Lamivudine Therapy In Chronic Hepatitis Research Articles

Lamivudine therapy for chronic hepatitis B in children: a meta-analysis

BackgroundCurrently, there is no consensus on the effects and safety of lamivudine therapy for chronic hepatitis B (CHB) in children.MethodBoth English and Chinese databases were searched comprehensively. An odds ratio (OR) and a standard mean difference (SMD) were used to assess the effects and safety of lamivudine therapy for CHB in children.ResultsThirteen eligible studies were included in our analysis. The rates of Hepatitis B virus (HBV) response, biochemical response, hepatitis B e antigen (HBeAg) loss, HBeAg seroconversion, and hepatitis B surface antigen (HBsAg) loss were significantly higher in the lamivudine (LAM) therapy group than in the control group. The changes in children’s weight and height were similar between the two groups.ConclusionsLAM therapy was efficacious for CHB in children. Additionally, it had no side effect on children’s height and weight.

Lamivudine therapy in HBeAg negative chronic hepatitis B patients

Background: Lamivudine therapy in chronic hepatitis B (CHB) treatment is not encouraged because of its lower resistance barrier. In this study, we aimed to investigate the long-term efficacy of lamivudine treatment in HBeAg negative CHB patients. Methods & Materials: This retrospective study is conducted in three different tertiary care hospitals. Virological response (VR) is defined as undetectable HBV DNA by a sensitive PCR assay during therapy. Partial virological response (PVR) is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients. Virological breakthrough also called as relapse is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the lowest value of HBV DNA level on therapy. Results: A total of 145 patients (57,9% male) were evaluated. Theirmean agewas 44,6 years and 23 (15,9%) of themwere treated with interferons previously. The median value of the ISHAK histological activity index (HAI) and fibrosis were 6 (range: 2-16) and 1 (range: 1-5). Themeanvalue of ALT, AST, andHBVDNAwere57U/L, 42 U/L and 1.189.806 IU/mL, respectively. Treatment of fifty-three (36,6%) patientswas switched tomore potent drugs due to PVR (29; 20%) or relapse (24; 16,6%). Relapse was observed between 13 and 36 months in majority of relapsers (12 cases in 13 to 24 months and 8 cases in 25 to 36months). VRwas observed in 92 (63,4%) and their median time on lamivudine therapy was 34,5 months (range: 6-78 months). Baseline characteristics of virologic responders and switched group were shown in Table 1. Conclusion: Our results showed that more than 60% patients maintain viral suppression more than thirty months. Lamivudine can still be a reliable drug especially in low-income countries because of its low cost. However, lamivudine should be used with more caution in patients who have low thrombocyte and high HAI, fibrosis, ALT, and AST levels.

Pretreatment and on-treatment indicators of virologic breakthrough of lamivudine therapy in chronic hepatitis B patients: an Egyptian study.

The primary objectives of hepatitis B treatment include improved clinical and histological progression as well as virus eradication. For many years, lamivudine was a first-line therapy for treating hepatitis B virus (HBV) infection. However, its long-term use is associated with high resistance rates (up to 70% after 5 years) due to mutations in the viral YMDD motif. The purpose of this study was to outline factors responsible for the development of viral resistance during long-term lamivudine therapy. Initially, 230 patients receiving lamivudine therapy for chronic hepatitis B (CHB) infection were enrolled in the study. All subjects received follow-ups in the first year to assess viral and biochemical responses. Only 136 and 104 patients received follow-up assessments during the second and third years of treatment, respectively. Viral breakthrough (VBT) occurred in 49 of 230 patients (21.3%). Hepatitis B "e" antigen (HBeAg) status before treatment was significantly associated with VBT in the first 2 years of treatment; however, this effect was not significant in the third year. Pre-treatment HBV DNA levels were predictive of VBT in the HBeAg-positive subgroup after all years of treatment (P = 0.001, P = 0.002, and P = 0.002, respectively). These levels were also predictive in the HBeAg-negative subgroup after 1 year of treatment (P = 0.001). In resource-poor communities, financial concerns drive the selection of antiviral therapy to treat CHB. Lamivudine monotherapy is a relatively cheap and effective treatment to manage CHB. However, consistent follow-ups and treatment modifications appear essential to prevent long-term treatment failure.

Differential roles of serum hepatitis B virus DNA and hepatitis B surface antigen level in predicting virological breakthrough in patients receiving lamivudine therapy

The role of serum hepatitis B surface antigen (HBsAg) level in determining virological breakthrough (VB) for patients with hepatitis B virus (HBV) infection receiving lamivudine remains unclear. The study aimed to evaluate the impact of serum HBsAg levels on VB among patients receiving lamivudine therapy, especially in a setting of low HBV viral load. Two hundred sixty-eight consecutive treatment-naïve patients who underwent lamivudine therapy for chronic hepatitis B were enrolled. Factors in terms of VB were analyzed by multivariate analysis. After a median treatment duration of 67.1 weeks, 102 patients had VB. Multivariate analysis showed that positive hepatitis B e antigen (HBeAg) (hazard ratio 2.165, P = 0.026) and HBV DNA levels ≥ 2000 IU/mL after 6 months of lamivudine therapy (hazard ratio 5.236, P = 0.001) were independent risk factors predicting VB. The cumulative VB rates stratified by HBeAg-positive and -negative at 3 years were 44.7% and 26.3%, respectively. At 3 years, the cumulative VB rates stratified by the HBV DNA < 2000 and ≥ 2000 IU/mL after 6 months of therapy were 25.5% and 79.4%, respectively. For HBeAg-positive patients with serum HBV DNA < 2000 IU/mL after 6 months of therapy, baseline HBsAg levels ≥ 20,000 IU/mL was the only risk factor associated with VB. For chronic hepatitis B patients treated with lamivudine, serum HBV DNA level > 2000 IU/mL after 6 months of therapy could predict subsequent VB. In patients with lower on-treatment viral load, baseline serum HBsAg level is associated with the emergence of VB, especially for those with serum positive HBeAg.

Detection of HBV Resistance to Lamivudine in Patients with Chronic Hepatitis B Using Zip Nucleic Acid Probes in Kerman, Southeast of Iran

HBV infection is contagious and may be transmitted vertically or horizontally by blood products and body secretions. Over 50% of Iranian carriers have contracted the infection prenatally, making this the most likely route of transmission of HBV in Iran. This study assesses the resistance to Lamivudine in patients with chronic hepatitis B infection using a new ZNA probe Real Time PCR method. To evaluate the effectiveness of Lamivudine therapy for chronic hepatitis B infection, a study was conducted on 70 patients (63 men and 7 women), who had received the drug first line. All patients were tested for the presence of HBsAg and HBeAg, the serum ALT level and the HBV DNA load before and after treatment. In all samples resistance to Lamivudine was tested with the ZNA Probe. Our results showed that ZNA Probe Real Time PCR method could detect wild type,YMDD, and its mutants, tyrosine-isoleucine-aspartate-aspartate and tyrosine-valine-aspartate-Aspartate. Among an estimated seventy patients with chronic hepatitis B infection, 18 (25.7%) were resistant to lamivudine. Only one patient was negative for presence of HBS-Ag (5.6%) and two patients were negative for HBe-Ag (11.1%). Real-time PCR with Zip nucleic acid probes is a sensitive, specific and rapid detection method for mutations in the YMDD motif, which will be essential for monitoring patients undergoing Lamivudine antiviral therapy.

Correlation of the occurrence of YMDD mutations with HBV genotypes, HBV-DNA levels, and HBeAg status in Chinese patients with chronic hepatitis B during lamivudine treatment

Continuous lamivudine therapy is associated with high rates of YMDD mutations, which are the main causes of drug resistance. The current study explores the association of the emergence of YMDD mutations with pretherapy HBV genotype, HBV-DNA levels, HBeAg status, and serum alanine aminotransferase (ALT) levels in Chinese patients receiving lamivudine therapy for chronic hepatitis B. A total of 319 chronic hepatitis B patients who received lamivudine therapy for more than a year were enrolled in this study. YMDD mutations, HBV genotype, HBV-DNA levels, HBeAg status, and ALT levels were determined prior to their lamivudine treatment and every three months for a year of this therapy. Among the 319 patients, 137 (42.95%) were infected with genotype B and 182 (57.05%) with genotype C. Up to 94 patients (29.47%) developed YMDD mutations within one year of lamivudine therapy. Furthermore, 50 patients with HBV genotype B and 44 patients with genotype C developed YMDD mutations (36.50% vs 24.18%, P<0.05). Logistic regression analysis showed that pretherapy HBV genotype, HBV-DNA levels, and HBeAg status are independent factors for the emergence of YMDD mutations (HBV genotype: OR=2.159, 95% CI 1.291-3.609, P=0.003; HBV-DNA: OR=1.653, 95% CI 1.231-2.218, P=0.001; HBeAg: OR=2.021, 95% CI 1.201-3.399, P=0.008). HBV genotype, HBV-DNA levels, and HBeAg status at baseline are the independent factors associated with the emergence of YMDD mutations among Chinese patients receiving lamivudine therapy for chronic hepatitis B. These findings are helpful to the development of therapeutic strategies for these patients.

Is there a role for MICA in ulcerative colitis?

on the management of chronic hepatitis B: a 2008 update. Hepatol. Int. 2008; 3: 263–83. 4 Wong VW, Wong GL, Yan KK et al. Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010; 51: 1945–53. 5 Song BC, Suh DJ, Lee HC, Chung YH, Lee YS. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 2000; 32: 803–6. 6 Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology 2003; 38: 1267–73. 7 Byun KS, Kwon OS, Kim JH et al. Factors related to post-treatment relapse in chronic hepatitis B patients who lost HBeAg after lamivudine therapy. J. Gastroenterol. Hepatol. 2005; 20: 1838–42. 8 Lee HW, Lee HJ, Hwang JS et al. 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. 9 Wang L, Liu F, Liu YD et al. 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. 10 Fung J, Lai CL, Tanaka Y et al. 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. 11 Ryu SH, Chung YH, Choi MH et al. Long-term additional lamivudine therapy enhances durability of lamivudine-induced HBeAg loss: a prospective study. J. Hepatol. 2003; 39: 614–19. 12 Liu F, Wang L, Li XY et al. Poor durability of lamivudine effectiveness despite stringent cessation criterion: a propsective clinical study in HBeAg-negative chronic hepatitis B. J. Gastroenterol. Hepatol. 2011; 26: 456–60. 13 Shouval D, Lai CL, Chang TT et al. Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy. J. Hepatol. 2009; 50: 289–95. 14 Chen CJ, Yang HI, Su J et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65–73. 15 Chen G, Lin W, Shen F, Iloeje UH, London WT, Evans AA. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am. J. Gastroenterol. 2006; 101: 1797–803. 16 Yuen MF, Tanaka Y, Fong DY et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J. Hepatol. 2009; 50: 80–8. 17 Reijnders JG, Perquin MJ, Zhang N, Hansen BE, Janssen HL. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology 2010; 139: 491–8.

The molecular basis of the failed immune response in chronic HBV: Therapeutic implications

There is a pressing need to develop new immunotherapeutic interventions in chronic hepatitis B virus (HBV) infection in order to limit the high costs and risks of toxicity or viral resistance associated with maintenance antiviral treatment. Here we review recent advances in our understanding of the molecular defects underlying the profound T cell depletion characteristic of these patients. We propose that T cells are driven to apoptosis by the combination of a persistent, high antigen load and excessive inhibitory signals encountered in the hepatic microenvironment. The feasibility of boosting sustained antiviral control by targeted reversal of key tolerising mechanisms is discussed.

Association of baseline viral factors with response to lamivudine therapy in chronic hepatitis B patients with high serum alanine aminotransferase levels

With the exception of alanine aminotransferase (ALT) level, baseline factors predictive of therapeutic response to lamivudine in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remain unknown. We thus studied the influence of pre-therapy viral factors on end-of-treatment responses to lamivudine. A total of 116 treatment-naive HBeAg-positive CHB patients who had pre-therapy ALT level >5x the upper limit of normal (ULN) and received lamivudine for 12-18 months were enrolled. HBeAg seroclearance and combined HBeAg seroclearance, ALT normalization and undetectable hepatitis B virus DNA at the end of therapy were defined as primary and secondary endpoints, respectively. Pre-therapy viral factors including viral load, genotype, precore (PC) stop codon status, basal core promoter status and pre-S deletion were determined to correlate with therapeutic endpoints. The frequency of patients with detectable PC stop codon mutation (G1896A), basal core promoter mutation (A1762T/G1764A) and pre-S deletion at baseline was 22.4%, 21.6% and 12.1%, respectively. After the end of 12-18 months of lamivudine therapy, the overall HBeAg seroclearance rate was 56.0%. Patients with HBeAg seroclearance had a higher prevalence of baseline PC stop codon mutation than those without (30.8% versus 11.8%; P=0.015). By using multivariate analyses, the odds ratio of patients with the PC stop codon mutation to develop HBeAg seroclearance was 3.33 (P=0.024). The presence of the PC stop codon mutation also correlated with the combined response. For lamivudine-treated HBeAg-positive CHB patients with pre-therapy ALT levels >5xULN, the PC stop codon mutation could predict a higher HBeAg seroclearance rate at the end of 12-18 months of therapy.

Pretreatment and on-treatment predictors of viral breakthrough in lamivudine therapy for chronic hepatitis B

There are remarkable advances in the treatment of chronic hepatitis B (CHB) in the last few years. Unfortunately, prolonged antiviral treatment is associated with increasing risk of drug resistance/viral breakthrough (VBT), which may lead to flare-up and rapid decompensation. We have designed this study to predict the pretreatment and on-treatment factors responsible for development of VBT. This study was conducted during the period of February 2000 to November 2007. We have included 423 patients who received lamivudine (LAM) therapy for at least 1 year and at least 2 follow-ups at 6 months' interval. Follow-up period was 12-78 months. Chi-square test, student's t test, and logistic regression analysis were performed to prove the validity. Of the 423 study cases, 367 (86.8%) were of male patients and 261 (61.7%) patients were HBeAg positive; the age of the patients was 30.8 +/- 12.9 years. Development of VBT was 4.4, 22.8, 45.3, and 74% at 1, 2, 3, and 4 or more years, respectively. Pretreatment high HBV DNA (P = 0.005) and female sex (P = 0.01) were associated with VBT and pretherapy ALT (P = 0.698), HBeAg status (P = 0.273), and age (P = 0.059) were not associated. Duration of treatment, failure to lose HBeAg at 1 year, and HBV DNA nonresponder at 6 months were significantly (P = 0.001) associated with development of VBT. Persistence of HBeAg at 1 year and HBV DNA nonresponder at 6 months are good predictors of development of VBT.

A higher alanine aminotransferase level correlates with earlier hepatitis B e antigen seroconversion in lamivudine‐treated chronic hepatitis B patients

A pretherapy serum alanine aminotransferase (ALT) level above five times the upper limit of normal (ULN) is known to predict hepatitis B e antigen (HBeAg) seroconversion during lamivudine therapy for chronic hepatitis B patients. However, whether an even higher pretherapy serum ALT value or other viral factors could affect treatment responses remains unclear. A total of 253 HBeAg-positive chronic hepatitis B patients who had a pretherapy serum ALT level over five times ULN and received lamivudine for 12-18 months were retrospectively collected. Among these patients, 38% had received prior lamivudine treatment. HBeAg seroconversion was the primary endpoint of treatment. Baseline clinical and viral features were compared between responders and non-responders at the end of treatment and 6 months post-treatment. At the end of therapy, the overall HBeAg seroconversion rate was 33.6%. For lamivudine-naïve patients, the HBeAg seroconversion rate was 37.8%. Subgroup analysis showed that patients with pretherapy ALT levels over 10 times ULN had a significantly higher HBeAg seroconversion rate than those with a pretherapy ALT level between five and 10 times ULN at 3 months (P=0.045) and 6 months (P=0.037) of lamivudine treatment. No significant difference was found in terms of pretherapy serum ALT values, viral load and genotypes between seroconverters and non-seroconverters. For lamivudine-treated HBeAg-positive patients with pretherapy ALT levels over five times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however, neither ALT levels nor viral factors correlate with higher response rates after 12-18 months of treatment.

Lamivudine Therapy for Korean Children with Chronic Hepatitis B

PurposeLamivudine 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 MethodsBetween 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.ResultsSeroconversion 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.ConclusionLamivudine therapy had a significant effect on HBeAg seroconversion and HBV-DNA disappearance, and ALT normalization for Korean children with chronic hepatitis B.

Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection

Prolonged lamivudine therapy has two major problems: breakthrough hepatitis during treatment and relapse of aminotransferase (ALT) after cessation of the therapy. The aim of this study was to examine factors that could predict ALT flare after stopping lamivudine therapy. We analyzed 22 Japanese patients with chronic hepatitis B infection, in whom lamivudine therapy was stopped after HBV DNA level had been gone undetectable (<3.7LGE/ml) during at least six consecutive months. The post-treatment followed up was carried for 28 months in median (range 9-41). HBV core-related antigen (HBcrAg) assay was assessed using newly developed assay. After cessation of lamivudine therapy, 11 patients (50%) had relapsed (reactivation of serum ALT >80IU/l, relapsers) and remaining 11 (50%) did not relapse (non-relapsers). In the univariate comparison of relapsers versus non-relapsers, HBcrAg level at lamivudine cessation point (4.5+/-1.0 versus 3.4+/-0.9; p=0.0145) has been shown as a significant predictive factor for non-relapse. All patients with HBcrAg <3.0logU/ml at the cessation point had no ALT flares. Multivariate analysis on effects of 10 factors (age, sex, cirrhosis, pretreatment ALT level, HBV DNA level, HBcrAg level, mean months till undetectable HBV DNA, duration of undetectable HBV DNA and HBcrAg level at lamivudine cessation point), indicated that HBcrAg level at lamivudine cessation point <3.4log U/ml was the only independent predictive factor for absence of the post-treatment relapse. HBcrAg level at lamivudine cessation point might be useful as a prognostic predictor of response to lamivudine therapy cessation. The measurement of HBcrAg is a useful additional test for monitoring chronic HBV infection.

Clinical significance of hepatitis B e antigen level easurement during long-term lamivudine therapy in chronic hepatitis B patients with e antigen positive

To determine the changes of quantitative hepatitis B e antigen (HBeAg) that predicts early detection of non-response or breakthrough to long-term lamivudine (LAM) therapy. Among HBeAg positive chronic hepatitis B patients who failed to achieve HBeAg seroconversion within 12 mo, we retrospectively analyzed 220 patients who had received LAM more than 24 mo. The mean duration of LAM therapy was 36 (range, 24-72) mo. HBeAg seroconversion after the first 12 mo of LAM therapy was achieved in 53 (24.1%) patients. Viral breakthrough was observed in 105 (47.7%) patients. To find out whether the changing patterns of HBeAg levels can predict the outcome of LAM therapy, we analyzed the reduction rates of HBeAg levels during LAM therapy. Using the decrease more than 90% of pretreatment HBeAg levels, the sensitivity and specificity of response were 96.2% and 70.1%, respectively. Patients were divided into 3 groups according to the reduction patterns of the decrease of quantitative HBeAg: decrescendo, decrescendo-crescendo, no change or fluctuating groups. The optimal time to predict non-response or breakthrough was the first 9 mo of therapy. At 9 mo of therapy, 49 (92.5%) of 53 patients who had achieved HBeAg seroconversion were included in the decrescendo group. On the contrary, in the no change or fluctuating group, only four (7.5%) had achieved HBeAg seroconversion. Among patients who did not show the continuous decrease of HBeAg levels at 9 mo, 95.2% (negative predictive value) failed to achieve HBeAg seroconversion. Almost all patients who failed to show a continuous decrease of HBeAg levels at 9 mo of LAM therapy were non-response or breakthrough. Therefore, monitoring changes of HBeAg levels during LAM therapy in HBeAg positive chronic hepatitis B may be valuable for identifying patients who are at high risk of non-response or breakthrough.

Successful lamivudine therapy for chronic hepatitis B in the family

Hepatitis B virus infection is a global public health problem since it is a leading cause of liver cirrhosis and hepatocellular carcinoma. An optimal treatment is needed to reduce mortality. Current therapies for chronic hepatitis B include standard and pegilated interferon-alfa and nucleoside and nucleotide analogies, primarily lamivudine and adefovir. Each of the therapies, however has various limitations. In this paper we presented a father and his daughter with chronic hepatitis B, successfully treated with lamivudine. In the linked cases of chronic hepatitis B, the choice of antiviral medicine in some patients could also be made on the basis of its efficacy in the persons previously treated with it, even without determining virus genotype.

Poor response to 18‐month lamivudine monotherapy in chronic hepatitis B patients with IgM anti‐HBc and acute exacerbation

Appearance of immunoglobulin class M antibody against hepatitis B core antigen is a predictor of beneficial response to interferon-alpha therapy in chronic hepatitis B patients, but its relationship with the efficacy of lamivudine therapy remains unclear. To investigate the outcome of lamivudine therapy in chronic hepatitis B patients with immunoglobulin class M antibody against hepatitis B core antigen and acute exacerbation. Chronic hepatitis B patients with acute exacerbation receiving a national-wide therapeutic trial of 18-month lamivudine monotherapy were enrolled for the analysis. Four consecutive seronegative patients were recruited as individual matching controls of one positive subject. Immunoglobulin class M antibody against hepatitis B core antigen in serum was assayed monthly by an automated microparticle enzyme immunoassay. Fifteen (8.9%) of 167 chronic hepatitis B patients with acute exacerbation were seropositive for IgM anti-HBc. Thus 60 seronegative patients were consecutively recruited as control group. At the end of therapy, two (13.3%) of the 15 seropositive patients achieved a sustained response, significantly lower than 26 (43.3%) of the control group. Appearance of immunoglobulin class M antibody against hepatitis B core antigen in chronic hepatitis B patients with acute exacerbation is a predictor of poor response to lamivudine monotherapy. This is clinically relevant to the decision-making in treating chronic hepatitis B patients with acute exacerbation.

Changes in different regions of hepatitis B virus gene in hepatitis B ‘e’ antigen‐negative patients with chronic hepatitis B: the effect of long‐term lamivudine therapy

Lamivudine therapy for chronic hepatitis B has been associated with changes in different regions of the hepatitis B virus nucleotide sequence. To study changes in the sequences of polymerase and precore/core promoter regions of hepatitis B virus, before and during 5 years of therapy with lamivudine. Eighty consecutive samples were taken from 10 chronic hepatitis B 'e' antigen-negative patients. Nine patients carried hepatitis B virus precore mutations during the study. Before therapy, wild type was replaced by A1896 in two (20%) cases. During treatment, A1896 reverted transitory to wild type in five cases (50%) and in one case wild type was replaced by A1896. The continuous detection of precore mutations during therapy was associated with a lower response rate. YMDD mutations were observed in nine cases and both, L180M and M204V/I mutations were simultaneously detected in six cases. About 75% of the patients with M204V mutations were responders and none with M204I or mixed pattern sustained response. Hepatitis B 'e' antigen-negative patients exhibit changes in the precore regions both spontaneously and under lamivudine therapy, the transitory reversion to wild type being most frequently witnessed. Patients carrying M204V mutations are more likely to respond to therapy. If, in further studies, these results are confirmed some patients with YMDD mutations could benefit from prolonging the duration of lamivudine therapy.

Virus and transaminase levels determine the emergence of drug resistance during long-term lamivudine therapy in chronic hepatitis B

The results of earlier studies on determinants for the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants (rtM204 I/V) were controversial. The aim was to evaluate the impact of viral factors, host factors, host-viral interaction and drug factor on the emergence of rtM204 I/V. 56 non-cirrhotic and 58 cirrhotic patients received lamivudine therapy for a median of 34 (12-60) months. rtM204 I/V emerged in 37 noncirrhotic and 36 cirrhotic patients. Stepwise logistic regression analysis showed that baseline hepatitis B e antigen (HBeAg) status [odds ratio (OR), 7.728; 95% confidental interval (CI), 2.886-12.957; P=0.0026], HBV-DNA level (OR, 3.756; 95% CI, 1.058-5.089; P=0.0202), alanine transaminase (ALT) level (OR, 6.285; 95% CI, 1.057-11.990; P=0.00246) and treatment duration (OR, 19.88; 95% CI, 8.652-31.762; P<0.0004) were independent determinants for the emergence of rtM204 I/V. Further categorical analysis and correlation test disclosed that patients with HBeAg positivity, HBV-DNA>500 pg/ml and ALT <5x upper limit of normal had significantly higher mutation rates. HBeAg status, HBV-DNA, ALT levels and treatment duration are the major determinants for the YMDD mutation during lamivudine therapy, and should be considered in designing the therapeutic strategy.

Polymerase Domain B Mutation Is Associated with Hepatitis Relapse during Long-Term Lamivudine Therapy for Chronic Hepatitis B

Breakthrough hepatitis remains the major issue in long-term lamivudine therapy for chronic hepatitis B. However, the emergence of drug-resistant hepatitis B virus (HBV) is not always accompanied by a relapse of hepatitis. To elucidate factors predictive of breakthrough hepatitis, 53 patients with genotype C of HBV on long-term lamivudine therapy were analyzed. HBV reappeared during therapy in 19 patients with a cumulative incidence of 15% at 1 year, 34% at 2 years, and 60% at 3 years. Within this group, breakthrough hepatitis developed in 12 patients (63%). A polymerase gene domain B mutation (rt180M) emerged in 13 patients, and domain C mutations (rt204I, rt204V) were found in 19 patients. The rt180M mutation was associated with breakthrough hepatitis (p < 0.05) with a positive predictive value of 85% and a negative predictive value of 83%. Patients with the rt180M mutation had higher HBV-DNA levels during viral breakthrough compared to patients with rt180wt (p < 0.05). The mutational pattern of rt204 was not associated with breakthrough hepatitis. In conclusion, genotypic assays for the rt180M mutation after viral breakthrough may be useful in predicting the risk of breakthrough hepatitis and in deciding when to initiate alternative or additive nucleoside analogue therapy.

Interferon-$alpha; for hepatitis C: antiviral or immunotherapy?

Interferon-$alpha; for hepatitis C: antiviral or immunotherapy?