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Detection of synthetic thymidine analogues after their incorporation into replicating DNA during the S-phase of the cell cycle is a widely exploited methodology for evaluating proliferative activity, tracing dividing and post-mitotic cells, and determining cell-cycle parameters both in vitro and in vivo. To produce valid quantitative readouts for in vivo experiments with single intraperitoneal delivery of a particular nucleotide, it is necessary to determine the time interval during which a synthetic thymidine analogue can be incorporated into newly synthesized DNA, and the time by which the nucleotide is cleared from the blood serum. To date, using a variety of methods, only the bioavailability time of tritiated thymidine and 5-bromo-2'-deoxyuridine (BrdU) have been evaluated. Recent advances in double- and triple-S-phase labeling using 5-iodo-2'-deoxyuridine (IdU), 5-chloro-2'-deoxyuridine (CldU), and 5-ethynyl-2'-deoxyuridine (EdU) have raised the question of the bioavailability time of these modified nucleotides. Here, we examined their labeling kinetics in vivo and evaluated label clearance from blood serum after single intraperitoneal delivery to mice at doses equimolar to the saturation dose of BrdU (150 mg/kg). We found that under these conditions, all the examined thymidine analogues exhibit similar labeling kinetics and clearance rates from the blood serum. Our results indicate that all thymidine analogues delivered at the indicated doses have similar bioavailability times (approximately 1 h). Our findings are significant for the practical use of multiple S-phase labeling with any combinations of BrdU, IdU, CldU, and EdU and for obtaining valid labeling readouts., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Study Aims: The aim of this study was to enlighten the controversy about the renal safety of entecavir, tenofovir, and telbivudine treatments in chronic hepatitis B (CHB) patients by comparing these treatments in real-world conditions., Patients and Methods: We retrospectively enrolled 104 treatment-naive patients with CHB monoinfection into our study. Patients were treated with entecavir monotherapy (n=38), tenofovir monotherapy (n=35), or telbivudine monotherapy (n=31). We then compared and statistically analyzed the effects of these drugs on the estimated glomerular filtration rate (eGFR) over a 24-month follow-up period., Results: In the entecavir group, time-dependent change in eGFR was not statistically significant (p = 0.357). There was a statistically significant increase in eGFR in the telbivudine group at 12 months (p<0.001) and at 24 months (p<0.001) and, in contrast, a statistically significant decrease in the tenofovir group at 12 months (p<0.001) and at 24 months (p<0.001). There was no significant relationship between entecavir and eGFR change (p = 0.763). We found that tenofovir and telbivudine were independent predictors of eGFR change (decrease in eGFR, p<0.001 and increase in eGFR, p = 0.001, respectively)., Conclusions: We recommend close follow-up of renal functions, especially for patients treated with tenofovir. Telbivudine was superior to the other drugs in terms of renal function. We conclude that an individualized therapy program considering treatment efficacy and side effects is the best option for patients., Competing Interests: The authors declare that they have no conflict of interest, (© Acta Gastro-Enterologica Belgica.)

Background: Thymidine analogs and didanosine (ddI) have been associated with redistribution of body fat from subcutaneous adipose tissue (SAT) to visceral adipose tissue (VAT), which, in turn, is a risk factor for cardiovascular disease. We explored differences in adipose tissue distribution between people living with HIV (PLWH) with prior exposure to thymidine analogs and/or ddI, without exposure, and uninfected controls and the association with cardiovascular disease risk factors., Methods: In all, 761 PLWH from the Copenhagen Comorbidity in HIV Infection study, and 2283 age and sex-matched uninfected controls from the Copenhagen General Population Study were included. PLWH were stratified according to prior exposure to thymidine analogs and/or ddI. VAT and SAT were determined by abdominal computed tomography scan. Hypotheses were tested using regression analyses., Results: Exposure to thymidine analogs and/or ddI was associated with 21.6 cm larger VAT (13.8-29.3) compared to HIV infection without exposure. HIV-negative status was associated with similar VAT compared to HIV infection without exposure. Cumulative exposure to thymidine analogs and/or ddI [3.7 cm per year (2.3-5.1)], but not time since discontinuation [-1.1 cm per year (-3.4 to 1.1)], was associated with VAT. Prior exposure to thymidine analogs and/or ddI was associated with excess risk of hypertension [adjusted odds ratio (aOR) 1.62 (1.13-2.31)], hypercholesterolemia [aOR 1.49 (1.06-2.11)], and low high-density lipoprotein [aOR 1.40 (0.99-1.99)]., Conclusions: This study suggests a potentially irreversible and harmful association of thymidine analogs and ddI with VAT accumulation, which appears be involved in the increased risk of hypertension, hypercholesterolemia, and low high-density lipoprotein found in PLWH with prior exposure to thymidine analogs and/or ddI, even years after treatment discontinuation.

The aim of this study was to evaluate clinical efficacy of telbivudine in treatment of hepatitis B virus-associated glomerulonephritis (HBV-GN).A total of 43 HBV-GN patients combined with chronic hepatitis B were treated with telbivudine for 104 weeks. Serum levels of HBV DNA viral load, HBeAg, HBeAb, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Cr), and 24-hour urinary protein were evaluated after telbivudine treatment of 12, 24, 52, 76, and 104 weeks. Estimated glomerular filtration rate (eGFR) was calculated at baseline, 24 weeks, 52 weeks, and 104 weeks of treatment, respectively. Complete remission (CR) was defined as urinary protein <0.3 g/day, with normal ALT, AST, Cr, and eGFR. Criteria for partial remission include: 24-hour urinary protein excretion decreased by >50% compared with baseline level, and ALT and AST decreased >50%.Proteinuria level gradually decreased in patients with HBV-GN after telbivudine treatment. The percentages of PR + CR were 90.7% and 95.3%, respectively, at 52 and 104 weeks. Compared to baseline, eGFR were significantly increased from 69.2 ± 23.1 mL/min/1.73 m to 116.2 ± 26.3 mL/min/1.73 m at 104 weeks of treatment. Multivariate analysis indicated that baseline HBV DNA viral load (odds ratio [OR] = 1.19, 95% confidence interval [CI] 1.11-2.19, P = .02) and baseline urinary protein (OR = 1.08, 95% CI 1.04-2.44, P = .03) were independent risk factors associated with CR after telbivudine treatment among patients with HBV-GN.Our study demonstrates that telbivudine can be used to treat HBV-GN and effectively improve eGFR in these patients.

Background/aim: Our previous cDNA microarray study revealed increased cellular mRNA levels of a panel of genes, including kallikrein-8 (KLK8), after long-term telbivudine treatment in chronic hepatitis B patients. The aim of this study was to verify whether serum protein levels of KLK8, a cancer-related enzyme, are indeed increased after telbivudine treatment., Patients and Methods: A total of 83 chronic hepatitis B patients receiving telbivudine for >2 years were retrospectively analyzed. Serum KLK8 protein and estimated glomerular filtration rate (eGFR) changes were compared before and after treatment., Results: Both serum KLK8 protein and eGFR increased significantly after long-term telbivudine treatment (paired t-test: KLK8, p<0.001; eGFR, p=0.001). No direct correlation was found between KLK8 increase and eGFR change. However, eGFR change was positively associated with post-treatment KLK8 levels following adjustment for body height (p<0.001)., Conclusion: Telbivudine treatment resulted in increased levels of serum KLK8 protein. Furthermore, eGFR increase was associated with body height-adjusted, post-treatment KLK8 levels., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Creatine kinase elevation is commonly reported in telbivudine-treated patients. However, little is known about the relationship between this adverse drug reaction and plasma concentration. In this study, a sensitive, rapid and safe quantitative bioanalytical method has been established by using LC-MS/MS for the determination of telbivudine in a clinical study of chronic hepatitis B patients. The assay was linear in a dynamic 10-10,000 ng/mL range (r 2 > 0.999) and total analysis time was 6 min in this method. The validated method was applied to quantitatively determine plasma concentration in chronic hepatitis B patients during long-term telbivudine treatment. The results revealed that telbivudine concentration in the creatine kinase-elevated group (707.92-2788.78 ng/mL) was significantly higher than those with normal creatine kinase (412.63-1108.32 ng/mL). This method was adapted for therapeutic drug monitoring., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Telbivudine can cause severe side effects, including myositis, neuritis, rhabdomyolysis, and lactic acidosis. However, reported cases of telbivudine leading to multiple organ failure are rare. Here, we report a case of telbivudine-induced severe polymyositis, lactic acidosis, and multiple organ failure., Case Presentation: A 30-year-old Chinese man with hepatitis B virus infection received antiviral treatment with 600 mg of telbivudine daily for more than 11 months. He developed progressive weakness and myalgia, and subsequently experienced palpitations, chest tightness, lethargy, hypotension, and hypoxemia. Blood tests showed markedly elevated levels of alanine aminotransferase (955 U/L), aspartate aminotransferase (1375 U/L), blood urea nitrogen (14.9 mmol/L), creatine kinase (peak at 8050 U/L), and blood lactate (>20.0 mmol/L). His symptoms improved after continuous renal replacement therapy and short-term methylprednisolone treatment. Hyperbaric oxygen therapy, physical therapy, and rehabilitation for more than 2 months led to recovery of muscle strength to the normal range., Conclusions: We conclude that continuous renal replacement and steroid therapies play key roles in stabilizing telbivudine-induced severe rhabdomyolysis, lactic acidosis, and multiple organ failure. Hyperbaric oxygen, physical therapy, and rehabilitation may aid in functional recovery after the acute phase of lactic acidosis and organ failure.

Hepatitis B virus infection is currently the most important cause of chronic viral hepatitis worldwide and is one of the most frequent causes of end-stage liver disease. With the international implementation of the hepatitis B vaccine and combined prophylaxis for infants born to HBsAg(+) mothers, the prevalence of hepatitis B has decreased remarkably. However, intra-uterine transmission has become a critical bottleneck for eliminating hepatitis B infection. The efficacy of nucleos(t)ide analogs on inhibiting hepatitis B replication has been widely confirmed, and the quality of life and the survival of individuals with chronic hepatitis B (CHB) have improved to a great degree. However, with the availability of long-term antiviral treatment and the ever increasing ageing population, renal disorders should be considered when choosing antiviral medicines. The antiviral efficacy and safety of telbivudine (LdT) have been shown in patients with CHB infection, and LdT is approved as a class B drug for pregnancy. Furthermore, the renal protective function of LdT has been demonstrated recently. In this review, we will focus on the efficacy and safety of LdT in gravidas with CHB infection, as well as the renal protective function of LdT in CHB patients. LdT might provide physicians with a solid option for effectively treating patients with CHB, especially gravidas or those either with or at risk of renal impairment., (© 2017 John Wiley & Sons Ltd.)

Chronic hepatitis B (CHB) patients with higher hepatitis B virus (HBV) load (higher viral load [HVL], HBV DNA ≥1 × 10 7 copies/mL) require antiviral therapy, but data for evaluating the long-term outcome of this therapy with antiviral agents remain limited. We comparatively evaluated the efficacy and the safety of nucleoside analogues in 179 noncirrhotic CHB patients with HVL over 5 years. The HBeAg-positive (n = 104) or HBeAg-negative (n = 75) patients were treated consecutively with telbivudine (LdT, n = 88) or entecavir (ETV, n = 91) and evaluated for viral response, drug resistance and safety. HBV DNA, viral serology, biochemistries, HBV mutation and off-therapy relapse were determined. The cumulative rates of HBV DNA negativity were 86.4% and 94.5% for LdT and ETV at year 5, respectively. The rates of early viral response (EVR, HBV DNA <10 3 copies/mL at month 6) under LdT and ETV treatments were 58.0% and 34.1%, respectively (P < .05). Hepatitis B e antigen (HBeAg) and Hepatitis B surface antigen (HBsAg) loss-seroconversions were 47.7% and 18.2% on LdT and 16.5% and 2.2% on ETV (P < .01). Eighteen patients (age 28.2 ± 3.1) experienced HBsAg loss-seroconversion, followed by 33 ± 4.6 month off-therapy without a relapse. Viral mutations and serum creatine kinase elevation were 9.1% and 8.0% on LdT, but only 1.1% and 0% on ETV. Both LdT and ETV suppressed HBV replication in HVL CHB patients within 5 years. LdT therapy achieved a higher EVR, HBeAg and HBsAg seroconversion, especially in the younger patients, whereas ETV caused lower drug resistance and fewer adverse events. This finding might help to identify the optimal treatment for CHB patients with HVL., (© 2017 John Wiley & Sons Ltd.)

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 < 1 lg IU/mL decline of HBsAg level from baseline who underwent at least 24 weeks of Peg-IFNα-2a therapy were included. Enrolled patients were randomized to receive either telbivudine (600 mg/d, n = 95) or entecavir (0.5 mg/d, n = 95) for 208 consecutive weeks. Six patients were lost to follow-up (4 patients in the telbivudine group and 2 in the entecavir group). Treatment was combined with adefovir when week 24 HBV DNA levels declined to <2 lg IU/mL versus baseline, when viral breakthrough occurred during treatment,or when HBV DNA remained detectable at 52 weeks (HBV DNA ≥500 IU/mL). Responses and safety were assessed after 208 weeks of treatment. There were no significant differences among the baseline characteristics, including age, gender, and ALT, HBV DNA, HBsAg or HBeAg levels. After 208 weeks of treatment, there was no significant difference in the rates of undetectable HBV DNA (HBV DNA<500 IU/mL) between the telbivudine group and the entecavir group (84/91,92.31% vs 88/93,94.62%, respectively, P = .525). More patients in the telbivudine group than the entecavir group achieved HBeAg clearance (74.73% vs 46.24%, respectively, P < .001) and HBeAg seroconversion (64.84% vs 38.71%, respectively, P < .001). Univariate analysis (Enter, a = 0.05) of both groups showed that telbivudine, male gender and baseline HBeAg levels were significantly correlated with HBeAg seroconversion after 208 weeks of sequential therapy. Cox regression analysis (Enter, a = 0.05) of the telbivudine group showed that the HBeAg seroconversion rate at 208 weeks was significantly correlated with gender (male) (P = .006, HR=4.406), baseline HBeAg level (P = .005, HR=0.433) and 24 w-HBeAg level reduction of more than 0.5 lg IU/ml from baseline (P = .027, HR=0.487). All patients tolerated sequential telbivudine treatment; only slightly elevated creatine kinase levels were observed. Stratification analysis found that patients with baseline HBeAg levels less than 3 lg COI who switched to telbivudine may have had significantly improved HBeAg seroconversion rates. In conclusion, telbivudine promotes HBeAg seroconversion that merits investigation in HBeAg-positive CHB patients with suboptimal responses to 24 weeks of Peg-IFNα-2a therapy. We would suggest that patients with baseline HBeAg levels under 3 lg COI switch to telbivudine to achieve higher HBeAg seroconversion rates and use the early reductions in HBeAg levels (24 weeks) to guide treatment., (© 2017 John Wiley & Sons Ltd.)

Women with chronic hepatitis B should maintain nucleotide analogue treatment to prevent disease progression during pregnancy. The aim of this study was to prospectively evaluate the efficacy and safety of telbivudine used throughout pregnancy for preventing hepatitis B virus (HBV) mother-to-child transmission (MTCT). From January 2012 to June 2014, women who were receiving telbivudine therapy and became pregnant were enrolled in group A at 28 weeks of gestation. Pregnant women with an HBV DNA level >10 6  IU/mL were enrolled in either group B (telbivudine started at 28 weeks of gestation) or group C (control group without treatment). MTCT was defined as infants who were positive for serum hepatitis B surface antigen at 7 months after birth. There were 41, 179 and 177 pregnant women (397 infants) enrolled in groups A, B and C, respectively. The HBV DNA load at 28 weeks of gestation and delivery was 1.50 ± 0.62 vs 1.45 ± 0.61, 8.05 ± 0.37 vs 4.24 ± 0.89 and 7.94 ± 0.62 vs 7.86 ± 0.73 log 10 IU/mL in groups A, B and C, respectively. The rate of MTCT in group C was 4.60%, which was significantly higher than the rates in groups A and B (0% and 0.6%, respectively) (P = .043). The difference between group A and group B was not significant. The rates of neonatal congenital abnormalities were 2.4%, 0.6% and 2.3% in groups A, B and C, respectively, and there were no significant differences (P = .140). Telbivudine used throughout pregnancy may be safe and effective for mothers and infants, but it may not enhance the efficacy of an HBV MTCT block compared with treatment starting at 28 weeks of gestation (NCT02253485)., (© 2017 John Wiley & Sons Ltd.)

The management of hepatitis B virus (HBV) infection in pregnancy is a unique issue. Telbivudine (LdT) is recommended to block HBV mother-to-child transmission (MTCT) in the third trimester. However, the safety of LdT treatment during the entire pregnancy for the long-term growth of infants is unclear. The aim of this study was to evaluate the efficacy and long-term safety of LdT for the entire pregnancy period. This retrospective cohort study included 40 pregnant women and 43 children from 2011 to 2017. The antiviral effects and maternal abnormalities were evaluated. In addition, adverse events regarding infants at delivery and HBV vaccination outcomes were recorded. The status of physical development in the children during follow-up was also evaluated. Among pregnant women, the rates of HBV DNA flare were 5.00% during pregnancy and 7.50% postpartum, and the HBeAg seroconversion rates were 7.50% during pregnancy and 7.50% postpartum. No severe maternal abnormalities were observed. Regarding the infants, no one was positive for HBsAg, and only one infant was negative for anti-HBs in children over 7 months of age. Furthermore, no birth defects or severe adverse events were observed at delivery, and 97.67% normal height and 93.02% normal weight in children were observed on follow-up until 5 years of age. In conclusion, LdT use for the entire pregnancy is both effective for treating pregnant women and blocking HBV MTCT. Moreover, LdT is safe for women and infants. Most importantly, the long-term follow-up indicated that LdT is safe and does not affect the growth of children., (© 2017 John Wiley & Sons Ltd.)

Nucleos(t)ide analogues (NUCs) and interferon have been used for several decades to treat chronic hepatitis B; however, the therapeutic response remains unsatisfactory. Although NUC therapy exhibits potent on-treatment viral suppression, frequent off-therapy virological relapses suggest an indefinite treatment course. Interferon modulates the innate and adaptive antiviral immune responses and thus increases the chance of viral eradication. Interferon therapy has the advantage of a finite duration, absence of drug resistance, and durable posttreatment responses. Therefore, the combination of NUCs and interferon can theoretically facilitate a synergistic therapeutic effect. This paper summarizes the current strategies of various combination therapies into three categories: the simultaneous "dual" strategy, sequential combination "add-on" strategy, and "switch" strategy. Generally, dual therapy exhibits greater on-treatment and off-therapy viral suppression and lower drug resistance compared with NUC monotherapy. Compared with interferon monotherapy, dual therapy has greater on-treatment viral suppression but shows no difference in off-therapy sustained virological responses. Specific add-on or switch strategies provide promising on-treatment efficacy in select patients. Pretreatment or on-treatment quantitative hepatitis B surface antigen and e antigen are predictive for the treatment efficacy of combination therapy. The optimal schedule of combination regimens and individualized therapy remain to be comprehensively evaluated.

Objective: Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2 -/- ) mice by 2- to 3-fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: (1) deoxynucleosides might be the major active agents and (2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy., Methods: To test these hypotheses, we assessed two therapies in Tk2 -/- mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP., Results: We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2 -/- animals compared to dCMP+dTMP., Interpretation: Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641-652., (© 2017 American Neurological Association.)

Background and Aims: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a mini-chromosome essential for HBV replication, is supposed to be resistant to nucleos(t)ide analogue treatment. We investigated the effect of long-term nucleos(t)ide analogue treatment on cccDNA., Methods: Among 129 patients who had been enrolled in previous international nucleos(t)ide analogue clinical trials and had liver biopsies at baseline and one year after treatment, we recruited 43 patients on long-term continuous treatment for 72 to 145months for a third liver biopsy. Serum HBV DNA, hepatitis B surface antigen (HBsAg) levels, total intrahepatic HBV DNA (ihHBV DNA), cccDNA, HBV pregenomic RNA (pgRNA) as well as histologic changes were examined., Results: At the time of the third biopsy, serum HBV DNA levels were undetectable in all but one patient. The median levels of HBsAg, ihHBV DNA, and cccDNA were 2.88logIU/ml, 0.03copies/cell, and 0.01copies/cell, respectively. Compared to baseline levels, there was reduction of HBsAg levels by 0.54log (71.46%), ihHBV DNA levels by 2.81log (99.84%), and cccDNA levels by 2.94log (99.89%), with 49% having cccDNA levels below the detection limit. One patient had undetectable HBsAg. The median pgRNA level, measured only in the third biopsy, was 0.021copies/cell, with 40% of patients having undetectable pgRNA., Conclusions: Long-term nucleos(t)ide analogue treatment induced marked depletion of cccDNA in the majority of patients while serum HBsAg levels, though reduced, were detectable in all but one patient. Whether cccDNA depletion is sustained and associated with better patient outcome requires further study., Lay Summary: It is generally presumed that a form of hepatitis B virus DNA, called covalently closed circular DNA (cccDNA), which hides inside the nuclei of liver cells of patients with chronic hepatitis B, cannot be reduced by antiviral treatment. The present study showed that with prolonged treatment (median period 126months), cccDNA can be markedly reduced, with 49% of liver biopsies having undetectable cccDNA. This suggests that viral replication capacity would be very low after prolonged antiviral treatment., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aim: The efficacy of telbivudine for breaking vertical transmission of hepatitis B virus has been well established. Data on the risk of postpartum flare after telbivudine withdrawal and efficacy of extended antiviral therapy after delivery are limited., Methods: Chronic hepatitis B virus-infected women who received telbivudine beginning at week 24 or 28 of gestation were enrolled and then followed up to 52 weeks postpartum. Virological and biochemical parameters were assessed., Results: Of the 241 women who finished 52 weeks of follow-up, 33.6% had elevated serum alanine aminotransferase (ALT) during pregnancy. Telbivudine administration resulted in ALT normalization in 85.2% before delivery. Compared with women having a normal ALT level throughout pregnancy, those with elevated ALT had a significantly higher rate of ALT flare after telbivudine withdrawal (25.0% vs 11.9%; χ 2  = 4.273, P = 0.039). Multivariate analysis indicated that only ALT elevation during pregnancy correlated with postpartum flare after telbivudine withdrawal. Those women with elevated ALT during pregnancy continued antiviral treatment to 52 weeks postpartum and had a significantly higher HBeAg seroconversion rate (P = 0.001) and a notable decrease in HBsAg titers (P = 0.001)., Conclusion: It is safe for the majority of women to withdraw telbivudine after delivery, whereas exciting serological response encourages extended antiviral therapy for mother with ALT elevation during pregnancy., (© 2016 The Authors Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Chronic renal failure is a frequent complication in liver transplantation. Telbivudine, anti-hepatitis B virus (HBV) nucleoside, can improve renal function. It is interesting if using telbivudine for prophylaxis of HBV recurrence has additional value on renal function improvement. 120 liver transplant recipients with lamivudine prophylaxis for HBV recurrence were 1 : 1 randomized into lamivudine-continuous ( n = 60) and telbivudine-replacement ( n = 60) groups. Fifty-eight patients in lamivudine-continuous group and 54 in telbivudine-replacement group completed the study. In telbivudine-replacement group, the estimated glomerular filtration rate (eGRF) was improved from 63.0 ± 16.3 ml/min to 72.8 ± 21.1 ml/min at 12 months after telbivudine administration ( p = 0.003). Stratifying the patients according to renal function staging, the eGRF was improved from 74.7 ± 6.9 ml/min to 84.2 ± 16.6 ml/min ( p = 0.002) in 32 stage II patients and from 48.2 ± 7.3 ml/min to 59.7 ± 11.8 ml/min in 20 stage III patients after 12 months of telbivudine administration ( p < 0.001). Eleven (18.3%) patients with telbivudine developed polyneuritis during the trial and post hoc following-up. In conclusion, renal function was improved by telbivudine in liver transplant recipients with long-term chronic kidney disease. However, the high incidence of polyneuritis induced by telbivudine has to be closely monitored. This trial is registered with ClinicalTrials NCT02447705.

Hepatitis B virus (HBV) infection is one of the most serious health problems worldwide with a high risk for cirrhosis and liver cancer. Several antiviral agents have been approved for the treatment of chronic hepatitis B, leading to a rapid reduction in HBV DNA and normalization of serum alanine aminotransferase levels. Telbivudine, a potent inhibitor of HBV replication, has been shown to be well tolerated. Because of the emergence of drug resistance, optimization strategies for telbivudine therapy have been shown to improve patient responses. Optimal baseline characteristics in so-called super-responders have been used to predict the virological response. Baseline HBV DNA levels < 9 log 10 copies/mL (2 × 10 8  IU/mL) or alanine aminotransferase levels of more than or equal to twofold the upper limit of normal in HBeAg-positive patients and HBV DNA < 7 log 10 copies/mL (2 × 10 6  IU/mL) in HBeAg-negative patients were strong predictors for virological response. In addition, the roadmap model, based on early virological response at week 24 of therapy, is considered as a powerful tool to identify patients at risk of treatment failure (HBV DNA ≥ 300 copies/mL, i.e. 60 IU/mL) and to reduce the risk of antiviral resistance. When considering pre-treatment characteristics and on-treatment responses, telbivudine may provide physicians with a wide choice of options to effectively treat patients with chronic hepatitis B, especially those with or at risk of renal impairment, or women of childbearing age., (© 2016 The Authors Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Chronic hepatitis B infection remains a significant health issue worldwide. This study evaluated the efficacy and safety of combined therapy using lamivudine plus adefovir (LAM+ADV) versus telbivudine plus adefovir (LdT+ADV) and the corresponding renal function change and safety., Methods: This study enrolled a total of 171 patients (110 patients received LAM+ADV and 60 patients received LdT+ADV). We analyzed the changes in renal function using the estimated glomerular filtration rate (eGFR). The DNA undetectable rate, hepatitis B e antigen (HBeAg) seroconversion rate, and alanine aminotransferase (ALT) normalization rate were analyzed. We checked the serum uric acid, phosphate and creatine kinase, and lactic acid levels to analyze safety. We observed these patients for 48 to 240 weeks and checked their serum profile every 6 months., Results: There was no statistically significant difference between the two groups in anti-hepatitis B virus (HBV) efficacy in terms of DNA undetectable rate, ALT normalization rate, and HBeAg seroconversion rate. Both the LAM+ADV and LdT+ADV groups had stable or improved renal function. However, a higher eGFR was found in the LdT+ADV group with continuous serum fluctuation during 3 years of combined therapy as well as a higher serum creatine kinase level., Conclusions: Long-term LdT+ADV combined therapy and LAM+ADV combined therapy were both associated with stable or improved renal function. The clinical efficacy was similar between the two groups, but the LdT group had a higher serum creatine kinase level. We need to monitor the data regularly in clinical practice., Competing Interests: The authors have declared that no competing interests exist.

Background: Tenofovir disoproxil fumarate (TDF) is newly available for treatment of chronic hepatitis B patients in China. To date, no study has been conducted to examine the cost-effectiveness of this treatment. The aim of this study was to estimate the cost-effectiveness of TDF versus four oral nucleos(t)ide analogs [lamivudine (LAM), adefovir (ADV), telbivudine (LdT), and entecavir (ETV)] and from a pharmacoeconomic perspective to assess current drug pricing for TDF., Methods: Based on Chinese healthcare perspectives, a Markov model was applied to simulate the lifetime (40-year time span) costs and quality-adjusted life-years (QALYs) for five different monotherapy strategies. Two kinds of rescue combination strategies (base-case: LAM + ADV then ETV + ADV; alternative: directly using ETV + ADV) were separately considered for treatment of patients refractory to monotherapy. Model parameters (including disease transition, cost, and utility) were obtained from previous Chinese population studies. Both branded and generic drugs were separately analyzed. Study model uncertainties were assessed by one-way and probabilistic sensitivity analyses. Two-way sensitivity analysis was used to explore uncertainties between efficacy and price of TDF., Results: In the base-case analysis, the lowest lifetime cost and the best cost-effectiveness ratio were obtained by ETV, which was considered the reference treatment. LAM, ADV, and LdT treatments had significantly greater costs and lower efficacies. Compared to ETV, TDF was more effective but also more expensive. The incremental cost-effectiveness ratios of TDF versus ETV were much higher than the willing-to-pay threshold of $20,466 US dollars (USD) per QALY gained (3 × gross domestic product per capita of China, 2014). TDF would be the most cost-effective strategy if the annual cost did not exceed $2260 USD and $1600 USD for branded and generic drugs, respectively., Conclusions: For Chinese chronic hepatitis B patients, ETV is still the most cost-effective strategy over TDF and other nucleos(t)ide analogs, with a threshold of $20,466 USD/QALY gained.

Inhibition of both the de novo (DNP) and salvage (NSP) pathways of nucleoside synthesis has been demonstrated to impair leukemia cells. We endeavored to determine whether this approach would be efficacious in glioblastoma. To diminish nucleoside biosynthesis, we utilized compound DI-39, which selectively targets NSP, in combination with thymidine (dT), which selectively targets DNP. We employed in vitro and ex vivo models to determine the effects of pretreatment with dT + DI-39 on brain tumor stem cells (BTSC). Here, we demonstrate that this combinatorial therapy elicits a differential response across a spectrum of human patient-derived glioblastoma cultures. As determined by apoptotic markers, most cultures were relatively resistant to treatment, although a subset was highly sensitive. Sensitivity was unrelated to S-phase delay and to DNA damage induced by treatment. Bioinformatics analysis indicated that response across cultures was associated with the transcription factor PAX3 (associated with resistance) and with canonical pathways, including the nucleotide excision repair pathway, PTEN (associated with resistance), PI3K/AKT (associated with sensitivity), and ErbB2-ErbB3. Our in vitro assays demonstrated that, in sensitive cultures, clonal sphere formation was reduced upon removal from pretreatment. In contrast, in a resistant culture, clonal sphere formation was slightly increased upon removal from pretreatment. Moreover, in an intracranial xenograft model, pretreatment of a sensitive culture caused significantly smaller and fewer tumors. In a resistant culture, tumors were equivalent irrespective of pretreatment. These results indicate that, in the subset of sensitive glioblastoma, BTSCs are targeted by inhibition of pyrimidine synthesis. Mol Cancer Ther; 15(6); 1271-8. ©2016 AACR., (©2016 American Association for Cancer Research.)

Aim: To investigate serum interleukin (IL)-38 level and its clinical role in predicting virological response (VR) to telbivudine (LdT) in patients with chronic hepatitis B (CHB)., Methods: The study participants were divided into two groups; one group consisted of 43 healthy controls (HCs) and the other group consisted of 46 patients with hepatitis B e antigen-positive CHB. All patients were administered 600 mg of oral LdT daily for 52 wk, and they visited physicians every 12 wk for physical examination and laboratory tests. Serum IL-38 levels were determined using ELISA. The concentrations of serum Th1- and Th2-type cytokines were measured using the cytometric bead array (CBA) method., Results: Serum levels of IL-38 at baseline in all patients were higher than those in HCs [306.97 (123.26-492.79) pg/mL vs 184.50 (135.56-292.16) pg/mL, P = 0.019]; the levels returned to normal after the first 12 wk of treatment with LdT [175.51 (103.90-331.91) pg/mL vs 184.50 (135.56-292.16) pg/mL, P > 0.05]. Serum IL-38 levels at baseline were positively associated with serum aspartate aminotransferase levels in patients with CHB (r = 0.311, P = 0.036). Higher levels of serum IL-38 at baseline were associated with a greater probability of VR to LdT treatment at 24 wk (48.15% vs 15.79%, P = 0.023) and 52 wk (66.67% vs 36.84%, P = 0.044). The levels of serum IL-38 in patients with primary non-response at week 12 after treatment initiation were lower than those in patients with primary response [64.44 (49.85-172.08) pg/mL vs 190.54 (121.35-355.28) pg/mL, P = 0.036]. Serum IL-38 levels were correlated with serum IL-6 and IL-12 levels in patients with CHB during treatment with LdT., Conclusion: Elevated serum IL-38 levels in untreated CHB patients reflect ongoing liver injury. Higher serum IL-38 levels before treatment indicate a greater probability of VR to LdT treatment.

Objective: To investigate the efficacy and safety of 104-week sequential therapy with telbivudine or entecavir in HBeAg-positive chronic hepatitis B (CHB) patients with suboptimal responses to 24-week pegylated interferon-α-2a (PEG-IFN-α-2a) therapy., Methods: A total of 130 HBeAg-positive CHB patients with HBV DNA≥5.0 lg IU/ml and a reduction in HBsAg quantitation < 1 lg IU/ml compared with baseline who received PEG-IFN-α-2a therapy for 24 weeks were enrolled and randomly divided into telbivudine group and entecavir group, and 5 of them were lost. HBeAg clearance rate and seroconversion rate, HBV DNA clearance rate, safety, and drug resistance rate at week 104 were observed. The t-test, chi-square test, or multivariate Cox regression analysis were used for statistical analysis of different types of data., Results: At week 104 of treatment, HBV DNA clearance rate showed no significant difference between the telbivudine group and entecavir group (P = 0.363), and the telbivudine group had significantly higher HBeAg clearance rate and HBeAg seroconversion rate than the entecavir group (HBeAg clearance rate: 61.29% vs 23.81%, P < 0.01; HBeAg seroconversion rate: 51.61% vs 19.05%, P < 0.01). Male sex and telbivudine therapy were baseline predictors of HBeAg seroconversion. The multivariate Cox regression analysis (Forward LR, a = 0.05) showed that the presence or absence of HBeAg seroconversion at week 104 was significantly associated with male sex (HR = 4.917), a reduction in HBsAg > 0.5 lg IU/ml at week 12 of treatment compared baseline (HR = 3.514), and a reduction in HBeAg > 1 lg COI at week 12 of treatment compared baseline (HR = 8.651)., Conclusion: In HBeAg-positive CHB patients with suboptimal responses to 24-week PEG-IFNα-2a therapy, the sequential therapy with telbivudine helps achieve better HBeAg clearance rate and seroconversion rate compared with the sequential therapy with entecavir and can be used as a therapeutic regimen for such patients. A reduction in HBeAg > 1 lg COI at week 12 of treatment compared baseline can be used as a predictive factor for HBeAg seroconversion at week 104.

There are few studies directly comparing the efficacy and safety of telbivudine and entecavir. The present prospective cohort study aimed to evaluate the long-term efficacy and safety of these compounds in 196 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B for a median follow-up period of 172 weeks; 97 were treated with telbivudine and 99 were treated with entecavir. Patients showing suboptimal responses could also take adefovir at 24-48 weeks and all patients with viral breakthrough were started on adefovir. The 240-week cumulative proportions of patients showing undetectable hepatitis B DNA levels and serum alanine transaminase (ALT) normalization were similar in the two study groups. Viral breakthrough developed in 14% of the telbivudine group and in 2% of the entecavir group (p 0.002). Interestingly, the cumulative proportions of patients treated with entecavir and telbivudine showing HBeAg seroconversion were 12% versus 21% at 48 weeks (p 0.041), 15% versus 38% at 96 weeks (p 0.001), 24% versus 50% at 144 weeks (p 0.001), 33% versus 53% at 192 weeks (p 0.004) and 36% versus 53% at 240 weeks (p 0.005), respectively. Patients treated with telbivudine were therefore significantly more likely to show HBeAg seroconversion than those receiving entecavir and similar results were observed in study sub-groups matched for age, serum ALT, and HBV DNA levels. A safety analysis identified no differences between grade 3/4 creatine kinase elevations in the study groups and only telbivudine was associated with improved kidney function., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background/purpose: A subgroup analysis of a GLOBE study identified subgroups of chronic hepatitis B (CHB) patients with excellent outcomes to telbivudine (LdT) treatment. The aim of this study was to validate this concept using a real-world clinical population., Methods: This prospective, retrospective, and multicenter study examined both HBeAg-positive and HBeAg-negative CHB patients treated with LdT for 2 years., Results: A total of 116 CHB patients were recruited. Of the 64 HBeAg-positive patients, 35 had favorable baseline characteristics [hepatitis B virus (HBV) DNA ≤ 9 log(10) copies/mL and alanine aminotransferase ≥ 2× the upper limit of normal (ULN)], but only 40% (14/35) achieved polymerase chain reaction (PCR) negativity at week 24. Among the 14 patients with favorable baseline characteristics and on-treatment response, the rates of virologic, biochemical, and serologic response and genotypic resistance were 78.6% (11/14), 64.3% (9/14), 50% (7/14), and 7.1% (1/14), respectively, at week 104 of therapy. Of the 52 HBeAg-negative patients, 34 met the criteria of a baseline serum HBV-DNA level less than 7 log(10) copies/mL, and 29 (85.3%) achieved PCR negativity at week 24. Among the 29 patients with favorable baseline characteristics and on-treatment response, the rates of virologic and biochemical response and genotypic resistance were 96.6% (28/29), 72.4% (21/29), and 6.9% (2/29), respectively. In addition, the PCR negativity at week 24 was the only factor associated with the virologic response and genotypic resistance to LdT treatment., Conclusion: The efficacy and resistance to LdT treatment in CHB patients with favorable predictors were comparable between a real-world clinical population and the GLOBE study. In addition, PCR negativity at week 24 could predict virologic response and genotypic resistance to LdT treatment.

This study aims to assess the nephrotoxicity and efficacy of tenofovir disoproxil fumarate (tenofovir), telbivudine and entecavir. A retrospective study of 587 patients with chronic hepatitis B treated with tenofovir (n = 170), telbivudine (n = 184) and entecavir (n = 233) for at least 1 year. Renal function and efficacy were assessed. The estimated glomerular filtration rate (eGFR) decreased significantly in the tenofovir group after a mean of 17 months treatment (from 92.2 to 85.6 mL/min/1.73 m(2), p < 0.001), but increased in the telbivudine group after a mean of 32 months of treatment (from 86.1 to 95 mL/min/1.73 m(2), p < 0.001). There was no significant change in eGFR in the entecavir group after a mean of 44 months. By multivariate analysis, pre-existing renal insufficiency (p = 0.003), tenofovir (p = 0.007) and diuretic treatment (p = 0.001) were independent predictors for renal function deterioration. Cumulative virological breakthrough was 0% in tenofovir after 2 years, 3.4% in entecavir after 7 years and 22.9% in telbivudine after 5 years. Liver cirrhosis (p = 0.008) and virological breakthrough (p = 0.040) were independently associated with increased risk of hepatocellular carcinoma development. Tenofovir may lead to deterioration in renal function as assessed by serial eGFR measurements. Although telbivudine appeared to be associated with an improvement in eGFR, it was associated with high rates of virological breakthrough, which was an independent risk factor for HCC development. With low rates of virological breakthrough and preservation of renal function, entecavir could be the best choice among these three agents., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: BMS-986001 is a thymidine analogue nucleoside reverse transcriptase inhibitor (NRTI) designed to maintain in-vitro antiviral activity while minimising off-target effects. We assessed the efficacy and safety of BMS-986001 versus tenofovir disoproxil fumarate in treatment-naive patients with HIV-1., Methods: In this phase 2b, randomised, active-controlled trial (AI467003), we recruited treatment-naive (no current or previous exposure to an antiretroviral drug for >1 week) adults (aged at least 18 years) with HIV-1 from 47 sites across Asia, Australia, Europe, North America, South Africa, and South America. Patients with plasma HIV-1 RNA greater than 5000 copies per mL and CD4 counts greater than 200 cells per μL were randomly assigned (2:2:2:3) to receive BMS-986001 100 mg, 200 mg, or 400 mg once a day or to receive tenofovir disoproxil fumarate 300 mg once a day; each allocation was given with efavirenz 600 mg once a day and lamivudine 300 mg once a day. Both patients and investigators were masked to BMS-986001 dose (achieved with similar looking placebo tablets), but not allocation up to and including week 48. The primary endpoints were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL and safety events (serious adverse events and adverse events leading to discontinuation) through week 24; the main analysis was with a modified intention-to-treat population. Resistance analysis was a secondary endpoint, and additional safety parameters were exploratory endpoints. This trial is registered with ClinicalTrials.gov, number NCT01489046, and the European Clinical Trials Database, number EudraCT 2011-003329-89., Findings: Patients were recruited between Jan 25, 2012, and Oct 3, 2012; 757 patients were assessed for eligibility and 301 were randomly assigned to receive either BMS-986001 once a day (67 patients to 100 mg, 67 to 200 mg, and 66 to 400 mg) or tenofovir disoproxil fumarate (n=101). 297 patients received at least one dose of study drug. At week 24, 57 (88%) of 65 patients for whom there were data in the 100 mg group, 54 (81%) of 67 in the 200 mg group, 62 (94%) of 66 in the 400 mg group achieved HIV-1 RNA less than 50 copies per mL, compared with 88 (89%) of 99 in the tenofovir disoproxil fumarate group (modified intention-to-treat population). BMS-986001 was generally well tolerated through week 48. Two patients had BMS-986001-related serious adverse events (atypical drug eruption and thrombocytopenia) and two in the tenofovir disoproxil fumarate group had study drug-related serious adverse events (potential drug-induced liver injury and depression or lipodystrophy) that led to discontinuation. NRTI resistance-associated mutations were reported in four (2%) of 198 patients, and non-NRTI mutations in 17 (9%) of 198 patients receiving BMS-986001 versus none of 99 and one (1%) of 99 patients receiving tenofovir disoproxil fumarate, respectively. Compared with tenofovir disoproxil fumarate, individuals in the BMS-986001 groups showed a smaller decrease in lumbar spine and hip bone mineral density but greater accumulation of limb and trunk fat, subcutaneous and visceral adipose tissue, and increased total cholesterol., Interpretation: BMS-986001 had similar efficacy to that of tenofovir disoproxil fumarate and was associated with a smaller decrease in bone mineral density; however, greater resistance and gains in both peripheral and central fat accumulation were recorded for the investigational drug. Bristol-Myers Squibb has discontinued its involvement in the development of BMS-986001, and future decisions on development will be made by Oncolys BioPharma., Funding: Bristol-Myers Squibb., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In this report we describe studies with N5-2OH, a carboranyl thymidine analog (CTA), which is a substrate for thymidine kinase 1 (TK1), using the F98 rat glioma model. In vivo BNCT studies have demonstrated that intracerebral (i.c.) osmotic pump infusion of N5-2OH yielded survival data equivalent to those obtained with i.v. administration of boronophenylalanine (BPA). The combination of N5-2OH and BPA resulted in a modest increase in MST of F98 glioma bearing rats compared to a statistically significant increase with the RG2 glioma model, as has been previously reported by us (Barth et al., 2008). This had lead us to synthesize a second generation of CTAs that have improved in vitro enzyme kinetics and in vivo tumor uptake (Agarwal et al., 2015)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background/aims: The aim of this study was to evaluate the estimated glomerular filtration rate (eGFR) during telbivudine (LdT) versus entecavir (ETV) treatment in chronic hepatitis B (CHB) patients with underlying comorbidities such as diabetes mellitus (DM), hypertension, and cirrhosis., Methods: From 2010 to 2012, 116 CHB patients treated with LdT and 578 treated with ETV were compared in this real-practice cohort. The mean changes in eGFR (Modification of Diet in Renal Disease [MDRD] formula) from baseline to months 6, 12, and 18 were analyzed using a linear mixed model., Results: In LdT-treated patients, the mean eGFR increased by 7.6% at month 18 compared with the eGFR at baseline (MDRD formula in mL/min/1.73 m(2)). However, in ETV-treated patients, the mean eGFR decreased by 4.1% at month 18 compared with the eGFR at baseline. In the LdT-treated patients with DM, hypertension, cirrhosis or low eGFR <90 mL/min/1.73 m(2), the mean eGFR showed a steady improvement, whereas the mean eGFR was reduced in the same subgroups of ETV-treated patients., Conclusions: The eGFR gradually increased over time during LdT treatment, especially in patients with mild abnormal eGFR at baseline, and in those with DM, hypertension, and cirrhosis, whereas a reduction in eGFR was seen with ETV treatment.

Introduction: The long-term goal of chronic hepatitis B (CHB) treatment is improvement of liver disease and prevention of cirrhosis. The aim of this study was to assess whether prolonged telbivudine treatment improves liver inflammation and fibrosis. The primary objective was to evaluate the proportion of patients with absence/minimal inflammation (Knodell necroinflammatory score ≤3) on liver biopsy at Year 5., Methods: Fifty-seven patients aged 16-70 years with a clinical history of CHB and active viral replication (38 hepatitis B e antigen [HBeAg] positive and 19 HBeAg negative) were followed for 6 years: 33 received telbivudine 600 mg/day continuously for 5 years; 24 received lamivudine 100 mg/day for 2 years and then telbivudine for 3 years. Liver biopsies were taken pre-treatment and after 5 years of treatment., Results: At baseline, mean (standard deviation) serum hepatitis B virus (HBV) DNA load was 8.5 (1.7) log10 copies/mL, Knodell necroinflammatory score was 7.6 (2.9), and Ishak fibrosis score was 2.2 (1.1). After antiviral treatment (median duration: 261 weeks), liver histology improved with increased proportions of patients with absence/minimal liver inflammation (Knodell necroinflammatory score ≤3), from 16% (9/57) at baseline to 98% (56/57), and absence/minimal fibrosis (Ishak score ≤1), from 25% (14/57) at baseline to 84% (48/57). At Year 5, HBV DNA load was <300 copies/mL for all patients; cumulative HBeAg loss and seroconversion rates were 88% and 77%, respectively. At Year 6, 95% of patients with abnormal baseline glomerular filtration rate (60-90 mL/min/1.73 m(2)) improved to normal GFR (>90 mL/min/1.73 m(2))., Conclusion: Long-term telbivudine treatment with profound and durable viral suppression significantly improved liver histology, thus achieving the long-term goals of CHB treatment. FibroScan(®) results after 5 and 6 years of treatment (in almost 20% of patients) were consistent with this information., Funding: Novartis and National Science and Technology Major Project (2012ZX10002003)., Trial Registration: ClinicalTrials.gov # NCT00877149.

Background: Research has shown that hepatitis B virus (HBV) genotypes are closely linked to the clinical manifestations, treatment, and prognosis of the disease., Objective: To study the association between genotype and drug-resistant HBV mutations in 620 Chinese patients with chronic HBV infection., Methods: HBV DNA levels were determined using real-time quantitative PCR in plasma samples. Microarrays were performed for the simultaneous detection of HBV genotypes (HBV/B, C, and D) and drug-resistance-related hotspot mutations. A portion of the samples analyzed using microarrays was selected randomly and the data were confirmed using direct DNA sequencing., Results: Most samples were genotype C (471/620; 76.0%), followed by genotype B (149/620; 24.0%). Among the 620 patient samples, 17 (2.7%) had nucleotide analogs (NA) resistance-related mutations. Of these, nine and eight patients carried lamivudine (LAM)-/telbivudine (LdT)-resistance mutations (rtL180M, rtM204I/V) and adefovir (ADV)-resistance mutations (rtA181T/V, rtN236T), respectively. No patients had both lamivudine (LAM)- and either adefovir (ADV) or entecavir (ETV) resistance mutations. Additionally, out of the 620 patient samples, 64.0% (397/620) were also detected with the precore stop-codon mutation (G1896A) by microarray assay., Conclusion: The results of the current study revealed that the prevalence of nucleotide analogs (NA)-resistance in Chinese hospitalized HBV-positive patients was so low that intensive nucleotide analogs (NA)-resistance testing before nucleotide analog (NA) treatment might not be required. In addition, the present study suggests that chronic HBV patients with genotype C were infected with fitter viruses and had an increased prevalence of nucleotide analogs (NA)-resistance mutations compared to genotype B virus., (Copyright © 2015 Elsevier Editora Ltda. All rights reserved.)

Objectives: We studied the growth and development of children prenatally exposed to telbivudine used to treat chronic hepatitis B virus (HBV) infection in their mothers., Methods: Maternal abnormalities during pregnancy and delivery and infant congenital anomalies, physical development status, developmental quotient (DQ), HBV vertical transmission status, and HBV vaccination outcomes of 54 infants were evaluated (2010-2013)., Results: No fetal abnormalities were observed during pregnancy or delivery. Postpartum, three infants (5.56%) had abnormalities: ankyloglossia, cutaneous hemangioma, and vaginal canal leak. Height and weight were within the normal range at birth and at 6 weeks, but were higher than the reference at 12 months (p<0.05). Body mass index increased gradually with age (p<0.05). DQ scores were normal (84.81%, 229/270) in 37 children (68.52%), abnormal or suspicious for a developmental delay (15.19%, 41/270) in 17 children (31.48%), and indicated a developmental delay (4.07%, 11/270) in seven children (12.96%). There were no significant differences in developmental delay between children prenatally exposed to telbivudine and controls (p>0.05). HBV vertical transmission was successfully blocked in all infants. The effective HBV vaccination rate was 98.15% (53/54)., Conclusions: The growth and development of children prenatally exposed to telbivudine was normal, indicating that telbivudine treatment during pregnancy is safe and effective., (Copyright © 2015. Published by Elsevier Ltd.)

The rate of hepatitis B virus (HBV) infection is high in the Chinese population, and the implications of HBV infection are widely recognized, and membranous nephropathy is the most common renal lesion to be associated with HBV infection. Minimal change disease (MCD) is one of the most important histopathological characteristics in patients with nephrotic syndrome. There is no any study to report that HBV infection is associated with the etiology of MCD. Herein, we report four MCD patients with HBV infection and speculate that there is an association of HBV infection with the pathological type of MCD. In this study, we also reported the treatment schedule for these four MCD patients, and found that the anti-virus alone and combination of anti-virus with immunosuppressive agent could obtain a benefit for MCD patients with HBV infection. However, a well-designed study should be performed to confirm this association.

Background: Folic acid prevents neural tube closure defects (NTDs), but the causal metabolic pathways have not been established. Serine hydroxymethyltransferase 1 (SHMT1) is an essential scaffold protein in folate-dependent de novo thymidylate synthesis in the nucleus. SHMT1-deficient mice provide a model to investigate folic acid-responsive NTDs wherein disruption of de novo thymidylate synthesis impairs neural tube closure., Objective: We examined the effects of maternal supplementation with the pyrimidine nucleosides uridine, thymidine, or deoxyuridine with and without folate deficiency on NTD incidence in the Shmt1 mouse model., Design: Shmt1(+/+) and Shmt1(-/-) female mice fed folate-replete or folate-deficient diets and supplemented with uridine, thymidine, or deoxyuridine were bred, and litters (n = 10-23 per group) were examined for the presence of NTDs. Biomarkers of impaired folate status and metabolism were measured, including plasma nucleosides, hepatic uracil content, maternal plasma folate concentrations, and incorporation of nucleoside precursors into DNA., Results: Shmt1(+/-) and Shmt1(-/-) embryos from dams fed the folate-deficient diet were susceptible to NTDs. No NTDs were observed in litters from dams fed the folate-deficient diet supplemented with deoxyuridine. Surprisingly, uridine supplementation increased NTD incidence, independent of embryo genotype and dietary folic acid. These dietary nucleosides did not affect maternal hepatic uracil accumulation in DNA but did affect plasma folate concentrations., Conclusions: Maternal deoxyuridine supplementation prevented NTDs in dams fed the folate-deficient diet, whereas maternal uridine supplementation increased NTD incidence, independent of folate and embryo genotype. These findings provide new insights into the metabolic impairments and mechanisms of folate-responsive NTDs resulting from decreased Shmt1 expression., (© 2015 American Society for Nutrition.)

Chronic hepatitis B (CHB) is a global health problem, causing liver failure, cirrhosis and hepatocellular carcinoma. CHB treatment aims to prevent liver-related complication. The treatment of CHB infection includes monotherapy with either interferons (IFNs) or nucleos(t)ide (NUC) analogs. IFNs have moderate antiviral effects, and their use is limited by side effects. With the availability of NUCs, IFN-intolerant and decompensated cirrhotic patients began to be treated. Lamivudine and telbivudine, nucleoside analogs, have low genetic barrier to resistance. Adefovir, a nucleotide analog, has moderate potency and potential nephrotoxicity. Entecavir and tenofovir, with their high potency, high genetic barrier to resistance and favorable safety profile are the standard of care in CHB treatment. Long-term use of NUCs with maintained viral suppression results in a decrease in liver-related complications.

Unlabelled: Little observational data exist describing telbivudine (LdT) or lamivudine (LAM) use in late pregnancy for preventing hepatitis B mother-to-child transmission (MTCT) in real-world settings. During the period of January 2009 to March 2011, we enrolled hepatitis B e antigen-positive mothers with HBV DNA >6 log10 copies/mL in China. At gestation week 28, the mothers received LdT or LAM until postpartum week 4 or no treatment (NTx). The study endpoints were the safety of LdT/LAM use and MTCT rates. Of the 700 mothers enrolled, 648 (LdT/LAM/NTx=252/51/345) completed the 52-week study with 661 infants (LdT/LAM/NTx=257/52/352). On treatment, viral rebound occurred in 1.6% of mothers, all resulting from medication noncompliance. There was no genotypic mutation detected. At delivery, significantly lower HBV DNA levels were noted in mothers who received LdT or LAM versus NTx. Alanine aminotransferase flares were observed in 17.1% of treated mothers versus 6.3% of untreated mothers (P < 0.001). At birth, hepatitis B surface antigen (HBsAg) was detected in 20% and 24% of newborns in the treated and NTx groups, respectively. At week 52, an intention-to-treat analysis indicated 2.2% (95% confidence [CI]: 0.6-3.8) of HBsAg+ infants from the treated group versus 7.6% (95% CI: 4.9-10.3) in the NTx group (P50.001) and no difference of HBsAg+ rate between infants in the LdT and LAM groups(1.9% vs. 3.7%; P=0.758). On-treatment analysis indicated 0% of HBsAg+ infants in the treated group versus 2.84% in the NTx group (P=0.002). There were no differences for gestational age or infants' height, weight, Apgar scores, or birth defect rates between infants from the treated and untreated groups., Conclusions: LdT and LAM use in late pregnancy for highly viremic mothers was equally effective in reducing MTCT. The treatment was well tolerated with no safety concerns identified.

Nucleoside reverse transcriptase inhibitors (NRTIs)/nucleotide reverse transcriptase inhibitors are key components of combination antiretroviral therapy for HIV infection. First-generation NRTIs are associated with mitochondrial toxicity in patients, mainly due to inhibition of human DNA polymerase γ (hDNA polγ) that manifests as adverse events such as lipodystrophy, lactic acidosis, myopathy, cardiomyopathy, or nephropathy in patients. In chronic nonclinical studies in rodents and nonrodents, eukaryotic (host) mitochondrial toxicity manifests as some drug-specific toxicities similar to human toxicity. BMS-986001, a novel thymidine analog with minimal hDNA polγ inhibition, has demonstrated antiretroviral activity in early clinical studies. The primary toxicity of BMS-986001 in rats and monkeys is bone marrow dyserythropoiesis with associated decreases in red blood cell mass. Additionally, at high doses, severe platelet reductions accompanied by cutaneous petechiae began during weeks 8 and 11 in 3 of 60 monkeys in chronic toxicity studies. In a 6-month study, platelet reductions required euthanasia of the 2 affected monkeys (300 mg/kg/d) at week 14, but with dose reduction (200 mg/kg/d) remaining monkeys had no platelet changes. One affected monkey (200 mg/kg/d) in a 9-month study completed dosing and its platelet counts recovered during a 1-month recovery. Formation of platelet-bound immunoglobulin in the presence of BMS-986001, together with rapid and complete platelet recovery in the absence of BMS-986001, suggested that platelet decreases in monkeys may be immune mediated. No findings indicative of mitochondrial toxicity were observed in rats or monkeys given BMS-986001, suggesting an improved safety profile compared to marketed NRTI or tenofovir disoproxil fumarate., (© The Author(s) 2014.)

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., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background and Aim: There is limited data on the efficacy and outcome of telbivudine (LdT) therapy in patients with chronic hepatitis B and compensated cirrhosis. We evaluated LdT as first-line therapy in these patients and compared with those treated with entecavir (ETV)., Methods: We consecutively enrolled 88 chronic hepatitis B patients with compensated cirrhosis primarily treated with LdT at least for 2 years or less than 2 years but developed resistance, and evaluated the efficacy and clinical outcomes. Meanwhile, we matched a control group who treated with ETV for comparison., Results: In LdT group, alanine aminotransferase normalization (65.8%), hepatitis B e antigen seroconversion (39.8%), hepatitis B virus (HBV) DNA undetectablility (71.6%), and virologic resistance (23.9%) were noted after 2 years treatment. Compared with ETV group, there were significant difference in HBV DNA undetectablility (P < 0.001) and virologic resistance (P < 0.001). In addition, the decline of serum hepatitis B surface antigen levels, hepatocellular carcinoma development, mortality, disease progression, and the change of renal function were similar. Cox regression analysis showed that pretreatment low albumin level and high model for end-stage liver disease scores were risk factors for disease progression., Conclusions: These results indicated that although LdT and ETV are similar in clinical outcomes for patients with HBV-related compensated cirrhosis, LdT still had lower HBV undetectablility and higher resistant rate after 2 years treatment, which was a challenge for being as first-line therapy in these patients who need lifelong therapy.

Objective: To prospectively observe the long-term antiviral efficacy and safety of telbivudine (LDT) administered as a monotherapy and as a combination therapy with adefovir dipivoxil (ADV) in patients diagnosed with chronic hepatitis B (CHB) and positivity for hepatitis B e antigen (HBeAg)., Methods: A total of 140 patients with HBeAg-positive CHB were randomly divided into treatment groups for LDT monotherapy (n = 75; 600 mg orally, once daily) and LDT+ADV combination therapy (n = 65; LDT 600 mg plus ADV 10 mg orally, once daily). The shortest treatment course was 96 weeks and the longest was 240 weeks. At treatment weeks 12, 24, 48?, 96, 144, 192, and 240 patients were tested for hepatitis B virus (HBV) DNA, HBeAg seroconversion and ALT normalization time; in addition, the incidence and type of adverse drug reactions were recorded. Data were statistically analyzed to determine the significance of differences observed between groups., Results: The rate of patients experiencing more than or equal to 2 log HBV DNA reduction was higher in the LDT + ADV group (92.3%(60/65) vs. LDT: 86.7%(65/75), X2 = 1.58). The HBV DNA negative rates of the LDT and LDT + ADV groups were 62.7% and 61.5% (X2 = 0.01) at week 24, 76.0% and 81.5% (X2 = 0.63) at week 48, 80.0% and 89.2% (X2 = 2.2) at week 96, 78.3% and 93.3% (X2 = 3.24) at week 144, 83.7% and 91.7% (X2 = 0.47) at week 192, and 93.3% and 88.9% at week 240 (comparison between two groups for each point P more than 0.05); both groups showed higher early and rapid sustained HBV DNA negative rates. For the HBeAg seroconversion, the rates of the LDT and LDT + ADV groups were 17.3% and 23.1% (X2 = 0.71) at week 24, 29.3% and 30.8% (X2 = 0.03) at week 48, 42.7% and 40.0% (X2 = 0.10) at week 96, 55.0% and 43.3% (X2 = 1.08) at week 144, 55.8% and 66.7% (X2 = 0.45) at week 192, and 63.3% and 66.7% at week 240; however, pairwise comparison showed no statistically significant differences between the groups (P more than 0.05). Similarly, there was no significant difference between the two groups in incidence of resistance at week 48 (4.0% and 1.5%), week 96 (5.3% and 3.1%), week 144 (10.0% and 3.3%, X2 = 1.23), week 192 (11.6% and 8.3%), and week 240 (13.3% and 11.1%) (all P more than 0.05). Three patients experienced muscle soreness (LDT, n = 2; LDT + ADV, n = 1) and two patients experienced increased creatine phosphokinase (LDT, n = 1; LDT + ADV, n = 1); all side effects resolved spontaneously or with symptom-appropriate treatment., Conclusion: The long-term efficacy of LDT as a monotherapy or as a combination therapy with ADV was similar and the two different treatment approaches were associated with similar rates of resistance. The long-term safety was good for both treatment approaches.

There are limited data comparing the clinical outcomes between telbivudine and entecavir. We consecutively enrolled 115 telbivudine-naive and 115 entecavir-naive chronic hepatitis B patients, who were matched for age, sex, hepatitis B e antigen (HBeAg) status and cirrhosis, and treated for at least 2 years or less than 2 years but had developed resistance. Except for the rate of HBeAg seroconversion, which was similar, patients in the entecavir group had better clinical outcomes than those in the telbivudine group for alanine aminotransferase normalization (85.2% vs 78.4%, p <0.048), undetectable HBV DNA (96.5% vs 74.8%, p <0.001), and viral resistance (0.9% vs 21.7%, p <0.001) after 2 years of treatment, After applying roadmap or super-responders concepts, entecavir still had better outcomes than telbivudine in undetectable HBV DNA and viral resistance. The cumulative incidence of hepatocellular carcinoma development was similar between telbivudine-naive and entecavir-naive patients (p 0.565). In renal function analysis, there were significantly more patients with estimated glomerular filtration rate (eGFR) category improvement in both the telbivudine and entecavir groups at year 1 (p 0.006 and p 0.047, respectively). The rate of virological improvement was significantly higher with entecavir than with telbivudine after 2 years of treatment, whether applying the concepts of roadmap or super-responders. The incidence of hepatocellular carcinoma was similar between telbivudine and entecavir. Both telbivudine and entecavir were associated with eGFR improvement, especially in patients with renal insufficiency., (© 2013 The Authors Clinical Microbiology and Infection ©2013 European Society of Clinical Microbiology and Infectious Diseases.)

We evaluated second-line salvage therapy with adefovir + telbivudine (group 1), adefovir followed by adefovir + telbivudine (group 2), or lamivudine + adefovir followed by adefovir + telbivudine (group 3) in hepatitis B patients with an inadequate virologic response to lamivudine treatment. Simple linear regression analysis showed that for each additional month of treatment, the most significant reduction in viral load occurred in group 1 (HBV DNA [Log10 IU/mL]: group 1, -0.149; group 2, -0.081; group 3, -0.123). Generalized estimating equation analysis revealed that compared to group 1, hepatitis B virus (HBV) DNA levels were 1.203 and 0.443 Log10 IU/mL higher in groups 2 and 3, respectively. Overall, a significant reduction in viral load (-0.060 Log10 IU/mL) was observed for each additional month of treatment. Adefovir + telbivudine treatment resulted in a significant reduction in HBV DNA levels. Moreover, telbivudine treatment resulted in a significant reduction in viral load (-0.050 Log10 IU/mL) compared to lamivudine treatment after the emergence of lamivudine resistance.

Aims/hypothesis: Long-term labelling of mice with halogenated thymidine analogues is an established method for quantifying the contribution of beta cell proliferation to in vivo beta cell mass expansion in (re)generation models. The method is believed to give accurate information on the accrued number of cycling beta cells over a period of time. Multiple thymidine analogue labelling is applied for evaluating the duration of postmitotic quiescence in beta cells. We hypothesise, however, that long-term labelling by thymidine analogues hampers beta cell proliferation., Methods: Thymidine analogues were administered for 7-14 days via the i.p. route to neonatal mice, or via drinking water to young mice with normal pancreases or adult mice with injured pancreases. The proliferation of insulin-positive cells was assessed by their expression of the proliferation markers Ki67 or phosphorylated histone H3 and by their incorporation of nucleotide analogues., Results: In the mouse models of beta cell proliferation investigated herein, long-term administration of thymidine analogues decreased the percentage of Ki67(+) and phosphorylated histone H3(+) beta cells as compared with administration of normal drinking water. Proliferation was restored by washout of the analogue. Labelling with one analogue decreased the subsequent incorporation of another analogue by beta cells., Conclusions/interpretation: Long-term labelling with halogenated thymidine analogues is a biased method that underestimates the proliferation and re-division potential of mouse beta cells.

3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH) is a first generation 3-carboranyl thymidine analog (3CTA) that has been intensively studied as a boron-10 ((10)B) delivery agent for neutron capture therapy (NCT). N5-2OH is an excellent substrate of thymidine kinase 1 and its favorable biodistribution profile in rodents led to successful preclinical NCT of rats bearing intracerebral RG2 glioma. The present study explored cellular influx and efflux mechanisms of N5-2OH, as well as its intracellular anabolism beyond the monophosphate level. N5-2OH entered cultured human CCRF-CEM cells via passive diffusion, whereas the multidrug resistance-associated protein 4 appeared to be a major mediator of N5-2OH monophosphate efflux. N5-2OH was effectively monophosphorylated in cultured murine L929 [thymidine kinase 1 (TK1(+))] cells whereas formation of N5-2OH monophosphate was markedly lower in L929 (TK1(-)) cell variants. Further metabolism to the di- and triphosphate forms was not observed in any of the cell lines. Regardless of monophosphorylation, parental N5-2OH was the major intracellular component in both TK1(+) and TK1(-) cells. Phosphate transfer experiments with enzyme preparations showed that N5-2OH monophosphate, as well as the monophosphate of a second 3-carboranyl thymidine analog [3-[5-(o-carboran-1-yl)pentan-1-yl]thymidine (N5)], were not substrates of thymidine monophosphate kinase. Surprisingly, N5-diphosphate was phosphorylated by nucleoside diphosphate kinase although N5-triphosphate apparently was not a substrate of DNA polymerase. Our results provide valuable information on the cellular metabolism and pharmacokinetic profile of 3-carboranyl thymidine analogs.

Objective: To investigate the therapeutic benefit of sequential interferon alpha-1b (IFNa-1b) in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) who showed early complete response to telbivudine (LdT) treatment, and to explore the clinical value of serum hepatitis B surface antigen (HBsAg) for predicting sustained virological response (SVR)., Methods: Twenty HBeAg+ CHB patients who had shown a complete response to LdT therapy before treatment week 52 were divided into two treatment groups: one continued on the LdT treatment for an additional 6 months, and the other switched to IFNa-1b for 6 months. Each patient presented for follow-up examinations at 1, 2, 3, 6, 9, 12, 18, 24, 30 and 36 months after treatment cessation. Serum levels of alanine aminotransferase (ALT) and creatinine were detected by an automated biochemical analyzer. HBV DNA load was determined by real-time PCR. HBsAg and HBeAg levels were assessed by chemiluminescence., Results: The relapse rate was lower in the group treated with sequential IFN than in the group who continued LdT treatment (30% vs. 40%, P more than 0.05). The area under the receiver operating characteristic curve at week 24 (0.689) was significantly higher than at week 12 and week 48 (0.652 vs. 0.545, P less than 0.05). Decline in serum HBsAg levels at week 24 were predictive of SVR after treatment cessation. Patients showing a decrease more than 1000 IU/ml in serum HBsAg levels at week 24 had a significantly higher SVR rate than the patients who showed a decrease less than 1000 IU/ ml (90.9%(10/11) vs. 33.3%(3/9), P less than 0.05). At the end of treatment, patients showing a decrease less than 200 IU/ml of serum HBsAg levels had a significantly higher SVR rate than those showing more than 200 IU/ml (100% vs. 53.3%, P less than 0.05)., Conclusion: Sequential IFNa-1b consolidation therapy does not reduce the rate of relapse after treatment cessation. However, patients with a decrease in serum HBsAg levels of more than 1000 IU/ml at treatment week 24 are more likely to achieve SVR.