Efficacy of different nucleoside analog rescue therapies for entecavir-resistant chronic hepatitis B patients.
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ABSTRACT: Background
Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue.Methods
Patients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups.Results
The rate of ETV resistance among all HBV-resistant variants increased from 6.04% in 2011 to 15.02% in 2017. TDF monotherapy and TDF combination groups showed similar rates of negative HBV DNA at 48 weeks (74.07% vs 70.00%, P > 0.05), while the ETV and ADV group showed the worst virologic response (28.00%). Also, TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function among the three groups.Conclusions
TDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.
SUBMITTER: Shang J
PROVIDER: S-EPMC8420064 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We designed, synthesized, and characterized a novel nucleoside analog, (1S,3S,5S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-hydroxy-1-(hydroxymethyl)-2-methylene-cyclopentanecarbonitrile, or 4'-cyano-methylenecarbocyclic-2'-deoxyguanosine (CMCdG), and evaluated its anti-hepatitis B virus (anti-HBV) activity, safety, and related features. CMCdG's in vitro activity was determined using quantitative PCR and Southern blotting assays, and its cytotoxicity was determined with a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, while its in vivo activity and safety were determined in human liver-chimeric mice infected with wild-type HBV genotype Ce (HBVWTCe) and an entecavir (ETV)-resistant HBV variant containing the amino acid substitutions L180M, S202G, and M204V (HBVETV-RL180M/S202G/M204V). CMCdG potently inhibited HBV production in HepG2.2.15 cells (50% inhibitory concentration [IC50], ∼30 nM) and HBVWTCe plasmid-transfected Huh7 cells (IC50, 206 nM) and efficiently suppressed ETV-resistant HBVETV-RL180M/S202G/M204V (IC50, 2,657 nM), while it showed no or little cytotoxicity (50% cytotoxic concentration, >500 μM in most hepatocytic cells examined). Two-week peroral administration of CMCdG (1 mg/kg of body weight/day once a day [q.d.]) to HBVWTCe-infected human liver-chimeric mice reduced the level of viremia by ∼2 logs. CMCdG also reduced the level of HBVETV-RL180M/S202G/M204V viremia by ∼1 log in HBVETV-RL180M/S202G/M204V-infected human liver-chimeric mice, while ETV (1 mg/kg/day q.d.) completely failed to reduce the viremia. None of the CMCdG-treated mice had significant drug-related changes in body weights or serum human albumin levels. Structural analyses using homology modeling, semiempirical quantum methods, and molecular dynamics revealed that although ETV triphosphate (TP) forms good van der Waals contacts with L180 and M204 of HBVWTCe reverse transcriptase (RT), its contacts with the M180 substitution are totally lost in the HBVETV-RL180M/S202G/M204V RT complex. However, CMCdG-TP retains good contacts with both the HBVWTCe RT and HBVETV-RL180M/S202G/M204V RT complexes. The present data warrant further studies toward the development of CMCdG as a potential therapeutic for patients infected with drug-resistant HBV and shed light on the further development of more potent and safer anti-HBV agents.
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Project description:BACKGROUND:Currently, there is no consensus on the efficacy and safety of the entecavir (ETV) monotherapy versus the ETV-based combination therapy for chronic hepatitis B. METHODS:A comprehensive literature search was performed on the comparison of ETV-based combination therapy and monotherapy for chronical hepatitis B (CHB) patients in the PubMed, Embase, Web of Science, the Cochrane Libraries, and the Chinese BioMedical Literature Database. Both dichotomous and continuous variables were extracted, and pooled outcomes were expressed as odds ratio (OR) or mean difference (MD). RESULTS:We included randomized clinical trials (RCTs) and cohorts involving Group A: nucleos(t)ide-naive patients (four RCTs, n?=?719 patients), Group B: nucleos(t)ide-resistant patients (four cohorts, n?=?196 patients), and Group C: entecavir-treated patients with undetectable hepatitis B virus DNA (two RCTs and two cohorts, n?=?297). Group A. ETV monotherapy was better for rates of undetectable HBV DNA, while the rates of the HBV DNA levels at the end of treatment, HBeAg Loss, ALT normalization were similar between the two groups [MD, -0.85 (95% CI, -0.173-0.03); OR, 0.92 (95% CI, 0.24-3.56); OR, 1.31 (95% CI, 0.17-9.82)]; Group B. ETV monotherapy was better for rates of undetectable HBV DNA, while the rates of the HBV DNA levels at the end of treatment, HBeAg Loss, ALT normalization were similar; Group C. The ETV-based combination therapy was better for the rate of HBV DNA relapse. CONCLUSION:Based on the current data, ETV-based combination therapy seemed to be no better than ETV monotherapy. Further studies are needed to verify this conclusion.
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| S-EPMC2716833 | biostudies-other
Project description:Nucleoside analogues (NAs) have been the most frequently used treatment option for chronic hepatitis B patients. However, they may have genotoxic potentials due to their interference with nucleic acid metabolism. Entecavir, a deoxyguanosine analog, is one of the most widely used oral antiviral NAs against hepatitis B virus. It has reported that entecavir gave positive responses in both genotoxicity and carcinogenicity assays. However the genotoxic mechanism of entecavir remains elusive. To evaluate the genotoxic mechanisms, we analyzed the effect of entecavir on a panel of chicken DT40 B-lymphocyte isogenic mutant cell line deficient in DNA repair and damage tolerance pathways. Our results showed that Parp1-/- mutant cells defective in single-strand break (SSB) repair were the most sensitive to entecavir. Brca1-/-, Ubc13-/- and translesion-DNA-synthesis deficient cells including Rad18-/- and Rev3-/- were hypersensitive to entecavir. XPA-/- mutant deficient in nucleotide excision repair was also slightly sensitive to entecavir. ?-H2AX foci forming assay confirmed the existence of DNA damage by entecavir in Parp1-/-, Rad18-/- and Brca1-/- mutants. Karyotype assay further showed entecavir-induced chromosomal aberrations, especially the chromosome gaps in Parp1-/-, Brca1-/-, Rad18-/- and Rev3-/- cells when compared with wild-type cells. These genetic comprehensive studies clearly identified the genotoxic potentials of entecavir and suggested that SSB and postreplication repair pathways may suppress entecavir-induced genotoxicity.
| S-EPMC4723259 | biostudies-literature
Project description:The efficacy of entecavir (ETV) and tenofovir (TDF) for the treatment of nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients has been little studied. Here, we compare the efficacy of both ETV and TDF in NA-experienced CHB patients without detectable genotypic resistance. This retrospective cohort study included consecutive NA-experienced patients who had neither current nor previous genotypic resistance and had received ETV or TDF for at least 6 months. Overall, 202 patients (146 patients in the ETV group and 56 in the TDF group) were analyzed. The cumulative probabilities of complete virologic suppression (CVS) at month 12 were 76.1% in the ETV group and 95.0% in the TDF group (P<0.001), respectively. The TDF-treated group achieved CVS more rapidly than the ETV group for both Hepatitis B e antigen (HBeAg)-negative and -positive patients (P = 0.006 and < 0.001, respectively), and for those with both low (< 2,000 IU/mL) and high (? 2,000 IU/mL) HBV DNA levels (P = 0.01 and 0.002, respectively). TDF group had an increased probability of achieving CVS (hazard ratio, 2.242; 95% confidence interval, 1.587-3.165; P = 0.001), after adjustment for HBV DNA level, the presence of HBeAg, and a history of CVS during prior treatment. During the treatment period, 23 patients (15.8%) in the ETV group developed virologic breakthrough, compared to none in the TDF group. The cumulative probabilities of developing virologic breakthrough and ETV-resistance at month 24 were 9.7% and 5.3%, respectively. In conclusion, TDF is preferable to ETV for achieving CVS in NA-experienced CHB patients without genotypic resistance.
| S-EPMC4488001 | biostudies-literature
Project description:The objective of this study was to evaluate the effectiveness and safety of entecavir (ETV) and interferon (IFN) combination therapy in the treatment of chronic hepatitis B (CHB) mono-infection via a meta-analysis of randomized controlled trials (RCTs). All eligible RCTs evaluating combination therapy for treating CHB were identified from nine electronic databases. A meta-analysis was performed in accordance with the Cochrane Systemic Review handbook. Eleven trials encompassing 1010 participants were included in this meta-analysis. It showed that at 12 and ≥ 96 weeks of therapy, the combination of ETV and IFN was not better than ETV in improving the undetectable HBV DNA (12 weeks: RR=1.12, 95% CI=0.88-1.42; ≥ 96 weeks: RR = 0.64, 95% CI=0.21-1.98, respectively) and HBeAg seroconversion rates (12 weeks: RR=1.35, 95% CI=0.60-3.04; ≥ 96 weeks: RR=1.36, 95% CI=0.75-2.64, respectively). But at 48 weeks of therapy and approximately 2 years of follow up, combination therapy was superior to ETV in improving the undetectable HBV DNA (48 weeks: RR=1.46, 95% CI=1.13-1.90; follow up: RR=2.20, 95% CI=1.26-3.81, respectively) and HBeAg seroconversion rates (48 weeks: RR=1.82, 95% CI=1.44-2.30; follow up: RR=1.92, 95% CI=1.19-3.11, respectively). When compared to IFN group, at 24 and 48 weeks of therapy, combination group showed a greater undetectable HBV DNA (24 weeks: RR=2.14, 95% CI=1.59-2.89; 48 weeks: RR=2.28, 95% CI=1.54-3.37, respectively) and ALT normalization rate (24 weeks: RR=1.56, 95% CI= 1.24-1.96; 48 weeks: RR=1.55, 95% CI = 1.16-2.07, respectively). At 48 weeks of therapy, combination group achieved a greater HBeAg seroconversion rate than IFN (48 weeks: RR=1.58, 95% CI=1.24-2.00). No significant differences were observed in the side effects of the three therapies. So we can conclude that ETV and IFN combination therapy is more effective than ETV or IFN mono-therapy in CHB treatment. ETV, IFN, and the combination of the two are safe in CHB treatment.
| S-EPMC4520608 | biostudies-literature
Project description:Background and objectivesPegylated interferon alpha-2a (peg-IFN α-2a) and entecavir (ETV) are both recommended as the first-line antiviral drugs for chronic hepatitis B (CHB) at present. We aimed to compare the efficacy and safety between peg-IFN α-2a and ETV initial therapy in children and adolescents with CHB and investigate the potential factors affecting the treatment response during the first 48 weeks.MethodsWe retrospectively selected 70 treatment-naïve children and adolescents with CHB who received peg-IFN α-2a(n = 26) or ETV(n = 44) as initial therapy and completed 48-week follow-up for data analysis. Blood samples before treatment were collected from 26 patients of the cohort to assess the cytokine profiles.ResultsWe found that initial peg-IFN therapy results in higher rates of hepatitis B surface antigen (HBsAg) serological response (SR) but lower rates of virological and biochemical response rates compared to ETV at week 48. As for achieving hepatitis B e antigen (HBeAg) SR, peg-IFN was comparable to ETV in the univariate analysis and turned out to be better than ETV after adjustment for important baseline factors. We also found that elevated pre-treatment IL-18 level was significantly associated with HBeAg SR, and remained as the only independent factor of predicting HBeAg SR after adjustment for other important factors. No serious adverse effects of the 2 drugs were reported during the 48-week follow-up.Conclusionscomparing to ETV, peg-IFN was superior in achieving HBsAg and HBeAg SR; higher baseline IL-18 levels were independently associated with HBeAg SR in this study of children and adolescents with CHB.
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