NUC Therapy Research Articles

Finite versus Indefinite Nucleos(t)ide Analogue Therapy of Patients with Chronic Hepatitis B Exhibiting Negative HBsAg Levels after Treatment.

Aim To determine whether a decrease in HBsAg to <0.05 IU/mL could be a criterion for cessation of finite nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). Methods This was a retrospective analysis of 6715 patients with CHB between January 1998 and May 2016. Patients were followed up every 12–24 weeks. Among 104 patients achieving HBsAg levels < 0.05 IU/mL, 71 were eligible for inclusion in the analysis: 31 received finite NUC therapy, and 40 received indefinite NUC therapy. In the finite therapy group, 9 patients received no NUC consolidation therapy, 6 received short-term (<1 year) consolidation, and 16 received long-term (>1 year) consolidation. The outcome measures were alanine aminotransferase (ALT), total bilirubin, albumin, hepatitis B virus DNA, and HBsAg levels. Results Baseline parameters and characteristics at the time when HBsAg levels had fallen to <0.05 IU/mL were similar between the finite and indefinite therapy groups. No patients experienced viral breakthrough/relapse during a median follow-up of 120 weeks. There were little or no differences in long-term outcomes between the finite and indefinite therapy groups and between the short-term and long-term consolidation groups. Conclusions Discontinuation of NUCs may be acceptable in patients whose HBsAg levels fall to <0.05 IU/mL. Consolidation therapy lasting <1 year appears adequate to prevent poor long-term prognosis.

Real-world tertiary referral centre experience stopping nucleos(t)ide analogue therapy in patients with chronic hepatitis B.

BACKGROUND: Identifying strategies for stopping nucleos(t)ide analogues (NUC) in patients with chronic hepatitis B (CHB) is a major goal in CHB management. Our study describes our tertiary-centre experience stopping nucleos(t)ide analogues (NUC) in CHB. METHODS: We conducted a retrospective cohort study of all individuals with CHB seen at the Calgary Liver Unit between January 2009 and May 2020 who stopped NUC. We collected baseline demographics and HBV lab parameters before and after stopping NUC with results stratified by off-treatment durability. Clinical flare was defined as alanine aminotransferase (ALT) over twice the upper limit of normal and virological flare as HBV DNA >2000 IU/mL. RESULTS: Forty-seven (3.5%) of the 1337 individuals with CHB stopped NUC therapy. During follow-up, six patients (12.8%) restarted NUCs because of a flare. All flares occurred within six months of discontinuation. Median time to restart treatment was 90 days (Q1 65, Q3 133). Upon restarting, all showed suppression of HBV DNA and ALT normalization. Factors associated with restarting NUC therapy included hepatitis B e antigen (HBeAg) positive status at first appointment and longer NUC consolidation therapy. Age, sex, ethnicity, liver stiffness measurement, choice of NUC, and quantitative hepatitis B surface antigen (qHBsAg) level at stopping were not associated with sustained response off-treatment. Six patients had functional cure with HBsAg loss. CONCLUSIONS: Stopping long-term NUC is feasible in HBeAg negative CHB. Hepatic flares can occur despite low levels of qHBsAg. Finite NUC therapy can be considered in eligible patients who are adherent to close monitoring and follow-up, particularly in the first six months after stopping NUC therapy.

From the Editor’s Desk...

From the Editor’s Desk...

Long-Term Effectiveness, Safety, and Patient-Reported Outcomes of Self-Administered Subcutaneous Hepatitis B Immunoglobulin in Liver Post-Transplant Hepatitis B Prophylaxis: A Prospective Non-Interventional Study.

BackgroundSelf-administered subcutaneous hepatitis B immunoglobulin (s.c. HBIg) in combination with nucleos(t)ide analogs (NUCs) has proved to be effective and safe in preventing hepatitis B virus (HBV) reinfection after liver transplantation.Material/MethodsThis non-interventional, prospective, single-arm, multicenter, international study collected data on long-term effectiveness, safety, patient satisfaction (Treatment Satisfaction Questionnaire for Medication, TSQM-11), and quality of life (EQ-5D questionnaire) in routine practice over a 2-year treatment period. Data analysis was based on 195 adults (82.1% male) transplanted for HBV-related liver diseases and treated with s.c. HBIg with/without NUC(s).ResultsHBV recurrence (seropositivity of HBV surface antigen and/or HBV DNA) was observed in 7/195 (3.6%) patients (annual rate: 2.01%). Hepatocellular carcinoma (HCC) recurred in 4/83 (4.8%) patients transplanted for HBV-HCC (annual rate: 2.88%). Twenty-nine adverse drug reactions occurred in 16/195 (8.2%) patients. Convenience and overall satisfaction scores of the TSQM-11 were significantly (P<0.05) improved under treatment at the 3-month, 2-year, and last follow-up visits. Quality of life remained constant over the entire observation period (EQ-5D index [P≥0.075]). S.c. HBIg was mainly self-administered (6458/9021 administrations, 71.6%) at home (8514/9021 administrations, 94.4%).ConclusionsThe results indicate long-term effectiveness and safety of s.c. HBIg in combination with NUC therapy in preventing post-transplant HBV reinfection under real-life conditions. The convenience of the therapy contributed to the high overall treatment satisfaction and acceptance by the patients.

Finite nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B: From an "option" to an "active recommendation".

Nucleos(t)ide analogue (Nuc) including entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide may suppress hepatitis B virus (HBV) DNA profoundly but have no direct action on covalently closed circular DNA, which is a very stable template for HBV production. Therefore, decades of long-term Nuc therapy are required to maintain HBV suppression and to achieve hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative patients. However, there are concerns including financial burden, adherence, and willingness for indefinite long-term Nuc therapy. Patients lost to follow-up and hence not monitored may risk severe relapse that may deteriorate to hepatic decompensation or even hepatic failure. Cessation of Nuc therapy in HBeAg-negative patients was initially considered in early 2000s. Earlier findings in Asian patients that finite Nuc therapy over 2-3 years is feasible and safe have founded Asian-Pacific Association for the Study of Liver stopping rule since 2008. Subsequent studies have confirmed the feasibility and safety of the strategy of finite Nuc therapy, which has finally been accepted as "an option" by American and European liver associations since 2016. More recent large studies since 2018 have further confirmed the pivotal finding of greatly increased HBsAg loss rate (~5-year 39%) after stopping Nuc therapy. With the high HBsAg loss rate as the main justification, the paradigm shift from indefinite long-term therapy to finite Nuc therapy in HBeAg-negative patients has been changing from an "option" to an "active recommendation" aiming to achieve HBsAg loss. More studies are needed to fine-tuning the strategy, including research for the optimal duration of consolidation therapy, timing to stop, and to start retreatment.

Model to predict on-treatment restoration of functional HBV-specific CD8+ cell response foresees off-treatment HBV control in eAg-negative chronic hepatitis B.

SummaryBackgroundHepatitis B virus (HBV)‐specific CD8+ cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off‐treatment HBV control in e‐antigen‐negative chronic hepatitis B (CHBe(−)).AimTo predict this response with variables involved in T‐cell exhaustion for use as a treatment stopping tool.MethodsIn NUC‐treated CHBe(−) patients, we considered a functional response in cases with HBV‐specific CD8+ cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off‐treatment follow‐up according to LRM likelihood.ResultsWe developed an LRM that predicted the presence of a proliferative type I cytokine‐secreting CD8+ cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off‐treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability.ConclusionsShort‐term low‐level antigen exposure and early long‐term NUC treatment influence the restoration of a functional HBV‐specific CD8+ cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off‐treatment HBV control and HBsAg decline and loss.

Current Trend in Antiviral Therapy for Chronic Hepatitis B.

Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.

Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels

Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p <0.001), and in patients with lower HBsAg (aHR 0.243, p <0.001) and HBV core-related antigen (HBcrAg) (aHR 0.718, p= 0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/ml) and HBcrAg (<2log vs. ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490-4.174, p= 0.001). The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal. A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core-related antigen levels as factors associated with an increased chance of HBsAg loss.

Predicting the risk of hepatocellular carcinoma in chronic hepatitis B patients receiving antiviral therapy: Validating the CAMD and AASL scores in China.

We aimed to validate the predictive value of the cirrhosis, age, male sex, and diabetes (CAMD) score and age, albumin, sex, and liver cirrhosis (AASL) score for chronic hepatitis B (CHB) patients, treated with nucleos(t)ide analogues (NUCs) in Northeast China. From January 2009 to June 2020, 945 patients diagnosed with CHB who received NUC therapy at China-Japan Union Hospital of Jilin University were included. Comprehensive medical records were retrospectively analyzed, and the predictive values of the CAMD score and AASL score for hepatocellular carcinoma (HCC) were evaluated. A total of 58 patients (5.94%) were diagnosed with HCC. Multivariate analysis revealed that age [odds ratio (OR) = 1.041, 95% confidence interval (CI) 1.009-1.073, P < 0.011] and cirrhosis (OR = 3.297, 95% CI 1.383-7.861, P < 0.007) were independent predictors of HCC. Either the CAMD or AASL score was significantly higher in the HCC group compared to the non-HCC group. The area under the receiver operating characteristic (ROC) curve (AUC) of CAMD and AASL was 0.721 (95% CI 0.663-0.780) and 0.718 (95% CI 0.662-0.774), respectively. Risk stratification using either CAMD or AASL revealed significant differences in the one-, three-, and five-year cumulative incidence rates of HCC between the low-, intermediate-, and high-risk groups (all P < 0.001, log-rank test). Both CAMD and AASL scores have predictive value for HCC risk of CHB patients in Northeast China. In future, the optimal monitoring frequency and methods should be personalized.

Association analysis of KIR/HLA genotype with liver cirrhosis, hepatocellular carcinoma, and NUC freedom in chronic hepatitis B patients

Natural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. No significant associations of KIR/HLA pairs were detected in terms of liver cirrhosis development. The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) [30.8% vs. 14.9%, odds ratio (OR) 2.53, P = 0.015]. The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusion, this study indicated remarkable associations of KIR/HLA with HCC development (KIR2DS3) and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients, although the number of cases was insufficient for statistical purposes. Additional multi-center analyses of larger groups are needed to clarify whether KIR/HLA pairs play a role in HBV patient status.

Determinants of re-compensation in patients with hepatitis B virus-related decompensated cirrhosis starting antiviral therapy.

Despite antiviral therapy, liver function often fails to recover in patients with hepatitis B virus (HBV)-related decompensated cirrhosis. To establish a prognostic model to predict re-compensation in patients starting potent nucleos(t)ide analogue (NUC) therapy METHODS: We analysed 311 consecutive patients with HBV-related decompensated cirrhosis treated with entecavir or tenofovir. The primary outcome was re-compensation, defined as recovery to a Child-Pugh score of 5. The BC2AID score was developed from a cohort of 152 subjects based on competing risk models and validated in another cohort of 159 subjects. Re-compensation occurred in 57.2% and 66.7% of the subjects in the derivation and validation cohorts, respectively. Six independent predictors for re-compensation were identified in the derivation cohort and these comprised the BC2AID score: bilirubin ≤5mg/dL (adjusted sub-distribution hazard ratio [aSHR] 2.18), absence of severe complications (aSHR 2.78), alpha-fetoprotein (AFP) ≥50ng/mL (aSHR 2.54), alanine aminotransferase ≥200IU/L (aSHR 2.62), international normalised ratio ≤1.5 (aSHR 2.37) and ≤6months from initial decompensation until initiation of NUCs (aSHR 4.79). In the validation cohort, the area under the receiver operating characteristic curve of the BC2AID score for re-compensation within 1year of NUC therapy was significantly higher than that of the Child-Pugh, MELD, MELDNa and BE3A scores (0.813 vs 0.691, 0.638, 0.645 and 0.624, respectively; all P<0.05). Six clinical parameters, including AFP and the timing of antiviral therapy, were combined into a scoring system to accurately predict early re-compensation in patients with HBV-related decompensated cirrhosis.

The Impact of Nucleos(t)ide Analogs Off-Therapy Among Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis.

Background and Aim: Although most chronic hepatitis B (CHB) patients achieve effective virological suppression after receiving long-term nucleos(t)ide analogs (Nucs) therapy, the safety of off-therapy is controversial under the monitor.Methods: We identified studies through searching PubMed, Embase, Cochrane Library, and Web of Science from January 1990 to February 2021. The eligible studies compare the long outcomes between discontinued and continued Nucs treatments groups among CHB patients. This study was conducted to investigate long-term outcomes, including biochemical, serological, and virological outcomes, as well as hepatocellular carcinoma (HCC) development rate between discontinued and maintained Nucs therapy groups among CHB patients.Results: Five eligible studies covering 1,425 patients were selected for meta-analysis. Our result exhibits that patients with Nucs off-treatment have a higher risk of alanine aminotransferase (ALT) flares-up than those who continued Nucs therapy under the monitor (OR = 9.39, 95%CI = 3.87–22.78). Nucs off-therapy patients have a higher virological bound incidence (OR = 617.96, 95%CI = 112.48–3,395.14) and a higher HBV DNA level (OR = 9.39, 95%CI = 3.87–22.78) than those who continued Nucs therapy. There was no statistically significant difference in the risk of hyperbilirubinaemia, hepatic decompensation, and HCC development between both two groups. Patients in Nucs off-therapy group demonstrate a higher HBsAg loss rate than those in the continued group (OR = 7.10, 95%CI = 6.68–13.69).Conclusions: Nucs off-therapy patients may exhibit a higher chance of achieving HBsAg loss than those who continue Nucs therapy. It requires close monitoring after Nucs off-therapy and timely restarting of Nucs therapy when ALT concentrations increase.

Discontinuation of antiviral therapy in chronic hepatitis B patients

Nucleos(t)ide analogs (NUC) are the first-line therapy for patients with chronic hepatitis B (CHB) recommended by most current guidelines. NUC therapy decreases progression of liver disease, reduces the risk of liver-related complications, and improves the quality of life of patients with CHB. Although indefinite or long-term NUC therapy is usually recommended, this strategy raises several concerns, such as side-effects, adherence, costs, and patient willingness to stop therapy. Recent data showed the feasibility, efficacy, and safety of stopping antiviral therapy in carefully selected CHB patients, leading to its incorporation in international guidelines. Patients who discontinue NUC have a higher likelihood of hepatitis B surface antigen (HBsAg) loss compared to patients who continue on therapy. Recommendations pertaining endpoints allowing safety discontinuation of NUC therapy differ among international guidelines. For hepatitis B e antigen (HBeAg)-positive patients, durable HBeAg seroconversion is considered an acceptable treatment endpoint. For HBeAg-negative patients, some guidelines propose undetectability hepatitis B virus DNA for at least 2 or 3 years, while others consider HBsAg loss as the only acceptable endpoint. CHB patients who stop therapy should remain under strict clinical and laboratorial follow-up protocols to detect and manage relapses in a timely manner. No reliable predictor of relapse has been consistently identified to date, although quantitative HBsAg has been increasingly studied as a reliable biomarker to predict safe NUC discontinuation.

Treatment Adherence to Nucleos(t)ide Analogs in Chinese Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma: A Single-Center Cross-Sectional Study.

PurposeChronic hepatitis B virus (HBV) infection is a crucial risk factor in the occurrence and development of hepatocellular carcinoma (HCC). Antiviral therapy is very important for patients with HBV-related HCC. To maintain undetectable level of HBV DNA, patients must take nucleos(t)ide analogues (NUCs) appropriately and regularly. We explored the adherence of Chinese patients with HBV-related HCC to antiviral treatment.Patients and MethodsOne-hundred and eighty-one patients were included in a cross-sectional study between August 2020 and February 2021. A structured questionnaire was used to interview patients, and a form was applied to collect data from electronic medical records. Medication adherence was measured using a visual analog scale. Data of the adherent group and non-adherent group were compared using Student’s t-test and the chi-square test. Multivariate logistic regression analysis was employed to explore independent risk factors that affected adherence behavior.ResultsHigh adherence was reported in 46.4% of patients with HBV-related HCC. Patients with high adherence were more likely to be women (P = 0.02), shun alcohol (P = 0.01), take NUCs other than entecavir (P = 0.04), and pay attention to their titer of HBV DNA (P = 0.05). Sex, alcohol consumption, and taking entecavir were independent risk factors for low adherence (P < 0.05). The prevalence of virological breakthrough was lower in patients who adhered to NUC therapy than in those who did not, but the difference was not significant (P = 0.31).ConclusionThe adherence of patients with HBV-related HCC to NUC therapy was low. More attention should be paid to adherence of antiviral therapy in patients with HBV-related HCC.

Finite Antiviral Therapy in Chronic Hepatitis B Patients with Cirrhosis.

Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.

Increasing Number of Individuals Receiving Hepatitis B nucleos(t)ide Analogs Therapy in Germany, 2008-2019.

Background: Germany is a low prevalence country for hepatitis B virus (HBV) infection with higher prevalence in vulnerable groups. The number of treated chronic hepatitis B (CHB) patients is unknown. We aimed to determine the number of CHB patients treated with nucleos(t)ide analogs (NUCs), the treatment costs within the statutory health insurance (SHI) in Germany and per patient per month.Methods: Data on pharmacy bills of NUCs to patients with SHI between 2008 and 2019 were purchased from Insight Health™ and described. Negative binomial regression was used for trend analysis.Results: Number of patients increased between 2008 and 2019 (4.9% per year) with little changes in treatment options. Overall prescription costs were increasing (6.7% per year on average) until the introduction of tenofovir and entecavir generics in 2017 after which costs decreased by 31% in 2019. Average therapy costs peaked at 498 Euro per patient per month in 2016 and decreased to 214 Euro in 2019. Prescriptions changed from 30 to 90 pills per pack over time. HBV therapy was prescribed to 97% by three medical specialist groups, mainly specialists in internal medicine (63%), followed by hospital-based outpatient clinics (20%) and general practitioners (15%). Contrary to guideline recommendation, adefovir was still prescribed after 2011 for 1–5% of patients albeit with decreasing tendency. Prescriptions per 100,000 inhabitants were highest in Berlin and Hamburg.Conclusion: Our data shows, that the number of treated CHB patients increased steadily, while NUC therapy costs decreased. We recommend continued testing and treatment for those eligible to prevent advanced liver disease and possibly decrease further transmission of HBV.

Antiviral therapy after curative treatment of hepatocellular carcinoma in patients with chronic hepatitis B infection: Is tenofovir or entecavir preferred?

Antiviral therapy after curative treatment of hepatocellular carcinoma in patients with chronic hepatitis B infection: Is tenofovir or entecavir preferred?

Hepatitis B Flare After Cessation of Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B: To Retreat or Not to Retreat.

Finite nucleos(t)ide analogue (Nuc) therapy in HBV suppressed hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B may substantially increase hepatitis B surface antigen (HBsAg) loss rate after cessation of therapy, in which "no retreatment" is a strong predictor for HBsAg loss. However, the main safety concern of no retreatment is hepatitis flare leading to hepatic decompensation or even fatality. Hence it is crucial to make retreatment decision that is not too soon to allow sufficient immune clearance facilitating further HBsAg decline towards HBsAg loss and, more importantly, not too late to prevent adverse outcomes. This review discussed and evaluated the presentations and pathogenesis of hepatitis B flare, with emphasis on issues surrounding off-Nuc hepatitis B flare in HBeAg-negative patients. The advantage and deficiency of retreatment decision based on current biochemical marker(s) alone were reviewed. The concept of immune clearance and its clinical application of combined HBsAg/ALT kinetics during hepatitis flare in the differentiation between two types of hepatitis flare were also reviewed. The utility of combined HBsAg/ALT kinetics for retreatment decision was proposed and elaborated in detail. The feasibility, application and underlying pathobiologic mechanism(s) of this approach require further investigation. Studies on the role of immunologic and/or other viral markers in retreatment decision are also needed. In conclusion, combined qHBsAg/ALT kinetics seems to be better than current biochemical marker(s) alone in the differentiation of types of hepatitis flare for better decision that retreatment is not necessary or not too soon for "host-dominating flare" to allow sufficient immune clearance response facilitating further HBsAg decline towards HBsAg loss, and not too late for "virus-dominating flare", to prevent adverse outcome such as hepatic decompensation.

The impact of hepatitis flare on HBeAg loss was effective mainly in the first year of Nucleot(s)ide therapy in chronic hepatitis B.

HBeAg loss during nucleos(t)ide analogue (Nuc) therapy is significantly higher in patients with hepatitis flare (ALT≥5-times upper limited of normal). It is not clear whether ALT level higher above the hepatitis flare leads to greater HBeAg loss rate nor its durability. This study aimed to investigate the impact of pretherapy ALT level on HBeAg loss in each year of Nuc treatment. Entecavir or Tenofovir treated HBeAg-positive chronic hepatitis B (CHB) patients were recruited consecutively. Patients with prior treatment history that experienced HBeAg seroconversion and reversion were excluded. Pretherapy age, gender, cirrhosis, genotype, ALT, HBsAg and HBV DNA levels were analysed. The hazard function was calculated for the probability of HBeAg loss in each year. Of the 290 patients, the 3-year cumulative HBeAg loss rate was 58.1%, higher in patients with hepatitis flare than those without (67.6% vs. 39.6%, P<0.001). The HBeAg loss rate in the first year correlated positively with higher ALT levels at a stepwise fashion. The hazard function in patients with hepatitis flare was 0.74 at half year, then dropped to 0.33 by the first year and was lower thereafter to a rate closer to that of the patients without hepatitis flare. In conclusion, the impact of pretherapy ALT levels on HBeAg loss rate was not long-lasting and was effective mainly in the first year of Nuc therapy. Strategies such as adding an immune-modulating agent may help enhance HBeAg loss rate after the first year of Nuc therapy for those who remained HBeAg positive. Word count: 249 (<250).

Early and late recurrence of surgically resected hepatitis B virus-related hepatocellular carcinoma on nucleos(t)ide analogues therapy

Hepatocellular carcinoma (HCC) is a highly recurrent tumor. Antiviral therapy with nucleos(t)ide analogues (NUCs) may reduce the risk of recurrence in hepatitis B virus (HBV)-related HCC. The risk factors associated with recurrence in HCC patients after surgical resection and with NUCs treatment should be delineated. Consecutive 339 HBV-related HCC patients receiving surgical resection of HCC with NUCs therapy (including 256 entecavir, 36 tenofovir, and 18 lamivudine) after the surgery were retrospectively reviewed. Factors related to the recurrence-free survival (RFS) and overall survival (OS) were evaluated. After a median of 48.5 months of follow-up, 183 (54%) patients developed HCC recurrence, with the 5-year RFS of 42.8% and OS of 79%. Male gender (HR=1.736, p=0.037), baseline HBsAg level >200 IU/ml (HR=1.748, p=0.008), platelet count ≦100 (109/L) (HR=1.592, p=0.023), presence of microscopic vascular invasion (MVI) (HR=1.499, p=0.026), safety cut margin of ≦0.5cm (HR=1.507, p=0.013), and Ishak fibrosis score 5-6 (HR=1.579, p=0.009) were independent factors associated with RFS in multivariate analysis. While tumor burden, platelet count, MVI, and safety cut margin were factors associated with early recurrence; baseline HBsAg level, and platelet count were independent factors associated with late recurrence. Ishak fibrosis score 5-6, poor differentiation, MVI, diabetes mellitus were factors associated with OS in multivariate analysis. For HBV-HCC patients on NUCs treatment, tumor factors are associated with early recurrence, while HBsAg level and thrombocytopenia determines late recurrence. For patient with a high baseline HBsAg level, warning of higher risk of recurrence is required even under NUCs treatment.