Aldo Trylesinski

Telbivudine Improves Renal Function in Patients With Chronic Hepatitis B

BACKGROUND & AIMS There is a close relationship between chronic hepatitis B virus infection and chronic renal disease. We analyzed changes in renal function using different markers of glomerular filtration rate (GFR) in multiple studies of telbivudine treatment of patients with chronic hepatitis B virus infection. METHODS We used serum creatinine-based equations (ie, Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration) to estimate GFR (eGFR) in adults with chronic hepatitis B virus infection and compensated liver disease who participated in a phase III, randomized, double-blind study comparing the efficacy and safety of telbivudine (600 mg/d) and lamivudine (100 mg/d) for 2 years (the GLOBE study) and in long-term extension studies (4-6 years), as well as in patients with decompensated cirrhosis (2 years). RESULTS eGFRs calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations were concordant, indicating improved renal function in telbivudine-treated patients during the 2-year GLOBE study (there was an 8.5% increase in mean eGFR, based on the Modification of Diet in Renal Disease equation). Improved renal function was maintained for 4-6 years. Increased eGFR with telbivudine treatment was also observed in patients at increased risk for renal impairment: patients with baseline eGFRs of 60-89 mL/min/1.73 m(2) (+17.2%), older than 50 years (+11.4%), and with liver fibrosis/cirrhosis (+7.2% for patients with Ishak fibrosis score at 5-6). In decompensated patients with high renal risk, eGFR was also improved on telbivudine (+2.0%). CONCLUSIONS In global trials of patients with compensated and decompensated cirrhosis, long-term telbivudine therapy was associated with a sustained improvement of renal function-particularly among patients with increased risk of renal impairment. The mechanisms of this renal protective effect remain to be determined.

Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naïve patients with HBV-related decompensated cirrhosis

Summary.  Patients with decompensated cirrhosis owing to chronic hepatitis B viral (HBV) infection have a high morbidity/mortality rate, and the treatment remains a challenge. We studied the safety and efficacy of telbivudine and lamivudine in such patients. This noninferiority, double‐blind trial randomized 232 treatment‐naive patients with decompensated HBV (1:1) in 80 academic hospitals to receive once‐daily telbivudine 600 mg or lamivudine 100 mg for 104 weeks. Primary composite endpoint was proportion of patients with HBV DNA <10 000 copies/mL, normal alanine aminotransferase (ALT) and Child‐Turcotte‐Pugh score improvement/stabilization at week 52. Response rates using a post hoc modified endpoint (HBV DNA <300 copies/mL [57 IU/mL] and ALT normalization) in intent‐to‐treat analysis (missing = failure) were 56.3%vs 38.0% after 76 weeks (P = 0.018) and 45.6%vs 32.9% after 104 weeks (P = 0.093) for telbivudine vs lamivudine. Telbivudine treatment was an independent predictive factor for HBV DNA <300 copies/mL and ALT normalization (P = 0.037). Response rates with protocol‐defined composite endpoint in intent‐to‐treat analysis (M = F) were 56.2 vs 54.0% (noninferiority not achieved) and 39.1%vs 36.4% (noninferiority achieved) in telbivudine and lamivudine groups at 52 and 104 weeks. Telbivudine treatment was associated with a significant improvement in glomerular filtration rate compared to lamivudine treatment and was also associated with a trend for improvement in survival (87%vs 79%). No cases of lactic acidosis were reported. Telbivudine compared to lamivudine was associated with a higher rate of patients with both viral suppression and ALT normalization, a trend towards a higher rate of survival and significant improvement in glomerular filtration.

Efficacy and safety of continuous 4-year telbivudine treatment in patients with chronic hepatitis B

In the phase‐III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2‐year treatment in HBeAg‐positive and HBeAg‐negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine‐treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2‐year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per‐protocol population. Amongst 293 HBeAg‐positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg‐negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off‐treatment follow‐up). The cumulative 4‐year resistance rate was 10.6% for HBeAg‐positive and 10.0% for HBeAg‐negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m2 (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg‐positive and HBeAg‐negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg‐positive patients.

Telbivudine plus pegylated interferon alfa-2a in a randomized study in chronic hepatitis B is associated with an unexpected high rate of peripheral neuropathy

BACKGROUND & AIMS This study investigated the antiviral efficacy and safety of telbivudine in combination with pegylated interferon (PegIFN) alpha-2a in chronic hepatitis B (CHB) patients. METHODS This was a randomized, open-label, multicentre study, in treatment-naïve patients with HBeAg-positive CHB, comparing the efficacy and safety of telbivudine in combination with PegIFN alpha-2a with telbivudine monotherapy and PegIFN alpha-2a monotherapy. The study was terminated early due to increased rates of peripheral neuropathy in the combination-therapy group. RESULTS Of the 159 patients randomized (from 300 planned) 50 were assigned to combination therapy, 55 to telbivudine, 54 to PegIFN, and 110 (18, 49, and 43, respectively) reached week 24. Peripheral neuropathy occurred in 7/50, 1/54, and 0/54 patients in the three groups of safety populations, respectively. No relationship between the occurrence of peripheral neuropathy and other variables (e.g., pharmacokinetic data, treatment efficacy, ALT levels, creatine kinase elevations) were observed. At week 24, undetectable HBV DNA (<300 copies/ml) was achieved by 71% (12/17), 35% (17/48), and 7% (3/42) of patients, with available data receiving combination therapy, telbivudine monotherapy and PegIFN monotherapy, respectively (p = 0.022 for combination therapy vs. telbivudine; p<0.0001 for combination therapy vs. PegIFN). CONCLUSIONS Combination therapy carried an increased risk of peripheral neuropathy. Despite the rapid and profound reductions in HBV DNA levels, combination therapy with telbivudine and PegIFN should not be used.

52-Week Efficacy and Safety of Telbivudine with Conditional Tenofovir Intensification at Week 24 in HBeAg-Positive Chronic Hepatitis B

Background and Aims The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated. Methods A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52. Results 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52. Conclusions Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B. Trial Registration ClinicalTrials.gov NCT00651209

Adefovir dipivoxil is effective for the treatment of cirrhotic patients with lamivudine failure

Background/Aims: Data on the efficacy of adefovir dipivoxil (ADV) in elderly and cirrhotic patients with lamivudine‐resistant (LAM‐R) chronic hepatitis B are scarce. This retrospective cohort study evaluated the safety and efficacy of ADV in this specific patient population.

Comprehensive review of telbivudine in pregnant women with chronic hepatitis B

AIM To achieve an evidence-based conclusion regarding the safety and efficacy of telbivudine during pregnancy. METHODS A pooled analysis of data from a literature search reported 1739 pregnancy outcomes (1673 live births) from 1725 non-overlapping pregnant women treated with telbivudine. The prevalence of live birth defects (3.6/1000) was similar to that of the non-antiviral controls (3.0/1000) and not increased as compared with overall prevalence (14.5 to 60/1000). No target organ toxicity was identified. The prevalence of spontaneous abortion in pregnant women treated with telbivudine (4.2/1000) was not increased compared with the overall prevalence (16/1000). The mother-to-child transmission rate was significantly reduced in pregnant women treated with telbivudine (0.70%) compared to those treated with the non-antiviral controls (11.9%; P < 0.0001) or compared to the historical rates of hepatitis B virus (HBV)-infected population without antiviral treatment (10%-15%). RESULTS Cumulatively 489 pregnancy cases have been reported in the telbivudine pharmacovigilance database (with a cut-off date 31 August 2014), of those, 308 had known pregnancy outcomes with 249 cases of live births (239 cases of live birth without congenital anomaly and 10 cases of live birth with congenital anomaly). In the latest antiretroviral pregnancy registry report (1 January 1989 through 31 January 2015) of 27 patients exposed to telbivudine during pregnancy (18, 6 and 3 during first, second and third trimester, respectively) 19 live births were reported and there were no cases of birth defects reported. CONCLUSION Telbivudine treatment during pregnancy presents a favorable safety profile without increased rates of live birth defects, spontaneous abortion or elective termination, or fetal/neonatal toxicity. Exposure to telbivudine in the first, second and third trimester of pregnancy has been shown to significantly reduce the risk of HBV transmission from mother to child on the basis of standard immune prophylaxis procedure.

Efficacy of telbivudine with conditional tenofovir intensification in patients with chronic hepatitis B: results from the 2-year roadmap strategy

Background: A 2-year roadmap study was conducted to evaluate the efficacy and safety of tenofovir intensification at Week 24 in patients with chronic hepatitis B (CHB) receiving telbivudine. Scope: A prospective multicenter study was conducted in treatment-naive patients with hepatitis B e antigen (HBeAg)-positive CHB. All patients received telbivudine (600 mg/day) until Week 24. Thereafter, patients with detectable hepatitis B virus (HBV) DNA (≥300 copies/mL) were administered tenofovir (300 mg/day) plus telbivudine, and patients with undetectable HBV DNA continued telbivudine monotherapy until Week 104. The primary endpoint was the proportion of patients with undetectable HBV DNA (<300 copies/mL) at Weeks 52 and 104. Findings: A total of 105 patients were enrolled in the trial, of which 100 were eligible for efficacy analysis. Undetectable HBV DNA levels were observed at Week 24 in 55 patients who continued on with telbivudine monotherapy. The remaining 45 patients with detectable HBV DNA received tenofovir add-on therapy. With monotherapy, 100% (55/55) and 94.5% (52/55) of patients achieved HBV DNA <300 copies/mL at Weeks 52 and 104, respectively; the corresponding values for patients with add-on therapy were 84.4% (38/45) and 93.3% (42/45). Overall, undetectable HBV DNA (<300 copies/mL) was found in 93% (93/100) and 94% (94/100) of patients at Weeks 52 and 104, respectively. HBeAg seroconversion rate was 44.4% (44/99) at Week 104 for the overall patient population. One patient in the monotherapy group and six in the intensification group demonstrated HBsAg clearance at Week 104. HBsAg seroconversion was observed in four patients at Week 104, all belonged to the tenofovir intensification group. Eight patients sustained HBsAg loss during a posttreatment follow-up period of 16 weeks. Alanine aminotransferase (ALT) normalization was constant in the telbivudine monotherapy group, whereas a progressive improvement was observed in the tenofovir intensification group. Two patients in the monotherapy and none in the intensification group experienced viral breakthrough by Week 104. There were no reports of myopathy in either group. The mean changes in estimated glomerular filtration rate (eGFR), estimated using the Modification of Diet in Renal Disease (MDRD) formula, from baseline to Week 104 were +6.145 mL/min/1.73 m2 (p=0.0230) and +7.954 mL/min/1.73 m2 (p=0.0154) in the telbivudine monotherapy and tenofovir intensification groups, respectively. The incidence of serious AEs was four in the telbivudine monotherapy and two in the tenofovir intensification group. The main limitation of this study was limited sample size, which made the power of the observation low, and the absence of a comparative subgroup to assess the progression of patients with detectable HBV DNA without treatment intensification. Conclusions: Data from this 2-year roadmap study confirmed that telbivudine with add-on tenofovir was effective and well tolerated in patients with CHB. Telbivudine was associated with an improvement in eGFR from baseline in both the groups.

745 eGFR IMPROVEMENT IN CHRONIC HEPATITIS B PATIENTS WITH TELBIVUDINE TREATMENT IS INDEPENDENT OF ANTIVIRAL ACTIVITY

vs. 32% (p =0.015), and prior ADV 14% vs. 25% (p =0.044). Tenofovir (TFV) PK parameters (AUCt, Cmax, Tmax) in MRI were comparable to historical data in NRF, and there was no correlation between steady-state TFV exposures (AUCt) and BL CrCL. TDF was well tolerated overall; 3 patients (1.1%) discontinued the study early for an AE (2-MRI and 1-NRF). No patients had a confirmed increase in serum creatinine of ≥0.5mg/dL, and 1% (2-NRF) had transient PO4 <2mg/dL. Nine MRI patients had CLCr <50mL/min (pre-treatment range: 49–61mL/min) that stabilized with dose adjustment. No differences were observed in % change in spine or hip BMD over 96 weeks, and no clinically relevant bone loss was noted in either group. At Week 96 there was no significant difference (missing=failure) in % with HBVDNA <400 copies/mL, or rates of ALT normalization or HBeAg loss/seroconversion. Conclusions: The safety, PK, and efficacy of patients with MRI receiving TDF were similar to NRF patients; in MRI patients there was no evidence of increased risk for renalor bone-related complications.

438 BASELINE AND WEEK 24 HBeAg LEVELS ARE ASSOCIATED WITH TELBIVUDINE TREATMENT RESPONSE IN THE 2410 ROADMAP STUDY IN CHRONIC HEPATITIS B

Results: The slope of changes in LSMs over time in years is shown in Figure 1. LSMs changes over time (expressed in DkPa/month) showed a slight faster pattern of fibrosis regression at the beginning (first two years) and a slow steady pattern later during a follow-up period of four years. Improvement in fibrosis was seen in 33/55 patients (60%) (drop of −2.06±1.6 in kPa). Importantly, regression of cirrhosis (initial LSM >12kPa) to less than 6.1 kPa was observed in 3/55 (5.4%) patients. Worsening of LSMwas observed in 3 cases due to other liver disease cofactors. The baseline median LSM was 9.2±3.1 kPa. LSMs significantly decreased during the follow-up period after the start of NA treatment (8.4±0.9, 7.8±1.3, 7.3±1.9 and 6.8±1.6 kPa at years 1, 2, 3 and 4, respectively). Conclusions: LSMs changes annually showed an early faster and a later steady pattern of fibrosis regression over time as measured by transient elastography for chronic HBeAg (−) hepatitis treated with NA. Also LSMs showed a slight improvement of fibrosis in the first 4 years. Longer follow-up of these patients by TE is necessary to assess fibrosis regression in chronic hepatitis B patients under antiviral therapy.