Incidence And Predictors of Relapse After Stopping Antiviral Therapy In Pediatric Chronic Hepatitis B

Objective: The objective was to evaluate the incidence of relapse after stopping antiviral therapy and to identify the predictors of relapse. Methods: All HBsAg positive children with who had been on antivirals for at least 2 years with undetectable HBV-DNA and normal alanine-aminotransferase (ALT) on three consecutive occasions over last 12 months were included. Antivirals were stopped if liver biopsy showed histological activity index <5 and fibrosis (metavir) <3. Children were monitored for virological relapse (elevation of HBV-DNA >2000 IU/mL) and biochemical relapse (ALT levels >2 × upper limit of normal (ULN)). Those having biochemical relapse were started on pegylated interferon alpha-2b based sequential therapy. Results: Antivirals were stopped in 31 HBsAg positive children. Virological and biochemical relapse was seen in 12 (38.7%) and 5 (16.1%) children within 12 months of stopping antiviral treatment. Majority of virological relapse occurred within a month and biochemical relapses within 6 months of stopping therapy. HBeAg positive status at the time of stopping antiviral therapy (HR: 7.206, p =0.005) and longer time taken for HBV-DNA to become undetectable while on antivirals (HR: 1.030, p=0.037) were found to be the 2 independent predictors of relapse after stopping antiviral treatment. Conclusion: Discontinuation of antiviral treatment in children with CHB resulted in relapse in one third of the patients. Relapse was more common in those with HBeAg positivity at the time of stopping therapy and in those with longer time taken for HBV-DNA to become undetectable on antivirals.

HBeAg-positive patients with HBsAg < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation

Background Nucleos(t)ide analogues (NAs) cessation is not widely practiced and remains a controversial, but highly relevant subject in patients infected with hepatitis B virus (HBV). We aimed to explore the related factors for safe NAs cessation. Methods This is a multicenter prospective cohort study. Overall, 139 initially HBV e antigen (HBeAg)-positive patients meeting the stopping criteria were included in 12 hospitals in China. Enrolled patients ceased NAs and were followed up every 3 months for 24 months or until clinical relapse (CR). Results The 24 month cumulative rates of virological relapse (VR), CR, HBeAg reversion and HBV surface antigen (HBsAg) loss were 50.4, 24.5, 11.5 and 9.4%, respectively. Patients with end of treatment (EOT) HBsAg < 100 IU/mL plus negative HBV RNA had the lowest 24 month cumulative VR rate (5 vs 58%, p < 0.001). EOT HBsAg ≥ 2 log10 IU/mL [odds ratio (OR) = 6.686, p = 0.006], EOT positive HBV RNA (OR = 3.453, p = 0.008) and EOT hepatitis B core-related antigen (HBcrAg) ≥ 4log U/mL (OR = 3.702, p = 0.002) were found to independently predict the risk of VR. To predict VR, the area under the receiver-operating characteristic (AUROC) value of the EOT HBsAg < 100 IU/mL plus EOT HBV RNA negative was 0.698 (p < 0.001), which was higher than other parameters alone or combinations. Conclusions NAs cessation is suitable only for a small and selected patients. An EOT HBsAg < 100 IU/mL and EOT negative HBV RNA identified a patient with low risk of off-treatment VR.

Quantification and epigenetic evaluation of the residual pool of hepatitis B covalently closed circular DNA in long-term nucleoside analogue-treated patients

Hepatitis B virus (HBV) covalently closed circular (ccc)DNA is the key genomic form responsible for viral persistence and virological relapse after treatment withdrawal. The assessment of residual intrahepatic cccDNA levels and activity after long-term nucleos(t)ide analogues therapy still represents a technical challenge. Quantitative (q)PCR, rolling circle amplification (RCA) and droplet digital (dd)PCR assays were used to quantify residual intrahepatic cccDNA in liver biopsies from 56 chronically HBV infected patients after 3 to 5 years of telbivudine treatment. Activity of residual cccDNA was evaluated by quantifying 3.5 kB HBV RNA (preC/pgRNA) and by assessing cccDNA-associated histone tails post-transcriptional modifications (PTMs) by micro-chromatin immunoprecipitation. Long-term telbivudine treatment resulted in serum HBV DNA suppression, with most of the patients reaching undetectable levels. Despite 38 out of 56 patients had undetectable cccDNA when assessed by qPCR, RCA and ddPCR assays detected cccDNA in all-but-one negative samples. Low preC/pgRNA level in telbivudine-treated samples was associated with enrichment for cccDNA histone PTMs related to repressed transcription. No difference in cccDNA levels was found according to serum viral markers evolution. This panel of cccDNA evaluation techniques should provide an added value for the new proof-of-concept clinical trials aiming at a functional cure of chronic hepatitis B.

Cessation of nucleos(t)ide analogues therapy in chronic hepatitis B: a systematic review and meta-analysis

Background: To address the possibility of safe cessation of nucleos(t)ide analogues (NAs) therapy in chronic hepatitis B (CHB) and to identify factors associated with off-NAs virological relapse (VR). Methods: A published work search was performed to identify all published studies including patients who ceased NAs and were followed for ≥12 months. A meta-analysis was performed. Results: Twenty-six studies involving 2573 patients who discontinued NAs were included. The pooled rate of off-NAs VR was 0.64, being lower in initially hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients (0.62 versus 0.63, P = 0.731). The pooled rates of VR were 0.48, 0.56, 0.61, 0.53, 0.71 and 0.65 at 6, 12, 24, 36, 48 and 60 months after NAs cessation, respectively, being relatively lower in initially HBeAg-positive (0.36, 0.50, 0.58, 0.49, 0.50, 0.60) than HBeAg-negative patients (0.51, 0.56, 0.67, 0.59, 0.53, 0.65) (P = 0.400) . The pooled rate of biochemical relapse was 0.45, being lower in initially HBeAg-positive than HBeAg-negative patients (0.43 versus 0.51, P = 0.572). The pooled rates of hepatitis B surface antigen (HBsAg) loss and seroconversion was 0.09 and 0.06, respectively. The pooled rates of VR at 12 months after NAs cessation were significantly different between duration of on-NAs virological response ≤24 months and >24 months in all patients (0.55 versus 0.41, P = 0.011), initially HBeAg-positive patients (0.59 versus 0.41, P = 0.031), and initially HBeAg-negative patients (0.53 versus 0.37, P = 0.025). Conclusions: Cessation of NAs therapy seems to be safe in a small subset of CHB patients. On-NAs virological response >24 months reduces the risk of off-NAs VR.

Cessation of nucleos(t)ide analogues therapy in chronic hepatitis B: a systematic review and meta-analysis

BackgroudTo address the possibility of safe cessation of nucleos(t)ide analogues (NAs) therapy in chronic hepatitis B (CHB) and to identify factors associated with off-NAs virological relapse (VR).MethodsA published work search was performed to identify all published studies including patients who ceased NAs and were followed for ≥12 months. A meta-analysis was performed.ResultsTwenty-six studies involving 2573 patients who discontinued NAs were included. The pooled rate of off-NAs VR was 0.63, being lower in initially hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients (0.57 versus 0.62, P = 0.732). The pooled rates of VR were 0.47, 0.55, 0.61, 0.51, 0.73 and 0.64 at 6, 12, 24, 36, 48 and 60 months after NAs cessation, respectively, being relatively lower in initially HBeAg-positive (0.31, 0.45, 0.55, 0.44, 0.48, 0.52) than HBeAg-negative patients (0.50, 0.55, 0.69, 0.57, 0.53, 0.68) ( P = 0.405). The pooled rate of biochemical relapse was 0.44, being lower in initially HBeAg-positive than HBeAg-negative patients (0.43 versus 0.48, P = 0.554). The pooled rates of hepatitis B surface antigen (HBsAg) loss and seroconversion was 0.09 and 0.06, respectively. The pooled rates of VR at 12 months after NAs cessation were significantly different between duration of on-NAs virological response ≤24 months and >24 months in all patients (0.55 versus 0.41, P = 0.011), initially HBeAg-positive patients (0.59 versus 0.41, P = 0.031), and initially HBeAg-negative patients (0.53 versus 0.37, P = 0.025).ConclusionsCessation of NAs therapy seems to be safe in a small subset of CHB patients. On-NAs virological response >24 months reduces the risk of off-NAs VR.

Cessation of nucleos(t)ide analogues therapy in chronic hepatitis B: a systematic review and meta-analysis

Backgroud: To address the possibility of safe cessation of nucleos(t)ide analogues (NAs) therapy in chronic hepatitis B (CHB) and to identify factors associated with off-NAs virological relapse (VR). Methods: A published work search was performed to identify all published studies including patients who ceased NAs and were followed for ≥12 months. A meta-analysis was performed. Results: Twenty-six studies involving 2573 patients who discontinued NAs were included. The pooled rate of off-NAs VR was 0.63, being lower in initially hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients (0.57 versus 0.62, P = 0.732). The pooled rates of VR were 0.47, 0.55, 0.61, 0.51, 0.73 and 0.64 at 6, 12, 24, 36, 48 and 60 months after NAs cessation, respectively, being relatively lower in initially HBeAg-positive (0.31, 0.45, 0.55, 0.44, 0.48, 0.52) than HBeAg-negative patients (0.50, 0.55, 0.69, 0.57, 0.53, 0.68) ( P = 0.405). The pooled rate of biochemical relapse was 0.44, being lower in initially HBeAg-positive than HBeAg-negative patients (0.43 versus 0.48, P = 0.554). The pooled rates of hepatitis B surface antigen (HBsAg) loss and seroconversion was 0.09 and 0.06, respectively. The pooled rates of VR at 12 months after NAs cessation were significantly different between duration of on-NAs virological response ≤24 months and >24 months in all patients (0.55 versus 0.41, P = 0.011), initially HBeAg-positive patients (0.59 versus 0.41, P = 0.031), and initially HBeAg-negative patients (0.53 versus 0.37, P = 0.025). Conclusions: Safe cessation of NAs therapy seems to be feasible in a substantial proportion of CHB patients. On-NAs virological response >24 months reduces the risk of off-NAs VR. Stopping NAs treatment may have an impact on long-term HBsAg decline and HBsAg clearance.

Cessation of nucleos(t)ide analogues therapy in chronic hepatitis B: a systematic review and meta-analysis

Background To address the possibility of safe cessation of nucleos(t)ide analogues (NAs) therapy in chronic hepatitis B (CHB) and to identify factors associated with off-NAs virological relapse (VR). Methods A published work search was performed to identify all published studies including patients who ceased NAs and were followed for ≥12 months. A meta-analysis was performed. Results Twenty-six studies involving 2573 patients who discontinued NAs were included. The pooled rate of off-NAs VR was 0.63, being lower in initially hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients (0.57 versus 0.62, P = 0.732). The pooled rates of VR were 0.47, 0.55, 0.61, 0.51, 0.73 and 0.64 at 6, 12, 24, 36, 48 and 60 months after NAs cessation, respectively, being relatively lower in initially HBeAg–positive (0.31, 0.45, 0.55, 0.44, 0.48, 0.52) than HBeAg-negative patients (0.50, 0.55, 0.69, 0.57, 0.53, 0.68) (P = 0.405). The pooled rate of biochemical relapse was 0.44, being lower in initially HBeAg-positive than HBeAg-negative patients (0.43 versus 0.48, P = 0.554). The pooled rates of hepatitis B surface antigen loss and seroconversion was 0.09 and 0.06, respectively. The pooled rates of VR at 12 months after NAs cessation were significant different between duration of on-NAs virological response ≤24 months and >24 months in all patients (0.55 versus 0.41, P = 0.011), initially HBeAg-positive patients (0.59 versus 0.41, P = 0.031), and initially HBeAg-negative patients (0.53 versus 0.37, P = 0.025). Conclusions Safe cessation of NAs therapy seems to be feasible in a substantial proportion of CHB patients. On-NAs virological response >24 months reduces the risk of off-NAs VR. Stopping NAs treatment may have an impact on long-term HBsAg decline and also HBsAg clearance.

IL-28B genotypes as predictors of long-term outcome in patients with hepatitis C-related severe liver injury

Introduction: Patients with severe fibrosis or cirrhosis are at high risk for liver-related complications, even after successful antiviral treatment and/or regression of fibrosis. These are the first published results concerning the role of IL-28B genotypes as predictors of the durability of sustained virological response (SVR) and long-term outcome, in patients with baseline severe fibrosis and cirrhosis caused by hepatitis C (HCV) infection. Methodology: Genetic testing for three different single nucleotide polymorphisms (SNP) near the IL28B gene, rs12979860, rs12980275 and rs8099917, was performed in 42 patients with HCV-related advanced fibrosis and cirrhosis, who achieved SVR after successful interferon-based treatment. Baseline clinical and laboratory parameters were analysed, as well as IL28B genotype association with late virological relapse, fibrosis progression and clinical outcomes. Results: The most prevalent genotypes in all three tested SNP positions were: CCrs12979860 genotype in 69% of patients, GTrs8099917 in 78.6% and GGrs12980275 in 47.6% of patients. The presence of IL28B CCrs12979860 genotype was identified as a negative predictor of late virological relapse. Further analysis did not confirm the association of other IL28B genotypes with the progression of fibrosis and clinical outcomes. Conclusions: Varying long-term prognosis in patients with HCV-related severe fibrosis and cirrhosis is due to multiple interactions between host genetic factors, virus and environment. These are first published results demonstrating the significance of IL28B CCrs12979860 genotype as a negative predictor of late virological relapse. A further investigation concerning genetic factors is necessary to identify patients under risk for late relapse, complications and unfavorable outcomes, so that they can be reevaluated and offered new treatment options.