Prediction model for hepatitis B e antigen seroconversion in chronic hepatitis B with peginterferon-alfa treated based on a responseguided therapy strategy

BACKGROUND Models for predicting hepatitis B e antigen(HBeAg)seroconversion in patients with HBeAg-positive chronic hepatitis B(CHB)after nucleos(t)ide analog treatment are rare.AIM To establish a simple scoring model based on a response-guided therapy(RGT)strategy for predicting HBeAg seroconversion and hepatitis B surface antigen(HBsAg)clearance.METHODS In this study,75 previously treated patients with HBeAg-positive CHB underwent a 52-week peginterferon-alfa(PEG-IFNα)treatment and a 24-wk follow-up.Logistic regression analysis was used to assess parameters at baseline,week 12,and week 24 to predict HBeAg seroconversion at 24 wk post-treatment.The two best predictors at each time point were used to establish a prediction model for PEG-IFNαtherapy efficacy.Parameters at each time point that met the corresponding optimal cutoff thresholds were scored as 1 or 0.RESULTS The two most meaningful predictors were HBsAg≤1000 IU/mL and HBeAg≤3 S/CO at baseline,HBsAg≤600 IU/mL and HBeAg≤3 S/CO at week 12,and HBsAg≤300 IU/mL and HBeAg≤2 S/CO at week 24.With a total score of 0 vs 2 at baseline,week 12,and week 24,the response rates were 23.8%,15.2%,and 11.1%vs 81.8%,80.0%,and 82.4%,respectively,and the HBsAg clearance rates were 2.4%,3.0%,and 0.0%,vs 54.5%,40.0%,and 41.2%,respectively.CONCLUSION We successfully established a predictive model and diagnosis-treatment process using the RGT strategy to predict HBeAg and HBsAg seroconversion in patients with HBeAg-positive CHB undergoing PEG-IFNαtherapy.

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

AIM： 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. METHODS： Among HBeAg positive chronic hepatitis B patients who failed to achieve HBeAg seroconversion within 12 too, we retrospectively analyzed 220 patients who had received LAM more than 24 too. RESULTS： 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 too, 95.2% （negative predictive value） failed to achieve HBeAg seroconversion. CONCLUSION： 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.

Long-term alpha interferon and lamivudine combination therapy in non-responder patients with anti-HBe-positive chronic hepatitis B:Results of an open,controlled trial

AIM: To investigate the safety and efficacy of long-term combination therapy with alpha interferon and lamivudine in non-responsive patients with anti-HBe-positive chronic hepatitis B.METHODS: 34 patients received combination treatment (1 month lamivudine, 12 month lamivudine+interferon, 6month lamivudine), 24 received lamivudine (12 months),24 received interferon (12 months). Interferon was administered at 6 MU tiw and lamivudine at 100 mg orally once daily. Patients were followed up for 6 months after treatment.RESULTS: At the end of treatment, HBV DNA negativity rates were 88 % with lamivudine+interferon, 99 % with lamivudine and 55 % with interferon, (P=0.004, combination therapy vs. interferon, and P=0.001 lamivudine vs.interferon), and serum transaminase normalization rates were 84 %, 91% and 53 % (P=0.01 combination therapy vs. interferon, and P=0.012 lamivudine vs. interferon). Six months later, HBV DNA negativity rates were 44 % with lamivudine+interferon, 33 % with lamivudine and 25 % with interferon, and serum transaminase normalization rates were 61%, 42 % and 45 %, respectively, without statistical significance. No YMDD variants were observed with lamivudine+interferon (vs. 12 % with lamivudine). The combination therapy appeared to be safe. CONCLUSION: Although viral clearance and transaminase normalization are slower with long-term lamivudine+interferon than that with lamivudine alone, the combination regimen seems to provide more lasting benefits and to protect against the appearance of YMDD variants. Studies with other regimens regarding sequence and duration are needed.

TT virus infection in patients with chronic hepatitis B and response of TTV to lamivudine

AIM: To investigate the responses of TT virus (TTV) and hepatitis B virus (HBV) to a long-term lamivudine therapy.METHODS: Sixteen patients infected with both TTV and HBV were treated with lamivudine 100 mg daily for 30 months. Blood samples were drawn at the beginning of the therapy and subsequently at month 3, 6, 9, 12 and 30.Serum TTV was quantified by real time PCR and serum HBV was detected by hybridization assay and nested polymerase chain reaction.RESULTS: TTV infection was detected in 100 % of HBV-infected patients. Loss of serum TTV DNA after one year of treatment occurred in 1/16 (6 %) patients. At the end of therapy, TTV DNA was positive in 94 % of them. The decline of HBV viremia was evident at 3 months after therapy and the response rate was 31%, 44 %, 63 %, 50 % and 50 %at month 3, 6, 9, 12 and 30, respectively.CONCLUSION: TTV replication is not sensitive to lamivudine and is highly prevalent in HBV-infected patients.

De novo combination therapy with lamivudine and adefovir dipivoxil in chronic hepatitis B patients

AIM:To investigate the appropriate time for combination therapy in HBeAg positive chronic hepatitis B(CHB) patients with decompensated cirrhosis.METHODS:Thirty HBeAg positive CHB patients with decompensated cirrhosis were enrolled in the study.All of the patients were given 48 wk combination therapy with lamivudine(LAM) and adefovir dipivoxil(ADV) .Briefly,10 patients were given the de novo combination therapy with LAM and ADV,whereas the other 20 patients received ADV in addition to LAM after hepatitis B virus(HBV) genetic mutation.RESULTS:Serum alanine aminotransferase and total bilirubin were both improved in the two groups at 4,12,24 and 48 wk after treatment.Serum albumin was also improved at 24 and 48 wk after combination therapy in both groups.The serum HBV DNA level wasstill detectable in every patient in the two groups at 4 and 12 wk after combination treatment.However,in the de novo combination group,serum HBV DNA levels in 4(40%) and 9(90%) patients was decreased to below 1×10 3 copies/mL at 24 and 48 wk after the combination treatment,respectively.In parallel,serum HBV DNA levels in 2(20%) and 8(40%) patients in the add-on combination group became undetectable at 24 and 48 wk after combination treatment,respectively.Furthermore,6(60%) patients in the de novo combination group achieved HBeAg seroconversion after 48 wk treatment,whereas only 4(20%) patients in the add-on combination group achieved seroconversion.Child-Pugh score of patients in the de novo combination group was better than that of patients in the add-on combination group after 48 wk treatment.Moreover,patients in the de novo combination group had a significantly decreased serum creatinine level and elevated red blood cell counts.CONCLUSION:De novo combination therapy with LAM and ADV was better than add-on combination therapy in terms of Child-Pugh score,virus inhibition and renal function.

Pegylated IFN-α2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

AIM： To investigate the role of pegylated-interferon （IFN）α-2b in the management of patients with lamivudineresistant chronic hepatitis B. METHODS： Twenty consecutive anti-HBe positive patients were treated with pegylated IFN α-2b （100 IJg sc once weekly） for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison. RESULTS： Nine patients （45%） had a partial virological end-treatment response; seven patients （35%） showed complete virological end-treatment response. Eight patients （40%） showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders （four out of seven patients vs none out of six patients, respectively; P=0.1）. Patients without virological endtreatment response showed significant worsening of fibrosis [median score 2 （range, 1 to 3） vs median score 3 （range, 1 to 4）], in the first and second biopsy respectively （P=0.014）, whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies （n = 5）. Nevertheless, after 12 mo of follow-up, only onepatient （5%） showed sustained virological response and only 2 patients （10%） showed sustained biochemical response. Two patients （10%） discontinued pegylated ]FN both after 6 mo of treatment due to flu-like symptoms. CONCLUSION： Pegylated IFNα-2b, when added to ongoing lamivudine therapy in patients with lamivudineresistant chronic hepatitis B, induces sustained responses only in a small minority of cases.

A 3-year clinical trial of lamivudine in treatment of patients with chronic hepatitis B

BACKGROUND: Lamivudine was approved for the treat- ment of chronic hepatitis B in China in 1999; however the long-term result has not yet been reported in detail. This clinical trial was to evaluate the long-term efficacy and safe- ty of 3-year lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepa- titis B virus (HBV). METHODS: This multi-center, randomized, double-blind, placebo controlled trial began from 1996 to 1999. A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily (322 patients) or placebo (107) for the first 12 weeks. All patients were given subsequently open labelled lamivudine 100 mg/d for a total of 156 weeks. RESULTS: After 12-week lamivudine therapy, the levels of serum HBV DNA decreased rapidly. The negativity of HBV DNA (<1.6 pg/ml) at week 12 was 92.2% in the lamivudine group, whereas it was only 14.1% in the place- bo group (P<0.01). After 1-year lamivudine treatment, 72.7% of the patients showed undetectable serum HBV DNA (<1.6 pg/ml). At the end of 3 years, serum HBV DNA continued to be substantially suppressed with a me- dian level below a detectable level in patients with non-YM- DD variant HBV, which was increased to 86 mEq/ml (bD- NA method, equivalent hybridization method 10 pg/ml) in patients with YMDD mutation. At the end of 1, 2 and 3 years, the rates of HBeAg loss were 9.5%, 16.8% and 20.0% respectively and the rates of HBeAg/anti-HBe sero- conversion were 8.3%, 11.5% and 17.3%. The rates of HBeAg loss and seroconversion were correlated with the baseline level of ALT. In patients with a baseline level of alanine transaminase (ALT)>2 × upper limit of normal (ULN) and ALT >5×ULN, the rates of HBeAg loss were 42.2% and 66.7%, and the rates of seroconversion were34.4% and 61.1% respectively (P<0.01) at the end of year 3. The levels of ALT at year 3 remained normal in 58.8% of patients whose baseline level of ALT was elevated, and in 79.1% of patients whose level of ALT was normal before treatment. YMDD mutations occurred in 12.1%, 49.7% and 70.5% of patients respectively at year 1, 2 and 3. In pa- tients with YMDD mutation, the levels of HBV DNA were increased slightly with mild to moderate elevation of ALT level. HBeAg loss and seroconversion were 20.0% and 15.1% in patients with YMDD mutation at the end of year 3, which were lower than those in non-variant patients (P<0.01). Adverse drug reactions or events varied gene- rally from mild to moderate. In 2 patients serious adverse events (fatigue and abdominal distension) were related to medication. ALT flares (ALT>5×ULN) occurred in 17 patients: 10 were YMDD mutants and 7 were non-mutants; all of them were relieved. No death occurred in the period of 3 years. CONCLUSION: Sustained inhibition of HBV replication and clinical improvement could be obtained after 3-year lamivudine therapy of good tolerance and safety.

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

BACKGROUND: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.METHODS: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.RESULTS: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).CONCLUSIONS: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.

Clinical features of chronic hepatitis B patients with YMDD mutation after lamivudine therapy

Objective: To study the clinical features of chronic hepatitis B (CHB) patients with tyrosine-methionine-aspartateaspartate (YMDD) mutation after lamivudine therapy. Methods: This investigation was a retrospective study of 63 CHB patients with YMDD mutation during lamivudine therapy. Clinical data, including period and types of YMDD mutation; hepatitis B virus (HBV) DNA levels and alanine aminotransferase (ALT) levels before and after YMDD mutation were measured. YMDD mutation in the HBV DNA polymerase gene was determined using polymerase chain reaction (PCR) and direct sequencing. HBV DNA quantification was determined using real-time PCR. Relevant serum markers of HBV were measured. The follow-up period was 12 months after YMDD mutation. Results: YMDD mutation occurred 7～44 months (median, 21.5 months) after the start of lamivudine therapy. The majority of the cases (42/63, 66.6%) had YMDD mutants detected between 12 and 24 months. Four types of YMDD mutation were observed in this study, rtL180M/M204V mutation was the predominant type (26/63, 41.3%). A proportion of patients (16/63, 25.4%; 12/63, 19.1%) had higher HBV DNA levels and ALT levels (after mutation vs before mutation),respectively. Conclusion: The majority of patients with YMDD mutants had similar or lower HBV DNA levels and ALT levels compared with baseline values. This subset of patients might have benefited from the continued lamivudine therapy. The patients with increased ALT and HBV DNA levels (breakthrough hepatitis) should benefit from the addition of a newer nucleotide analogue (e.g. adefovir).

Lamivudine resistance in children with chronic hepatitis B

Currently, although lamivudine(LAM) has a low genetic barrier, only interferon-alpha and LAM are available as a first-line treatment in children with chronic hepatitis B(CHB). LAM is a potent inhibitor of hepatitis B virusdeoxyribonucleic acid(HBV-DNA) polymerase replication by termination of the proviral HBV-DNA chain. LAM has a good safety and tolerability profile in CHB patients with hepatic decompensation. However, the main disadvantages of this HBV reverse transcriptase inhibitor are:(1) pre-existing covalently closed circular DNA cannot be eradicated by LAM, thus relapse after therapy withdrawal is frequent; and(2) although the longer LAMtreatment induced the higher seroconversion rate, the risk of viral resistance increased through the selection of YMDD(tyrosine, methionine, aspartate, aspartate) motif. Insufficient suppression of viral replication leads to the emergence of resistant strains that could result in virological breakthrough which is usually followed by biochemical breakthrough. Mutant strains affects additional resistance and cross resistance, leading to drug resistance in a significant number of CHB patients. In this case, efficacy of more powerful anti-viral agents with higher genetic barrier against development of resistance is diminished. Furthermore, strains that are resistant to LAM could bring about vaccine escape mutants, decreasing the efficacy of HBV vaccine. A more potent drug with a high genetic barrier to resistance needs to be approved as the first-line treatment option for CHB in children.

Two-year Observation of the Clinical Efficacy in Treating Chronic Hepatitis B Patients with Ganxian Recipe (肝纤方) and Lamivudine

Objective: To evaluate the clinical efficacy of Ganxian recipe (肝纤方, GXR) and lamivudine (LVD) in a two-year treatment of chronic hepatitis B (CHB). Methods: One hundred and twenty patients with CHB were randomly divided into the combinedly treated group (combined group) of 40 CHB patients who were treated with GXR combined with LVD. Another 40 CHB patients were treated with LVD alone (WM group), and still another 40 CHB patients were treated with GXR alone (TCM group). All these cases were randomly controlled and observed for two years. Results: Comprehensive efficacy: Total effective rate of the combined group (complete response and partial response) was 92.5%, while that of the WM group was 67.5% and TCM group 57.5%, respectively, with the difference between them was significant ( P <0.01); after treatment, the hepatic functions (AST, ALT, SB) of the three groups were all reduced, and the reduction in the combined group was particularly significant in comparison with the WM group or TCM group, P <0.05 or P < 0.01 respectively, suggesting that the effect in the combined group was better than that in the other two groups; the rate of tyrosine-methionine-aspartate-aspartate (YMDD) virus mutation: it was 7.5% in the combined group, 40.0% in the WM group, and 5.0% in the TCM group; liver fibrosis improvement parameter: after treatment, the results in the combined group got better than those in the other two groups. Conclusion: GXR could inhibit the appearance of YMDD after long-term application of LVD, and combined use has marked synergism.

Effect of lamivudinein in BeAg-positive chronic hepatitis B: Discordant effect on HBeAg and HBV DNA according to pretreatment ALT level

AM: To clarify differences in antiviral effect of the drug in patients with different ALT levels, we examined the changes in HBV markers in patients with high or low ALT levels with or without lamivudine treatment. METHODS: Thirty-seven HBeAg-positive patients were studied. Ten patients with ALT levels higher than 200 IU/L (group 1) and 8 patients with ALT below 200 IU/L (group 2) were treated orally with 100 mg/d of lamivudine. As untreated control, 9 patients with ALT above 200 IU/L (group 3) and 10 patients with ALT below 200 IU/L (group 4) were examined. ALT level, HBeAg/HBeAb status, and HBV DNA level were examined monthly for 11.9±0.4 mo. RESULTS: The ALT level normalized in all 10 patients of group 1, 7/8 of group 2, 4/9 of group 3, and 1/10 of group 4 within 6 mo (groups 1 vs2, P= NS; groups 1 vs 3, P= 0.002; groups 1 vs4, P<0.0001). HBV DNA fell below the detection limit in all 10 patients of group 1, 7/8 of group 2, 0/9 of group 3, and 0/10 of group 4 within 6 mo (groups 1 vs 2, P - NS). HBeAg became seronegative in 7/10 patients of group 1, 1/8 of group 2, 3/9 of group 3, and 0/10 of group 4 within 12 mo (groups 1 vs2, P= 0.02; groups 1 vs 3, P= NS). CONCLUSION: Our data suggest that HBeAg-positive patients with higher ALT levels can be considered good candidates for lamivudine therapy, probably because lamivudine accelerates the natural seroconversion of HBeAg, accompanied by HBV DNA loss, in these patients.

Serum vitamin D and vitamin-D-binding protein levels in children with chronic hepatitis B

BACKGROUND Vitamin D is an essential fat-soluble secosteroid hydroxylated by the liver to form the intermediate metabolite calcidiol{25-hydroxy vitamin D[25(OH)D]},which is a reliable indicator to investigate individual vitamin D status.Vitamin-D-binding protein(VDBP)is a multifunctional glycoprotein mainly synthesized in the liver and the major transport protein for vitamin D and its metabolites.Serum vitamin D and VDBP are both associated with hepatitis B.However,few studies have reported the relationship and clinical significance of vitamin D and VDBP with hepatitis B virus(HBV)replication and hepatic fibrosis in children with chronic hepatitis B(CHB).AIM To explore vitamin D and VDBP serum levels in children with CHB and the association of vitamin D and VDBP with HBV replication and hepatic fibrosis.METHODS We enrolled 204 children with CHB admitted to Hunan Children’Hospital in summer and autumn between 2018 and 2019 and 170 healthy controls.CHB patients included:164 hepatitis B e antigen(HBeAg)positive and 40 HBeAg negative;193 hepatitis B surface antigen(HBsAg)positive and 11 HBsAg negative;164 with detectable HBV deoxyribonucleic acid(DNA)and 40 with undetectable HBV DNA;131 with HBV genotype B and 23 with HBV genotype C;and 27 without hepatic fibrosis and 97 with hepatic fibrosis.Serum levels of 25(OH)D,VDBP,liver function markers,and other clinical parameters were collected to analyze their association with vitamin D and VDBP.Mann-Whitney U test,Kruskal-Wallis H test,or t test was used to analyze serum 25(OH)D and VDBP levels in different groups.Spearman rank correlation test was utilized to analyze the correlation of 25(OH)D and VDBP with other markers.Statistically significant factors determined by univariate analysis were further analyzed by binary multivariate logistic regression analysis.P<0.05 was considered statistically significant.RESULTS Children with CHB had lower serum 25(OH)D(56.64±17.89 nmoL/L)and VDBP[122.40(70.74-262.84μg/L)]levels than healthy controls had(P<0.001).Serum 25(OH)D and VDBP levels were significantly different among the different grades of hepatic fibrosis(P<0.05).VDBP levels in children with HBV genotype C,HBsAg,HBeAg,and detectable HBV DNA were significantly lower than those in children with HBV genotype B,no HBsAg,no HBeAg,and undetectable HBV DNA(P<0.05).Serum 25(OH)D level was negatively correlated with age and serum total bilirubin level(r=-0.396 and-0.280,respectively,P<0.001).Serum VDBP level was negatively correlated with HBV DNA(log10 IU/mL)(r=-0.272,P<0.001).Serum 25(OH)D level was not correlated with VDBP level(P>0.05).Univariate(P<0.05)and multivariate logistic regression analysis showed that low level of 25(OH)D(odds ratio=0.951,95%confidence interval:0.918-0.985)and high level of HBV DNA(odds ratio=1.445,95%confidence interval:1.163-1.794)were independently correlated with hepatic fibrosis(P<0.01).CONCLUSION Serum levels of 25(OH)D and VDBP are decreased in children with CHB.Serum VDBP level is negatively correlated with HBV replication.Low level of 25(OH)D is independently associated with hepatic fibrosis in children with CHB.There is no significant association between serum levels of 25(OH)D and VDBP.

Relationship between serum b2-microglobulin levels and virological breakthrough in HBeAg-negative chronic hepatitis B patients,under long-term treatment schedules including lamivudine

AIM: Predictive value of serum b2-microglobulin (b2m)levels for virological breakthrough (VB) in HBeAg-negative chronic hepatitis B (CHB) patients under long-term treatment schedules including lamivudine (LAM).METHODS: Serum b2m levels were calculated during treatment in 25 CHB patients under long-term LAM monotherapy (group A) and 12 patients under initial interferon plus LAM treatment followed by LAM monotherapy (group B), using the MEIA technology. We used Cox proportional hazard models in order to investigate the association between serum b2m levels and VB.RESULTS: Seven of 25 patients (28%), 9/25 (36%) and 14/25 (56%) from group A and 0/12, 2/12 (16.6%) and 3/12 (25%) from group B exhibited VB at months 12, 24 and 36 of treatment, respectively. All patients, from both groups, who did not show VB exhibited b2m elevation in mo 3. The duration of b2m elevation was significantly longer in the virological responder's subgroup from group A than the non-responder's one (7.3±2.6 vs 3.8±3.4 mo,P = 0.02). In comparison to group A patients whose b2m levels were increased at 3 mo, patients whose b2m levels were decreased had 4.6 times higher risk of experiencing VB (RR = 4.6, P = 0.024). When baseline variables were simultaneously included in the same Cox model, decreased b2m status was still associated with increased risk of VB (RR = 12.2, P = 0.03).CONCLUSION: In HBeAg-negative CHB patients under either long-term LAM monotherapy or initial combination treatment, serum b2m levels at 3 mo of treatment,compared to baseline ones, might be a predictor of risk for VB.

Antiviral efficacy of adefovir dipivoxil versus lamivudine in patients with chronic hepatitis B sequentially treated with lamivudine and adefovir due to lamivudine resistance

AIM： To compare the antiviral efficacy of adefovir （ADV） in lamivudine （LMV）-resistant patients with LMV treatment in nucleoside-naive patients, using serum samples collected sequentially during the course of treatment progressing from LMV to ADV.METHODS： Forty-four patients with chronic hepatitis B （CHB） were included. The patients were initially treated with LMV and then switched to ADV when LMV resistance developed. Antiviral efficacy was assessed by measuring the following： reduction in serum HBV DNA from baseline, HBV DNA negative conversion （defined as HBV DNA being undectable by the hybridization assay）, and HBV DNA response （either HBV DNA level ≤ 10^s copies/mL or a ≥ 2 log10 reduction from baseline HBV DNA level）.RESULTS： After two and six months of treatment, HBV DNA reduction was greater with LMV compared to ADV treatment （P = 0.021）. HBV DNA negative conversion rates were 64% and 27% after one month of LMV and ADV treatment respectively （P = 0.001）. Similarly, HBV DNA response rates were 74% and 51% after two months of LMV and ADV treatment respectively （P = 0.026）. The time taken to HBV DNA negative conversion and to HBV DNA response were both delayed in ADV treatment compared with LMV.CONCLUSION： The antiviral efficacy of ADV in LMV-resistant patients is slower and less potent than that with LMV in nucleoside-naive patients during the early course of treatment.

Combination of pegylated interferon and lamivudine for patients with chronic hepatitis B who have failed treatment

BACKGROUND: Treatment of chronic hepatitis B (CHB) alone with interferon or lamivudine alone or in combination is effective in only a small proportion of patients. Treatment of patients in whom antiviral therapy fails is challenging. This study was made to determine the efficacy of combined pegylated interferon alpha (peg-IFN) and lamivudine in patients with CHB who had failed to respond to antiviral treatment. METHODS: Twenty patients with CHB proven by liver biopsy, with ALT levels >1.5×ULN,HBV DNA levels>141 500 copies/ml, and previous treatment failure with an adequate regimen were treated with a combination of peg-IFN 1.5μg/kg and lamivudine 100 mg/day for 52 weeks and followed up for a further 24 weeks. Biochemical response was defined as normalization of ALT and DNA response as HBV DNA<141 500 copies/ml. Secondary efficacy measures included HBsAg loss, HBeAg loss and appearance of anti-HBe (in cases of HBeAg-positive patients). RESULTS: Twenty patients were treated, of whom 16 were HBeAg positive. At 52 weeks, normal ALT was seen in 10 (50%) (8 of 16 HBeAg+ and 2 of 4 HBeAg), HBV DNA response in 5 (25%) (5 of 16 in HBeAg+ and none in HBeAg-), and HBeAg loss with appearance of anti-HBe in 5 (31.3%) of the 16 HBeAg positive patients. At 76 weeks, 8 (80%) of the 10 patients with normal ALT at 52 weeks relapsed, with normal ALT only in 2 (10%) (1 of 16 HBeAg+ and 1 of 4 HBeAg-), and all 5 patients who had a DNA response at 52 weeks relapsed at 76 weeks and had no DNA response. HBeAg loss with appearance of anti-HBe was seen in 1 (6.3%) of 16 HBeAg-positive patients. None of the patients lost HBsAg. CONCLUSIONS: The combination of peg-IFN and lamivudine for 52 weeks is not effective for treatment of CHB patients with a failed treatment. New treatment strategies need to be developed.

Lamivudine therapy for children with chronic hepatitis B

AIM： To assess the effectiveness and side-effects of lamivudine therapy for children with chronic hepatitis B （CHB） who fail to respond to or have contraindications to interferon-α （IFN-α） therapy. METHODS： Fifty-nine children with CHB were treated with 100 mg lamivudine tablets given orally once daily for 12 too. Alanine aminotransferase （ALT） activity was evaluated monthly during the therapy and every 3 months after its discontinuation. HBe antigen, antiHBe antibodies, HBV DNA level in serum were evaluated at baseline and every six months during and after the lamivudine therapy. Sustained viral response （SVR） to lamivudine therapy was defined as permanent （not shorter than 6 mo after the end of the therapy）, namely ALl＂ activity normalization, seroconversion of HBeAg to anti-HBe antibodies, and undetectable viral HBV-DNA in serum （lower than 200 copies per mL）. The analysis of the side-effects of the lamivudine treatment was based upon interviews with the patients and their parents using a questionnaire concerning subjective and objective symptoms, clinical examinations, and laboratory tests performed during clinical visits monthly during the therapy, and every 3 mo after the therapy. RESULTS： ALT normalisation occurred in 47 （79.7%） patients between the first and 11^th mo of treatment （mean 4.4±2.95 mo, median 4.0 mo）, and in 18 （30.5%） of them after 2 mo of the therapy. There was no correlation between the time of ALT normalization and the children＇s age, the age of HBV infection, the duration of HBV infection, inflammation activity score （grading）, staging, ALT activity before treatment, serum HBV DNA level, and lamivudnie dose per kg of body weight. HBeAg/anti HBe seroconversion was achieved in 27.1% of cases.The higher rate of seroconversion was connected with lower serum HBV DNA level and longer duration of HBV infection. There was no connection between HBeAg/ anti HBeAb seroconversion and the children＇s age, age of HBV infection, grading, staging, ALT activity before treatment, and lamivudnie dose per kg of body weight. No complaints or clinical symptoms were observed during lamivudine therapy. Impairment of renal function or myelotoxic effect was noted in none of the patients. CONCLUSION： One year lamivudine therapy for children with chronic hepatitis B is effective and well tolerated. Seroconversion of HBeAg/HBeAb and SVR are connected with lower pre-treatment serum HBV DNA level.

Efficacy of 3 years of adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance

AIM: To study the effect of rescue monotherapy with adefovir (ADV) in patients with chronic hepatitis B (CHB) who developed drug resistance to lamivudine (LAM).

Biochemical response to lamivudine treatment in HBeAg negative chronic hepatitis B patients in Iran

AIM： To study the effect of a one-year lamivudine regimen in patients with chronic hepatitis B. METHODS： Medical records of HBeAg negative hepatitis B patients who attended a hepatitis clinic in Tehran between March 2002-March 2004 were evaluated. The patients received 100 mg lamivudine tablets once daily for at least 12 mo. Liver enzymes and complete blood count were checked at baseline and the end of treatment （12th mo） and 6 mo after discontinuation of treatment. RESULTS： Of all patients, 24 were excluded. Of 71 patients left, 58 （81.7%） were men. Mean age of the patients was 38 ± 14 years. Mean level of ALT in serum was 1437 ± 205 nkat/L at baseline with a significant reduction at the end of treatment to a mean level of 723 ± 92 nkat/L （P = 0.002）. In 38 patients （53.5%）, the ALT level was normal after one-year treatment. Five patients （7.3%） relapsed （biochemically） within 6 mo after discontinuing lamivudine therapy （the patients with good end of treatment response）. Mean level of AST in serum was 1060 ± 105 nkat/L at baseline which decreased significantly to 652 ± 75 nkat/L at the end of treatment （P = 0.002）. CONCLUSION： Over half （53.5%） of chronic hepatitis B patients with HBeAg negative have normal liver enzyme level at 12-mo lamivudine therapy.

Phase Ⅱb trial of in vivo electroporation mediated dualplasmid hepatitis B virus DNA vaccine in chronic hepatitis B patients under lamivudine therapy

AIM To assess the efficacy and safety of in vivo electroporation(EP)-mediated dual-plasmid hepatitis B virus(HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine(LAM) in patients with chronic hepatitis B. METHODS Two hundred and twenty-five patients were randomized to receive either LAM + vaccine(vaccine group, n = 109) or LAM + placebo(control group, n = 116). LAM treatment lasted 72 wk. Patients received the DNA vaccine or placebo by intramuscular injection mediated by EP at weeks 12(start of treatment with vaccine or placebo, SOT), 16, 24, and 36(end of treatment with vaccine or placebo, EOT). RESULTS In the modified intent-to-treat population, morepatients had a decrease in HBV DNA > 2 log10 IU/m L in the vaccine group at week 12 after EOT compared with the control group. A trend toward a difference in the number of patients with undetectable HBV DNA at week 28 after EOT was obtained. Adverse events were similar. In the dynamic per-protocol set, which excluded adefovir(ADV) add-on cases at each time point instantly after ADV administration due to LAM antiviral failure, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 and 28 after EOT compared with the control group. More patients with undetectable HBV DNA at week 28 after EOT in the vaccine group were also observed. Among patients with a viral load < 1000 copies/mL at week 12, more patients achieved HBeA g seroconversion in the vaccine group than among controls at week 36 after EOT, as well as less virological breakthrough and YMDD mutations. CONCLUSION The primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine could only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy.