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Comparison of lamividine and adefovir dipivoxil in the treatment of chronic hepatitis B
Leung Nancy
Hepatitis B Annual , 2005,
Abstract: Nucleot(s)ide analogues are making milestones in the treatment of chronic hepatitis B (CHB). Lamivudine was approved by FDA for the treatment of chronic hepatitis B in adult patients n 1998 (ZeffixTM HeptodinTM HeptovirTM Epivir-HBVTM Glaxo Wellcome). Adefovir dipivoxil was approved by FDA in 2002 (Hepsera, Gilead). Both were licensed and available in many countries. A comparison of their efficacy in the treatment of various subgroups of CHB patients will facilitate management decision and choice between these two agents. Lamivudine suppresses viral replication and reduces serum HBV DNA level by 3-4 log 10 after one year of therapy, associated with normalization of serum alanine aminotansferase and significant improvement in histologic activity index. In HBeAg positive CHB, HBeAg loss/seroconversion rate at the end of one year of therapy is 18-30%; higher pretreatment serum alanine aminotransferase (ALT) level is associated with higher HBeAg loss/ seroconversion. HBeAg loss/seroconversion increases on extended therapy. The durability of response off therapy declines with time. Clinical efficacy in HBeAg negative CHB is similar. However, the drawback of Lamivudine therapy is increasingly being recognized. The endpoint for therapy is difficult to define and viral response is often not durable. Long-term therapy runs the risk of emergence of lamivudine resistant mutants (YMDDm) at the rate of around 15-30% each year, with a cumulative 70% at the end of year 4. YMDDm viraemia is eventually associated with relapse of hepatitis and occasionally hepatic decompensation. In patients with maintained or sustained response, there was significant improvement in necroinflammatory activity. Reversion of fibrosis has also been observed. In patients with advanced fibrosis and cirrhosis, three years of Lamivudine therapy reduced disease progression and possibly reduced occurrence of hepatocellular carcinoma. Lamivudine has also established its role for patients with hepatic decompensation pending liver transplantation, HBsAg positive patients receiving chemotherapy or organ transplantation. Its role in CHB children and viraemic CHB pregnant mothers is less certain. The clinical benefit of Adefovir dipivoxil was initially recognized in patients with Lamivudine resistant YMDD mutants. Subsequent pivotal phase 3 placebo-controlled trials showed significant antiviral activity against both wild type and HBeAg negative HBV. Adefovir dipivoxil 10 mg daily showed significant clinical benefit in normalization of serum ALT and histologic improvement in both HBeAg positive and HBeA
Association of core promoter mutations of hepatitis B virus and viral load is different in HBeAg(+) and HBeAg(-) patients  [cached]
Andi Utama,Marlinang Diarta Siburian,Sigit Purwantomo,Mariana Destila Bayu Intan
World Journal of Gastroenterology , 2011,
Abstract: AIM: To identify the prevalence of hepatitis B e antigen (HBeAg) and to assess the association of hepatitis B virus (HBV) core promoter mutations and viral load in Indonesian patients.METHODS: Sixty-four patients with chronic hepatitis, 65 with liver cirrhosis and 50 with hepatocellular carcinoma were included in this study. HBeAg and hepatitis B e antibody (HBeAb) tests were performed using enzyme-linked immunosorbent assay and the mutations were analyzed by sequencing. Viral load was measured by real-time polymerase chain reaction.RESULTS: Of 179 patients, 108 (60.3%) were HBeAg(-) and 86 (79.6%) of these HBeAg(-) patients had been seroconverted. The A1896 mutation was not found in HBeAg(+) patients, however, this mutation was detected in 70.7% of HBeAg(-) patients. This mutation was frequently found when HBeAg was not expressed (87.7%), compared to that found in HBeAg seroconverted patients (65.1%). The A1899 mutation was also more prevalent in HBeAg(-) than in HBeAg(+) patients (P = 0.004). The T1762/A1764 mutation was frequently found in both HBeAg(+) and HBeAg(-) patients, however, the prevalence of this mutation did not significantly differ among the two groups (P = 0.054). In HBeAg(+) patients, the T1762/A1764 mutation was correlated with lower HBV DNA (P < 0.001). The A1899 mutation did not correlate with HBV DNA (P = 0.609). In HBeAg(-) patients, the T1762/A1764 mutation alone was not correlated with HBV DNA (P = 0.095), however, the presence of either the T1762/A1764 or A1896 mutations was associated with increased HBV DNA (P < 0.001).CONCLUSION: The percentage of HBeAg(-) patients is high in Indonesia, and most of the HBeAg(-) patients had been seroconverted. The A1896 mutation was most likely the major cause of HBeAg loss. The T1762/A1764 mutation alone was associated with lower viral loads in HBeAg(+) patients, but not in HBeAg(-) patients.
Simultaneous quantitation of serum HBV DNA and HBeAg can distinguish between slow and fast viral responses to antiviral therapy in patients with chronic hepatitis B
Silva, Luiz Caetano da;Nova, Maria Luiza da;Ono-Nita, Suzane Kioko;Pinho, Jo?o Renato Rebello;Sitnik, Roberta;Santos, Vera Aparecida dos;Carrilho, Flair José;
Revista do Instituto de Medicina Tropical de S?o Paulo , 2009, DOI: 10.1590/S0036-46652009000500005
Abstract: background: the quantitation of serum hbeag is not commonly used to monitor viral response to therapy in chronic hepatitis b. methods: in this study, 21 patients receiving varying therapies were followed and their viral response monitored by concomitant viral load and hbeag quantitation in order to study the meaning and the kinetics of both parameters. results: it was possible to distinguish between three different patterns of viral response. the first was characterized by a simultaneous decrease in serum hbv dna and hbeag. the second pattern was characterized by a decrease in serum hbeag but persistent detection of hbv dna. the third pattern was characterized by undetectable hbv dna with persistent hbeag positivity, which points to a non-response (pattern iii-b) except when hbeag levels showed a slow but steady drop, characterizing a "slow responder" patient (pattern iii-a). conclusions: the first pattern is compatible with a viral response. a long-term hbeag seropositivity with a slow and persistent decrease (pattern iii-a) is also compatible with a viral response and calls for a prolongation of anti-viral treatment.
DNA-guided hepatitis B treatment, viral load is essential, but not sufficient  [cached]
Rafael Bárcena Marugán, Silvia García Garzón
World Journal of Gastroenterology , 2009,
Abstract: Hepatitis B virus (HBV) infection is a global public health problem that concerns 350 million people worldwide. Individuals with chronic hepatitis B (CHB) are at increased risk of developing liver cirrhosis, hepatic de-compensation and hepatocellular carcinoma. To maintain undetectable viral load reduces chronic infection complications. There is no treatment that eradicates HBV infection. Current drugs are expensive, are associated with adverse events, and are of limited efficacy. Current guidelines try to standardize the clinical practice. Nevertheless, controversy remains about management of asymptomatic patients with CHB who are hepatitis B e antigen (HBeAg)-positive with normal alanine aminotransferase, and what is the cut-off value of viral load to distinguish HBeAg-negative CHB patients and inactive carriers. We discuss in detail why DNA level alone is not sufficient to begin treatment of CHB.
Comparison of serum hepatitis B virus replication markers in patients with chronic hepatitis B: studies on HBeAg/Anti-HBe system, viral dna polymerase and HBV-DNA
Pinho, Jo?o Renato Rebello;Fonseca, Luís Edmundo Pinto da;Song, Yu;Miyamoto, Yuriko;Carrilho, Flair José;Granato, Celso Francisco Hernandes;Silva, Luiz Caetano da;
Revista do Instituto de Medicina Tropical de S?o Paulo , 1989, DOI: 10.1590/S0036-46651989000500006
Abstract: the detection of hbv-dna in serum by molecular hybridization is the most sensitive and specific marker of replication and infectivity of hepatitis b virus and currently is proposed as a routine diagnostic technique in the follow-up of hbv - related diseases. comparing different techniques already described, we found that direct spotting of serum samples on nitrocellulose membranes under vacuum filtration, followed by denaturing and neutralizing washes is more practical, simple, sensible and reproducible. dna polymerase assay using phosphonoformic acid as specific viral inhibitor has shown 86.8% of concordance with hbv-dna detection, and so, it is an useful alternative in the follow-up of hepatitis b chronic patients. we found 19.2% hbeag positive samples with no other markers of viral replication and no anti-hbe positive sample had detectable hbv-dna. discordance between the 2 systems have been extensively described, and we confirm this for the first time in our country. molecular biological techniques are essential to determine the replication status of chronic hepatitis b patients.
Lower baseline ALT cut-off values and HBV DNA levels better differentiate HBeAg(-) chronic hepatitis B patients from inactive chronic carriers  [cached]
Nimer Assy, Zaza Beniashvili, Agness Djibre, Gattas Nasser, Maria Grosovski, William Nseir
World Journal of Gastroenterology , 2009,
Abstract: AIM: To determine whether new cut-off values for alanine aminotransferase (ALT) and baseline hepatitis B virus (HBV) DNA levels better differentiate HBeAg(-) chronic hepatitis B (CHB) patients from inactive chronic carriers.METHODS: Ninety-one patients [32 HBeAg(+) CHB, 19 inactive carriers and 40 HBeAg(-) CHB] were followed up for 2 years and were tested for HBV DNA levels by a PCR-based assay. ALT was tested twice during the last 6 mo using new cut-off values: ULN (upper limit of normal) 30 IU/L for males, 19 IU/L for females. Diagnostic accuracy, sensitivity, specificity, positive and negative predictive values were calculated by discriminant analysis.RESULTS: When using the revised ALT cut-off values, the lowest optimal HBV DNA level that differentiated HBeAg(-) CHB patients from inactive carriers was 50 000 copies/mL. The diagnostic accuracy of HBV DNA to determine inactive carriers with a cut-off of 50 000 copies/mL was similar to the previously recommended cut-off of 100 000 copies/mL (91%). HBV DNA levels were lower than the cut-off value in 95% of inactive carriers and in 28% of HBeAg(-) CHB patients. With ALT < 30 IU/L in men and < 19 IU/L in women and HBV DNA levels < 100 000 copies/mL, the risk of CHB is 5%. On the other hand, if ALT values were > 30 IU in men and > 19 IU in women and baseline HBV DNA levels were > 100 000 copies/mL, the risk is 86%.CONCLUSION: New cut-off values for ALT together with HBV DNA levels proposed by AASLD (American Association for the Study of Liver Diseases) and NIH (National Institute of Health) consensus seem appropriate to characterize inactive carriers.
HBeAg negative chronic Hepatitis B: An overview
Mamun-Al-Mahtab,Fazle Akbar S
Hepatitis B Annual , 2009,
Abstract: Over 350 million people worldwide are infected with hepatitis B virus (HBV), and patients with HBeAg-negative chronic hepatitis B constitute a major proportion of this population. Mutant varieties of HBV resulting from mutations in the precore or core promoter region of the viral genome give rise to HBeAg-negative CHB, and these cases must be differentiated from the inactive carrier state. These patients with HBeAg-negative CHB must be managed judiciously and in certain situations kept under close follow-up instead of rushing to treatment. However, this does not mean advocating adoption of a too conservative approach, allowing many to proceed to irreversible and progressive liver disease. This article provides an overview of the management of HBeAg-negative chronic hepatitis B.
Hepatitis B Viral DNA Decline at Loss of HBeAg Is Mainly Explained by Reduced cccDNA Load – Down-Regulated Transcription of PgRNA Has Limited Impact  [PDF]
Sebastian Malmstr?m, Simon B. Larsson, Charles Hannoun, Magnus Lindh
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036349
Abstract: Background Quantification of hepatitis B virus (HBV) DNA and surface antigen (HBsAg) serum levels have become increasingly important for the assessment of clinical stage and response to treatment for chronic hepatitis B. Effective immune clearance results in reduction of viremia by 4–5 log units and HBsAg levels by 2 log, but these processes are not well understood. Thus, it is uncertain to what extent mechanisms that inhibit transcription of the pregenomic RNA (pgRNA), an RNA intermediate, contribute to suppression of viremia. Likewise, it is unclear if transcriptional regulation is important for the excessive production of surface antigen (HBsAg) that is a hallmark of HBV infection. Methods HBV RNA and cccDNA were quantified in 19 liver biopsies from patients with chronic HBV infection, as well as in transfected Huh7.5 cells and in PLC/PRF/5 cells carrying integrated HBV genome. Results Patients negative for HBeAg had 2.15 log lower levels of cccDNA in liver tissue, 4.84 log lower serum levels of HBV DNA and 1.45 log lower serum levels of HBsAg, than HBeAg-positive patients. The pgRNA in liver tissue correlated strongly with cccDNA (R2 = 0.87, p<0.0001) and HBV DNA levels in serum (R2 = 0.81, p<0.0001), whereas S-RNA correlated strongly with cccDNA (R2 = 0.65, p<0.0001) and HBsAg levels (R2 = 0.57, p = 0.0003). The S-RNA/pgRNA ratio was higher in HBeAg-negative patients (ratio 40 vs. 3, p = 0.01) and in PLC/PRF/5 cells, and was in transfected Huh7.5 cells not influenced by mutations in the HBV core promoter. Conclusion The reduction of viremia that is observed after loss of HBeAg was mainly explained by reduced cccDNA load in the liver, whereas the contribution of down-regulation of pgRNA transcription was relatively small. Enhanced transcription of S-RNA does not explain excessive production of HBsAg.
Clinical course of chronic hepatitis B patients who were off-treated after lamivudine treatment: analysis of 138 consecutive patients  [cached]
Jin Young-Joo,Kim Kang,Yoo Dong-jun,Shim Ju
Virology Journal , 2012, DOI: 10.1186/1743-422x-9-239
Abstract: Background/aims Little is known about the long-term outcome of chronic hepatitis B (CHB) patients who discontinued antiviral therapy. We intended to analyze the long-term outcome of CHB patients who discontinued lamivudine therapy and to evaluate predictors for post-treatment outcome. Material/methods From 2007 to 2008, 138 lamivudine off-treated CHB patients with alanine aminotransferase normalization were consecutively enrolled. Post-treatment virologic relapse, biochemical breakthrough, hepatitis flare, and retreatment results were retrospectively analyzed. Results Among 138 patients, 102 were initially HBeAg-positive at the start of lamivudine treatment. Virologic relapse, biochemical breakthrough, and hepatitis flare were observed in 45.2, 52.9, and 12.7% of HBeAg-positive and 29.4, 30.6, and 8.3% of HBeAg-negative patients during the median follow-up of 28 and 30 months, respectively. The cumulative virologic relapse and biochemical breakthrough rates were significantly lower in patients with HBV DNA <50 copies/mL than 50-104 copies/mL at lamivudine cessation. Hepatitis flare was observed in 4.8 and 11.8% of HBeAg-positive and HBeAg-negative patients with HBV DNA <50copies/mL, respectively. Thirty-eight among 138 patients received retreatment and most of them achieved biochemical (37/38) and virologic response (35/38) within 1 year of retreatment. Undetectable serum HBV DNA (<50 copies/mL) and young age at lamivudine cessation were inversely associated with virologic relapse. Undetectable HBV DNA at cessation, female, and initial HBeAg-negative were inversely associated with biochemical breakthrough. Conclusions Post-treatment virologic relapse and biochemical breakthrough incidence were low in patients who achieved undetectable viral titer at lamivudine cessation. Retreatment after biochemical breakthrough or virologic relapse was safe and effective. Intermittent antiviral therapy might be cautiously considered in appropriately selected CHB patients.
Viral and host factors related with histopathologyc activity in patients with chronic hepatitis B and moderate or intermittently elevated alanine aminotransferase levels
Molina Pérez,E.; Castroagudín,J. F.; Aguilera Guirao,A.; Otero Antón,E.; Tomé Martínez de Rituerto,S.; Mera Calvi?o,J.; Rodríguez Calvi?o,J. J.; Domínguez Mu?oz,J. E.;
Revista Espa?ola de Enfermedades Digestivas , 2010, DOI: 10.4321/S1130-01082010000900002
Abstract: objective: viral and host factors are related with progression of pathological lesion in chronic hepatitis b. we analyzed these factors in patients with moderate or intermittently elevated alt levels, and its threshold that determinate significant histological activity. patients and methods: retrospective analyses of viral and host parameters in 89 consecutive chronic hepatitis b patients biopsied because of moderate or intermittently elevated alt levels [1-2 x uln (uln = 39 iu/ml)] and/or dna-hbv > 2 x 103 iu/ml in antihbe+ patients. it was analyzed age, gender, alt levels, hbeag, viral load and genotype. it was considered advanced histological lesion a knodell score (ks) > 7 and histological lesion indicating treatment, lobular inflammation ≥ 2 or fibrosis ≥ 2 according to scheuer classification. results: ks > 7 and histological lesion indicating treatment was found in 47.8 and 60.7% respectively. it was observed relationship between age, male gender, alt levels and viral load with histological damage (p < 0.05). frequency of advanced lesion indicating treatment was upper in patients with alt levels > uln (69.1 vs. 47.1%, p = 0.04). there were not significant upper frequencies of advanced lesion when a cut-off of 40 years or dna-hbv > 2 x 103 iu/ml viral load or serological status hbeag was considerate. histological activity was lesser in genotype d patients than those infected with others genotypes (p < 0.05). conclusion: upper frequency of advanced histological lesion in chronic hepatitis b patients with moderate or intermittently elevated alt levels make recommended liver biopsy, independent of viral load and serological status hbeag. other factors like age, gender or genotype can help to indicate biopsy in individual cases.
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