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John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral drugs such as ganciclovir, stavudine, didanosine, cidofovir, oseltamivir, adefovir dipivoxil, tenofovir disoproxil fumarate, tenofovir alafenamide, sofosbuvir, and remdesivir.

The treatment of multidrug-resistant (MDR) chronic hepatitis B (CHB) is challenging. Herein, we report a multicenter prospective cohort study for the evaluation of tenofovir disoproxil fumarate (TDF)-based therapy for MDR CHB in a real-life setting. The inclusion criteria comprised patients with resistance to more than two nucleos(t)ide analogue (NA) classes and hepatitis B virus (HBV) DNA level of ≥200 IU/mL. The primary end-point was virologic response (VR), defined as undetectable HBV DNA (

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG-interferon alpha-2a (PEG-IFN alpha-2a) is the only effective treatment but its long-term clinical impact is unclear. the aim of this study was to investigate the long-term outcome after 48 weeks of pegylated interferon alpha-2a therapy. We performed a retrospective follow-up study of the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-I trial). Patients had received 48 weeks of treatment with either PEG-IFN alpha-2a plus adefovir dipivoxil (ADV) (Group I), PEG-IFN alpha-2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver-related complications were defined as liver-related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child-Pugh scores B or C or an increase in Model for End-stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG-IFN alpha-2a. Follow-up data (at least 1 visit beyond post-treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow-up was 8.9 (1.6 - 13.4) years. 19 patients were retreated with IFN-based therapy: 42% (n = 8) in PEG-IFN alpha-2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long-term follow-up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. the annual event-free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long-term follow-up of a large randomized clinical trial suggests that off-treatment HDV RNA response to PEG-IFN alpha-2a treatment leads to improved clinical long-term outcome., German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig; German Liver Foundation; EASL registry grant, This study was funded by the German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig with a grand to the HepNet Study-House, the German Liver Foundation and an EASL registry grant.

Replication stress is a common feature of cancer cells. Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) signalling, a DNA damage repair (DDR) pathway, is activated by regions of single-stranded DNA (ssDNA) that can arise during replication stress. ATR delays cell cycle progression and prevents DNA replication fork collapse, which prohibits cell death and promotes proliferation. Several ATR inhibitors have been developed in order to restrain this protective mechanism in tumours. It is known, however, that despite other effective anticancer chemotherapy treatments targeting DDR pathways, resistance occurs. This begets the need to identify combination treatments to overcome resistance and prevent tumour cell growth. We conducted a drug screen to identify potential synergistic combination treatments by screening an ATR inhibitor (VE822) together with compounds from a bioactive small molecule library. The screen identified adefovir dipivoxil, a reverse transcriptase inhibitor and nucleoside analogue, as a compound that has increased cytotoxicity in the presence of ATR, but not ATM or DNA-dependant protein kinase (DNA-PK) inhibition. Here we demonstrate that adefovir dipivoxil induces DNA replication stress, activates ATR signalling and stalls cells in S phase. This simultaneous induction of replication stress and inhibition of ATR signalling lead to a marked increase in pan-nuclear γH2AX-positive cells, ssDNA accumulation and cell death, indicative of replication catastrophe.

This protocol for a Cochrane Review is out of date. Auhors have abandoned it.

Nucleoside and nucleotide analogues (NUCs) targeting hepatitis B virus are capable of selecting resistant viruses upon long-term administration as monotherapies. The prevalence of resistance-associated substitutions (RASs) and fitness-associated substitutions at baseline of NUC therapy and their impact on treatment responses remain unknown. A total of 232 treatment-naïve patients chronically infected with hepatitis B virus (HBV) consecutively referred for the first time to one of French reference centres were included. The nearly full-length HBV reverse transcriptase was sequenced by means of deep sequencing, and the sequences were analysed. RASs were detected in 25% of treatment-naïve patients, generally representing low proportions of the viral quasispecies. All amino acid positions known to be associated with HBV resistance to currently approved NUCs or with increased fitness of resistant variants were affected, except position 80. RASs at positions involved in lamivudine, telbivudine and adefovir resistance were the most frequently detected. All patients with RASs detectable by next-generation sequencing at baseline who were treatment-eligible and treated with currently recommended drugs achieved a virological response. The presence of pre-existing HBV RASs has no impact on the outcome of therapy if potent drugs with a high barrier to resistance are used.

Background Long term renal safety of antiviral agents against hepatitis B virus (HBV) has been debated. Aim To compare longitudinal trends of renal function among HBV mono-infected patients receiving entecavir (ETV), tenofovir disoproxil fumarate (TDF), and adefovir (ADV) in comparison to untreated subjects. Methods A retrospective cohort consisting of 815 patients with chronic HBV infection was constructed. Serial estimated glomerular filtration rate (eGFR) was compared to the expected rate of age-dependent decline in eGFR, derived from the National Health and Nutrition Examination Survey (NHANES) data. Generalised estimating equations and linear mixed-effects models were used to compare trends in eGFR (in mL/min/1.73m2 as a "unit"). Results In NHANES data (n = 23 051), each year of age was associated with a 0.86 unit decrease in eGFR in subjects without hypertension and 0.96 units with hypertension. The Stanford cohort consisted of patients who received ETV (n = 207), TDF (n = 191), ADV (n = 46) or no therapy (n = 371). After a median follow-up 4.0 (interquartile range: 1.9-6.5) years, there was no significant difference in the expected and observed rates of eGFR decline in untreated HBV patients. Patients receiving antiviral treatment experienced steeper reduction in renal function than expected. In the multivariable model, ETV was associated with eGFR loss at 1.81 units per year (P = 0.06, compared to untreated patients). TDF- and ADV-treated patients experienced significantly higher rate of eGFR loss at 2.21 and 2.63 units per year, respectively (both P Conclusion In this longitudinal cohort study, HBV patients receiving antiviral therapy, particularly TDF and ADV, experienced more rapid loss in eGFR.

Chronic hepatitis B (CHB) is one of the major causes of morbidity and mortality worldwide. Currently, clinically approved nucleos(t)ide analogs (NAs) are very efficient in reducing the load of hepatitis B virus (HBV) with minimum side effects. However, the long-term administration of antiviral drugs promotes HBV for potential drug resistance. To overcome this problem, combination therapies are administered, but HBV progressively altered mutations remain a threat. Therefore, optimally designed NAs are urgently needed to treat drug-resistant HBV. Herein, 2'-fluoro-6'-methylene carbocyclic adenosine (FMCA) and its phosphoramidate (FMCAP) have been discovered, which may be utilized in combination therapies for curing drug-resistant chronic hepatitis B. In preclinical studies, these carbocyclic NAs demonstrated potential anti-HBV activity against adefovir, as well as lamivudine (LMV/LAM) drug-resistant mutants. In vitro, these molecules have demonstrated significant activity against LMV/entecavir (ETV) triple mutants (L180M + S202G + M204V). Also, preliminary studies of FMCA/FMCAP in chimeric mice and female Non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models having the LMV/ETV triple mutant have shown a high rate of reduction of HBV DNA levels compared to ETV. In this review, we have summarized preclinical studies of FMCA and its phosphoramidate prodrug (FMCAP).

SummaryBackground Safety profile of nucleos(t)ide analogues is an important issue in view of its widespread use for decades in patients with chronic hepatitis B (CHB). Aim To review and evaluate the latest evidence on the safety profiles of the six approved nucleoside analogues. Methods Relevant articles related to nucleoside analogue safety were selected for review following extensive language- and date-unrestricted, electronic searches of the literature. Results Nephrotoxicity has been well reported in patients receiving older generations of nucleotide analogues, namely adefovir dipivoxil and tenofovir disoproxil fumarate (TDF). Yet risks of renal failure and renal replacement therapy were similar in patients treated with nucleoside analogues versus nucleotide analogues in real-life setting. Bone toxicity is closely related to nucleoside analogue effect on renal proximal tubular and phosphaturia. Real-life data demonstrated increased risk of hip fracture in patients receiving adefovir but not TDF. The newly approved tenofovir alafenamide (TAF) has improved renal and bone safety profiles compared to TDF. Long-term use of nucleoside analogues eg entecavir does not increase the risk of other cancers. Muscular toxicity may be seen in telbivudine-treated patients so regular monitoring is advised. Peripheral neuropathy and lactic acidosis are rare adverse events. Latest international guidelines support the use of TDF, telbivudine and lamivudine during pregnancy; breastfeeding is not contraindicated during TDF therapy. Conclusions Long-term safety profile of nucleoside analogues is now better defined with more data from large real-life cohorts and clinical trials with long-term follow-up. The new nucleotide analogue, TAF is now available with favourable renal and bone safety profiles.

The purpose of the study was to compare the efficacy and safety of 208-week sequential therapy with telbivudine and entecavir in HBeAg-positive chronic hepatitis B (CHB) patients with suboptimal responses to 24 weeks of Peg-IFNα-2a therapy. This was an open-label, randomized, controlled, "real-life" trial. HBeAg-positive CHB patients with serum HBV DNA ≥5.0 lg IU/mL and a

Aim Little is currently known regarding the impact on tubular function in patients with chronic hepatitis B (CHB) under long-term use of nucleos(t)ide analogs. Previous studies showed that neutrophil gelatinase-associated lipocalin (NGAL) elevation was associated with renal tubular injury. We evaluated renal function markers and bone mineral density (BMD) in patients treated long-term with adefovir dipivoxil (ADV) or entecavir (ETV). Methods In this cross-sectional study,we enrolled 78 patients (ADV: 36, ETV: 42), and 21 patients matched for age, observation time, and baseline estimated glomerular filtration rate (eGFR) from each group. Results Patients treated with ADV showed a significant increase in serum creatinine and urine β2-microglobulin, and decreased eGFR, and BMD. Furthermore, the median levels of NGAL in patients treated with ADV are significantly higher than those of ETV (12.5 ng/mL vs. 2.5 ng/mL P = 0.020). The proportions of patients with proteinuria and phosphate

Aims Little clinical data are available regarding re-establishing the effective inhibition of entecavir (ETV)-resistant mutants. In this retrospective study, we aimed to compare the efficacies of four treatment regimens as rescue therapy for those chronic hepatitis B (CHB) patients with ETV resistance. Methods A total of 65 patients with ETV resistance were assigned either with tenofovir disoproxil fumarate (TDF) monotherapy (n = 21), ETV (0.5 mg) plus adefovir (ADV) combination therapy (n = 19), ETV (1.0 mg) monotherapy (n = 11) or ETV (0.5 mg) plus TDF combination therapy (n = 14). The efficacy and safety of four treatment regimens were compared. Results There were no significant differences among the four study groups in baseline characteristics, including HBV DNA levels (χ2 = 0.749, P = 0.862) and hepatitis B e antigen-positivity (χ2 = 0.099, P = 0.992). The median reduction in serum HBV DNA level from baseline at week 48 was -2.37 ± 1.07 log10 IU ml-1 , -2.16 ± 0.81 log10 IU ml-1 , -1.17 ± 1.23 log10 IU ml-1 and -2.49 ± 1.10 log10 IU ml-1 , respectively (F = 4.078, P = 0.011). The TDF group and ETV (0.5 mg) + TDF group have the highest undetectable HBV DNA rate (76.19% vs. 78.57%) compared to the ETV (0.5 mg) + ADV group and the ETV (1.0 mg) group (63.16% vs. 18.18%, respectively). Two patients in the ETV (1.0 mg) group experienced virological breakthrough at week 48 and was attributed to poor drug adherence. Conclusions TDF monotherapy appeared to deliver the highest undetectable HBV DNA rate in patients with ETV resistance, and ADV plus ETV combination therapy could be another choice for patients with financial restraint.

BACKGROUND/AIMS Serum hepatitis B s antigen (HBsAg) levels might be used as a predictor of virological breakthrough or of sustained off-treatment virological response in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. We evaluated the changes of HBsAg in those patients under nucleos(t)ide analogue(s) [NA(s)] therapy for ≥12 months. METHODS We included 99 HBeAg-negative CHB patients treated with low-genetic barrier NA(s) for a mean of 66 months (lamivudine: 66, adefovir: 6, lamivudine plus adefovir: 11 and telbivudine: 16) and 86 HBeAg-negative CHB patients treated under entecavir or tenofovir for a mean of 30 months as the comparison group. RESULTS Compared to baseline, HBsAg levels decreased by a median of 162, 1525, 943, 1545, 2163 and 3859 IU/mL at 6, 12, 24, 36, 48 and 60 months of therapy with low-genetic barrier NA(s) respectively. The 6-, 12-, 24-, 36-, 48- and 60-month cumulative rates of HBsAg

Aim In chronic hepatitis B patients receiving 10 mg adefovir, dose reduction is recommended when renal injury appears. However, recovery is not always achieved and markers that recommend switching to another antiviral agent are unknown. We investigated adefovir-related renal injury, recovery after dose reduction, and their predictors. Methods The renal injury in 77 chronic hepatitis B patients receiving 10 mg adefovir and recovery after dose reduction to alternate day administration in those with adefovir-related renal injury were assessed. The predictors for >20% estimated glomerular filtration rate (eGFR) decline following 10 mg adefovir administration and for >20% eGFR recovery after dose reduction were investigated. Results The adefovir dose was reduced in 26 patients (34%) at 59 ± 30 (mean ± SD) months of 10 mg adefovir administration because of decreases in eGFR (cumulative incidence 27%), serum phosphorus (9%) and uric acid (16%) levels, and increases in alkaline phosphatase (20%), bone type alkaline phosphatase (18%), urinary α1-microglobulin (18%) and urinary N-acetyl-β-D-glucosaminidase (18%) levels. ≥50 years of age at the start of 10 mg adefovir administration was the only significant predictor for >20% eGFR decline. The cumulative eGFR recovery rate was 42% at 42 ± 27 months after dose reduction, and ≥2.5 mg/dL of serum phosphorus level at dose reduction was the only significant predictor for >20% eGFR recovery after dose reduction. Conclusion The patients ≥50 years of age are predisposed to adefovir-related renal injury and switching to another antiviral agent rather than adefovir dose reduction is recommended when hypophosphatemia is observed.

Background/aims Nucleos(t)ide analogs (NAs) have made a hepatitis B immunoglobulin (HBIG)-sparing protocol an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, this approach is considered controversial in patients transplanted for HBV and hepatitis D (HDV) co-infection. Material/Methods All patients transplanted for HBV/HDV cirrhosis were evaluated. After LT, each patient received HBIG + NAs and then continued with NAs prophylaxis. All patients were followed up with HBV serum markers and HBV DNA, while anti-HDV/HDV RNA was performed in those with HBV recurrence. Results A total of 34 recipients were included (22 men, age: 46.7 ± 16 years). After HBIG discontinuation, NAs were received as monoprophylaxis (lamivudine [LAM]: 2, adefovir [AFV]: 1, entecavir: 9, tenofovir [TDF]: 12) or dual prophylaxis (LAM + AFV [or TDF]: 10 patients). Two (5.8%) of the 34 patients had HBV/HDV recurrence after HBIG withdrawal (median follow-up: 28 [range, 12–58] months). These 2 patients had undetectable HBV DNA at LT. Statistical analysis revealed that those with recurrence had received HBIG for shorter period, compared to those without recurrence (median: 9 vs. 28 months, P = 0.008). Conclusions We showed for the first time, to our knowledge, that maintenance therapy with NAs prophylaxis after HBIG discontinuation was effective against HBV/HDV recurrence, but it seems that a longer period of HBIG administration might be needed before it is withdrawn after LT.

Background The aim of this study was to determine the long-term efficacy of nucleos(t)ide analog (NA) and low-dose hepatitis B immunoglobulin (HBIG) combination treatment for preventing post-transplant hepatitis B virus (HBV) recurrence. Methods A total of 296 patients with HBV-associated liver disease who underwent liver transplantation (LT) were enrolled. A combination of a daily NA and low-dose HBIG was used after LT. Results The median follow-up period was 46 months. HBV recurrence occurred in eight patients. The cumulative probability of HBV recurrence at 1, 3, 5, and 7 years was 1%, 3%, 3%, and 4%, respectively. Seven were on lamivudine (LMV) or adefovir dipivoxil (ADV), or LMV and ADV and HBIG combination treatment and one entecavir (ETV) and HBIG. With Cox regression analysis, HBV recurrence was determined to be associated with the presence of hepatocellular cancer (HCC) prior to LT (HR: 12.3, P=.02). Overall, 44 patients died. Survival was significantly better in the ETV or tenofovir disoproxil fumarate (TDF) and HBIG group than the other group (P

We investigated the durability of virological response after lamivudine (LAM) discontinuation in LAM-resistant chronic hepatitis B (CHB) patients with complete virological response after LAM-adefovir (ADV) combination therapy. We enrolled 58 patients switched to ADV monotherapy with undetectable viral loads (

Background and Aim: We investigated the long-term efficacy of adefovir add-on lamivudine rescue therapy in lamivudine-resistant chronic hepatitis B and the optimal cutoff hepatitis B virus (HBV) DNA level that predicts complete virological response (CVR) among patients without CVR after 1 year of treatment. Methods: We reviewed 167 lamivudine-resistant chronic hepatitis B patients who received adefovir add-on rescue therapy for up to 5 years. Multivariate analysis, area under the receiver operating characteristic curves, and Youden index were used. Results: Median age was 47.0 years; 112 patients were male. Median baseline HBV DNA level was 6.6 log10 IU/mL; hepatitis B e antigen was positive in 130 (77.4%) patients. Five-year CVR, alanine aminotransferase normalization, hepatitis B e antigen seroconversion, and adefovir resistance rates were 86.9%, 92.5%, 16.7%, and 6.0%, respectively. One-year HBV DNA level independently associated with CVR. Optimal cutoff HBV DNA level to predict CVR among patients who failed to achieve CVR at 1 year was 800 IU/mL (area under receiver operating characteristic curve 0.752; sensitivity 49.3%, specificity 93.5%). During the 5-year treatment, 92.1% of patients with favorable response (HBV DNA

On the basis of potent antiviral activity of adefovir (1) and tenofovir (2), which are representative acyclic nucleoside phosphonates, bioisosteric acyclic selenonucleoside phosphonates seleno-adefovir (3) and seleno-tenofovir (4) were designed and synthesized from diethyl(iodomethyl)phosphonate (7) by using diselenide chemistry.

Background and Aim In the past decade, many chronic hepatitis B (CHB) patients have undergone sequential treatment with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) to manage antiviral resistance or insufficient suppression of HBV-DNA. Very limited data are available on the efficacy of tenofovir (TDF) rescue regimens in patients with multidrug resistance (MDR). Methods We investigated the antiviral efficacy of TDF/LAM combination therapy versus TDF/ETV combination therapy in 52 patients who failed three previous antiviral therapies. Results The study subjects were treated with TDF/LAM combination therapy (n = 25) or TDF/ETV combination therapy (n = 27) for more than six months. Virologic response (VR) occurred in 39 (75%) patients (19 patients belonged to the TDF/LAM group and 20 patients belonged to the TDF/ETV group). The VR rates were not different between the TDF/LAM and TDF/ETV groups (56.0% vs 51.9% at month 12, and 72.0% vs 78.8% at month 18; log rank P = 0.515). In addition, treatment efficacy of TDF/LAM combination or TDF/ETV combination was not statistically different according to types of MDR. In multivariate analysis, absolute HBV-DNA level at the start of TDF rescue treatment (P

Summary Chronic hepatitis B virus (HBV) infection remains an important global burden with an estimated 240 million HBV carriers worldwide and more than half a million people dying annually from the consequences of the HBV infection. Besides interferon and pegylated interferon, there are five antiviral drugs [lamivudine, adefovir (dipivoxil), entecavir, telbivudine, and tenofovir disoproxil fumarate] that have proved effective in the treatment of chronic hepatitis B. These five antiviral drugs interfere with viral DNA synthesis, which consists of a step reminiscent of the reverse transcriptase step in the replicative cycle of HIV. None of the antiviral drugs, or interferon, are capable of eradicating the covalently closed circular DNA, which remains settled as an episome within the virus-infected hepatocytes. In the short-term (1–3 years), the use of antiviral treatment is aimed at reducing viral DNA below levels of detection, whereas in the long term (10 years and, possibly, lifelong), treatment is aimed at reducing the progression to cirrhosis, hepatocellular carcinoma, liver decompensation, and death. As long as the virus can hide as the episomal covalently closed circular DNA, attempts to envisage a definite cure of the HBV infection may seem fortuitous. Copyright © 2015 John Wiley & Sons, Ltd.

The presence of therapy-associated hepatitis B virus (HBV) variants is the main drawback of antiviral therapy for HBV infection. Moreover, drug-resistant variants are more insensitive to a second agent and more therapy-associated mutations will be present. To apply better nucleos(t)ide analogues (NA) and reduce the occurrence of resistance, the prevalence and types of drug-resistant mutations in acute hepatitis B patients were investigated in this study. One hundred three HBV DNA-positive patients with symptomatic acute hepatitis B that were observed from 2011 to 2013 were enrolled. Direct polymerase chain reaction sequencing was used firstly to screen HBV reverse-transcriptase domain to detect HBV mutants. Five lamivudine-resistant variants were identified. Clonal sequencing was performed for 5 resistance-positive samples and 10 other random samples. Interestingly, all detected samples harbored drug-resistant mutations, although with different percentage. Thirteen harbored lamivudine-related alone (five) or together with other NA related mutations (five with adefovir, one with entecavir, and one with telbivudine), and two of them harbored adefovir-related mutations. Also, mutations associated with four currently used NA were all detected, and the frequency is in accordance with the popularity of NA used in clinical practice. These data suggest that drug-resistant variants are present in patients with acute hepatitis B and NA should be applied more carefully for chronic hepatitis B patients developed from acute hepatitis B.

We evaluated the efficacy of tenofovir (TDF)-based rescue therapy and compared the outcomes of TDF monotherapy and TDF-based nucleoside analog (NA) combination therapy in patients with suboptimal response (SOR) to adefovir (ADV) with or without NAs in lamivudine (LAM)-resistant chronic hepatitis B. All study subjects received ADV with or without NAs due to prior LAM resistance, and were then switched to TDF-based rescue therapy due to SOR (hepatitis B virus DNA >20 IU/ml after at least 6 months of therapy). A total of 125 patients were eligible. The overall cumulative proportion of complete virologic response (CVR) was 64 of 74 patients (86.5%) at 48 weeks of treatment. During the follow-up period of 48 weeks, there was no significant difference in CVR rate (P = 0.750) between the TDF monotherapy (n = 18) and the TDF with NA groups (n = 107). Patients with ADV genotypic mutations showed inferior antiviral responses to TDF compared with the patients without ADV genotypic mutations, but this was not statistically significant (P = 0.069). Partial virological response to prior ADV therapy showed higher CVR rates compared to patients with non-response at 12 weeks (P = 0.013), but there was no significant difference after 24 (P = 0.076) and 48 weeks (P = 0.198) of treatment. TDF monotherapy is as effective as TDF plus NA combination therapy in patients with SOR to ADV-based rescue therapy and LAM resistance. TDF, with or without NAs, was effective even in cases of ADV resistance. J. Med. Virol. 87:1532–1538, 2015. © 2015 Wiley Periodicals, Inc.

A molecularly imprinted polymer has been synthesized to specifically extract adefovir, an antiviral drug, from serum and urine by dispersive solid-phase extraction before high-performance liquid chromatography with UV analysis. The imprinted polymers were prepared by bulk polymerization by a noncovalent imprinting method that involved the use of adefovir (template molecule) and functional monomer (methacrylic acid) complex prior to polymerization, ethylene glycol dimethacrylate as cross-linker, and chloroform as porogen. Molecular recognition properties, binding capacity, and selectivity of the molecularly imprinted polymers were evaluated and the results show that the obtained polymers have high specific retention and enrichment for adefovir in aqueous medium. The new imprinted polymer was utilized as a molecular sorbent for the separation of adefovir from human serum and urine. The serum and urine extraction of adefovir by the molecularly imprinted polymer followed by high-performance liquid chromatography showed a linear calibration curve in the range of 20-100 μg/L with excellent precisions (2.5 and 2.8% for 50 μg/L), respectively. The limit of detection and limit of quantization were determined in serum (7.62 and 15.1 μg/L), and urine (5.45 and 16 μg/L). The recoveries for serum and urine samples were found to be 88.2-93.5 and 84.3-90.2%, respectively.

Background and Aim Data about the efficacy of de novo combination therapies, or optimization strategy by adding the other drug based on the virological response at week 24 of low genetic barrier antiviral agents is still limited. This study aimed to compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE). Methods Adult patients without antiviral therapy within 6 months before screening with hepatitis B virus (HBV)-DNA ≥ 105 copies/mL, alanine aminotransferase 1.3–10 times upper limit of normal and compensated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV-DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued MONO until week 104. For all the patients receiving MONO, ADV would be added if virological breakthrough was confirmed. Results At week 104, more patients in COMBO and OPTIMIZE groups achieved HBV-DNA

In clinical practice, establishing a subsequent optimum treatment for chronic hepatitis B patients with a history of multiple NAs treatment failures, including a suboptimal response to a final therapy with combined ETV and ADV, is a complicated but crucial challenge. This study investigated the efficacy and safety of a tenofovir rescue regimen in these patients. A total of six eligible patients were enrolled and were switched to a tenofovir rescue regimen. At baseline, the genotypes and genotypic mutations of the reverse transcriptase and surface gene were determined by ultra-deep pyrosequencing, and further clonal analyses of the reverse transcriptase domain were performed to identify multidrug-resistant HBV strains. In addition, HBV DNA levels, serology, and biochemistry parameters were monitored at baseline and every 3 months, and abdominal ultrasonography was performed at baseline and every 6 months. All patients were confirmed to harbor LAM-related resistant HBV strains. After switching to the tenofovir rescue treatment, all patients had an undetectable level of HBV DNA within 6 months and achieved normalization of the ALT level within 9 months. These virological and biochemical responses persisted until the end of the observation period. None of the patients developed clinical deterioration or any adverse events related to the tenofovir therapy during the median 16.5-month follow-up. In conclusion, the tenofovir rescue regimen can be employed confidently as a highly effective and safe treatment choice following a suboptimal response to ETV plus ADV therapy for a subset of chronic hepatitis B patients with a history of multiple unsuccessful antiviral treatments. J. Med. Virol. 87:1013–1021, 2015. © 2015 Wiley Periodicals, Inc.

Acute hepatitis B, caused by hepatitis B virus (HBV) strains with drug resistant mutations or pre-core/basal core promoter (PC/BCP) mutations, is a public health concern, because this infection is often associated with poor disease outcome or difficulty in therapeutic choice. The HBV genotype, the prevalence of drug resistant mutations, and PC/BCP mutations in Korean patients with acute hepatitis B were studied. From 2006 to 2008, 36 patients with acute hepatitis B were enrolled prospectively in four general hospitals. Among them, 20 showed detectable HBV DNA (median value was 4.8 log copies/mL). HBV genotyping and analysis of HBV mutations that conferred resistance against lamivudine, adefovir, or entecavir and of PC/BCP mutations were performed using highly sensitive restriction fragment mass polymorphism (RFMP) analysis. All 20 patients were infected with HBV genotype C, which causes almost all cases of chronic hepatitis B in Korea. No patient showed mutations that conferred resistance against lamivudine (L180M, M204V/I), adefovir (A181T, N236S), or entecavir (I169M, A184T/V, S202I/G, M250V/I/L). However, four patients had BCP mutations, and two had PC mutations. Platelet counts were significantly lower in the four patients with PC/BCP mutations compared to those with wild type. In this study, all acute hepatitis B patients had genotype C HBV strains with no drug resistant mutations. However, 20% showed PC/BCP mutations. This highlights the need for further study on the significance of PC/BCP mutations.

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.

Aim There still remain many concerns about the present status of antiviral therapy for chronic hepatitis B in developing countries in Asia, where the monitoring systems of virological markers have not been well established, despite the high prevalence of hepatitis B virus (HBV) infection. To investigate it in Nepal, this prospective cohort study was conducted at the Teaching Hospital of Tribhuvan University in Kathmandu. Methods From 2007 to 2012, 65 patients were consecutively enrolled, 44 of whom received nucleoside analogs (NA), such as lamivudine (LMV), adefovir or tenofovir (TDF), on the decision of the local hepatologist. Virological determinations were performed in Japan, by using the serially collected serum samples at the Teaching Hospital. Statistical analysis was performed, using Mann–Whitney U-test or Fisher's exact test. Results The younger, especially female patients of reproductive age were more frequently prescribed with these NA, and an increased preference for the use of TDF was observed over time. However, there was insufficient follow up of the NA-treated patients in this cohort, and not a few patients developed emergence of NA-resistant HBV: known resistance to LMV in 3 patients and incidental resistance to non-administrated NA in four patients. Conclusion The results of the present study indicate that education for physicians as well as for infected patients regarding the proper use of NA, together with establishment of appropriate monitoring systems for virological markers, is warranted to prevent an increase in NA-resistant HBV infections in Nepal.

Background & AimsDifferences in intrahepatic gene expression patterns may be associated with therapy response in peginterferon-treated chronic hepatitis B (CHB) patients. MethodsWe employed gene expression profiling in baseline liver biopsies of 40 CHB patients (19 HBeAg-positive; 21 HBeAg-negative) treated with peginterferon and adefovir for 48weeks, and compared expression patterns of combined responders (HBeAg loss, HBV-DNA

AIM In this prospective study, we aimed to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Chinese chronic hepatitis B (CHB) patients after multiple nucleoside/nucleotide analog (NA) treatment failures. METHODS A total of 115 Chinese CHB patients with suboptimal response to two or more NA treatments were included in this study. All patients were changed to TDF (300 mg/day, oral administration) antiviral treatment for at least 72 weeks. Hepatitis B virus (HBV) polymerase (P) gene mutation screening for each patient was performed. In addition, virological, biochemical responses and estimated glomerular filtration rate (eGFR) of each patient at weeks 12, 24, 48 and 72 of TDF treatment were evaluated. RESULTS Seventy-six out of 115 patients had drug-resistance mutations (R(+) ), including 27 with adefovir (ADV)-associated mutations (35.5%) and 49 with lamivudine (LMV)-associated mutations (64.5%). For all included patients, complete viral response (CVR) of HBV DNA (

Background and Aim Suboptimal viral suppression with adefovir (ADV) poses a challenge in managing chronic hepatitis B. Few studies have evaluated the efficacy of entecavir (ETV) in ADV-experienced patients. Our aim is to assess treatment effectiveness of ETV in ADV-experienced patients. Methods ADV-experienced patients switched to ETV were enrolled from six US clinics. Patients completed a median of 24 months of ETV after switch. Patients were categorized into partial responders (detectable HBV-DNA at switch) or complete responders (undetectable HBV-DNA at switch) to ADV. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV-DNA

Background & Aims We evaluated the antiviral response of Asian or Pacific Islander (API) patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as pre-treatment hepatitis B virus (HBV) DNA ≥9 log10 copies/ml, following up to 288 weeks of tenofovir disoproxil fumarate (TDF) treatment. Methods A total of 205 HBeAg-negative and HBeAg-positive self-described API patients received 48 weeks of TDF 300 mg (HVL n = 18) or adefovir dipivoxil 10 mg (HVL n = 15) in a blinded fashion, followed by open-label TDF for an additional 240 weeks. The proportions of HVL vs. non-HVL patients with HBV DNA

A combination of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NUC) is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost, and thus several protocols for treatment with low-dose HBIG combined with NUC or HBIG-free regimens have been developed. This article reviews recent advances in post-OLT hepatitis B virus (HBV) control and future methodological directions. New NUC such as entecavir, tenofovir or lamivudine plus adefovir dipivoxil combinations induce a very low frequency of viral resistance. The withdrawal of HBIG after several months of OLT under new NUC continuation also has permissible effects. Even after HBV reactivation, NUC can usually achieve viral control when viral markers are strictly followed up. Another approach is to induce self-producing anti-HBV antibodies via vaccination with a hepatitis B surface antigen vaccine. However, HBV vaccination is not sufficiently effective in patients to treat liver cirrhosis type B after OLT because immune tolerance to the virus has already continued for several decades. Trials of its safety and cost-effectiveness are required. This review advocates a safe and economical approach to controlling post-OLT HBV recurrence.

We investigated the antiviral effect of entecavir in nucleos(t)ide analogue (NA)-naïve and NA-experienced chronic hepatitis B patients without virological response (VR, HBV DNA300 copies/mL) at week 24 or 48. A total of 369 NA-naïve and 181 NA-experienced patients treated with entecavir monotherapy were analysed. Of the 369 NA-naïve patients, 34 did not achieve VR at week 48. Of them, patients with HBV DNA ≤ 2000 copies/mL at week 48 achieved a higher VR rate than those with HBV DNA2000 copies/mL (18/23 vs 3/11, P = 0.004). Two naïve patients with HBV DNA2000 copies/mL developed entecavir- or lamivudine-resistant mutants. In 98 lamivudine-experienced patients without ever having lamivudine resistance, most patients with VR (72/72) and partial VR (300-10(4) copies/mL; 20/23) at week 24 or VR at week 48 (89/91) could maintain or achieve VR after prolonged therapy. In 75 patients with prior resistance to lamivudine, prolonged entecavir therapy led to low VR rate in those without VR at week 24 (13/45) or 48 (4/34) and high entecavir-resistance rate in those with or without VR at week 24 (6/30 with and 23/45 without) and 48 (8/41 with and 21/34 without). VR at week 48 was an independent predictor (HR 0.14, 95% CI 0.06-0.33) for entecavir-resistant mutant development among the 75 patients with prior lamivudine-resistant mutants. In conclusion, prolonged entecavir treatment resulted in a poor response in naïve patients with HBV DNA2000 copies/mL at week 48 and patients with prior lamivudine-resistant mutants without VR at week 24 or 48.

Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included "Hepatitis B virus infection," "children," "HBV," "interferon," "lamivudine," "adefovir," "entecavir," and "tenofovir." Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies.

Background & Aims Here, we evaluated the safety and immunogenicity of hepatitis B virus (HBV) DNA vaccine, HB-110, in mice and Korean patients with chronic hepatitis B (CHB) undergoing adefovir dipivoxil (ADV) treatment. Methods For animal study, mice (BALB/c or HBV transgenic) were immunized with mHB-110, and T-cell and antibody responses were evaluated. For clinical study, 27 patients randomly received either ADV alone or ADV in combination with HB-110. Liver function tests, serum HBV DNA levels and the presence of HBeAg/anti-HBe were analysed. T-cell responses were estimated by ELISPOT and FACS analysis. Results mHB-110 induced higher T-cell and antibody responses than mHB-100 in mice. No adverse effects were observed by HB-110 cotreated with ADV. HBV-specific T-cell responses were induced in a portion of patients in medium to high dose of HB-110. Interestingly, HB-110 exhibited positive effects on ALT normalization and maintenance of HBeAg seroconversion. One patient, who received high dose of HB-110 exhibited HBeAg seroconversion during vaccination, which correlated with vaccine-induced T-cell responses without ALT elevation. Conclusions HB-110 was safe and tolerable in CHB patients. In contrast to results in animal models, HB-110 in Korean patients exhibited weaker capability of inducing HBV-specific T-cell responses and HBeAg seroconversion than HB-100 in Caucasian patients. As Asian patients, who are generally infected via vertical transmission, appeared to have higher level of immune tolerance than Caucasian, novel approaches for breaking immune tolerance rather than enhancing immunogenicity may be more urgently demanded to develop effective therapeutic HBV DNA vaccines.

Oral nucleoside/nucleotide analogues (NAs) are the mainstay of therapy for patients with chronic hepatitis B and are generally well tolerated. Despite this, the safety profile of NAs is of paramount importance since the majority of patients will require long-term treatment. All NAs can potentially affect human DNA polymerase with decrease in mitochondrial DNA, leading to manifestations of mitochondrial toxicity. As a class effect, therefore, NAs can potentially cause extrahepatic conditions, such as myopathy, nephropathy, neuropathy, and lactic acidosis. Indeed, effects on muscles, including myopathy and creatine kinase elevations, have been described with clevudine and telbivudine use. Both adefovir and tenofovir are associated with dose-dependent nephropathy, predominantly affecting the proximal renal tubules. Neuropathy appears to be rare, and most commonly reported in patients receiving combination therapy with telbivudine and interferon. Increased risk of lactic acidosis has also been described for those with impaired liver and renal function taking entecavir. Loss of bone mineral density and hypophosphatemia have been described with the use of NAs, although the overwhelming studies have been with human immunodeficiency virus-infected patients. However, not all extrahepatic effects are detrimental. Recent evidence has suggested a potential renal beneficial effect with the use of telbivudine. The effect of NAs on pregnancy appears to be minimal for all NAs, with telbivudine and tenofovir having a more favorable category B rating. Ongoing pharmacovigilance is essential to identify new and monitor existing extrahepatic effects associated with NA use.

Background & Aims We examined the durability of the virological response after discontinuing lamivudine (LVD) in chronic hepatitis B (CHB) patients with LVD-resistant hepatitis B virus (HBV), who responded to LVD plus adefovir (ADV) combination therapy, and the outcome of switching to ADV monotherapy compared to maintaining combination therapy. Methods This study enrolled 72 patients with undetectable viral loads (≤12 IU/ml) and normal alanine aminotransferase levels after ADV add-on therapy for at least 6 months in LVD-resistant CHB patients. The enrolled patients were randomly assigned to continue with LVD–ADV combination therapy or switch to ADV monotherapy (n = 36 per group). Virological rebound was defined as HBV DNA detection at more than 12 IU/ml by quantitative polymerase chain reaction determined on two consecutive measurements. Results During 96 weeks of follow-up, 100% (36/36) of the patients in the LVD–ADV combination maintained group had persistently undetectable HBV DNA, compared with 94.4% (34/36) patients in the ADV monotherapy switched group. These two patients had undetectable HBV DNA after switching back to LVD–ADV combination therapy. There were no significant differences in the HBsAg levels between the two treatment groups during the 96-week follow-up period. Conclusions In our study, switching to ADV monotherapy resulted in sustained HBV DNA suppression in 94.4% of the patients for 96 weeks. Prior complete viral suppression with LVD–ADV combination therapy conferred a significant advantage in patients who switched to ADV monotherapy. LVD may be discontinued in patients who show a complete virological response to LVD–ADV combination therapy for at least 6 months.

HBeAg-negative chronic hepatitis B (CHB) is the most frequent and aggressive type of CHB. The current therapeutic options for CHB include pegylated-interferon-alfa (PEG-IFNα) and nucleos(t)ide analogues (NAs). NAs are well-tolerated and safe agents that effectively inhibit viral replication, but they should be given as long-term, probably lifelong therapy, in particular in HBeAg-negative CHB. Thus, the finite, usually 48-week, duration is the main advantage of PEG-IFNα, providing sustained virological responses (SVR) off-therapy in approximately one-fourth of patients with HBeAg-negative CHB and often leading to HBsAg loss. However, the limited efficacy is the main factor restricting the use of PEG-IFNα in CHB and therefore identifying the predictors of response is of great clinical importance. No reliable baseline predictors of response to PEG-IFNα have been identified to date, but certain studies have identified satisfactory predictors of post-PEG-IFNα response using on-treatment serological markers, mostly HBsAg levels. In particular, in HBeAg-negative CHB patients mostly with genotype D a lack of decline in HBsAg levels and a lack of decrease in HBV DNA levels ≥2 log10 copies/ml at week-12 has a nearly 100% negative predictive value for SVR off-treatment and is now recommended as a stopping rule for early discontinuation of ineffective PEG-IFNα. Prolonging PEG-IFNα therapy to 96 weeks seems to provide higher SVR rates but the application and efficacy of this approach requires further study. The combination of PEG-IFNα with NAs, mostly lamivudine, has not resulted in any therapeutic benefit so far, but newer combined approaches with PEG-IFNα and NA(s) are currently under study.

There are approximately 350 million hepatitis B virus (HBV) carriers worldwide. Chronic HBV infection increases the risk of liver cirrhosis and hepatocellular carcinoma. To date, two classes of antiviral drugs have been approved by the Food and Drug Administration for the treatment of hepatitis B, immunomodulators (interferon [IFN]-α and pegylated-interferon [PEG-IFN]-α) and nucleos(t)ide analogs (lamivudine, telbivudine, adefovir, tenofovir [TDF], and entecavir [ETV]). Of these, ETV, TDF, and PEG-IFN-α are the most effective and are currently recommended for anti-HBV therapy. However, these therapies are less than optimal because of their low rate of viral DNA and surface antigen clearance; thus, there exists a significant unmet medical need for safe and efficacious new anti-HBV drugs. Covering diverse chemical structures and mechanisms of action, non-nucleos(t)ide compounds offer great promise in the search for new anti-HBV drugs. This review summarizes the currently approved anti-HBV drugs and highlights advances in the identification and characterization of novel small molecule HBV inhibitors. We discuss the sources, structures, anti-HBV effects, mechanisms of action, and potential toxicities of these novel inhibitors.

Summary Background The treatment of chronic hepatitis B (CHB) in patients with chronic kidney disease (CKD) is based on nucleoside (lamivudine, telbivudine, entecavir) or nucleotide (adefovir, tenofovir) analogues (NAs), but it may be complex and the information is scarce. Entecavir and tenofovir represent the currently recommended first-line NAs for NA-naive CHB patients, while tenofovir is the NA of choice for CHB patients with resistance to nucleosides. Aim To review the efficacy and safety of NAs in adult CHB patients with CKD and to provide reasonable recommendations for their optimal management. Methods Literature search in PubMed/Medline and manual search of relevant articles, reviews and book chapters. Results NAs are cleared by kidneys and their dosage should be adjusted in patients with creatinine clearance

Substantial progress has been achieved in antiviral therapy for chronic hepatitis B; however, options for women of child-bearing age with HBeAg-positive chronic hepatitis B remain a challenge. In this study, we sought to determine whether de novo combination therapy of Adefovir plus Lamivudine was a super treatment for women of child-bearing age with HBeAg-positive chronic hepatitis B prior to conception. A total of 122 women patients of child-bearing age with HBeAg-positive chronic hepatitis B were randomly assigned to receive (i) 10 mg Adefovir plus 100 mg Lamivudine (64 patients) or (ii) 10 mg Adefovir monotherapy (58 patients), administrated orally once daily for 96 weeks. The therapeutic efficacy within each group was compared at weeks 48 and 96. The results showed that de novo combination therapy of Adefovir plus Lamivudine significantly reduced HBV-DNA detectability, and enhanced ALT normalization and HBeAg seroconversion in women of child-bearing age with HBeAg-positive chronic hepatitis B. No virological breakthrough and genotypic resistance were observed in the combination therapy group. Additionally, the combination therapy with Adefovir plus Lamivudine was well tolerated. This study suggests that de novo combination therapy of Adefovir plus Lamivudine offers a therapeutic advantage for women of child-bearing age with HBeAg-positive chronic hepatitis B when taken before conception.

Whether the combination of lamivudine (LAM) plus adefovir (ADV) de novo is more effective than entecavir (ETV) monotherapy in patients with HBV-associated decompensated cirrhosis is still controversial. We searched seven randomized controlled trials that included 411 patients in this meta-analysis. There are 205 and 206 patients in these two groups separately. The pooled risk ratio (RR) and mean difference (MD) were used to assess the treatment effects. ETV monotherapy significantly improved Child-Turcotte-Pugh (CTP) scores (MD = 0.33, 95%CI [0.21-0.44], P

Objective The aim of this study was to analyze the incidence and risk factors of de novo hepatitis B virus (HBV) infection from hepatitis B core antibody (anti-HBc)-positive donors in pediatric living donor liver transplantation (LDLT). Methods We retrospectively analyzed 46 recipients without pre-liver transplantation (LT) HBV infection evidence who underwent LDLT from October 2006 to May 2011 in our center. HBV markers, including hepatitis B surface antigen (HBsAg) and antibody (anti-HBs), anti-HBc, hepatitis B e antigen (HBeAg) and antibody (anti-HBe) were determined in both donors and recipients before LT and in recipients after LT. HBV DNA titer was measured if the recipients were strongly suspected of de novo HBV infection. Results Without prophylaxis, de novo HBV infection occurred in 11 of 46 recipients (23.9%) 6–36 months after LT. All 11 patients received grafts from anti-HBc-positive donors. The donors' baseline status and the characteristics of recipients at the time of transplantation were not associated with the acquisition of de novo hepatitis B infection. The overall 2-year survival rate of patients from anti-HBc-positive donors was 84.2%. Two de novo HBV-infected patients who had YMDD mutation were given adefovir combined with lamivudine, and their liver function gradually improved during the follow-up period. Conclusions Anti-HBc-positive donors can significantly increase the incidence of de novo HBV infection in HBsAg-negative recipients. Administration with adefovir in patients who are resistant to lamivudine seems to be an effective and safe way for de novo HBV infection.

Background and Aim Treatment end-point of therapy for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) includes HBeAg seroconversion, which ranges from 15% to 22% after 1 year of oral nucleos(t)ides according to clinical trials. Our goal was to determine the incidence and predictors of HBeAg seroconversion in such patients in routine clinical practice because they may differ than reported rates. Methods We conducted a retrospective cohort study of 333 consecutive treatment-naive HBeAg-positive patients who were treated for CHB between 1/2000 and 6/2010 at three gastroenterology and liver clinics in the USA. Primary study end-point was HBeAg seroconversion—loss of HBeAg and antibody to HBeAg (anti-HBe) development. Results The majority of patients were Asian (96%). Median treatment duration prior to HBeAg seroconversion was 50 (range 26–52) weeks. Of the 333 study patients, 25% received lamivudine, 16% adefovir, 51% entecavir, and 8% tenofovir. HBeAg seroconversion at month 12 was 8.2%. On multivariate analysis inclusive of age, gender, and antiviral agents, independent predictors for HBeAg seroconversion at month 12 were hepatitis B virus DNA 1.5 × upper normal limit (HR = 2.86 [1.05–7.81], P = 0.040), but not the choice of nucleos(t)ides. Conclusions The HBeAg seroconversion rate seen in clinical settings for oral nucleos(t)ides appears much lower than those reported in pivotal trials, especially in patients with lower ALT and higher HBV DNA levels. HBeAg-positive patients should be counseled about the high possibility of the long treatment duration required to achieve recommended treatment end-points.

Chronic hepatitis B is prevalent in the transplant setting and may cause significant complications. Effective control of viral replication is needed. Besides lamivudine, very little data are available on safety and efficacy of other drugs. We describe our experience with adefovir dipivoxil (ADV) in eight heart transplant recipients. Studies included a baseline liver biopsy, thrice-monthly clinical, biochemical, and virological evaluations, including genotyping and viral load, polymerase gene sequencing for resistance mutations, liver and kidney function tests, and liver ultrasound. Of eight patients, six had fibrosis score ≤2 and negative HBeAg and seven had hepatitis B virus (HBV) genotype D. Upon ADV start, median HBV-DNA was 5.8 logs IU/mL and alanine aminotransferase (ALT) levels were mostly normal. All patients had prior mild-to-moderate renal functional impairment. Seven of eight patients started ADV after a previous course of lamivudine. Five of these seven patients became HBV-DNA undetectable within eight months. One patient with low baseline viremia started ADV de novo and suppressed HBV-DNA. Median treatment duration was 66 months. ADV daily dose was halved in one patient due to renal function worsening. No ALT flares, hypophosphatemia, liver decompensation, liver cancer, or emergence of resistance was observed. Our data suggest that ADV may be a safe and effective rescue treatment for heart transplant recipients with lamivudine-resistant chronic hepatitis B.

Prominent in the current stage of antiviral drug development are: (i) for human immunodeficiency virus (HIV), the use of fixed-dose combinations (FDCs), the most recent example being Stribild(TM); (ii) for hepatitis C virus (HCV), the pleiade of direct-acting antivirals (DAAs) that should be formulated in the most appropriate combinations so as to obtain a cure of the infection; (iii)-(v) new strategies (i.e., AIC316, AIC246, and FV-100) for the treatment of herpesvirus infections: herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), respectively; (vi) the role of a new tenofovir prodrug, tenofovir alafenamide (TAF) (GS-7340) for the treatment of HIV infections; (vii) the potential use of poxvirus inhibitors (CMX001 and ST-246); (viii) the usefulness of new influenza virus inhibitors (peramivir and laninamivir octanoate); (ix) the position of the hepatitis B virus (HBV) inhibitors [lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate (TDF)]; and (x) the potential of new compounds such as FGI-103, FGI-104, FGI-106, dUY11, and LJ-001 for the treatment of filoviruses (i.e., Ebola). Whereas for HIV and HCV therapy is aimed at multiple-drug combinations, for all other viruses, HSV, CMV, VZV, pox, influenza, HBV, and filoviruses, current strategies are based on the use of single compounds.

The objective of this study was to compare the efficacy and safety of two rescue strategies for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with resistance to adefovir dipivoxil (ADV). This prospective study included 58 HBeAg-positive CHB patients with resistance to ADV; 30 patients underwent telbivudine (LdT) plus ADV combination therapy and 28 patients switched to entecavir (ETV) monotherapy. After 48 weeks of treatment, the rates of hepatitis B virus (HBV) DNA