Increase of Serum Kallikrein-8 Level After Long-term Telbivudine Treatment.

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.

Case report: lactic acidosis and rhabdomyolysis during telbivudine and tenofovir treatment for chronic hepatitis B.

BACKGROUND: Current treatment options for chronic hepatitis B (CHB) are pegylated interferon alpha and nucleoside analogues (NAs). NAs have relatively fewer side effects than interferon alpha, and generally well tolerated. Previously 12.9% of patients on telbivudine treatment were reported to develop severe elevation of serum creatine phosphokinase (CPK) levels, but related clinical disease, like lactic acidosis (LA) and rhabdomyolysis (RM) were rare. The pathophysiology may be mitochondrial toxicity, for the NAs inhibit not only hepatitis B virus (HBV) polymerase, but also the host mitochondrial DNA polymerase γ. As mitochondria are the main sites of oxidative phosphorylation, there will be an increase of pyruvate reduction to lactic acid and insufficient adenosine triphosphate. The accumulation of lactic acid causes LA, while lack of energy leads to cell dysfunction and mitochondria-associated disease, including RM. All five NAs, except tenofovir, have been reported causing LA and RM. Here we report the first case of CHB patients developing fatal LA and RM during telbivudine and tenofovir treatment. CASE PRESENTATION: The patient is a 51-year-old man who was hospitalized in November 2015. He had taken telbivudine regularly because of CHB. Later, tenofovir was added to antiviral treatment because of HBV resistance. Then he had myalgia, chest tightness and anorexia. The blood lactate was 12.7 mmol/L. The arterial blood gas analysis showed pH 7.25, base excess 21.1 mmol/L. CPK was 991 U/L, myoglobin was 1745 ng/ml and creatine was 83 µmol/L. Abdomen magnetic resonance revealed cirrhosis. Muscle biopsy revealed myogenic lesion with abnormality of mitochondria and fat metabolism. The patient was diagnosed with Hepatitis B envelope Antigen positive CHB, cirrhosis, LA and RM characterized by myalgia and elevated myoglobin. He was given tenofovir alone as antiviral treatment instead. After hemodialysis and 4 weeks` treatment of corticosteroids, his symptoms recovered, and blood lactate gradually returned to a normal range. CONCLUSIONS: This case shows that tenofovir may trigger muscle damage and fatal RM in combination with telbivudine treatment in CHB patients. Thus, patients receiving tenofovir and telbivudine should be closely monitored for muscular abnormalities, blood lactate level and other mitochondrial toxicity associated side effects.

Muscular damage in a patient with hepatitis B induced by beta-l-2'-deoxythymidine and detected by 18F-FDG PET/CT.

A 58 years old man under 2'-Deoxy-L-thymidine treatment for his hepatitis B was admitted to our hospital complaining for the last 2 months of recurrent upper abdomen discomfort, fatigue and weight loss of 10 kilograms and general muscular soreness, for 2 weeks. He had elevated creatine kinase (CK), myoglobin, CK-MB and other related or common laboratory findings. Fluorine-18- fluorodeoxyglucose positron emission tomography/ computed tomography (18F-FDG PET/CT) showed a diffuse, homogenous, moderately elevated glucose uptake in all muscle groups. Muscular damage induced by 2'-Deoxy-L-thymidine was suspected and the drug was discontinued. Muscle soreness and the biomarkers for muscular tissue damage improved. Fluorine-18-FDG PET/CT is useful to rule out malignancy and identify muscular tissue damage.

Telbivudine versus lamivudine and entecavir for treatment-naïve decompensated hepatitis B virus-related cirrhosis.

The long-term effects of telbivudine (TBV) on decompensated hepatitis B virus (HBV)-related cirrhosis were still not established. This study aimed to investigate the efficacy and safety of TBV in such cohort of patients as compared to lamivudine (LAM) and entecavir (ETV). We retrospectively evaluated 130 treatment-naïve patients with HBV-related decompensated cirrhosis who started treatment with TBV (n = 31), LAM (n = 45) or ETV (n = 54). After 24 months of treatment, cumulative virological response (VR) rates (HBV DNA <500 copies/mL) were 83.7, 65.3 and 89.1 % in TBV, LAM and ETV groups, respectively (p = 0.009). Reduction in HBV DNA levels in TBV was -3.66 ± 0.56, significantly higher than LAM (-3.34 ± 0.59; p < 0.05) and lower than ETV group (-3.98 ± 0.52; p < 0.05). The rates of HBeAg loss or seroconversion and normalization of alanine aminotransferase (ALT) were similar among the groups. Child-Turcotte-Pugh (CTP) score and model for end-stage liver disease score in TBV were significantly improved compared to at baseline without difference among the groups. TBV resulted in similar cumulative rates of survival and incidence of hepatocellular carcinoma (HCC) to LAM and ETV. Frequencies of complications from cirrhosis, including variceal bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis, were comparable among the groups. Four patients (16.7 %) in TBV displayed virological breakthrough, lower than LAM and higher than ETV (p = 0.004). Cox regression analysis showed that baseline HBV DNA (hazard ratio 0.743; 95 % confidence interval 0.582-949, p = 0.017) was an independent predictor for VR at 24 months. Long-term therapy with TBV was effective and safe in HBV-related decompensated cirrhosis.

Comparison of clinical efficacy and renal safety of telbivudine and entecavir in chronic hepatitis B patients receiving cytotoxic chemotherapy.

OBJECTIVE: Limited data is available on the clinical outcomes of telbivudine (LdT) and entecavir (ETV) in pre-emptive antiviral chemoprophylaxis. This study aimed to evaluate the clinical efficacy and renal safety of LdT and ETV in patients with chronic hepatitis B (CHB) who received cytotoxic chemotherapy. METHODS: Altogether 290 treatment-naïve CHB patients undergoing intense chemotherapy were enrolled to receive daily 600 mg of LdT or 0.5 mg of ETV as pre-emptive antiviral chemoprophylaxis. RESULTS: The ETV group had significantly higher proportion of patients with undetectable hepatitis B viral (HBV) DNA load compared with LdT at week 24 (73.0% vs 50.3%, P = 0.000). The cumulative rates of virological breakthrough in the LdT and ETV groups were 9.15% and 3.65% at the second year of therapy, respectively (P = 0.059), which was associated with detectable HBV DNA at week 24 (P = 0.000). The MELD score of the LdT group was significantly lower than that of the ETV group after the first year (4.53 vs 7.53, P = 0.002) and the second year (1.96 vs 7.09, P = 0.000) of antiviral therapy. Moreover, the estimated glomerular filtration rate (eGFR) was significantly improved in the LdT group than in the ETV group after two years of antiviral therapy. CONCLUSION: LdT has a lower clinical efficacy in viral suppression than ETV, but LdT is associated with greater extent of improvement in liver and renal functions of patients in pre-emptive prophylaxis for cytotoxic chemotherapy.

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial.

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.

Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience.

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.

Use of telbivudine in kidney transplant recipients with chronic hepatitis B virus infection: A preliminary experience.

Telbivudine is a relatively novel oral nucleoside analogue with favourable efficacy and tolerability in treatment-naïve chronic hepatitis B virus (HBV) infection, but its data in kidney transplant recipients (KTRs) was lacking. The efficacy and tolerability of telbivudine in four treatment-naïve HBsAg-positive KTRs were reviewed (treatment duration 54 (36-72) months) HBV DNA declined from 2.6 × 10(5) (7.8 × 10(3) -1.5 × 10(7) ) copies/mL at baseline to 170 (0.0-3.2 × 10(4) ) copies/mL at 12 months, and became undetectable at 24 and 36 months (P = 0.060, 0.118 and 0.005 compared with baseline). Alanine aminotransferase levels dropped from 46.5 (30-48) IU/mL at baseline to 28 (13-45) IU/mL, 34.5 (15-71) IU/mL and 26 (12-41) IU/mL at 12, 24 and 36 months, respectively (P = 0.109, 0.715 and 0.068 compared with baseline). Serum creatinine level and estimated glomerular filtration rate (eGFR) remained stable after 36 months of treatment (P all > 0.05 compared with baseline). No virological breakthrough, cirrhosis or hepatocellular carcinoma occurred. Our pilot data suggests that telbivudine has favourable efficacy and renal safety profiles in HBsAg-positive KTRs.

Comparison of efficacy and renal safety of telbivudine and entecavir in treatment-naive elderly patients with chronic hepatitis B.

BACKGROUND: Data comparing the clinical outcomes of telbivudine (LdT) and entecavir (ETV) in elderly patients with chronic hepatitis B are limited. GOALS: The aim of the present study was to compare the efficacy and renal safety of LdT and ETV in treatment-naive elderly (≥ 60 years) patients with chronic hepatitis B. METHODS: A total of 33 patients treated with LdT were consecutively enrolled in the study. Each patient was matched on the basis of age, sex, and baseline hepatitis B virus (HBV) DNA levels with three to four randomly selected controls treated with ETV. RESULTS: Clinical characteristics were comparable between the two groups. Higher cumulative HBeAg-seroconversion rates were observed in the LdT group than in the ETV group after 2 years (50 vs. 20%) and 3 years (50 vs. 26.67%) of treatment (all P<0.0001). Virological response rate at week 24 was significantly lower in the LdT group than it was in the ETV group (54.55 vs. 70.87%, P<0.0001), but no significant difference was noted in long-term cumulative rates of undetectable HBV DNA levels between the two groups (P=0.562). Virological breakthrough occurred in six (18.18%) LdT patients, with no such cases reported in the ETV group (P<0.0001). Antiviral resistance was strongly associated with LdT use and the absence of undetectable HBV DNA at weeks 12 and 24 (P<0.0001). During the study, significant improvement was observed in the estimated glomerular filtration rate and model for end-stage liver disease score in LdT versus ETV group. CONCLUSION: LdT has a lower clinical efficacy for viral suppression and a higher risk of antiviral resistance than does ETV. However, LdT resulted in higher HBeAg-seroconversion rates and better renoprotective effects than did ETV.

Long-Term Telbivudine Treatment Results in Resolution of Liver Inflammation and Fibrosis in Patients with Chronic Hepatitis B.

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.

ALT CHANGES AND ADVERSE EVENTS OF TELBIVUDINE IN HEPATITIS-B PATIENTS-AN EXPERIENCE OF 11 PATIENTS.

Hepatitis-B virus (HBV) infection is a major global health problem. Of the two billion people who have been infected, more than 350 million have chronic hepatitis. It is estimated that 235,000-328,000 people die annually due to liver cirrhosis and hepatocellular carcinoma, we assessed the short term outcomes of treatment with telbivudine in 11 adults aged 14-41 years with HBeAg-positive or HBeAg-negative chronic hepatitis-B (CHB). Treatment of chronic hepatitis-B patients with telbivudine shows 43.1% reduction in serum ALT with no significant adverse effects.

Maternal dietary uridine causes, and deoxyuridine prevents, neural tube closure defects in a mouse model of folate-responsive neural tube defects.

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.

Growth and development of children prenatally exposed to telbivudine administered for the treatment of chronic hepatitis B in their mothers.

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.

Telbivudine is associated with improvement of renal function in patients transplanted for HBV liver disease.

Recent studies showed that telbivudine in patients with hepatitis B virus (HBV) infection improved their glomerular filtration rate (GFR), but data regarding its impact on renal function in liver transplant (LT) recipients are very limited. We evaluated 17 consecutive recipients who received at baseline nucleos(t)ide analogue(s) (NAs) other than telbivudine for 12 months, and then they were switched to telbivudine prophylaxis for another 12 months. In each patient, laboratory data including evaluation of GFR (using MDRD and CKD-EPI) were prospectively recorded. The changes in GFR (ΔGFR) between baseline and after 12 months (1st period) and between telbivudine initiation and 24 months (2nd period) were evaluated. All patients remained serum HBsAg and HBV-DNA negative. GFR-MDRD at baseline, 12 months and 24 months were 72 ± 18, 67.8 ± 16 and 70.3 ± 12 mL/min, respectively, (P = 0.025 for comparison between 12 months and 24 months). ΔGFR at the 1st period was significantly lower, compared with ΔGFR at the 2nd period [mean ΔGFR-MDRD: -4.2 (range: -24-9) vs 2.5 (range: -7-22) mL/min, P = 0.013; mean ΔGFR-CKD-EPI: -4.2 (range: -19-10) vs 4.0 (range: -7-23) mL/min, P = 0.004], although the serum levels of calcineurin inhibitors were similar between the two periods. A second group of recipients (n = 17) who remained under the same nontelbivudine NA(s) for 24 months had a decline in the mean eGFR during the total follow-up period. In conclusion, we showed that telbivudine administration in LT recipients for HBV cirrhosis was effective and it was associated with significant improvement in renal function, but this remains to be confirmed in larger well-designed studies.

Lamivudine/telbivudine-associated neuromyopathy: neurogenic damage, mitochondrial dysfunction and mitochondrial DNA depletion.

AIMS: Myopathy or neuropathy has been associated with lamivudine/telbivudine therapy in hepatitis B patients. We aim to describe the pathological changes of lamivudine/telbivudine-associated neuromyopathy. METHODS: We retrospectively recruited six patients who were diagnosed with nucleotide analogues-associated myopathy or neuropathy. Muscle and nerve biopsy were performed, and the specimens were prepared for the light microscopy and electron microscopy. Genomic DNA was extracted from frozen muscle specimens, and the mitochondrial DNA (mtDNA) content was quantified by real-time PCR. RESULTS: Recovery of the myopathy can be achieved after the discontinuation or changing the drugs to entecavir. Muscle and nerve biopsy revealed similar changes under either the light or electronic microscopy in all the subjects. Quantitative real-time PCR revealed decrease of mtDNA content in the affected muscle. CONCLUSIONS: MtDNA depletion results in mitochondrial dysfunction in the lamivudine/telbivudine-associated neuromyopathy. Myopathy was characterised by mitochondrial dysfunction accompanied with neurogenic damage due to axonal neuropathy. Ultrastructure changes of mitochondria included vacuolisation, simplification of the cristae and homogenised matrix.

Reduction of infectivity in chronic hepatitis B virus carriers among healthcare providers and pregnant women by antiviral therapy.

The main purpose of therapy for infectious diseases is restoration or protection of the patient's health, but suppression or elimination of infectious agents is also important. In two well-defined situations, reduction of potential infectivity may be the main reason for therapy in hepatitis B virus (HBV) carriers who do not suffer from significant disease: (1) healthcare providers who perform exposure-prone procedures to prevent transmission of HBV to individuals, and (2) pregnant women in the third trimester to prevent transmission to the fetus. This article describes the necessity to recognize highly viremic HBV-infected individuals in these situations, the methods to estimate the risk of transmission, and the therapeutic possibilities to prevent transmission. With today's methods of monitoring HBV DNA, it is possible to reliably estimate the risk of transmission. The drugs entecavir or tenofovir are able to suppress infectivity of HBV carriers to levels acceptable for healthcare providers performing exposure-prone procedures. According to the CDC, 'chronic HBV infection in itself should not preclude the practice or study of medicine, surgery, dentistry, or allied health professions.' Treatment of pregnant women with very high levels of HBV DNA prevents the transmission to the fetus and further if the newborn receives immediate active/passive immunization against HBV.

A comparison of efficacy and safety of 2-year telbivudine and entecavir treatment in patients with chronic hepatitis B: a match-control study.

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.

Telbivudine protects renal function in patients with chronic hepatitis B infection in conjunction with adefovir-based combination therapy.

Previous studies have demonstrated that the treatment of chronic hepatitis B (CHB) infection with adefovir (ADV) can impair renal function. In contrast, treatment with telbivudine (LdT) improves renal function in CHB patients. The aim of this study was to evaluate the renoprotective effect of LdT in CHB patients receiving ADV-based combination therapy. The effects of treatment with ADV + LdT on renal function were compared to those resulting from treatment with ADV + entecavir (ETV), ADV + lamivudine (LAM), ADV alone and ETV alone. The consecutive cohort analysis included 831 CHB patients who received ADV + LdT, ADV + LAM, ADV + ETV, ADV alone or ETV alone for 96 weeks. Alterations in estimated glomerular filtration rate (eGFR) were compared between the five groups using a linear mixed-effects model. HBV DNA levels were also compared between the five groups during the 96-week period. Among the five treatment groups, significant improvements in eGFR were observed in the ADV + LdT and ADV + LAM groups over time (P < 0.001 for each group compared with baseline eGFR). In patients with a baseline eGFR between 50 and 90 mL/min, the change in eGFR was the most significant in the ADV + LdT group (+0.641 mL/min; P < 0.001). Age, gender, baseline eGFR and treatment option were significant predictive factors for eGFR changes. In conclusion, our results suggest that the combination therapy of LdT and ADV is significantly associated with renoprotective effects in CHB patients when compared with other ADV-based combination or single therapies.

A randomized controlled trial of sequential pegylated interferon-α and telbivudine or vice versa for 48 weeks in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Short-term treatment for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B remains unsatisfactory. The aim of our study was to compare the efficacy and safety of two sequential regimens of pegylated interferon (PEG-IFN)-α and telbivudine (LdT). METHODS: Adult patients with biopsy-proven HBeAg-negative chronic hepatitis B, elevated alanine aminotransferase (ALT) and serum HBV DNA ≥ 2,000 IU/ml were randomized 1:1 at baseline to receive PEG-IFN 180 µg/week for 24 weeks followed by LdT 600 mg/day for 24 weeks (PEG-IFN first), or vice versa (LdT first), plus 24-week follow-up; individuals with HCV, HDV or HIV coinfections and lamivudine resistance were excluded. Primary end points were serum HBV DNA<2,000 IU/ml and normal ALT at week 72. RESULTS: A total of 30 patients (86% male, median age 48 years) were enrolled: mean ±sd baseline serum HBV DNA was 5.56 ± 1.4 log IU/ml and ALT was 2.9 ± 2.5× upper limit of normal. At end of follow-up (week 72), HBV DNA<2,000 IU/ml was achieved in 13.3% of participants in the PEG-IFN first group versus 46.7% of those in the LdT first group (P=0.046). Mean ±sd ALT levels were significantly lower in the LdT first group (1.3 ± 0.9 versus 3.2 ± 2.7× upper limit of normal; P=0.03). PEG-IFN dose was reduced in 2 (7%) patients and 1 (7%) patient dropped out due to myalgia. CONCLUSIONS: Sequential treatment with 24 weeks PEG-IFN followed or preceded by 24 weeks of LdT is safe. Virological response rate at week 72 was significantly higher in patients treated with LdT followed by PEG-IFN than vice versa. A sequential antiviral regimen of LdT followed by PEG-IFN, if confirmed in larger series, could improve response rates compared with standard PEG-IFN monotherapy.

Telbivudine myopathy in a patient with chronic hepatitis B.

CASE: A 25-year-old man with hepatitis B virus (HBV) infection received antiviral treatment with telbivudine 600 mg daily. Six months after starting treatment, the patient developed progressive weakness and myalgia. Physical examination showed symmetrical proximal weakness. Blood tests at admission revealed positive hepatitis b surface antigen (HBs Ag), and, elevated creatine kinase (CK) level (1,614 U/L, normal range: 38-174 U/L). Aspartate aminotransferase was 64.7 U/L (normal range: 8-40 U/L), and LDH was 293 U/L (normal range: 80-285 U/L). Electrodiagnostic studies indicated myopathic changes. A muscle biopsy revealed myositis and no mitochondrial changes were found. Drug-induced myopathy was suspected and telbivudine was changed to entecavir. The muscle weakness and laboratory findings improved. CONCLUSION: A patient developed drug-induced myopathy during long-term treatment with telbivudine for chronic HBV. To promptly detect this reversible adverse event, monitoring of serum CK level and recognition of myopathic signs and symptoms are necessary. Further investigations are needed to clarify the possible mechanism of telbivudine-induced myopathy.