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Background: Chronic hepatitis B virus (HBV) infection is a global health threat for which there is an urgent need to develop novel therapeutics. Methods: Aurintricarboxylic acid (ATA) has been demonstrated with broad-spectrum antimicrobial and antiviral activities. In this study, we implemented ATA treatment in HBVinfected and HBV-transfected hepatocytes to uncover whether ATA inhibits HBV replication and its underlying mechanism. Results: HBV DNA levels were significantly reduced, while viral proteins or transcripts were not altered. In contrast, ATA treatment did not further deteriorate HBV DNAs, viral proteins, and transcripts in hepatocytes transfected by an HBV RNase H dead mutant. Moreover, ATA showed an inhibitory effect on DNA synthesis in hepatocytes transfected with lamivudine-resistant HBV mutants. Conclusions: ATA is a potent inhibitor of HBV replication by disrupting the RNase H activity of the viral polymerase. [ABSTRACT FROM AUTHOR]

Background/AimsThis study investigated the antiviral effects of tenofovir disoproxil fumarate (TDF) monotherapy in nucleos(t)ide analogue (NA)-naive and NA-experienced chronic hepatitis B (CHB) patients.MethodsCHB patients treated with TDF monotherapy (300 mg/day) for ≥12 weeks between December 2012 and July 2014 at a single center were retrospectively enrolled. Clinical, biochemical, and virological parameters were assessed every 12 weeks.ResultsIn total, 136 patients (median age 49 years, 96 males, 94 HBeAg positive, and 51 with liver cirrhosis) were included. Sixty-two patients were nucleos(t)ide (NA)-naïve, and 74 patients had prior NA therapy (NA-exp group), and 31 patients in the NA-exp group had lamivudine (LAM)-resistance (LAM-R group). The baseline serum hepatitis B virus (HBV) DNA level was 4.9±2.3 log IU/mL (mean±SD), and was higher in the NA-naïve group than in the NA-exp and LAM-R groups (5.9±2.0 log IU/mL vs 3.9±2.0 log IU/mL vs 4.2±1.7 log IU/mL, P

Background/AimsAdefovir dipivoxil (ADV) is a nucleotide analogue that is effective against lamivudine-resistant hepatitis B virus (HBV). The aim of this study was to determine the long-term clinical outcomes after ADV rescue therapy in decompensated patients infected with lamivudine-resistant HBV.MethodsIn total, 128 patients with a decompensated state and lamivudine-resistant HBV were treated with ADV at a dosage of 10 mg/day for a median of 33 months in this multicenter cohort study.ResultsFollowing ADV treatment, 86 (72.3%) of 119 patients experienced a decrease in Child-Pugh score of at least 2 points, and the overall end-stage liver disease score decreased from 16±5 to 14±10 (mean ± SD, P

Entecavir (ETV) plus adefovir (ADV) combination therapy is one of the useful treatment option for the patients with chronic hepatitis B (CHB) who had failed on prior nucleos(t) ide analogue (NA) treatments. This study compared the efficacies of the combinations of ETV 0.5 mg plus ADV and ETV 1.0 mg plus ADV in patients who had failed on prior multiple NA treatments. This retrospective analysis included 148 consecutive patients with CHB infection in Korea (n = 37 with ETV 0.5 mg plus ADV and n = 111 with ETV 1.0 mg plus ADV). The virological and biochemical responses were compared between the two groups. The cumulative probability of viral suppression of ETV 0.5 mg plus ADV was not inferior to that of ETV 1.0 mg plus ADV (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.38-1.08; P = 0.094). The changes in serum HBV DNA level in the ETV 0.5 mg plus ADV group were not different between the two groups over 12 months. Moreover, no significant difference was observed in acquiring ETV-resistant variants between the two groups during the treatment (HR, 0.95; P = 0.953). This study suggests the proof-of-concept that the lower dose of NA in combination with other NA might be the theoretical option for rescue combination therapy in patients with CHB who had failed on prior multiple NA treatments in order to reduce systemic exposure and possible side effects of NA. J. Med. Virol. 87:999-1007, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Adefovir dipivoxil, an oral prodrug of adefovir, is used in the treatment of lamivudine-resistant hepatitis B virus (HBV) infection. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN) were commonly reported in the past, when higher doses were used for the treatment of human immunodeficiency virus infection. However, nephrotoxicity is rare at lower doses that are currently recommended for the treatment of HBV infection. A 31-year-old female was detected to be hepatitis B surface antigen positive months after a kidney transplant. The patient was initiated on lamivudine, but developed resistance after 1 year of treatment, at which time low-dose adefovir was added. The patient developed renal allograft dysfunction after 10 months of starting adefovir. Serum creatinine increased from 1.1 mg/dl to 1.9 mg/dl, along with progressively increasing sub-nephrotic proteinuria. Renal allograft biopsy revealed features of ATN. After discontinuation of adefovir, proteinuria resolved and renal dysfunction improved slowly over the next 2 years. Adefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods. [ABSTRACT FROM AUTHOR]

To determine whether adefovir (ADV) in combination with entecavir (ETV) is more effective than with lamivudine (LAM) in patients with lamivudine-resistant chronic HBV infection, electronic databases were searched through May 10th, 2013 to obtain relevant trials which met the inclusion criteria. Meta-analysis was performed on randomized controlled trials (RCTs) and non-randomized studies. Four trials containing a total of 323 patients were included. Serum HBV DNA reductions after 3 and 6 months of treatment in the ETV + ADV group were greater than that of LAM + ADV group (mean difference (MD) = 0.90, 95% confidence interval (CI): 0.74-1.07, P < 0.00001; MD = 0.81, 95% CI: 0.57-1.06, P < 0.00001). The rate of 6 months HBV DNA undetectability with ETV and ADV was higher than that of LAM and ADV (relative risk (RR) = 1.63, 95% CI: 1.14-2.34, P < 0.007). There were higher rates of serum ALT normalization than those in LAM + ADV group after 6 months of treatment (RR = 1.40, 95% CI: 1.11-1.77, P < 0.005). The ETV + ADV group had lower viral breakthrough and genotypic mutation rates than LAM + ADV group after 12 months of treatment (RR = 0.24, 95% CI: 0.10-0.58, P = 0.002). The combination of ETV plus ADV is a more effective rescue therapy than LAM add-on ADV in patients with LAM-resistant HBV. [ABSTRACT FROM AUTHOR]

Purpose: Lamivudine (LAM) resistance is common on lamivudine monotherapy for chronic hepatitis B. This study examined the safety and efficacy of telbivudine (LDT) given with adefovir (ADV) versus ADV monotherapy in patients with chronic, lamivudine-resistant HBV infection. Methods: An open-label, 96 week study with planned recruitment of 150 HBeAg-positive, lamivudine-experienced Asian patients with a confirmed YMDD resistance mutation, randomized 1:1 to receive ADV alone or with LDT. The study was terminated early due to difficulty in enrolling monotherapy patients. At termination, 42 patients had received study medication for 8-61 weeks. Due to incomplete enrolment, summary statistics only were prepared, without significance testing. Results: A total of 42 patients underwent rescue therapy (switch to ADV or LDT + ADV; n = 21 per group). Median treatment duration was 48 weeks in both groups. HBV DNA changes from baseline were greater in the LDT + ADV arm at all time points (Week 48: −7.4 log vs. −4.9 log copies/ml), and serum DNA was undetectable (<300 copies/mL) at week 48 in 38.5% (5/13) on LDT + ADV versus 0% (0/9) on ADV monotherapy Two patients (9.6%) on ADV monotherapy experienced virologic breakthrough without evidence of ADV resistance, but none on LDT + ADV; and no confirmed ADV resistance was observed in any on-treatment sample. HBeAg loss occurred in three patients on LDT + ADV and one patient on ADV monotherapy through week 48. Safety profiles were similar between the arms. Conclusion: LDT + ADV combination treatment showed better outcomes against lamivudine resistant HBV than ADV alone, with a similar safety profile. [ABSTRACT FROM AUTHOR]

ABSTRACT Antiviral drug resistance is the most important factor contributing to treatment failure using nucleos(t)ide analogs such as lamivudine for chronic infection with hepatitis B virus (HBV). Development of a system supporting efficient replication of clinically resistant HBV strains is imperative, and new antiviral drugs are needed urgently to prevent selection of drug-resistant HBV mutants. A novel fluorinated cytidine analog, NCC (N-cyclopropyl-4′-azido-2′-deoxy-2′-fluoro-β-d-cytidine), was recently shown to strongly inhibit human HBV in vitro and in vivo. This study was designed to evaluate the antiviral activity of NCC against lamivudine-resistant HBV. We generated a stable cell line encoding the major pattern of lamivudine-resistant mutations rtL180M/M204V and designated it "HepG2.RL1". Immuno-transmission electron microscopic examination and enzyme-linked immunosorbent assay were used to detect secretion of HBV-specific particles and antigens. Quantification of extracellular DNA and intracellular DNA of HepG2.RL1 cells by quantitative real-time polymerase chain reaction revealed >625-fold and >5556-fold increases in the 50% inhibitory concentration of lamivudine, respectively, compared with that for the wild-type virus. The results showed that NCC inhibited DNA replication and HBeAg production in wild-type or lamivudine-resistant HBV in a dose-dependent manner. In conclusion, screening for antiviral compounds active against lamivudine-resistant HBV can be carried out with relative ease using hepG2.RL1 cells. NCC is a potential antiviral agent against wild-type HBV and clinical lamivudine-resistant HBV and deserves evaluation for the treatment of HBV infection.

Summary: Objectives: The aim of the current study was to compare the effectiveness of adefovir dipivoxil (ADV) monotherapy with that of combination ADV and lamivudine (LAM) therapy in the treatment of LAM-resistant chronic hepatitis B (CHB). Methods: Publications on the effectiveness of ADV monotherapy versus the combination of ADV and LAM therapy for the treatment of LAM-resistant CHB were identified by a search (up to year 2010) of the PubMed, HealthStar, ScienceDirect, and VIP databases. Biochemical response data (alanine aminotransferase normalization rate) and virological response data (serum hepatitis B virus DNA undetectable rate) were extracted and combined to obtain an integrated result. Results: The literature search yielded 11 articles, six of which reported randomized controlled trials; the remaining five reported prospective cohort studies. The summary odds ratio (OR) values of the biochemical response at 3, 6, 12, and >12 months were 1.60 (p =0.06), 1.30 (p =0.18), 1.77 (p =0.008), and 3.35 (p <0.00001), respectively. The summary OR values of the virological response at 3, 6, 12, and >12 months were 1.46 (p =0.21), 1.68 (p =0.04), 1.16 (p =0.54), and 1.87 (p =0.01), respectively. Conclusions: The effectiveness of the combination therapy was not obviously predominant over the monotherapy in short duration therapies; however, the combination therapy had a great advantage over monotherapy in both biochemical and virological response when the therapy duration was prolonged to >12 months. [Copyright &y& Elsevier]

Aim: To investigate retrospectively the long-term efficacy of various treatment strategies using adefovir dipivoxil (adefovir) in patients with lamivudine-resistant chronic hepatitis B., Methods: We included 154 consecutive patients in two treatment groups: the "add-on" group (n = 79), in which adefovir was added to ongoing lamivudine treatment due to lamivudine resistance, and the "switch/combination" group (n = 75), in which lamivudine was first switched to adefovir and then re-added later as needed. The "switch/combination" group was then divided into two subgroups depending on whether participants followed (group A, n = 30) or violated (group B, n = 45) a proposed treatment strategy that determined whether to add lamivudine based on the serum hepatitis B virus (HBV) DNA levels (< 60 IU/mL or not) after 6 mo of treatment (roadmap concept)., Results: The cumulative probability of virologic response (HBV DNA < 60 IU/mL) was higher in group A than in the "add-on" group and in group B (P < 0.001). In contrast, the cumulative probability of virologic breakthrough was lower in the "add-on" group than in group B (P = 0.002). Furthermore, the risk of virologic breakthrough in the multivariate analysis was significantly lower in the "add-on" group than in group A (hazard ratio = 0.096; 95%CI, 0.015-0.629; P = 0.015)., Conclusion: The selective combination of adefovir with lamivudine based upon early treatment responses increased the odds of virologic breakthrough relative to the use of uniform combination therapy from the beginning of treatment.