV maintenance group, patients were treated for a median of 53 months (range, 31-85 months), and 9 patients (53%) experienced viral breakthrough. Conclusions During short-term follow-up after ADV discontinuation, most patients (95%) exhibited viral relapse, whereas and viral breakthrough occurred in about half of patients (53%) maintained on ADV therapy. Therefore, the durability of virologic response after ADV discontinuation in LMV-R patients was unsatisfactory. In addition, and viral breakthrough was not infrequent in the ADV continuation group.
Collapse
Affiliation(s)
- Young Kul Jung
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
5
|
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
|
|
6
|
Abstract
The two main goals of hepatitis B therapy are durable viral suppression and avoidance of antiviral resistance. Recent treatment guidelines now recognize the importance of these treatment endpoints in the prevention of end-stage liver disease and hepatocellular carcinoma rather then other surrogate markers such as HBeAg seroconversion and serum alanine aminotransferase normalization, especially in patients who acquired hepatitis B virus infection early in life. A variety of therapeutic options are now available for the treatment of chronic hepatitis B infection, including four nucleos/tide analogues (i.e lamivudine, adefovir, entecavir and telbivudine), along with standard and pegylated interferon. Newer oral nucleos/tide analogues that include tenofovir, emtricitabine and clevudine are soon likely to be approved worldwide. Given the wide array of choices and the complex nature of chronic hepatitis B infection, selection of the appropriate therapeutic agent can be challenging for clinicians. Effective treatment decisions require an understanding of the natural history of hepatitis B and knowledge of its life cycle and molecular biology. This review includes the range of treatment options and criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients positive for the HBeAg.
Collapse
|
|
7
|
Feitelson MA, Clayton MM, Reis HM, Wu G, Lu EP. Pharmacotherapy of chronic viral hepatitis and hepatocellular carcinoma. Expert Opin Pharmacother 2008; 9:2233-45. [PMID: 18710349 DOI: 10.1517/14656566.9.13.2233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) is a major etiologic agent of chronic liver disease (CLD) and hepatocellular carcinoma. Drugs have been developed and shown to be effective against HBV replication. These treatments are often associated with the resolution of CLD. However, they are too expensive, not well tolerated, and result in the development of resistance when given as mono or salvage therapies. In addition, most of these drugs target only the virus polymerase. OBJECTIVE To revitalize the field, drugs with other targets and combination therapies need to be developed. METHODS Major advances in HBV and liver cancer drug development over the past decade, focusing on Phase III trials and FDA-approved compounds, are presented. RESULTS/DISCUSSION A number of potent nucleoside/nucleotide analogs are now available for treatment, but for the long-term management of CLD, the development of combination therapies will probably be required. Development of compounds with new virus targets will enhance the utility of combination therapies. Development of compounds to host targets altered prior to or after the development of liver cancer, as demonstrated by sorafenib, need to be developed. The goal is to devise drug cocktails that will yield sustained virus responses and halt disease progression and tumor development.
Collapse
Affiliation(s)
- Mark A Feitelson
- Temple University, Department of Biology, College of Science and Technology, Suite 409, BioLife Science Building, 1900 North 12th Street, Philadelphia, PA 19122, USA.
| | | | | | | | | |
Collapse
|
|
8
|
Abstract
The main goals of chronic hepatitis B treatment should be the long-term suppression of viral replication to minimize disease progression and the risk for the development of hepatocellular carcinoma. Treatment end-points, depending on surrogate markers alone, in particular hepatitis B e-antigen seroconversion, may not be ideal for patients who acquire the disease early in life. Currently-available drugs include interferons and oral nucleoside/nucleotide analogs. Although interferon therapy provides a finite treatment period, a significant proportion of patients may not respond, and long-term outcome is inconclusive. Long-term efficacy has been demonstrated for both lamivudine and adefovir. However, prolonged nucleoside/nucleotide analog therapy is associated with the emergence of drug-resistant mutations. Therefore, nucleoside/nucleotide analogs with a high genetic barrier and potent antiviral activity, such as entecavir, should be used to reduce the chance of developing drug-resistant mutations. Drugs with a low genetic barrier, including lamivudine and telbivudine, should be used in conjunction with early testing for antiviral response. This can predict favorable outcomes in the long term. The early detection of drug-resistant mutations should prompt clinicians to either add or switch to another agent with a different drug-resistance profile. There are currently no treatment models in the use of combination or sequential therapy in treatment-naïve patients. To date, long-term treatment appears to be the most effective option. Despite recent advances made with better understanding on the natural history of chronic hepatitis B infection and with newer antiviral drugs available, challenges remain with respect to treatment criteria, treatment end-points, and duration of treatment.
Collapse
Affiliation(s)
- James Fung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong
| | | | | |
Collapse
|
|
9
|
Abstract
PURPOSE Lamivudine is known to be very effective in suppressing hepatitis B virus replication and virus induced necroinflammation. The aim of this study was to evaluate lamivudine therapy efficacy, predictive factors, breakthrough, prevalence of YMDD mutation, and relapse rate in Korean children with chronic hepatitis B. MATERIALS AND METHODS Between August 1999 and February 2005, 60 children on lamivudine therapy for chronic hepatitis B were enrolled. Treatment response was defined as alanine aminotransferase (ALT) normalization, and HBeAg and HBV-DNA disappearance. RESULTS Seroconversion rates of HBeAg and HBV- DNA were 42% and 53%, respectively, and ALT normalization rate was 88%. Seroconversion rates of HBeAg (60.0%) and anti-HBe (60.0%) were higher in patients younger than 6 years. Seroconversion rate of HBV-DNA (68.4%) and normalization rate of serum ALT (94.7%) were highest in patients between 6 and 12 years. Seroconversion rates of all HBV markers were lowest in patients older than 12 years. Predicted 3 year cumulative seroconversion rates, were 70%, 68% for HBeAg, HBV-DNA, respectively. These were calculated by Kaplan-Meier method. Cox proportional hazard regression model showed that pre-treatment ALT was a positive predictive factor for seroconversion of HBeAg and HBV-DNA. Breakthrough phenomenon was noted in 6 patients, and 3 had a YMDD mutation. CONCLUSION Lamivudine therapy had a significant effect on HBeAg seroconversion and HBV-DNA disappearance, and ALT normalization for Korean children with chronic hepatitis B.
Collapse
Affiliation(s)
- Hong Koh
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
| | - Seoung Yon Baek
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
| | - Ki Sup Chung
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
| |
Collapse
|
|
10
|
Abstract
Chronic hepatitis B virus infection affects about 400 million people around the globe and causes approximately one million deaths a year. Since the discovery of interferon-α as a therapeutic option the treatment of hepatitis B has evolved fast and management has become increasingly complicated. The amount of viral replication reflected in the viral load (HBV-DNA) plays an important role in the development of cirrhosis and hepatocellular carcinoma. The current treatment modalities for chronic hepatitis B are immunomodulatory (interferons) and antiviral suppressants (nucleoside and nucleotide analogues) all with their own advantages and limitations. An overview of the treatment efficacy for both immunomodulatory as antiviral compounds is provided in order to provide the clinician insight into the factors influencing treatment outcome. With nucleoside or nucleotide analogues suppression of viral replication by 5-7 log10 is feasible, but not all patients respond to therapy. Known factors influencing treatment outcome are viral load, ALT levels and compliance. Many other factors which might influence treatment are scarcely investigated. Identifying the factors associated with response might result in stopping rules, so treatment could be adapted in an early stage to provide adequate treatment and avoid the development of resistance. The efficacy of compounds for the treatment of mutant virus and the cross-resistance is largely unknown. However, genotypic and phenotypic testing as well as small clinical trials provided some data on efficacy in this population. Discontinuation of nucleoside or nucleotide analogues frequently results in viral relapse; however, some patients have a sustained response. Data on the risk factors for relapse are necessary in order to determine when treatment can be discontinued safely. In conclusion: chronic hepatitis B has become a treatable disease; however, much research is needed to tailor therapy to an individual patient, to predict the sustainability of response and determine the best treatment for those failing treatment.
Collapse
Affiliation(s)
- W F Leemans
- Department of Gastroenterology and Hepatology, Room H 437, Erasmus MC, University Medical Center Rotterdam's-Gravendijkwal 230, Rotterdam, The Netherlands
| | | | | |
Collapse
|