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Little is known for factors associated with virologic breakthrough (VBT) after switching from nucleos(t)ide analogue (NA) to pegylated interferon alpha (Peg‐IFN‐α) for patients with chronic hepatitis B (CHB). Eighty patients who received 48‐week Peg‐IFN‐ɑ and NA combination therapy followed by Peg‐IFN‐ɑ monotherapy for additional 48 weeks were included in this study. HBV‐related markers including HBV DNA, HBsAg, HBcrAg, HBeAg, cccDNA, and immunological biomarkers were dynamically evaluated. Twelve (15.0%) patients experienced VBT after switching to Peg‐IFN‐ɑ and exhibited significantly lower rates of HBsAg loss after therapy completion (0% vs. 35.3%, p = 0.014). The patients with HBcrAg≥ 5 log10U/mL and HBsAg≥ 100 IU/mL had the highest risk of VBT and failed to achieve subsequent HBsAg clearance. Intrahepatic cccDNA level was significantly higher in patients with HBcrAg≥ 5 log10U/mL than those with HBcrAg< 5 log10U/mL. Notably, in contrast to patients with HBcrAg< 5 log10U/mL or with HBsAg< 100 IU/mL who had obviously restored HBV‐specific CD8+T cell, Tfh or B cell responses before NA cessation, those with HBcrAg≥ 5 log10U/mL or with HBsAg≥ 100 IU/mL exhibited lackluster immunities before NA cessation and notable diminished immune responses thereafter. Monitoring HBcrAg and HBsAg levels, which correlated with poor immune responses during sequential Peg‐IFN‐ɑ strategy, may help to avoid VBT and improve functional cure of CHB. [ABSTRACT FROM AUTHOR]

Serum hepatitis B virus (HBV) RNA is a new serological indicator reflecting viral replication with good clinical application prospects. This study aimed to clarify the dynamic changes of serum HBV RNA levels and the quasispecies of HBV RNA virus‐like particles in nucleos(t)ide analogues (NAs)‐experienced chronic hepatitis B (CHB) patients harboring NAs‐resistant mutations and their identifiable effects on NAs resistance. We included CHB patients who were on long‐term NAs treatment and with HBV DNA rebound. The longitudinally dynamics of serum HBV RNA levels were quantitatively detected, and the quasispecies differences between serum HBV DNA and serum HBV RNA were compared by high‐throughput sequencing. The effect of NAs concentration pressure on altering the resistance mutations quasispecies proportion of HBV DNA and HBV RNA in cell supernatant was analyzed in vitro. A total of 447 serum samples from 36 CHB patients treated with NAs were collected. The median follow‐up period was 47 months (about 4 years), and the longest follow‐up period was 117 months (about 10 years). Our results showed that HBV RNA could reflect virological breakthrough in 23 (64%, 23/36) patients, and serum HBV RNA rebound earlier than HBV DNA in 12 (52%, 12/23) patients. However, serum HBV RNA remained at a consistently high level and did not fluctuate significantly with the HBV DNA rebound in 6 of 36 patients. In addition, serum HBV RNA was not consistently detectable in 7 of the 36 patients, and their serum HBV RNA was undetectable even after HBV DNA had rebounded. The proportion of drug‐resistant mutations in HBV DNA was higher than that of HBV RNA by high‐throughput sequencing. The results of in vitro experiments showed that the viral strains with drug‐resistant mutation in HBV DNA in cell supernatants gradually become the dominant strains with the increase of NAs concentrations. Serum HBV RNA levels can reflect virological breakthrough in most NAs‐ treated CHB patients, but there are certain limitations. NAs alter the quasispecies composition of serum HBV DNA and serum HBV RNA, resulting in a higher detection rate of drug‐resistant mutations in serum HBV DNA than in serum HBV RNA. [ABSTRACT FROM AUTHOR]

Background & aim: Higher elevation of alanine aminotransferase (ALT) occasionally leads to severe outcomes in hepatitis B virus (HBV)-infected patients. Our aim is to investigate the HBV sequence mutations associated with higher ALT elevation. Materials & methods: We analyzed full-length HBV sequences from patients with or without higher ALT elevation. Results: Nucleotide mutations in precore and core regions, which are associated with severe hepatitis B, were found in two HBV-infected patients with higher ALT elevation. Amino acid mutations within the pre-S1, pre-S2 and S regions were also found in a patient with HBV virologic breakthrough during the use of nucleoside analogs. Conclusion: It may be useful for HBV-infected patients with higher ALT elevation to analyze full-length HBV genome. [ABSTRACT FROM AUTHOR]

Purpose of the Review: Poorly controlled hepatitis B increases the risk for liver-related morbidity. Although there are now six approved nucleos(t)ide analogues (NA) for the treatment of chronic hepatitis B (CHB), drug resistance and thus virologic breakthrough still exist. This review outlines a systematic approach to the management of virologic failure in patients with CHB treated with NAs. Recent Findings: Current NAs can be divided into older generation and newer generation agents, with newer generation agents associated with lower rates of virologic breakthrough. Both tenofovir dipovoxil fumarate (TDF) and tenofovir alafenamide (TAF) are equally as effective in addressing virologic breakthrough while on all other NAs. Entecavir is an effective treatment option for NA naïve patients only, with high rates of resistance to entecavir in those exposed to older NAs. Summary: The management of virologic breakthroughs should focus on identifying risk factors for future drug resistance and escalation to appropriate newer generation drug options to avoid long-term liver-related morbidity. [ABSTRACT FROM AUTHOR]

Background: A 2-year roadmap study was conducted to evaluate the efficacy and safety of tenofovir intensification at Week 24 in patients with chronic hepatitis B (CHB) receiving telbivudine. Scope: A prospective multicenter study was conducted in treatment-naive patients with hepatitis B e antigen (HBeAg)- positive CHB. All patients received telbivudine (600 mg/day) until Week 24. Thereafter, patients with detectable hepatitis B virus (HBV) DNA (≥300 copies/mL) were administered tenofovir (300 mg/day) plus telbivudine, and patients with undetectable HBV DNA continued telbivudine monotherapy until Week 104. The primary endpoint was the proportion of patients with undetectable HBV DNA (

Background: Telbivudine has been suggested to induce hepatitis B surface antigen (HBsAg) decline to the similar degree as pegylated interferon. We aimed to investigate whether telbivudine could further decrease HBsAg titer in patients who maintain undetectable serum hepatitis B virus (HBV) DNA after initial entecavir treatment. Methods: In this open-label trial, patients who had serum HBsAg and HBV DNA levels ≥1,000 IU/mL and <60 IU/mL, respectively, following entecavir (0.5 mg/day) treatment for HBeAg-positive chronic hepatitis B were randomized to either switch treatment to telbivudine (600 mg/day, n = 47) or continue entecavir (n = 50) for 48 weeks. Results: The baseline characteristics were comparable between groups including HBsAg levels (median, 3.41 log10 IU/mL). All patients had undetectable HBV DNA and normal alanine aminotransferase level. At week 48, the mean change in serum HBsAg levels was not significantly different between the telbivudine and entecavir groups (-0.03 log10 IU/mL vs. -0.05 log10 IU/mL; P = 0.57). No patient experienced HBsAg seroclearance or HBsAg decline >0.5 log10 IU/mL. Eleven patients (23.4%) in the telbivudine group, but none in the entecavir group, experienced virologic breakthrough (P < 0.001). Seven patients (14.9%) exhibited genotypic resistance mutations (M204I +/- L180M) during the virologic breakthrough. Conclusion: Sequential therapy with entecavir followed by telbivudine resulted in a high rate of virologic breakthrough and drug-resistance without any beneficial effect on HBsAg decline. These results do not support the use of low genetic barrier drugs as a switch treatment strategy in patients who achieve virologic response with high genetic barrier drugs. Trial Registration: NCT01595685 (date of trial registration: May 8, 2012). [ABSTRACT FROM AUTHOR]

Background and aims: In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen. Methods: In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1 mg) plus TDF (300 mg) and treated for 96 weeks. Results: At baseline, 62 % of patients were HBeAg(+) and mean HBV DNA was 4.4 logIU/mL. Patients had received ≥1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53 %), lamivudine (LVD 22 %), TDF (12 %), adefovir (ADV 4 %), or telbivudine (2 %), or combinations of these agents (7 %); 58 % had evidence of single- or multidrug resistance mutations (LVD 52 %, ETV 26 %; ADV 7 %). Response rates for HBV DNA <50 IU/mL were 76 % (70/92) at week 48 (primary endpoint), and 85 % (78/92) at week 96, including 80 % (16/20) in prior LVD failures, 100 % (4/4) in ADV failures, 82 % (9/11) in TDF failures, and 88 % (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed. Conclusions: In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96 weeks in the majority (85 %), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent. [ABSTRACT FROM AUTHOR]

Background Lamivudine monotherapy is effective in suppressing hepatitis B virus (HBV) replication to undetectable levels by PCR, in ameliorating liver disease and to some extent in achieving HBsAg seroconversion. Th is study aimed at assessing the virological and biochemical responses as well as breakthrough in HBeAg-negative chronic HBV (CHB) Egyptian patients receiving lamivudine therapy. Methods Th is retrospective study included 140 CHB patients with positive serum HBV-DNA by quantitative PCR assays and negative HBeAg who had never received prior anti-viral therapy for HBV. According to duration of lamivudine therapy (100 mg/day) patients were grouped into: group I (n=59) who received lamivudine for 1 year, group II (n=50) who received lamivudine for 2 years, and group III (n=31) who received lamivudine for 3 years. Results In group I, 76.3% patients had virologic response but this was reduced in group II and group III to 72% and 67.7% respectively. None of the patients in group I developed virologic breakthrough, whereas 12% and 25.8% in groups II and III respectively developed breakthrough. In group I, 25% of patients having high pre-treatment viremia showed virologic response compared to 84.6% and 83.3% having mild and moderate viremia respectively (P<0.01). However, in groups II and III, there was no significant relationship between pre-treatment viremia and virologic response. No significant relationship was found between pre-treatment viral load and incidence of breakthrough within each group. Conclusion Lamivudine remains one of the antiviral therapies for HBeAg negative CHB patients. The rates of maintained virologic and biochemical responses to lamivudine decrease in time due to selection of drug-resistant mutants and, hence, breakthrough. [ABSTRACT FROM AUTHOR]

Objective: High rate of resistance to lamivudine is a major problem in treating chronic hepatitis B (CHB) patients. We investigated the course of virologic breakthrough (VB) after emergence of YMDD mutants in CHB patients receiving lamivudine. Methods: Ninety-three consecutive HBeAg-positive CHB patients treated with lamivudine (100 mg/day) who developed YMDD mutants and VB were enrolled. The clinical breakthrough (CB) was defined by elevation of alanine aminotransferase (ALT) >2 times the upper limit of normal. Results: The median age was 47 years, and genotype of hepatitis B virus (HBV) was all C. The median duration of lamivudine administration was 39 months, and median pre-lamivudine ALT and HBV DNA were 165 IU/l and 1.2 × 108 copies/ml. In all patients, CB concurred with VB or appeared some months following VB. When patients were divided into two groups according to time sequence of two breakthroughs – group 1 (VB followed by CB, n = 68) and group 2 (concurrent VB and CB, n = 25) – there was no difference in patient and virologic characteristics between the two groups. The median time from VB to CB was 8 months in group 1. Conclusion: VB might eventually progress to CB in HBeAg-positive patients harboring YMDD mutants with high pretreatment ALT and HBV DNA. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Virologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alpha (Peg–IFN–ɑ). This study aimed to characterize the clinical and immunological features of VBT. In NAs-treated patients switching to Peg–IFN–ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8+T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication. 33 of 166 patients switching to Peg–IFN–ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2+monocyte and increased PD1+HBV-specific CD8+T cell during the early phase of Peg–IFN–ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2+CD68+macrophages but more PDL1+CD68+macrophages and PD1+CD8+T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8+T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1+monocytes and PD1+CD8+T cells were upregulated, whereas TLR2+monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers. In NAs-treated patients, lower TLR2+monocyte and increased PD1+HBV-specific CD8+T cell proportions potentially contribute to VBT after switching to Peg–IFN–ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels. Lower TLR2+monocytes and increased PD1+CD8+T cells contribute to VBT in CHB patients switching from NAs to Peg–IFN–ɑ. [Display omitted] • NAs-treated CHB patients with positive HBeAg or high HBcrAg are more likely to develop VBT after switching to Peg–IFN–ɑ. • Lower level of TLR2+monocyte and increased PD1+CD8+T cell during early switching treatment correlate with VBT. • Immunomodulation effect of IFN-ɑ on TLR2 and PD1/PDL1 pathway vary according to different HBeAg status or HBcrAg levels. • Combination of TLR2 activation and PD1/PDL1 pathway blockade may potentially prevent VBT. [ABSTRACT FROM AUTHOR]

The authors assessed the efficacy and antiviral resistance of 48-week clevudine therapy versus lamivudine in treatment of naïve patients with HBeAg positive chronic hepatitis B. In this retrospective study, a total of 116 HBeAg positive patients, who received 30 mg of clevudine once daily (n=53) or 100 mg of lamivudine once daily (n=63) for 48 weeks, were included. At week 48, clevudine therapy produced a significantly greater mean reductions in serum HBV DNA levels from baseline than lamivudine therapy (-5.2 vs. -4.2 log(10)IU/mL; P=0.005). Furthermore, a significantly higher proportion of patients on clevudine achieved negative serum HBV DNA by PCR (<13 IU/mL) at week 48 (60.4% vs. 38.1%; P=0.025). The incidence of virologic breakthrough in the clevudine group was significantly lower than in the lamivudine group (9.4% vs. 25.4%; P=0.031). However, rates of alanine aminotransferase normalization and HBeAg loss or seroconversion were similar in the two groups (83.0% vs. 81.0%, 11.3% vs. 11.1%; P=0.813, 1.000, respectively). In conclusion, clevudine is more potent for viral suppression and lower for antiviral resistance at week 48 than lamivudine in treatment of naïve patients with HBeAg positive chronic hepatitis B.