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.

Functional cure of chronic hepatitis B-hope or hype?

Chronic hepatitis B constitutes a substantial disease burden worldwide.The steps advocated by the World Health Organization in 2016 to eradicate hepatitis B by 2030 has failed to achieve significant progress,especially with respect to immu-nization coverage and linkage to care.The lack of governmental and public awar-eness regarding the long-term implications of hepatitis B burden cause under-funding of developmental projects.The presently approved treatment modalities have limited efficacy in complete viral eradication,hence the need for newer molecules to achieve functional cure(sustained undetectable hepatitis B surface antigen(HBsAg)and hepatitis B virus DNA in peripheral blood after a finite period of therapy).However,preliminary results from trials of novel therapies show their inadequacy to achieve this end by themselves but better performance with a low baseline serum HBsAg with nucleos(t)ide analogues(NA)treatment which need to be combined with/without pegylated interferon as an immu-nomodulator.Such therapy is limited by cost and adverse events and need to show incremental benefit over the standard of care(long-term NA therapy)with respect to efficacy and drug toxicities,making the development process tenuous.Thus,while such therapies continue to be tested,strategies should still focus on prevention of transmission by non-pharmaceutical measures,vaccination and increasing linkage to care.

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.

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).

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.

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).

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.

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.

Short-term entecavir versus lamivudine therapy for HBeAg-negative patients with acute-on-chronic hepatitis B liver failure

BACKGROUND: Selection of drugs for antiviral therapy of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) remains difficult. This study was undertaken to evaluate the short-term efficacy of entecavir versus lamivudine on hepatitis B e antigen (HBeAg)-negative patients with ACLF. METHODS: The data of 182 HBeAg-negative patients with ACLF were retrospectively collected from patient profiles of the hospital. In these patients, 93 HBeAg-negative patients with ACLF were treated orally with 0.5 mg of entecavir and 89 were treated orally with 100 mg of lamivudine every day. The gender and age were matched between the two groups. Biochemical items, the model for end-stage liver disease (MELD) score, and HBV DNA level were matched at baseline between the two groups and monitored during treatment. The 3-month mortalities of the two groups were compared. RESULTS: No significant differences were found in biochemical items, MELD score, and HBV DNA level at baseline (P】0.05). HBV DNA level decreased within 3 months in both groups (P【0.05), regardless of the pretreatment MELD score. In patients with the same range of pretreatment MELD scores, treatment duration, posttreatment HBV DNA levels, percentage of HBV DNA level 【2.7 lg copies/mL, biochemical items, MELD scores and 3-month mortality were similar in the two groups (all P】0.05). Pretreatment MELD score was not related to posttreatment HBV DNA levels (P】0.05), but related to a 3-month mortality in both groups (both P【0.001).CONCLUSIONS: In HBeAg-negative patients with ACLF, the short-term efficacy of entecavir versus lamivudine was similar. The degree of pretreatment liver failure significantly affected the outcome of treatment.

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.

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.

Impact of Lamivudine plus Adefovir therapy in chronic hepatitis B Iranian patients, resistant to Lamivudine treatment alone, on disease inhibition: A pilot study

AIM: To evaluate the impact of combination therapy with Lamivudine and Adefovir for treatment of chronic hepatitis B in Lamivudine-resistant patients. METHODS: Among the 110 adult chronic hepatitis B Iranian patients whom were treated with Lamivudine, for 36 months, nineteen patients (17%) with no any biochemical and viral responses to Lamivudine alone, were selected and enrolled in the study. Due to resistancy, Adefovir was added to Lamivudine, and continued for 30 months. We measured HBV_DNA viral load and serum AST, ALT in 0, 12, 24, 30 and 0, 6, 12, 18, 24, 30 months, respectively. RESULTS: Between biochemical and viral characteristics, Repeated Measure analysis identified just biochemical markers— Aspartate Aminotransferase level (AST) (P = 0.002) and Alanine Aminotransferase level (ALT) (P = 0.007) —as predictors of response to treatment, while, viral marker—HBV DNA load—was not statistically significant (P = 0.128). CONCLUSIONS: Treatment for a long time, such as 21.5 ± 8.8 months, with Lami- vudine and Adefovir, can cause liver enzymes including AST and ALT, decreasing and being normal. But, this finding is not indicative, for HBV-DNA viral load.

Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients

BACKGROUND The clinical and histological features of chronic hepatitis B(CHB)patients who fall into the"grey zone(GZ)"and do not fit into conventional natural phases are unclear.AIM To explore the impact of varying the threshold of alanine aminotransferase(ALT)levels in identifying significant liver injury among GZ patients.METHODS This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy.The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines.GZ CHB patients were classified into four groups:GZ-A(HBeAg positive,normal ALT levels,and HBV DNA≤10^(7) IU/mL),GZ-B(HBeAg positive,elevated ALT levels,and HBV DNA<10^(4) or>10^(7) IU/mL),GZC(HBeAg negative,normal ALT levels,and HBV DNA≥2000 IU/mL),and GZ-D(HBeAg negative,elevated ALT levels,and HBV DNA≤2000 IU/mL).Significant hepatic injury(SHI)was defined as the presence of notable liver inflammation(≥G2)and/or significant fibrosis(≥S2).RESULTS The results showed that 50.22%of patients were classified as GZ,and 63.7%of GZ patients developed SHI.The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria(35 U/L for men and 25 U/L for women)can more accurately identify patients with significant liver damage in the GZ phases.In total,the proportion of patients with ALT≤40 U/L who required antiviral therapy was 64.86%[(221+294)/794].When we lowered the ALT treatment threshold to the new criteria(30 U/L for men and 19 U/L for women),the same outcome was revealed,and the proportion of patients with ALT≤40 U/L who required antiviral therapy was 75.44%[(401+198)/794].Additionally,the proportion of SHI was 49.1%in patients under 30 years old and increased to 55.3%in patients over 30 years old(P=0.136).CONCLUSION These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.

Effects of different intervention methods on psychological flexibility,negative emotions and sleep quality in chronic hepatitis B

BACKGROUND Patients with chronic hepatitis B(CHB)experience various problems,including low psychological flexibility,negative emotions,and poor sleep quality.Therefore,effective nursing interventions are required to reduce adverse events.Acceptance and commitment therapy(ACT)combined with enabling cognitivebehavioral education(ECBE)can improve patients'psychological and sleep.Therefore,we speculate that this may also be effective in patients with CHB.AIM To investigate the effects of different intervention methods on psychological flexibility,negative emotions,and sleep quality in patients with CHB.METHODS This retrospective study examined clinical and evaluation data of 129 patients with CHB.Intervention methods were divided into a conventional group(routine nursing,n=69)and a combination group(ACT combined with ECBE,n=60).We observed changes in psychological flexibility,negative emotions,sleep quality,and self-care ability in both groups.Observation items were evaluated using the Acceptance and Action Questionnaire-2nd Edition(AAQ-II),Self-Rating Anxiety Scale(SAS),Self-Rating Depression Scale(SDS),Pittsburgh Sleep Quality Index(PSQI),and Exercise of Self-Care Agency Scale(ESCA).RESULTS Compared with the conventional group,the AAQ-II score of the combined group was lower(F_(between-group effect)=8.548;F_(time effects)=25.020;F_(interaction effects)=52.930;all P<0.001),the SAS score(t=5.445)and SDS score(t=7.076)were lower(all P<0.001),as were the PSQI dimensions(tsleep quality=4.581,tfall sleep time=2.826,tsleep time=2.436,tsleep efficiency=5.787,tsleep disorder=5.008,thypnotic drugs=3.786,tdaytime dysfunction=4.812);all P<0.05).The ESCA scores for all dimensions were higher(thealth knowledge level=6.994,t self-concept=5.902,tself-responsibility=19.820,tself-care skills=8.470;all P<0.001).CONCLUSION ACT combined with ECBE in patients with CHB can improve psychological flexibility and sleep quality,alleviate negative emotions,and improve self-care.

De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis

AIM:To compare efficacy of combined lamivudine(LAM)and adefovir dipivoxil(ADV)therapy with that of entecavir(ETV)monotherapy for hepatitis B virus(HBV)-related decompensated liver cirrhosis.METHODS:A total of 120 na ve patients with HBVrelated decompensated cirrhosis participated in this study.Sixty patients were treated with combined LAM and ADV therapy(LAM+ADV group),while the other60 were treated with ETV monotherapy(ETV group)for two years.Tests for liver and kidney function,alpha-fetoprotein,HBV serum markers,HBV DNA load,prothrombin time(PT),and ultrasonography or computed tomography scan of the liver were performed every1 to 3 mo.Repeated measure ANOVA and theχ2test were performed to compare the efficacy,side effects,and the cumulative survival rates at 48 and 96 wk.RESULTS:Forty-five patients in each group were observed for 96 wk.No significant differences in HBV DNA negative rates and alanine aminotransferase(ALT)normalization rates at weeks 48(χ2=2.12 and 2.88)and96(χ2=3.21 and 3.24)between the two groups were observed.Hepatitis B e antigen seroconversion rate in the LAM+ADV group at week 96 was significantly higher in the ETV group(43.5%vs 36.4%,χ2=4.09,P<0.05).Viral breakthrough occurred in 2 cases(4.4%)by week 48 and in 3 cases(6.7%)by week 96 in the LAM+ADV group,and no viral mutation was detected.In the ETV group,viral breakthrough occurred in 1 case(2.2%)at the end of week 96.An increase in albumin(F=18.9 and 17.3),decrease in total bilirubin and in ALT(F=16.5,17.1 and 23.7,24.8),reduced PT(F=22.7 and 24.5),and improved Child-Turcotte-Pugh and the model for end-stage liver disease scores(F=18.5,17.8,and 24.2,23.8)were observed in both groups.The cumulative rates of mortality and liver transplantation were 16.7%(10/60)and 18.3%(11/60)in the LAM+ADV and ETV groups,respectively.CONCLUSION:Both LAM+ADV combination therapy and ETV monotherapy can effectively inhibit HBV replication,improve liver function,and decrease mortality.

Interferon and lamivudine combination therapy versus lamivudine monotherapy for hepatitis B e antigen-negative hepatitis B treatment:a meta-analysis of randomized controlled trials

BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos (t)ide analogue monotherapy. Therefore, combination therapy of drugs with synergistic antiviral effects was proposed to have a sustained response in these patients. We compared the effect and safety of lamivudine monotherapy and its combination with IFN including conventional interferon (CON-IFN) and pegylated interferon (PEG-IFN) for HBeAg-negative CHB patients. DATA SOURCES: A group of three independent reviewers identified 9 eligible randomized controlled trials through electronic searches (MEDLINE, OVID, EMBASE, the Cochrane Library Clinical Trials Registry, and the Chinese Medical Database), manual searches, and contact with experts. Sustained virological and biochemical responses were defined as primary efficacy measures. We performed quantitative meta-analyses to assess differences between CON-IFN plus lamivudine combination and lamivudine monotherapy groups. RESULTS: No greater sustained virological and biochemical rates were found in patients receiving CON-IFN/lamivudine combination therapy [29.1% vs. 26.7%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.65-1.50, P=0.94, and 41.8% vs. 40.3%, OR=1.13, 95% CI 0.78-1.65, P=0.51, respectively],though a reduced YMDD mutation rate was achieved in the combination group [8.39% vs. 30.0%, OR=0.16, 95% CI 0.076-0.33, P<0.001]. However, data from one PEG-IFN trial showed greater sustained virological and biochemical rates in patients receiving combination therapy [response rate 19.5% vs. 6.6%, OR=3.42, 95% CI 1.71-6.84, P<0.001 and 60.0% vs. 44.2%, OR=1.88, 95% CI 1.23-2.85, P=0.003, respectively]. CONCLUSIONS: Addition of CON-IFN to lamivudine did not improve treatment efficacy but suppressed YMDD mutation by lamivudine. Combination of PEG-IFN and lamivudine might increase the sustained response, and further clinical trials are needed for confirmation.

Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy

Patients with chronic hepatitis B are at increased risk of hepatocellular carcinoma(HCC),while the inhibition of viral replication can represent a reasonable target for HCC prevention.Interferon-αtherapy results in decreased HCC risk,which is more evident in patients with high baseline HCC risk.The majority of chronic hepatitis B patients are treated with a nucleos(t)ide analogue(NA)for several reasons including the nonsustained response after interferon-α.The effect of the first licensed and low genetic barrier NA,lamivudine,on HCC incidence,has been repeatedly evaluated.Lamivudine,compared to no treatment,reduces the HCC incidence,which may increase again in cases with lamivudine resistance.Emerging data with the currently first-line NAs,entecavir and tenofovir,suggest that they also reduce the HCC incidence.The treatment benefit in reduction of the HCC incidence is always greater in patients with high baseline HCC risk,particularly cirrhotics,and without virological remission under entecavir/tenofovir.However,the HCC risk is not eliminated even in the vast majority of patients who remain in virological remission under entecavir/tenofovir.Therefore,patients at increased baseline HCC risk should continue to undergo HCC surveillance even if they have achieved complete long-term inhibition of viral replication and improvements in liver histology.

Choice of drugs in the treatment of chronic hepatitis B in pregnancy

The selection of antiviral drugs for chronic hepatitis B(CHB) treatment in pregnancy is very difficult since none of the drugs have been approved for use in pregnancy.Transmission from mother to newborn remains the most frequent route of infection in mothers with high viral load and positive hepatitis B e antigen status,even with the use of appropriate prophylaxis with hepatitis B virus(HBV) immunoglobulin and HBV vaccination.We read from the article written by Yi et al that lamivudine treatment in early pregnancy was safe and effective.However,we could not understand why adefovir dipivoxil(ADV) was used in three pregnancy cases,since ADV has been classified as pregnancy category C.In pregnancy,telbivudine or tenofovir should be selected when the treatment of CHB is necessary,since these drugs have been classified as Food and Drug Administration pregnancy risk category B.

Data mining-based analysis of acupoint selection patterns for chronic hepatitis B infection

Background:The purpose of this study was to identify the characteristics and principles of acupoints applied for treating chronic hepatitis B infection.Methods:The published clinical studies on acupuncture for the treatment of chronic hepatitis B infection were gathered from various databases,including SinoMed,Chongqing Vip,China National Knowledge Infrastructure,Wanfang,the Cochrane Library,PubMed,Web of Science and Embase.Excel 2019 was utilized to establish a database of acupuncture prescriptions and conduct statistics on the frequency,meridian application,distribution and specific points,as well as SPSS Modeler 18.0 and SPSS Statistics 26.0 to conduct association rule analysis and cluster analysis to investigate the characteristics and patterns of acupoint selection.Results:A total of 42 studies containing 47 acupoints were included,with a total frequency of 286 acupoints.The top five acupoints used were Zusanli(ST36),Ganshu(BL18),Yanglingquan(GB34),Sanyinjiao(SP6)and Taichong(LR3),and the most commonly used meridians was the Bladder Meridian of Foot-Taiyang.The majority of acupuncture points are located in the lower limbs,back,and lumbar regions,with a significant percentage of them being Five-Shu acupoints.The strongest acupoint combination identified was Zusanli(ST36)–Ganshu(BL18),in addition to which 13 association rules and 4 valid clusters were obtained.Conclusion:Zusanli(ST36)–Ganshu(BL18)could be considered a relatively reasonable prescription for treating chronic hepatitis B infection in clinical practice.However,further high-quality studies are needed.

Current and future antiviral drug therapies of hepatitis B chronic infection

Despite significant improvement in the management of chronic hepatitis B virus(HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host's immune system. Currently the approved therapeutic regimens include pegylated-interferon(IFN)-α and monotherapy with five nucleos(t)ide analogues(NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish long-term control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection.