Efficacy and safety of entecavir compared to lamivudine in nucleoside-naive patients with chronic hepatitis B: a randomized double-blind trial in China.
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ABSTRACT:
SUBMITTER: Yao G
PROVIDER: S-EPMC2716833 | biostudies-other | 2007 Sep
REPOSITORIES: biostudies-other
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Project description:PURPOSE: This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and safety of entecavir in Chinese patients with lamivudine-refractory chronic hepatitis B. METHODS: One hundred forty-five lamivudine-refractory patients with chronic hepatitis B were randomized to double-blind treatment with oral entecavir 1 mg (n = 116) or placebo (n = 29) daily for 12 weeks, followed by 36 weeks of open-label entecavir treatment. The primary efficacy endpoint was the mean change from baseline in serum hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR) assay at week 12. RESULTS: At week 12, the mean change from baseline in serum HBV DNA by PCR assay was -4.30 log(10) copies/ml for patients on entecavir compared to -0.15 log(10 )copies/ml for patients on placebo (P < .0001). Among patients with baseline serum alanine aminotransferase (ALT) >1 x upper limit of normal (ULN), a higher proportion of entecavir than placebo patients (68% vs. 6%, respectively) achieved ALT normalization by week 12 (P < .0001). After 48 weeks of entecavir treatment, the mean change in HBV DNA by PCR assay was -5.08 log(10) copies/ml, and 85% of patients with baseline ALT >1 x ULN had achieved ALT normalization. The safety profile of entecavir was similar to that of placebo during the first 12 weeks of blinded dosing. Entecavir was also well tolerated during 36 weeks of open-label treatment. CONCLUSIONS: Lamivudine-refractory chronic hepatitis B patients treated with entecavir demonstrated marked HBV DNA reduction and normalization of ALT in most cases. Entecavir treatment for 48 weeks was well tolerated.
| S-EPMC2716831 | biostudies-other
Project description:AimTo investigate the short-term and long-term efficacy of entecavir versus lamivudine in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure (ACLF).MethodsThis was a single center, prospective cohort study. Eligible, consecutive hospitalized patients received either entecavir 0.5 mg/d or lamivudine 100 mg/d. All patients were given standard comprehensive internal medicine. The primary endpoint was survival rate at day 60, and secondary endpoints were reduction in hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) levels, and improvement in Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores at day 60 and survival rate at week 52.ResultsOne hundred and nineteen eligible subjects were recruited from 176 patients with severe acute exacerbation of chronic hepatitis B: 65 were included in the entecavir group and 54 in the lamivudine group (full analysis set). No significant differences were found in patient baseline clinical parameters. At day 60, entecavir did not improve the probability of survival (P = 0.066), despite resulting in faster virological suppression (P < 0.001), higher rates of virological response (P < 0.05) and greater reductions in the CTP and MELD scores (all P < 0.05) than lamivudine. Intriguingly, at week 52, the probability of survival was higher in the entecavir group than in the lamivudine group [42/65 (64.6%) vs 26/54 (48.1%), respectively; P = 0.038]. The pretreatment MELD score (B, 1.357; 95%Cl: 2.138-7.062; P = 0.000) and virological response at day 30 (B, 1.556; 95%Cl: 1.811-12.411; P =0.002), were found to be good predictors for 52-wk survival.ConclusionEntecavir significantly reduced HBV DNA levels, decreased the CTP and MELD scores, and thereby improved the long-term survival rate in patients with spontaneous reactivation of hepatitis B presenting as ACLF.
| S-EPMC4000512 | biostudies-literature
Project description:Background/aimsAntiviral therapy is a key component in the management of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. However, whether the potent drug entecavir is more effective than a less potent drug, such as lamivudine, in HBV-related HCC is not clear.MethodsA retrospective cohort of 451 newly diagnosed, HBV-related HCC patients without antiviral therapy at diagnosis, who started antiviral therapy with either entecavir (n=249) or lamivudine (n=202), were enrolled.ResultsThe median survival was longer for the entecavir group than for the lamivudine group, and lamivudine use (vs entecavir) was an independent factor for mortality (hazard ratio [HR], 1.49; p=0.002). Lamivudine use (vs entecavir) was an independent risk factor for new-onset hepatic decompensation (HR, 1.67; p=0.010) in 318 patients without previous hepatic decompensation, and it was also an independent risk factor for recurrence after curative therapy (HR, 1.84; p=0.002) in 117 patients who received curative therapy. The findings were similar in a propensity score-matched cohort.ConclusionsOverall survival, decompensation-free survival, and recurrence-free survival were better in the entecavir-treated patients than in the lamivudine treated-patients, indicating that the potent antiviral drug should be the preferred choice in HBV-related HCC patients.
| S-EPMC5087934 | biostudies-literature
Project description:Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIVY115F/F116Y/Q151M) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIVY115F/F116Y/Q151M with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RTY115F/F116Y/Q151M:DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RTY115F/F116Y/Q151M/F160M/M184V:DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain ?-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV.
| S-EPMC7033138 | biostudies-literature
Project description:Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) replication in vitro and in vivo that is currently in clinical trials for the treatment of chronic HBV infections. A major limitation of the current HBV antiviral therapy, lamivudine (3TC), is the emergence of drug-resistant HBV in a majority of treated patients due to specific mutations in the nucleotide binding site of HBV DNA polymerase (HBV Pol). To determine the effects of 3TC resistance mutations on inhibition by ETV triphosphate (ETV-TP), a series of in vitro studies were performed. The inhibition of wild-type and 3TC-resistant HBV Pol by ETV-TP was measured using recombinant HBV nucleocapsids, and compared to that of 3TC-TP. These enzyme inhibition studies demonstrated that ETV-TP is a highly potent inhibitor of wild-type HBV Pol and is 100- to 300-fold more potent than 3TC-TP against 3TC-resistant HBV Pol. Cell culture assays were used to gauge the potential for antiviral cross-resistance of 3TC-resistant mutants to ETV. Results demonstrated that ETV inhibited the replication of 3TC-resistant HBV, but 20- to 30-fold higher concentrations were required. To gain further perspective regarding the potential therapeutic use of ETV, its phosphorylation was examined in hepatoma cells treated with extracellular concentrations representative of drug levels in plasma in ETV-treated patients. At these concentrations, intracellular ETV-TP accumulated to levels expected to inhibit the enzyme activity of both wild-type and 3TC-resistant HBV Pol. These findings are predictive of potent antiviral activity of ETV against both wild-type and 3TC-resistant HBV.
| S-EPMC127388 | biostudies-literature
Project description:Background/aimsSuboptimal responses to lamivudine or telbivudine plus adefovir (LAM/LdT+ADV) rescue therapy are common in patients with LAM-resistant hepatitis B virus (HBV) infections. We compared patients switched to entecavir plus tenofovir (ETV+TDF) to those maintained on LAM/LdT+ADV.MethodsThis prospective randomized controlled trial examined 91 patients whose serum HBV DNA levels were greater than 60 IU/mL after at least 24 weeks of treatment with LAM/LdT+ADV for LAM-resistant HBV. Patients were randomized to receive a new treatment (ETV+TDF, n=45) or maintained on the same treatment (LAM/LdT+ADV, n=46) for 48 weeks. Patients with baseline ADV resistance were excluded.ResultsCompared to LAM/LdT+ADV group, ETV+TDF group had more patients with a virologic response (42/45 [93.33%] vs. 3/46 [6.52%], P<0.001) and had a greater mean reduction in serum HBV DNA level from baseline (-4.16 vs. -0.37 log10 IU/mL, P<0.001). Multivariate analysis indicated that high baseline HBV DNA level (P=0.005) and LAM/LdT+ADV maintenance therapy (P=0.001) were negatively associated with virologic response. At week 48, additional ADV- or ETV-associated mutations were cleared in ETV+TDF group, but such mutations were present in 4.3% of patients in LAM/LdT+ADV group (P=0.106). The two groups had similar rates of adverse events.ConclusionETV+TDF combination treatment led to a significantly higher rate of virologic response compared to LAM/LdT+ADV combination treatment in patients with LAM-resistant HBV who had suboptimal responses to LAM/LdT+ADV regardless of HBV genotypic resistance profile (NCT01597934).
| S-EPMC7364362 | biostudies-literature
Project description:UNLABELLED:Certain nucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) are effective against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). However, both viruses often acquire NRTI resistance, making it crucial to develop more-potent agents that offer profound viral suppression. Here, we report that 4'-C-cyano-2-amino-2'-deoxyadenosine (CAdA) is a novel, highly potent inhibitor of both HBV (half maximal inhibitory concentration [IC50 ]?=?0.4 nM) and HIV-1 (IC50 ?=?0.4 nM). In contrast, the approved anti-HBV NRTI, entecavir (ETV), potently inhibits HBV (IC50 ?=?0.7 nM), but is much less active against HIV-1 (IC50 ?=?1,000 nM). Similarly, the highly potent HIV-1 inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA; IC50 ?=?0.3 nM) is less active against HBV (IC50 ?=?160 nM). Southern analysis using Huh-7 cells transfected with HBV-containing plasmids demonstrated that CAdA was potent against both wild-type (IC50 ?=?7.2 nM) and ETV-resistant HBV (IC50 ?=?69.6 nM for HBVETV-RL180M/S202G/M204V), whereas ETV failed to reduce HBVETV-RL180M/S202G/M204V DNA even at 1 ?M. Once-daily peroral administration of CAdA reduced HBVETV-RL180M/S202G/M204V viremia (P?=?0.0005) in human-liver-chimeric/ HBVETV-RL180M/S202G/M204V-infected mice, whereas ETV completely failed to reduce HBVETV-RL180M/S202G/M204V viremia. None of the mice had significant drug-related body-weight or serum human-albumin concentration changes. Molecular modeling suggests that a shallower HBV-RT hydrophobic pocket at the polymerase active site can better accommodate the slightly shorter 4'-cyano of CAdA-triphosphate (TP), but not the longer 4'-ethynyl of EFdA-TP. In contrast, the deeper HIV-1-RT pocket can efficiently accommodate the 4'-substitutions of both NRTIs. The ETV-TP's cyclopentyl ring can bind more efficiently at the shallow HBV-RT binding pocket. CONCLUSION:These data provide insights on the structural and functional associations of HBV- and HIV-1-RTs and show that CAdA may offer new therapeutic options for HBV patients.
| S-EPMC4589464 | biostudies-literature
Project description:A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudine-resistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV+ADV, n = 45) or continuation of lamivudine plus adefovir (LAM+ADV, n = 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log(10) IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV+ADV group than in the LAM+ADV group (n = 13, 29%, versus n = 2, 4%, respectively; P = 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV+ADV group than in the LAM+ADV group (-2.2 log(10) IU/ml versus -0.6 log(10) IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV+ADV group but in 15% of patients in the LAM+ADV group (P = 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus-adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy.
| S-EPMC3370750 | biostudies-literature
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.
| S-EPMC6437475 | biostudies-literature
Project description:Background/aimsLong-term data on antiviral therapy in Korean patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are limited. This study evaluated the efficacy and safety of entecavir (ETV) and lamivudine (LAM) over 240 weeks.MethodsTreatment-naive patients with HBeAg-negative CHB were randomized to receive ETV 0.5 mg/day or LAM 100 mg/day during the 96 week double-blind phase, followed by open-label treatment through week 240. The primary endpoint was the proportion of patients with virologic response (VR; hepatitis B virus [HBV] DNA<300 copies/mL) at week 24. Secondary objectives included alanine aminotransferase (ALT) normalization and emergence of ETV resistance (week 96), VR and log reduction in HBV DNA levels (week 240), and safety evaluation.ResultsIn total, 120 patients (>16 years old) were included (ETV, n=56; LAM, n=64). Baseline characteristics were comparable between the two groups. A significantly higher proportion of ETV-treated patients achieved VR compared to LAM at week 24 (92.9% vs. 67.2%, P=0.0006), week 96 (94.6% vs. 48.4%, P<0.0001), and week 240 (95.0% vs. 47.6%, P<0.0001). At week 96, ALT normalization was observed in 87.5% and 51.6% of ETV and LAM patients, respectively (P<0.0001). Virologic breakthrough occurred in one patient (1.8%) receiving ETV and 26 patients (42.6%) receiving LAM (P<0.0001) up to week 96. Emergence of resistance to ETV was not detected. The incidence of serious adverse events was low and unrelated to the study medications.ConclusionsLong-term ETV treatment was superior to LAM, with a significantly higher proportion of patients achieving VR. Both treatments were well tolerated.
| S-EPMC5760004 | biostudies-literature