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Background and Aim: In HBeAg negative chronic hepatitis B (CHB) patients, clinical relapse (CR) occurs more frequently, much earlier and often more severely after stopping tenofovir (TDF) and other nucleos(t)ide analogues (Nucs) than after stopping entecavir (ETV). It is unknown whether off-Nuc hepatitis flare can be alleviated by switching from one Nuc to another., Methods: HBeAg-negative CHB patients who had stopped Nuc according to the APASL stopping rule and had been followed-up for > 48 weeks after Nuc cessation were recruited. Patients were classified as four groups: ETV monotherapy (mono-ETV), TDF monotherapy (mono-TDF), switched to ETV (switch-ETV), and switched to TDF (switch-TDF). Both switch groups had switched to the replacement Nuc > 12 weeks prior to end of therapy. Propensity score matching (PSM) was performed to minimize confounders among groups. Cox regression analysis was used to identify risks factors for off-Nuc CR and flares., Results: A total of 1309 patients (1022 mono-ETV, 219 mono-TDF, 40 switch-ETV and 28 switch-TDF) were enrolled. The median time to CR was 39, 13, 38 and 14 weeks in mono-ETV, mono-TDF, switch-ETV and switch-TDF respectively (P < 0.001). After PSM, the mono-ETV (adjusted HR: 0.39, P < 0.001) and switch-ETV patients (adjusted HR: 0.41, P = 0.003) had both significantly later occurrence and lower rates of CR and flare., Conclusion: In summary, the incidence and timing of CR was determined by ETV or TDF in the last 3 months prior to end of treatment. Patients treated with non-ETV-Nuc switched to ETV > 12 weeks before end of the original Nuc therapy may reduce/defer CR., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Adefovir (ADV) is an anti-retroviral drug, which can be used to treat acquired immune deficiency syndrome (AIDS) and chronic hepatitis B (CHB), so its quantitative analysis is of great significance. In this work, zirconium molybdate (ZrMo 2 O 8 ) was synthesized by a wet chemical method, and a composite with multi-walled carbon nanotubes (MWCNTs) was made. ZrMo 2 O 8 -MWCNTs composite was dropped onto the surface of a glassy carbon electrode (GCE) to prepare ZrMo 2 O 8 -MWCNTs/GCE, and ZrMo 2 O 8 -MWCNTs/GCE was used in the electrochemical detection of ADV for the first time. The preparation method is fast and simple. The materials were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and cyclic voltammetry (CV). It was electrochemically analysed by differential pulse voltammetry (DPV). Compared with single-material modified electrodes, ZrMo 2 O 8 -MWCNTs/GCE showed a vastly improved electrochemical response to ADV. Moreover, the sensor complements the study of the electrochemical detection of ADV. Under optimal conditions, the proposed electrochemical method showed a wide linear range (from 1 to 100 μM) and a low detection limit (0.253 μM). It was successfully tested in serum and urine. In addition, the sensor has the advantages of a simple preparation, fast response, good reproducibility and repeatability. It may be helpful in the potential applications of other substances with similar structures.

Abstract: The dissociation constants of Adefovir ({[2-(6-amino-9H-purine-9-l)ethoxi]methyl}phosphoric acid) used in the treatment of hepatitis B and Cidofovir ({[2-(6-amino-9H-purine-9-l)ethoxi]methyl}phosphoric acid), used in the treatment of cytomegalovirus retinitis in AIDS patients, together with the stability constants of its Cu2+, Ni2+, Zn2+, Co2+, Ca2+, and Mg2+ complexes were studied by potentiometric titration. Adefovir and Cidofovir were abbreviated to PMEA and HPMPC. All measurements were obtained under two sets of conditions: at 298K and ionic strength (I) of 0.1moldm−3 (NaCl) and at 310K and I of 0.16moldm−3 (NaCl), corresponding to the conditions of human blood. Equilibrium constants in aqueous solution were calculated using the program SUPERQUAD. Also, solvent effects on the equilibrium constants of the ligands were examined. Moreover, all coordination studies were carried out with the ligand/metal molar ratios of 1:1. This ligand/metal stoichiometric ratio was spectrometrically determined using Job's method. [Copyright &y& Elsevier]

Aim The therapeutic effect of interferon ( IFN)-α plus adefovir ( ADV) combination therapy versus IFN-α monotherapy in chronic hepatitis B ( CHB) treatment remains under debate. The objective of the present study was to compare the efficacy between these two regimens in CHB treatment. Methods MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, National Knowledge Infrastructure, WANFANG and VIP databases were searched until 15 April 2012. All randomized controlled trials ( RCT) comparing IFN-α plus ADV combination therapy versus IFN-α monotherapy for treating CHB patients were included. Review Manager ver. 5.1.0 was used for meta-analysis. Results Our results showed that the rate of undetectable serum hepatitis B virus ( HBV) DNA was significantly higher in the IFN-α plus ADV combination group than in the IFN-α monotherapy group, both at 24 weeks (relative risk [ RR] = 1.74, 95% confidence interval [ CI] = 1.47-2.05, P < 0.00001) and 48 weeks ( RR = 1.56, 95% CI = 1.35-1.80, P < 0.00001) of treatment and after treatment ( RR = 1.35, 95% CI = 1.10-1.66, P = 0.004). The serum hepatitis B e-antigen ( HBe Ag) negativation and HBe Ag seroconversion rates were also higher in the combination group. However, a greater hepatitis B surface antigen loss rate was not found in the combination group. Forty-eight weeks of combination therapy improved the alanine aminotransferase normalization rate, but did not improve the rate of undetectable HBV DNA or that of HBe Ag seroconversion as compared with 24 weeks of combination therapy. Conclusion Based on the current studies, the efficacy of IFN-α plus ADV combination therapy is superior to IFN-α monotherapy. [ABSTRACT FROM AUTHOR]

Currently available antiviral treatment for chronic hepatitis B virus infection can be divided into two classes of therapeutic agents: nucleos(t)ide analogues (NAs) and interferon (IFN). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy; the advantages of IFN include a finite course of treatment, absence of drug resistance, and an opportunity to obtain a post-treatment durable response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Here, we have reviewed previous reports of either simultaneous or sequential combination therapy with NA and IFN for chronic hepatitis B patients. In previous studies comparing the lamivudine/IFN combination and lamivudine monotherapy in a finite course, combination therapy was associated with higher rates of sustained post-treatment response and lower rates of drug resistance than lamivudine monotherapy. However, NAs such as lamivudine are generally administered indefinitely because of high rates of post-treatment relapse. In addition, concern for drug resistance has decreased significantly with newer, high-potency NAs even when administered alone. In previous studies comparing the lamivudine/IFN combination and IFN monotherapy, the combination therapy showed greater on-treatment viral suppression, but no difference was observed in the post-treatment sustained response. Thus, whether combination therapy confers an additional benefit compared to monotherapy for treating chronic hepatitis B remains unclear. The efficacy of IFN in combination with a more potent NA, such as entecavir or tenofovir, remains to be comprehensively evaluated. [ABSTRACT FROM AUTHOR]

Background. In this paper, we explore nephrogenic hypophosphatemic osteomalacia associated with low-dose adefovir dipivoxil (ADV) therapy. Methods. Five patients who were treated with ADV for >2 years were included in this study. The metabolic index of phosphate and calcium, renal tubular function, renal function and pathological changes of the patients were investigated. Results. Two male and three female patients were studied. All of the patients presented with a reduced serum phosphate level (0.38-0.60 mmol/L) accompanied with hyperphosphaturia at 10.9-23.8 mmol/24 h. The serum potassium level was also reduced or at lower range (2.56-3.54 mmol/L), but the 24-h urinary potassium was relatively increased. Urinalysis also demonstrated increased excretion of glucose in four patients. Urine protein electrophoresis showed low-to-moderate molecular weight protein. Three patients manifested urine acidification function impairment. Four patients had accompanying renal insufficiency. Three patients had difficulty walking and presented with a reduction in height (2.5-14 cm). Renal biopsy revealed that most of the glomeruli were normal accompanied by mild interstitial fibrosis with inflammatory cell infiltration. ADV treatment was subsequently ceased. Patients were treated with regular phosphate supplementation, citrate acid potassium and calcium bicarbonate. After 6-month treatment, the bone pain was significantly alleviated. Serum creatinine of one patient returned to normal levels and two patients who had difficulty walking were able to walk independently. Conclusions. The current study showed long-term and low-dose ADV treatment in a Chinese population may lead to proximal tubular impairment, metabolic acidosis, hypophosphatemia, hypokalemia, metabolic bone disease, renal osteopathia and renal functional damage. [ABSTRACT FROM AUTHOR]

Obj'ective To compare treatment outcome, drug resistance rate, and safety between initial combination therapy with lamivudine (LAM ) plus adefovir dipivoxil (ADV ) and monotherapy with entecavir (ETV ) in the treatment of HBeAg - positive chronic hepatitis B ( CHB ) . Methods Fifty - six HBeAg - positive CHB patients, who received treatment in The First People's Hospital of Foshan from May 2008 to February 2010, were divided into combination therapy group and monotherapy group using a random number table. The combination therapy group received LAM (100 mg/d ) plus ADV (10 mg/d ) once daily for 48 weeks, while the monotherapy group received ETV (0.5 mg/d ) once daily for 48 weeks. Te alanine aminotransferase (ALT ) normalization rate, hepatitis B virus (HBV ) DNA clearance rate, and HBeAg clearance rate were compared between the two groups by chi - square test. Results After 48 weeks of treatment, the ALT normali-zation rate showed no significant difference between the two groups (?² =1.018, P>0.05 ), but after 36 weeks of treatment, the ALT nor-malization rate was significantly higher in the monotherapy group than in the combination therapy group (?² =4.082, P <0.05) . After 12 and 48 weeks of treatment, the HBV DNA clearance rate showed no significant diference between the two groups (?² = 1. 167, P >0.05; ?² =1.976, P >0.05), but after 24 and 36 weeks of treatment, the HBV DNA clearance rate was significantly higher in the monotherapy group than in the combination therapy group (?² = 5.600, P < 0. 05 ; ?² = 9.164, P<0.05) . There was no significant diference in HBeAg clearance rate between the two groups. over the course of treatment, neither group developed drug resistance, and the two therapies had good safety. Conclusion Both initial combination therapy with LAM and ADV and monotherapy with ETV produce a good clinical effect in HBeAg - positive CHB patients after 48 weeks of treatment. ALT normalization and HBV DNA clearance occur earlier in patients receiving ETV alone than those receiving LAM plus ADV. The two therapies have good safety, cause liitle drug resistance, and produce good treatment outcome and hold promise for clinical application. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of Entecavir (ETV) plus adefovir (ADV) for chronic hepatitis B (CHB) patients after multiple nucleos(t)ide analogue (NAs) failure treatment. Methods: Hepatitis B e antigen (HBeAg)-positive patients who had a suboptimal response or developed resistance to two or more previous NAs treatments were included, and all subjects were treated with ETV in combination with ADV for ⩾ 24 months. Complete virologic response (CVR) was defined as an undetectability of serum hepatitis B virus (HBV) DNA level during treatment. Safety assessment was based on the increasing of serum creatinine and creatine kinase levels. Results: A total of 45 eligible patients were included. Twenty-five patients had been treated with lamivudine (LAM) or telbivudine (LdT) and developed genotypic resistance. Resistance to ADV was present in 18 patients and 4 patients had a suboptimal response to ETV. Two patients had a resistance to both LAM and ADV. The cumulative probabilities of CVR at 12 and 24 months of ETV + ADV treatment were 88.9% (40/45) and 97.8% (44/45), respectively. Although one patient failed to achieve CVR, its serum HBV DNA level decreased by 3.3 log copies/mL after 24 months of combination therapy. The cumulative probability of HBeAg seroconversion was 15.6% (7/45) and 26.7% (12/45) at 12 and 24 months of treatment, respectively. History of prior exposure to specific NAs did not make a difference to ETV + ADV treatment outcome. There were no significant adverse events related to ETV + ADV therapy observed in the study subjects. Conclusion: ETV + ADV can be used as an effective and safe rescue therapy in patients after multiple NA therapy failures, especially in the areas where tenofovir is not yet available. [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy of entecavir (ETV) monotherapy up to 4 years in nucleos(t)ide analog (NA)-experienced and -naïve subjects. Methods: One hundred sixty NA-experienced and 282 naïve chronic hepatitis B patients who were treated with ETV were enrolled. Of the 160 NA-experienced patients, 49 had prior lamivudine (LAM)-resistant mutants, 18 had resistant mutants to LAM followed by adefovir (ADV) after switching to ADV sequential therapy (LAM/ADV resistance), and 9 had prior ADV-resistant mutants. NA-resistant mutants were detected by line probe assay. Results: Four years of ETV therapy resulted in virological response (VR, HBV DNA < 300 copies/ml), HBeAg seroconversion, and ETV-resistant mutants development in 98.2, 45.2, and <1 % of naïve patients, respectively. LAM- and ADV-experienced patients who never developed LAM-resistant mutants had similar VR and ETV-resistant mutant rates to NA-naïve patients. In contrast, prior LAM-resistant mutants were significantly associated with higher ETV-resistant mutants development and reduced VR rates. Patients with prior LAM-resistant mutants but not at baseline had a lower rate of ETV-resistant mutants compared to those with baseline LAM-resistant mutants [hazard ratio (HR): 0.58, 95 % confidence interval (CI): 0.35-0.95] and those who had LAM/ADV resistance (HR:0.16, 95 % CI:1.0.03-0.76). Early add-on ADV achieved VR in eight of nine patients with ETV-resistant mutants when HBV DNA was <2 × 10 copies/ml. Conclusions: Entecavir was highly efficacious and low resistance in NA-naïve, LAM-, or ADV-experienced patients without LAM-resistant mutants. Patients with prior LAM-resistant mutants but not at baseline had lower ETV-resistant mutant rates compared to those with baseline LAM-resistant mutants or LAM/ADV resistance. [ABSTRACT FROM AUTHOR]

Background/Aims: In patientswith lamivudine (LAM)-resistant chronic hepatitis B (CHB)receivingadefovir (ADV) add-on LAM therapy, insufficient viral suppression or the appearance of additional ADV resistance has remained unresolved. This study determined the partial virological response (PVR) criteria to predict a virological response (VR) at week 96 in these patients. Methods: 96 patients with LAM-resistant CHB (ADV add-on LAM therapy >2 years) were analyzed. For predicting VR at week 96, the area under the receiver operating characteristic curve values at different time points were compared to establish the optimal time point, and the maximal Youden index was calculated to determine the optimal cut-off hepatitis B virus (HBV) DNA level. Results: 50 (52.1%) patients achieved VR at 2 years after ADV add-on LAM therapy. The optimal PVR criteria were determined to be HBV DNA 500 IU/ml at week 48. 44 (45.8%) patients who met optimal PVR criteria showed a significantly higher risk for detectable HBV DNA levels at week 96 than those with a favorable VR (HBVDNA <500 IU/ml) at week 48. Conclusions: This study suggested optimal PVR criteria in patients with LAM-resistant CHB receiving ADV add-on LAM therapy. Modification of the antiviral agent regimen should be considered if the serum HBV DNA level exceeds 500 IU/ml at week 48. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The introduction of the new DAAs Entecavir and Tenofovir have had a major impact on liver transplant for hepatitis B virus (HBV) infection. These agents have been shown to rescue patients with decompensated HBV in a manner similar to Lamivudine but without the same concern about resistance. The use of these agents post liver transplant with HBIG reduce HBV recurrence to <1 %. Increasingly they are being used to reduce long term use of HBIG although the timing of HBIG withdrawal and whether it should be applied to all HBV infected recipients requires further study. [ABSTRACT FROM AUTHOR]

Background: The efficacy of adefovir (ADV) plus entecavir (ETV) combination in patients with chronic hepatitis B (CHB) who developed multidrug refractoriness had not been fully evaluated. We aimed to evaluate the efficacy of ADV plus ETV as compared to that of lamivudine (LAM) plus ADV in the patients with antiviral refractoriness to sequential LAM monotherapy and then ADV monotherapy. Methods: Twenty-seven patients were treated with a combination of ADV plus ETV and 63 patients were treated with a combination of LAM plus ADV. The virological and biochemical parameters were compared between the two groups, retrospectively. Results: Treatment with a combination of ADV plus ETV produced significantly superior virological response than that of a combination of LAM plus ADV. At 12 months, the HBV DNA declined more in the ADV plus ETV group than in the LAM plus ADV (−4.52 ± 1.956 vs. −2.65 ± 1.723 logIU/mL; p = 0.001). The rate of a complete response at 12 months was greater in the ADV plus ETV group than that in the LAM plus ADV group (63.16 vs. 14.81 %, p < 0.001). Conclusion: In the patients with CHB refractory to both LAM and ADV, the response to ADV plus ETV was significantly superior compared to that of the LAM plus ADV in suppressing HBV DNA. The result indicates that ADV plus ETV can be used as a bridging therapy in the patients with refractoriness to both LAM and ADV, especially in the areas where tenofovir is not yet available. [ABSTRACT FROM AUTHOR]

Background/Aims: To investigate pre-existing hepatitis B virus (HBV) quasispecies and the genotypic evolution of several variants. Methods: From six patients with lamivudine (LAM) failure, serum samples at pretreatment, 6 months of LAM therapy, and virologic breakthrough were obtained. One hundred clones with HBV inserts in each patient were sequenced at each time point. Pretreatment serum samples were also analyzed from six patients who achieved good responses to LAM therapy. Results: Among the six patients with LAM failure, the analysis of 100 clones from patient 1 revealed the substitutions L180M in 1% of clones and V173L in 2% of clones. Patient 2 had substitutions of L80V, W153Q, and L180M. In patient 3, mutations conferring resistance to adefovir at V84I (5%), I169L (1%), and N236H (7%) and entecavir at S202G (2%) were detected. Patient 4 had mutations at T128N (1%), I169L (1%), V173L (2%), A181V (1%), and Q215H (1%). In patient 5, M204V/I was detected in 1% and 2% of clones, respectively. L80I and V173L were also identified in patient 6. In the six patients who responded to LAM, the degree of overall quasispecies was less than those with LAM failure. Conclusions: Various HBV quasispecies associated with drug resistance existed before treatment, and the quasispecies dynamically changed through LAM therapy. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Health care decision makers are increasingly concerned about the value of chronic hepatitis B (CHB) treatments in China. This analysis aims at estimating the relative value of entecavir as a first-line option at treatment initiation and for different treatment durations from a holistic perspective. Methods: CHB was simulated by using a Markov disease transition model with disease states based on available natural history data. The model assumed 5-year treatment duration with entecavir, lamivudine, telbivudine, and adefovir based on published clinical data. The speed of disease progression varies by viral load and hepatitis B “e” antigen status. Direct medical costs included medication and management of liver complications. The primary output was the estimated cost savings of entecavir per patient per day versus the comparator. Results: For treatment duration of 5 years and a follow-up period of 30 years, entecavir treatment was translated into specific patient benefit of an estimated cost saving of $2.69 per day compared with no treatment. In addition, long-term usage of entecavir resulted in daily $2.33 and $1.73 cost saving compared with short-term usage (1-year and 2-year, respectively). Among available treatment options in China, entecavir treatment exhibited about $0.90 to $1.81 daily cost saving versus the comparators. The detailed daily cost saving of entecavir is summarized as follows—entecavir versus lamivudine: $1.81, entecavir versus telbivudine: $0.90, entecavir versus adefovir: $2.02, and entecavir versus generic adefovir: $1.37. Conclusions: Long-term usage of entecavir exhibits the characteristics of a favorable CHB treatment, which translates into economic value as opposed to either no treatment or alternative strategies. [Copyright &y& Elsevier]

Osteomalacia is a metabolic bone disease that leads to softening of the bones and can be caused by hypophosphatemia. Large clinical studies of low-dose adefovir dipivoxil (adefovir) have found no evidence of renal tubular dysfunction leading to hypophosphatemia after 48 weeks of treatment. We report two cases of low-dose adefovir-induced hypophosphatemic osteomalacia that initially presented with diffuse musculoskeletal pain. The first patient was a 62-year-old man with a 2-year history of bone pain involving the dorsal mid-thorax, lower anterior chest wall, right sacroiliac joint area, and both knees. The patient had been receiving adefovir for 5 years before confirmation of hypophosphatemia and urinary phosphate wasting. Bone scintigraphy revealed multifocal lesions including multiple ribs, costochondral junctions, costovertebral junctions, sacrum, both posterior iliac bones, both proximal tibia, right calcaneus, and the left second metatarsophalangeal joint area, which were suggestive of metabolic bone disorder. Bone pain was significantly reduced within 3 months after supplementation with phosphate and calcitriol. The second patient was a 54-year-old male who presented with an 18-month history of severe bone pain of the right medial knee and low back. The patient had been taking adefovir for approximately 40 months before the development of bone pain. Laboratory data revealed hypophosphatemia and vitamin D deficiency. Bone scintigraphy showed increased uptake in bilateral ribs, sternum, both scapulae, both costovertebral junctions, both pelvic bones, medial cortex of the right proximal femur, right proximal tibia, and the left lateral tarsal bone. The symptoms improved by changing the antiviral agent from adefovir to entecavir. Because osteomalacia often presents with diffuse bone pain, non-specific radiologic findings and non-characteristic routine serum biochemical changes, the disease can be confused with various musculoskeletal diseases and a high index of suspicion is necessary for an early diagnosis in patients receiving adefovir therapy. [ABSTRACT FROM AUTHOR]

Objectives. To compare the efficacy of rescue therapies in lamivudine (LAM)-resistant chronic hepatitis B (CHB) infections including: (1) adefovir dipivoxil (ADV) monotherapy, (2) ADV plus LAM combination therapy and (3) entecavir (ETV) 1.0 mg monotherapy. Materials and methods. The authors designed a multicenter-retrospective study. Eight institutions participated in the study from Korea. Results. A total of 343 LAM-resistant CHB patients were enrolled. The proportion of patients with undetectable serum hepatitis B virus (HBV) DNA levels at month 24 after the initiation of rescue therapy was higher in the ADV plus LAM combination therapy group (39/64, 60.9%) than in the ADV monotherapy (50/126, 39.7%) and ETV 1.0 mg monotherapy (19/48, 39.6%) groups ( p = 0.014). Mean serum HBV DNA levels at 24 months were 2.07 ± 1.21 log10 IU/ml in the ADV plus LAM combination therapy group, 2.74 ± 1.74 log10 IU/ml in the ADV monotherapy group and 3.08 ± 1.97 log10 IU/ml in the ETV 1.0 mg monotherapy group ( p = 0.014). In multivariate analysis, a finding of undetectable serum HBV DNA level at 6 months and ADV plus LAM combination therapy (vs. ADV) was an independent factor for predicting undetectable serum HBV DNA at month 24 (odds ratio, 1.003; 95% confidence interval, 1.000-1.006; p = 0.026). Conclusions. ADV plus LAM combination therapy is more effective in reducing viral load than switching to ADV or ETV 1.0 mg in patients with LAM-resistant CHB. [ABSTRACT FROM AUTHOR]

Background. Currently, there is no consensus on the recommendation of peginterferon alfa (pegIFNα) to chronic hepatitis B (CHB) patients with poor viral response (EVR). This study aimed to assess the sustained curative efficacy of adefovir (ADV) add-on therapy in optimizing pegIFNα monotherapy. Methods. A total of 85 hepatitis B e antigen (HBeAg)-positive CHB patients with poor virological response at month 6 after starting pegIFNα-2a were enrolled, and received either pegIFNα-2a continuing monotherapy (group A, n = 51) or add-on therapy with ADV (group B, n = 34). The treatment duration for all patients was 6 months, and the sustained responses after the end of treatment were evaluated between two groups. Results. The baseline characteristics were comparable between two groups. At months 6 after treatment completion, the sustained virological response (SVR) rates were 31.4% and 73.5%, the sustained biochemical response (SBR) rates were 39.2% and 85.3% in group A and group B respectively, and the difference in either SVR or SBR was statistically significant (both p < 0.001). As compared to patients in group A, significantly more patients in group B obtained HBeAg loss (19.6% vs. 55.9%, p = 0.001) and seroconversion (13.7% vs. 41.2%, p = 0.004). Conclusion: ADV add-on therapy could significantly improve and sustain the curative efficacy of CHB patient with poor virological response to pegIFNα-2a monotherapy, but further large well-designed randomized controlled trials are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Products that are currently used in the treatment of chronic hepatitis B include interferon-alpha ( IFNa: standard or pegylated) ( PEG- IFNa) and nucleos(t)ide analogues ( NAs). NAs are used in most HBeAg-negative chronic hepatitis B patients for several reasons. They can be prescribed to all chronic HBV patients, even those with contraindications to IFNa; and even IFNa candidates are usually treated with NAs because of their advantages. Administration of NAs is easier (one oral tablet per day compared with subcutaneous IFNa injections), tolerance is excellent and the safety profile is good, whereas IFNa may have adverse events and often worsens the patients' quality of life. The current first-line NA options, entecavir ( ETV) and tenofovir ( TDV), have minimal or no risk of long-term resistance and a virological response is achieved in almost 100% of adherent HBeAg-negative patients, thus modifying the long-term outcome. The need for long-term, perhaps indefinite, treatment is the main limitation of NAs and the finite duration (48 weeks), the main advantage of IFNa, especially in young patients of reproductive age. However, at most 25% of IFNa-treated HBeAg-negative patients achieve a sustained off-treatment response and therefore >75% of them will eventually receive NAs, even if they start with IFNa. As there will always be concerns about safety and family planning issues with long-term NA therapy, NAs should be used carefully, particularly in young chronic hepatitis B patients with mild liver disease. Novel therapeutic options are needed to increase the rates of HBsAg loss and sustained off-treatment responses. [ABSTRACT FROM AUTHOR]

Background Management of lamivudine-resistant chronic hepatitis B ( CHB) remains challenging, as inappropriate choice of treatment may cause multidrug resistance. Until now, randomized trials directly comparing adding adefovir and switching to entecavir monotherapy have not been reported. Aims This multicentre prospective randomized study was designed to compare the efficacy of these two strategies. Methods Two hundred and nineteen lamivudine-resistant CHB patients were randomized to either adefovir-lamivudine combination group or entecavir monotherapy group ( n = 110 vs. 109), and followed up for 24 months. Results One hundred and eighty patients completed this study. At month 24, virological response rate [hepatitis B virus ( HBV) DNA <60 IU/ml] was higher in the adefovir-lamivudine combination group compared with entecavir group (56.7% vs. 40%, P = 0.025), although biochemical and serological response rates were not significantly different. Genotypic resistance (9.2% vs. 24.6%, P = 0.005) and combined viral breakthrough (2.0% vs. 17.6%, P < 0.001) were more frequent in the entecavir group. However, by subgroup analysis, virological response rates were not significantly different between the two therapies in HBeAg-positive patients (44.9% vs. 35.7%, P = 0.268) or in patients with high baseline HBV DNA (≥7 log IU/ml) (40.7% vs. 31.3%, P = 0.320) at month 24. Conclusion This study showed that adefovir-lamivudine combination provides significantly higher antiviral efficacy and the lower resistance rate compared with the entecavir monotherapy in the management of lamivudine-resistant CHB. However, it had limited efficacy in HBeAg-positive patients or in patients with high baseline HBV DNA. [ABSTRACT FROM AUTHOR]

. Hepatitis B e antigen (HBeAg) negative hepatitis B virus (HBV) infections caused by precore (PC) or basal core promoter (BCP) mutations are associated with disease progression and complications. PC or BCP mutations may enhance the replication capacity of distinct drug-resistance-associated polymerase mutations, but their effect on adefovir-resistant HBV mutants is unclear. Importantly, BCP mutations were an independent risk factor for virological breakthrough in lamivudine-resistant patients treated with adefovir. We aimed at addressing the functional consequences of PC and BCP mutations on the replication and drug susceptibility of adefovir-resistant HBV mutants. Therefore, HBV constructs with wild type (WT) or adefovir-resistant rtN236T, rtA181V and rtA181T mutations, with or without concomitant PC or BCP mutations, were analysed in vitro using molecular assays. The adefovir-resistant polymerase mutations rtN236T, rtA181V and rtA181T showed a drastically reduced viral replication compared with WT. Interestingly, additional PC or BCP mutations enhanced the reduced replication efficacy of adefovir-resistant constructs and restored HBV replication to WT level. HBV rtA181T mutants displayed abolished hepatitis B surface antigen (HBsAg) secretion, owing to a sW172* stop codon in the overlapping envelope gene. All rtN236T- or rtA181V/T-containing constructs, regardless of concomitant PC or BCP mutations, were resistant to adefovir, but remained susceptible to telbivudine, entecavir and tenofovir. In conclusion, adefovir drug resistance mutations reduced viral replication, which can be significantly increased by additional HBeAg-suppressing PC or BCP mutations. Because increased HBV replication in HBeAg-negative patients has been associated with an unfavourable clinical course, close monitoring appears indispensable during adefovir treatment in HBeAg-negative patients. [ABSTRACT FROM AUTHOR]

Abstract: In this review article, a number of milestones in the antiviral research field on nucleosides and nucleotides are reviewed in which the author played a significant part, especially in the initial stages of their development. Highlighted are the amino acyl esters of acyclovir, particularly valacyclovir (VACV), brivudin (BVDU) and the valine ester of Cf1743 (FV-100), the 2′,3′-dideoxynucleosides (nucleoside reverse transcriptase inhibitors, NRTIs), the acyclic nucleoside phosphonates (S)-HPMPA, (S)-HPMPC (cidofovir) and alkoxyalkyl esters thereof (HDP-, ODE-CDV), adefovir and adefovir dipivoxil, tenofovir and tenofovir disoproxil fumarate (TDF), combinations containing TDF and emtricitabine, i.e., Truvada®, Atripla®, Complera®/Eviplera® and the Quad pill, and the phosphonoamidate derivatives GS-7340, GS-9131, GS-9191 and GS-9219. [Copyright &y& Elsevier]

We report on how adefovir-induced membranous nephropathy related to hepatitis B was caused by lamivudine-resistant virus after a liver transplant due to Byler's disease. In 1980, a 2-year-old girl was diagnosed with Byler's disease (familial progressive familial intrahepatic cholestasis). In 1994 (at the age of 14 years) she underwent a liver transplant with her father as the donor. In 2003, hematuria and proteinuria appeared and shortly afterwards her renal function rapidly decreased. A renal biopsy showed atypical membranous nephropathy, which suggested the possibility of a secondary renal disease. The patient had suffered from chronic hepatitis type B (HBV). In 2001 she was administered lamivudine which is an antiviral drug; it was around this time that hematuria and proteinuria appeared as well as an increase of the virus titer. We believed the HBV-related membranous nephropathy was the cause of the virus titer and the renal histology. We concluded that the patient's condition had become resistant to lamivudine medication. Therefore, in February 2004 we administered adefovir, a new drug at the time, to treat the HBV. In April 2004, the HB virus titer decreased and the hematuria and proteinuria decreased. The patient's renal function also showed improvement. HBV-associated nephropathy is caused by HBV antigen deposition in the glomeruli. Generally the first choice of treatment is antivirus therapy. There are many reports demonstrating that administration of interferon and lamivudine are effective; however, there are few reports that show adefovir as an effective treatment for HBV-associated nephropathy. [ABSTRACT FROM AUTHOR]

Background: Emergence of resistance was recognized shortly after the introduction of lamivudine. This 10 year retrospective study investigates resistance to lamivudine and the modifications of antiviral strategies required. Patients and methods: Two hundred and nine patients were treated with lamivudine. Sixty seven out of 209 patients were excluded from the present study. HBVDNA was tested using the PCR assay and genotypic resistance was performed using the direct PCR sequencing. Results: In the 125 patients initially treated with lamivudine monotherapy: A) 48 (38.4%) patients with a mean time of 63.6±26.2 months under lamivudine treatment have normal ALT levels with negative (19%) or low (<1×102) HBVDNA levels, 10% developed cirrhosis, 1 HCC and 6% cleared HBsAg. B) Resistance was developed in 61.60% patients within 45±23.84 months of lamivudine treatment. These patients were: 1) either switched to adefovir (9), entecavir (2) or tenofovir (2) or adefovir was added to lamivudine (21) for a short time and then they were switched to adefovir alone. Six out of 34 patients developed cirrhosis and 4 HCC while on treatment. 2) or adefovir was added-on to lamivudine (43). In 39 out of 43 treatment is ongoing while on virological response. No one developed cirrhosis or HCC. C) Seventeen patients received de novo combination therapy with lamivudine and adefovir and 2 out of 17 (11.7%) showed resistance to adefovir after 24 months of therapy. Conclusions: Our results showed that a) approximately 38.4% of patients maintain viral suppression more than 5 years of lamivudine treatment and b) rescue therapy with add-on adefovir to ongoing lamivudine, seems to be a better treatment strategy associated with long term benefit regarding disease complications. [ABSTRACT FROM AUTHOR]

To clarify the factors associated with delayed reduction of HBV DNA during combination treatment with adefovir dipivoxil (ADV) and lamivudine (LAM) for patients with LAM-resistant hepatitis B virus (HBV), factors including patient characteristics, viral mutations, and drug metabolism were investigated during a 5-year observation period. Delayed reduction of HBV DNA was defined as delayed viral response of detectable HBV DNA after 3 years of combination therapy. Of 67 consecutive patients, 47 attained undetectable HBV DNA after 3 years of combination therapy, and the mean therapeutic duration was 5 years (range: 3.0-8.4 years). The patients with delayed viral response had high levels of HBV DNA and HBe antigen, while those with negative or low levels of HBe antigen were also negative for HBV DNA, even if they had high levels of HBV DNA. In the multivariate analysis with the proportional hazards model, a high baseline level of HBe antigen was negatively associated with viral decline to an undetectable level ( P = 0.013). A higher baseline of HBe antigen corresponded to a lower annual decline in HBV DNA (R = −0.38, P = 0.004). No patients showed ADV-resistant mutations in the HBV reverse transcriptase region. Trough concentrations of LAM and ADV showed no clear associations with viral response. HBe antigen levels at the initiation of therapy, and reductions in these levels during therapy are predictive of the therapeutic response to combination therapy with ADV and LAM for patients with LAM-resistant HBV. J. Med. Virol. 84:1562-1570, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]