Early clinical efficacy of pegylated interferon treatment in patients with different phases of chronic HBV infection: A real-world analysis.

Although there are therapeutic advantages for hepatitis B virus (HBV) withpegylated interferon alpha (peg-IFNα) treatment compared with nucleos(t)ide analog (NAs) therapy, the effect difference in infected population at different phases has not been well established. We studied the clinical efficacy of peg-IFNα in two populations with HBV infection, including inactive HBsAg carrier (IHC) and chronic hepatitis B (CHB). A total of 328 HBV-infected patients were included in this real-world analysis. Patients were divided into two groups according to the infected stages. Peg-IFNα monotherapy or combination therapy with NAs were used in IHCs, and peg-IFNα added-on NAs therapy was applied to patients with CHB. The primary efficacy endpoint was HBsAg loss at Week 24. Results: The Kaplan-Meier cumulative rates of HBsAg loss were 39.50% (n = 47/119) in IHC group and 28.71% (n = 60/209) in CHB group at Week 24 (p < .05). After Propensity Score Matching (PSM), the HBsAg loss rates were 36.84% (n = 35/95) and 32.63% (n = 31/95), respectively (p > .05). Patients with baseline HBsAg level < 100 IU/ml achieved higher rates of HBsAg clearance in IHC and CHB group (before PSM: 47.44% vs. 42.86%, after PSM: 49.12% vs. 45.83%, all p values > .05). Baseline HBsAg level and its level decline from baseline to Week 12 can be as the predictors for HBsAg loss at Week 24 in both groups. Hence, the efficacy of HBsAg clearance was broadly similar between IHCs and NA-treated CHB patients during the early peg-IFNα therapy. A significant downward trend of HBsAg level was observed in both groups during peg-IFNα therapy.

Risk factors for hepatocellular carcinoma at baseline and 1 year after initiation of nucleos(t)ide analog therapy for chronic hepatitis B.

Nucleos(t)ide analogs (NAs) cannot completely suppress the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to identify the risk factors for HCC development in naïve CHB patients treated with current NA. Patients receiving NA (n = 905) were recruited retrospectively from the 17 hospitals of the Japanese Red Cross Liver Study Group. All treatment-naïve patients had been receiving current NA continuously for more than 1 year until the end of the follow-up. We analyzed the accuracy of predictive risk score using the area under receiver operating characteristic curve. The albumin-bilirubin (ALBI) score was significantly improved by NA therapy (-0.171 ± 0.396; p < 0.001 at Week 48). A total of 72 (8.0%) patients developed HCC over a median follow-up of 6.2 (1.03-15.7) years. An independent predictive factor of HCC development was older age, cirrhosis, lower platelet counts at baseline and ALBI score, and alpha-fetoprotein (AFP) at 1 year after NA therapy according to multivariate analysis. The accuracy was assessed using the PAGE-B, mPAGE-B, aMAP, APA-B, and REAL-B scores that included these factors. Discrimination was generally acceptable for these models. aMAP and REAL-B demonstrated high discrimination with 0.866/0.862 and 0.833/0.859 for 3- and 5-year prediction from the status of 1 year after NA therapy, respectively. Baseline age and platelet count, as well as ALBI and AFP one year after NA, were useful for stratifying carcinogenesis risk. The aMAP and REAL-B scores were validated with high accuracy in Japanese CHB patients.

Outcome of nucleos(t)ide analog cessation in patients with treatment for prevention of or against hepatitis B virus reactivation.

AIM: We retrospectively investigated patients with administration of nucleos(t)ide analogs (NAs) for prevention of or against hepatitis B virus (HBV) reactivation, and their clinical outcomes after cessation of the NA. METHODS: We enrolled 180 patients who were positive for HBsAg when they started immunosuppressive therapy or chemotherapy and an NA was administered to prevent HBV reactivation (HBV carrier group), and 82 patients with resolved HBV infection who started administration of an NA after HBV reactivation (de novo HBV group). Cessation of the NA depended on each physician's judgment without definite criteria. RESULTS: A total of 27 patients in the HBV carrier group and 22 in the de novo HBV group stopped NA therapy. In the HBV carrier group, 16 patients experienced virological relapse, which was defined as HBV DNA levels ≥20 IU/ml, and one with hematological disease had an alanine aminotransferase flare after cessation of NA. Of the 16 patients, the NA was reintroduced in three, whereas, the remaining 13 had low levels of HBV DNA and no alanine aminotransferase flare. In the de novo HBV group, virological relapse occurred in six patients, and one with hematological disease had an alanine aminotransferase flare after cessation of the NA. The NA was reintroduced in four of the six patients. CONCLUSIONS: We may be able to consider to cease NA therapy proactively in HBV carriers and resolved patients with non-hematological disease, if their primary diseases are under remission after completion of immunosuppressive therapy or chemotherapy. However, careful follow up is necessary after stopping NA therapy.

Possible biological mechanisms of entecavir versus tenofovir disoproxil fumarate on reducing the risk of hepatocellular carcinoma.

Hepatitis B virus (HBV) is a life-threatening infectious virus associated with the risk of liver failure and hepatocellular carcinoma (HCC). Regarding HBV treatment, the recent development of nucleoside/nucleotide analogs (NUC), HBV reverse transcriptase inhibitors, enabled favorable viral control as well as improved prognosis in patients with chronic hepatitis B. However, NUC fails to clear HBV because the formation of covalently closed circular DNA or HBV surface antigen occurs upstream of the point of action of NUC. Recently, we found that acyclic nucleoside phosphonates (ANP) such as adefovir or tenofovir, but not lamivudine or entecavir, induced IFN-λ3 productions in the gastrointestinal tract and modulated lipopolysaccharide (LPS)-mediated cytokine profiles in peripheral blood mononuclear cells, such as interleukin (IL)-12p70 induction and IL-10 inhibition, which are immunologically favorable cytokine profiles for HBV elimination. Furthermore, IFN-α, in combination with ANP, showed additional and synergistic effects on IFN-λ3 and IL-12p70 production, respectively, while not affecting IL-10 levels. Mechanistic analyses of the cytokine modulation by ANP revealed that ANP blocked the mammalian target of the rapamycin (mTOR) pathway by inhibiting Akt translocation to the plasma membrane, thereby inhibiting Akt phosphorylation. As it has been reported that IFN-λ inhibits tumor growth directly or indirectly and the mTOR pathway is generally activated in most cancer cells, ANP might have potential anti-HCC effects. Our in vitro and ex vivo findings might stir the debate on whether types of NUC affect the risk of HBV-related HCC incidence.

Management of hepatitis B virus (HBV) reactivation in patients with resolved HBV infection based on a highly sensitive HB core-related antigen assay.

AIMS: To prevent hepatitis B virus (HBV) reactivation-related hepatitis, we examined the clinical usefulness of a highly sensitive HB core-related antigen (iTACT-HBcrAg) assay in patients with resolved HBV infection after nucleos(t)ide analog (NA) treatment for HBV reactivation. METHODS: We retrospectively analyzed 27 patients with resolved HBV infection who experienced HBV reactivation (defined as HBV DNA levels of 1.3 log IU/ml or more), and who received systemic chemotherapies for hematological malignancies between 2008 and 2020. iTACT-HBcrAg, HBsAg-HQ, and antibodies against hepatitis B surface antigen (anti-HBs) were measured using samples stored after HBV reactivation. The lower limit of quantification for iTACT-HBcrAg was 2.0 log U/ml. RESULTS: HBV reactivation was diagnosed at a median HBV DNA level of 1.8 log IU/ml, and then all patients received NA treatment. No patient had HBV-related hepatitis with a median maximum HBV DNA level of 2.0 log IU/ml. The positivities of iTACT-HBcrAg and HBsAg-HQ were 96% and 52% after HBV reactivation, respectively. Of 25 patients with detectable iTACT-HBcrAg at the initiation of NA treatment, 17 (68%) achieved iTACT-HBcrAg loss. Median durations from NA treatment to HBV DNA loss and iTACT-HBcrAg loss or the last follow-up were 35 and 175 days, respectively. Recurrence of HBV reactivation after NA cessation was not observed in seven of eight patients who achieved iTACT-HBcrAg loss or seropositive for anti-HBs during follow-up, except for one without anti-HBs after allogeneic transplantation. CONCLUSIONS: iTACT-HBcrAg could be a potential surrogate marker for diagnosing early-stage HBV reactivation as well as safe cessation of NA treatment in patients with resolved HBV infection after HBV reactivation.

Changes of cytokine levels and T cell surface molecules in patients with chronic hepatitis B and the association with functional cure.

This study aimed to examine changes in levels of cytokine and T cell surface molecules in chronic hepatitis B (CHB) patients receiving sequential interferon therapy following 1-year nucleos(t)ide analogs (NAs) treatment. Cytokine levels were measured in 30 patients, and T cell surface molecule expression was measured in 48 patients receiving sequential interferon therapy and 24 patients only receiving NA mono-therapy. An HBsAg titer of <0.05 IU/ml was defined as a "functional cure." In the cured group (HBsAg < 0.05 IU/ml), a decreasing probability was observed in IFN-γ (after Week 0), and IL-22 and IP-10 (after Week 12). In the non-cured group (HBsAg ≥ 0.05 IU/ml), a probability of slightly decreasing was observed for IFN-γ (after Week 12), and a probability of increasing IP-10 concentration (after Week 0) was observed. Generalized estimating equation (GEE) analyses showed significant differences in the levels of IL-10, IL-23, CCL-3, IL-1ß, IL-2, and IL-12P70 between the two groups. In GEE analysis, there were significant differences in expressions of CD45RO+ between the cured group and the non-cured group. The frequencies of T cells expressing Tim-3, CD62L, and CD152 were significantly lower in the sequential interferon therapy group than in the NA mono-therapy group. Changes in cytokine levels (IFN-γ, IP-10, IL-10, IL-23, CCL-3, IL-1ß, IL-2, and IL-12P70) and T cell surface molecules (CD45RO+ ) may predict HBsAg seroconversion in CHB patients receiving sequential interferon therapy. The period from Weeks 12 to 24 during sequential interferon therapy may be a critical time of immune status change.

Factors associated with non-compliance with breastfeeding recommendation: a retrospective survey in hepatitis B virus-infected mothers who had taken Nucleos(t)ide analogs during pregnancy.

BACKGROUND: We encourage Hepatitis B virus-infected mothers to breastfeed postpartum, even when continuing pregnancy category B nucleos(t)ide analogs (NAs) treatment. However, a large proportion of the Hepatitis B virus-infected mothers were noncompliant with this breastfeeding recommendation. This study aimed to investigate the factors associated with noncompliance with breastfeeding recommendation in Hepatitis B virus-infected mothers who had received NAs treatment during pregnancy. METHODS: A total of 155 mothers with chronic hepatitis B receiving NAs treatment for preventing mother-to-child transmission during the late gestation period were included and divided into exclusive breastfeeding (n = 63), mixed feeding (n = 34), and artificial feeding (n = 58) groups according to the postpartum feeding methods. Independent variables associated with feeding methods were analyzed using logistic regression analysis. RESULTS: Compared to the breastfeeding and mixed feeding groups, the artificial feeding group had significantly more multiparity, later postpartum timing of stopping NAs treatment, and a lower proportion of having knowledge of NAs medications (all P < 0.05). In addition, multivariable logistic regression analysis confirmed that multiparity, later postpartum timing of stopping NAs treatment, and lacking knowledge of medication were independent factors associated with noncompliance with breastfeeding recommendation. CONCLUSIONS: Hepatitis B virus-infected mothers who stopped NAs treatment at late postpartum period or had less knowledge of medication were more likely to be noncompliant with breastfeeding recommendation. Strengthening health education for participants taking NAs may be an important method to improve compliance with breastfeeding recommendation.

[Clinical significance and management strategies of low-level viremia during the treatment of chronic hepatitis B].

Chronic hepatitis B and its related complications seriously endanger the lives and health of our country people. Although the first-line nucleos(t)ide analogs such as entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide fumarate can inhibit virus replication to a certain extent, delay or prevent disease progression, and reduce the incidence of hepatitis B-related liver cancer, but in clinical practice, HBV DNA positivity is still detected continuously or intermittently in the serum of some patients. Therefore, low-level viremia has received widespread attention and triggered discussion, and has become the difficulties and hotspot of antiviral treatment of chronic hepatitis B. This article summarizes and discusses the definition and incidence in line with the main guidelines and studies, impact of disease control and clinical prognosis, and the current treatment options in order to provide definite reference for the management of low-level viremia during antiviral therapy in patients with chronic hepatitis B.

Serum Mac-2-Binding Protein Glycosylation Isomer at Virological Remission Predicts Hepatocellular Carcinoma and Death in Chronic Hepatitis B-Related Cirrhosis.

BACKGROUND: To investigate serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels in predicting hepatocellular carcinoma (HCC) and mortality at virological remission (VR, HBV DNA <20 IU/mL) following antiviral therapy in chronic hepatitis B (CHB) patients with cirrhosis. METHODS: This retrospective cohort study included patients with CHB-related Child-Pugh A cirrhosis undergoing long-term antiviral therapy. Serum M2BPGi levels were quantified and multivariable Cox proportional hazards regression models were used to identify risk predictors for HCC and death. RESULTS: A total of 126 and 145 patients were included in the derivation and validation cohorts, respectively. The mean age was 56, and the mean M2BPGi level was 1.86 cut-off index (COI) in the derivation cohort. After adjustment for confounders, a higher M2BPGi level at VR significantly predicted HCC (hazard ratio [HR]: 1.58, 95% confidence interval [CI]: 1.19-2.10, P=0.002) and death (HR: 2.17, 95% CI: 1.02-4.62, P=0.044). The M2BPGi ≥3 COI significantly increased the risk of HCC and death in the derivation and validation cohorts. Serial M2BPGi levels declined significantly (P=0.0001) in non-HCC patients only, and remained significantly lower than those who developed HCC afterwards (P=0.039). CONCLUSIONS: Serum M2BPGi levels at antiviral therapy-induced VR predict HCC development and death in patients with CHB-related Child-Pugh A cirrhosis.

Histological response to combination therapy with nucleos(t)ide analogs and peginterferon alpha in treatment-naïve chronic hepatitis B patients.

Although nucleos(t)ide analog (NA) monotherapy is effective in hepatitis B virus suppression and fibrosis regression, serological response rates are not satisfactory. Studies assessing the benefits of combination therapy with NAs and peginterferon alpha (PegIFNα) in patients with chronic hepatitis B (CHB) have produced conflicting results and mainly focused on serological outcomes. Histological changes in response to combination therapy have not been evaluated in real-world practice. This study aimed to evaluate the histological changes in response to NA-PegIFNα combination therapy in CHB patients and to comprehensively compare the efficacy of NA-PegIFNα combination therapy and NA monotherapy. We conducted a retrospective analysis of data from 40 CHB patients who underwent either NA-PegIFNα combination therapy or NA monotherapy. Changes in histology at 48 weeks after treatment initiation were evaluated. Serological characteristics were also analysed and compared between the NA-PegIFNα combination therapy and NA monotherapy groups and between histological responders and nonresponders. Compared to baseline biopsies, both fibrosis staging and necroinflammatory grading scores were significantly lower in the second biopsies examined post-treatment in both groups. Nearly all patients experienced a reduction in inflammation (87.5% in both groups), but there was a subgroup of patients who exhibited either no significant improvement or fibrosis progression (33.3% and 31.2% in the NA monotherapy and NA-PegIFNα combination therapy groups, respectively). Nearly, all patients achieved ALT normalization and sustained virological response (SVR) after 48 weeks of antiviral treatment. Approximately one-third of individuals (36.8% and 30% in the two groups, respectively) achieved HBeAg loss at 48 weeks after treatment initiation. Although there were no significant differences in overall rates of histological, biochemical, virological and serological responses between the two groups, an earlier virological response and a higher cumulative SVR rate over time were observed during long-term follow-up in patients treated with NA-PegIFNα combination therapy (P = 0.0129). Trends of more rapid HBeAg loss and a higher cumulative HBeAg loss rate throughout long-term follow-up were also observed but were not statistically significant. The ALT normalization rates at 24 and 48 weeks after treatment initiation were associated with the histological response. Significant regression of fibrosis and resolution of necroinflammation were induced with either NA-PegIFNα combination therapy or NA monotherapy. Significant biochemical, virological and serological responses were observed in both groups, and the response rates at 48 weeks were similar in the two groups. Over time during long-term follow-up, the virological and serological responses were faster and superior following the combination regimen.

Switching to tenofovir disoproxil fumarate vs continuing treatment in patients with chronic hepatitis B who maintain long-term virological response to entecavir therapy: A randomized trial.

No controlled trial in patients with chronic hepatitis B virus (HBV) infection on long-term entecavir (ETV) treatment, comparing switching to tenofovir disoproxil fumarate (TDF) with continuing the therapy, has been reported. Twenty-seven nucleos(t)ide-naïve patients with chronic HBV who underwent ETV therapy for ≥5 years and maintained virological response were included and randomized into two groups: one group continued ETV, and the other switched to TDF, in a 1:2 ratio. The primary endpoint was changed from baseline in serum hepatitis B surface antigen (HBsAg) level at week 48. The baseline characteristics were not different between nineteen patients in the TDF group and eight patients in the ETV group. Mean decreases in HBsAg level at week 48 were 0.023 and 0.042 log10 IU/mL in the TDF and ETV groups, respectively (P = 0.94). The mean drops in hepatitis B core-related antigens were also not different between the TDF and ETV groups at week 48 (P = 0.80). HBV DNA was sustainedly <2.1 log 10 copies/mL in all patients throughout the study period. In contrast, the mean aminotransferase levels were significantly higher in the TDF group than in the ETV group at weeks 12, 24, and 36, although being within the reference range. Estimated glomerular filtration rate was lower in the TDF group than in the ETV group at weeks 24 (P = 0.016) and 48 (P = 0.003). In conclusion, we could not find the effect on reducing HBsAg level by switching to TDF in chronic hepatitis B patients with maintained virological response to ETV for ≥5 years.

2'-Fluoro-6'-methylene carbocyclic adenosine and its phosphoramidate prodrug: A novel anti-HBV agent, active against drug-resistant HBV mutants.

Chronic hepatitis B (CHB) is one of the major causes of morbidity and mortality worldwide. Currently, clinically approved nucleos(t)ide analogs (NAs) are very efficient in reducing the load of hepatitis B virus (HBV) with minimum side effects. However, the long-term administration of antiviral drugs promotes HBV for potential drug resistance. To overcome this problem, combination therapies are administered, but HBV progressively altered mutations remain a threat. Therefore, optimally designed NAs are urgently needed to treat drug-resistant HBV. Herein, 2'-fluoro-6'-methylene carbocyclic adenosine (FMCA) and its phosphoramidate (FMCAP) have been discovered, which may be utilized in combination therapies for curing drug-resistant chronic hepatitis B. In preclinical studies, these carbocyclic NAs demonstrated potential anti-HBV activity against adefovir, as well as lamivudine (LMV/LAM) drug-resistant mutants. In vitro, these molecules have demonstrated significant activity against LMV/entecavir (ETV) triple mutants (L180M + S202G + M204V). Also, preliminary studies of FMCA/FMCAP in chimeric mice and female Non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models having the LMV/ETV triple mutant have shown a high rate of reduction of HBV DNA levels compared to ETV. In this review, we have summarized preclinical studies of FMCA and its phosphoramidate prodrug (FMCAP).

Risk factors for exacerbation of gastroesophageal varices and portosystemic encephalopathy during treatment with nucleos(t)ide analogs for hepatitis B virus-related cirrhosis.

AIM: The aim of this study was to determine the risk factors for worsening of gastroesophageal varices (GEVs) and development of portosystemic encephalopathy in patients with hepatitis B virus (HBV)-related cirrhosis during nucleos(t)ide analog (NA) treatment. METHODS: One hundred and thirty-seven patients with HBV-related cirrhosis were enrolled in this retrospective cohort study. Findings of portal hemodynamics with computed tomography, liver function, and endoscopic examinations during NA treatment were assessed. RESULTS: Among 137 patients, feeding vessels for GEVs (left gastric vein, posterior gastric vein, and short gastric vein) were present in 56 (41%) patients, and extrahepatic portosystemic shunt (paraesophageal vein, paraumbilicul vein, and splenorenal shunt) were present in 36 (26%) patients at the start of NA treatment. Although NA treatment was successful, significant improvements were not observed in portosystemic collateral vessels 3 years after NA treatment and GEVs were exacerbated in 48 (35%) patients. The cumulative 5- and 10-year exacerbation rate of GEVs was 27% and 50%, respectively. By multivariate analysis, the existence of feeding vessels for GEVs at the start of NA treatment was the independent predictive factor for the exacerbation of GEVs (P < 0.001). Eight patients who had extrahepatic portosystemic shunt at the start of NA treatment developed portosystemic encephalopathy during follow-up. The 3- and 5-year incidence of that was 5% and 8%, respectively. CONCLUSIONS: The presence of portosystemic collateral vessels at the start of NA treatment increases the risk of GEVs worsening and development of portosystemic encephalopathy in patients with HBV-related cirrhosis, despite improvement of liver function and success in reducing viral loads with NA treatment.

Pronounced decline of serum HBsAg in chronic hepatitis B patients with long-term effective nucleos(t)ide analogs therapy.

AIMS: This study aims to investigate the kinetics of serum HBsAg levels in chronic hepatitis B patients with long-term nucleos(t)ide analogs (NAs) therapy. METHODS: This was a retrospective clinical study. Serum HBsAg in serial samples of 94 patients, who received at least 8 years of NAs therapy, were measured using Elecsys® HBsAg II Quant Assay. RESULTS: In this cohort, serum HBsAg levels reduced from 3.80 log10 IU/mL at baseline to 2.72 log10 IU/mL at year 8 (p < .001), and the percentage of patients with HBsAg <1000 IU/mL increased from 14.9% at baseline to 55.3% at year 8 (p < .001). The reduction of serum HBsAg did not differ significantly between patients stratified by baseline virological parameters and type of antiviral agents. But as compared to patients without HBeAg seroconversion, HBsAg levels were significant lower in patients with HBeAg seroconversion (3.19 vs. 2.47 log10 IU/mL at year 8, p = .001). As compared to patients with slow (0-1 log10 IU/mL) or steady HBsAg(≤0 log10 IU/mL) decline at year 1, patients with a rapid HBsAg (≥1 log10 IU/mL) decline had a significantly lower HBsAg levels from year 2 to 8. However, Cox regression analysis showed that only absolute HBsAg levels at year 1 was an independent predictor of subsequent HBsAg <1000 IU/mL at year 8 of antiviral therapy(HR 0.242, p = .004). CONCLUSION: Pronounced HBsAg declines could be achieved in patients after long-term effective therapy with NAs, and on-treatment low serum HBsAg level at year 1 might be a predictor of serum HBsAg <1000 IU/mL at year 8.

Time-varying serum gradient of hepatitis B surface antigen predicts risk of relapses after off-NA therapy.

BACKGROUND: The serum gradient of hepatitis B surface antigen (HBsAg) varies over time after cessation of nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB). The association between the time-varying HBsAg serum gradient and risk of relapse has not been elucidated. METHODS: This multicenter cohort study prospectively enrolled CHB patients who discontinued 3 year-NA treatment. Eligible patients were serologically negative for HBeAg and viral DNA at NA cessation. The participants (n = 140) were followed every 3 months through HBsAg quantification. Virological and clinical relapses were defined as viral DNA levels >2000 IU/mL and alanine aminotransferase (ALT) levels >80 U/mL, respectively. The association of time-varying HBsAg levels with relapses was assessed through a time-dependent Cox analysis. RESULTS: During a median follow-up of 19.9 (interquartile range [IQR], 10.6-25.3) months, virological and clinical relapses occurred in 94 and 49 patients, with a 2-year cumulative incidence of 79.2% (95% confidence interval [CI], 70.9%-86.4%) and 42.9% (95% CI, 34.1%-52.8%), respectively. The serum level of HBsAg was associated with virological (P < 0.001) and clinical (P = 0.01) relapses in a dose-response manner, with adjusted hazard ratios of 2.10 (95% CI, 1.45-3.04) and 2.32 (95% CI, 1.28-4.21). Among the patients (n = 19) whose HBsAg levels ever dropped below 10 IU/mL, only one and three patients subsequently developed clinical and virological relapses. CONCLUSION: The serum gradient of HBsAg measured throughout the off-therapy observation is associated with the subsequent occurrence of virological and clinical relapses in CHB patients who discontinue NA treatment.

Clinical characteristics and outcomes of patients with recurrent chronic hepatitis B after nucleos(t)ide analog withdrawal with stringent cessation criteria: A prospective cohort study.

AIM: The aim of this study was to explore the clinical characteristics and outcomes of patients with recurrent chronic hepatitis B meeting the cessation criteria outlined by the 2008 Asian Pacific Association for the Study of the Liver guidelines. METHODS: In total, 223 chronic hepatitis B patients who met the cessation criteria and discontinued nucleos(t)ide analog therapy were prospectively included. They were monitored monthly during the first 4 months and every 3-6 months thereafter. Early relapse was defined as viral relapse (serum hepatitis B virus [HBV] DNA >104 copies/mL) confirmed within 3 months after cessation. RESULTS: Of the 38 hepatitis B e antigen (HBeAg)-positive relapse cases, 44.7%, 65.8%, 76.3% and 89.5% occurred within 3 months, 6 months, 12 months, and 48 months, respectively; in the 49 HBeAg-negative relapse cases, 44.9%, 51.0%, 77.6% and 91.8% occurred within 3, 6, 12 and 36 months, respectively. Time to undetectable HBV DNA was a predictive factor of early relapse. Viral relapses were accompanied by elevated alanine aminotransferase in 70 (80.5%) patients. A peak alanine aminotransferase 10 times over the upper limit of normal after relapse was observed in 15.8% of the HBeAg-positive and 22.4% of the HBeAg-negative patients. Hepatic decompensation and liver failure were not observed. CONCLUSIONS: For HBeAg-positive and HBeAg-negative patients meeting stringent cessation criteria, at least 4 years and 3 years of close follow-up are necessary. For those with a longer time to undetectable HBV DNA, more attention should be paid to the early stages after cessation. Nucleos(t)ide analog withdrawal in selected non-cirrhotic patients is generally safe, although close monitoring and timely intervention are needed.

Long-term outcomes of hepatitis B virus-related cirrhosis treated with nucleos(t)ide analogs.

BACKGROUND/PURPOSE: This study aimed to evaluate the outcomes of chronic hepatitis B patients with cirrhosis who received long-term nucleos(t)ide analog therapy. METHODS: A total of 546 consecutive cirrhotic patients treated with entecavir (n = 359), telbivudine (n = 104), or tenofovir (n = 83) for chronic hepatitis B were enrolled. The incidence of hepatocellular carcinoma (HCC) and overall survival were evaluated. RESULTS: During a median follow-up of 39 months, 56 (10.3%) patients developed HCC and 14 (2.6%) patients died. These outcomes were not associated with different antiviral use. Cox proportional hazard analysis showed that old age (≥60 years) [hazard ratio (HR), 1.74; p = 0.046], statin use (HR, 2.42; p = 0.017), low platelet count (<100,000/µL; HR, 2.00; p = 0.039), and variceal bleeding history (HR, 5.12; p < 0.001) were independent factors for HCC development. With regard to survival, Child-Pugh B/C (HR, 3.78; p = 0.039) and low platelet count (<105/µL; HR, 7.82; p = 0.049) were independent factors. The estimated glomerular filtration rate significantly increased in patients receiving telbivudine (p = 0.047), but decreased in those receiving tenofovir (p < 0.001) at Year 2. Tenofovir use (HR, 1.98; p = 0.005) was one of the independent factors associated with the progression of chronic kidney disease stage. CONCLUSION: Long-term nucleos(t)ide analog therapy does not guarantee against the HCC development and mortality in chronic hepatitis B-related cirrhotic patients. Careful HCC surveillance is necessary in patients with old age, statin use, low platelet count, and variceal bleeding history.

Combined Analysis of the Prevalence of Drug-Resistant Hepatitis B Virus in Antiviral Therapy-Experienced Patients in Europe (CAPRE).

BACKGROUND: European guidelines recommend treatment of chronic hepatitis B virus infection (CHB) with the nucleos(t)ide analogs (NAs) entecavir or tenofovir. However, many European CHB patients have been exposed to other NAs, which are associated with therapy failure and resistance. The CAPRE study was performed to gain insight in prevalence and characteristics of NA resistance in Europe. METHODS: A survey was performed on genotypic resistance testing results acquired during routine monitoring of CHB patients with detectable serum hepatitis B virus DNA in European tertiary referral centers. RESULTS: Data from 1568 patients were included. The majority (73.8%) were exposed to lamivudine monotherapy. Drug-resistant strains were detected in 52.7%. The most frequently encountered primary mutation was M204V/I (48.7%), followed by A181T/V (3.8%) and N236T (2.6%). In patients exposed to entecavir (n = 102), full resistance was present in 35.3%. Independent risk factors for resistance were age, viral load, and lamivudine exposure (P < .001). CONCLUSIONS: These findings support resistance testing in cases of apparent NA therapy failure. This survey highlights the impact of exposure to lamivudine and adefovir on development of drug resistance and cross-resistance. Continued use of these NAs needs to be reconsidered at a pan-European level.

The long-term benefits of nucleos(t)ide analogs in compensated HBV cirrhotic patients with no or small esophageal varices: A 12-year prospective cohort study.

BACKGROUND & AIMS: Esophageal varices (EV) are a marker of disease severity in compensated cirrhosis due to hepatitis B virus (HBV) which predicts also the risk of hepatocellular carcinoma (HCC), clinical decompensation and anticipated liver related death. The dynamics and prognostic significance of EV in patients under long-term HBV suppression by nucleos(t)ide analogs (NUC), are poorly known. METHODS: A standardized protocol (Baveno) including 414 upper gastrointestinal (GI) endoscopies was applied to 107 HBeAg-negative compensated cirrhotic patients (93% Child-Pugh A) during a median of 12 (range 2 to 17) years of NUC therapy. Patients who initially started on lamivudine (LMV) and then developed resistance (LMV-R), were rescued by early administration of adefovir, or were switched to tenofovir. Surveillance included serum HBV DNA every three months and abdominal ultrasound every six months. RESULTS: Twenty-seven patients had baseline F1 EV which regressed in 18, remained unchanged in eight and progressed in one patient; the 12-year cumulative incidence of EV regression was 83% (95% CI: 52-92%). De novo F1/F2 EV developed in 6/80 patients with a 12-year cumulative incidence of 10% (95% CI: 5-20%). Six of seven patients with de novo varices or progression of pre-existing varices had either a clinical breakthrough due to LMV-R and/or developed a HCC. No bleedings from ruptured EV occurred, 12 patients died (9 HCC) and 15 were transplanted (13 HCC): the 12-year cumulative incidence of HCC and overall survival was 33% (95% CI: 24-42%) and 76% (95% CI: 67-83%), respectively. CONCLUSIONS: Long-term pharmacological suppression of HBV in HBeAg-seronegative patients with compensated cirrhosis leads to a significant regression of pre-existing EV accompanied by a negligible risk of developing de novo EV.

Extended survival of patients with persistently suppressed hepatitis B transplanted for hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has become a major cause of liver-related death and indication to liver transplantation (LT) in patients with chronic hepatitis B virus (HBV) infection following the widespread adoption of antiviral therapy with nucleos(t)ide analogs (NUCs). Yet, the long-term outcome of patients undergoing liver transplantation for an HCC developed during effective NUC treatment is unknown. METHODS: We evaluated 101 patients with persistently compensated cirrhosis who were consecutively transplanted for HCC in two centers in Milan. At LT, 91 (90%) patients had undetectable serum HBV DNA (<12 IU/ml) and 90 (89%) were within Milan criteria (MC). All patients received post-transplant HBV prophylaxis with specific immunoglobulins (HBIgs) and NUCs. End-points were long-term patient survival and recurrence of HCC and HBV. RESULTS: During 106 (range 3-165) months following LT, HCC recurred in 11 (11%) patients (nine beyond MC at explant, two with HBV recurrence). Age (HR 1.1, 95%CI 1.0-1.2, P = 0.04) and exceeding MC (HR 9.6, 95%CI 2.9-32, P < 0.0001) were the only independent pretransplant predictors of tumour recurrence. The 10-year cumulative rate of HCC recurrence was 7% among patients transplanted within MC compared with 45% among those beyond MC at LT (P = 0.004). Overall, 18 patients (18%, nine HCC, nine non liver-related events) died with a 10-year cumulative probability of overall and liver-related survival of 79% and 89% respectively. CONCLUSIONS: Extended survival of HBV cirrhotics transplanted for HCC can be achieved by coupling MC at listing with persistent pharmacological suppression of HBV.