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 NCT0065120

Role of regulatory T cells in natural immunity and sustained pharmacological control of chronic hepatitis B infection

Background/Aim: The effectiveness of hepatitis B virus therapy is reflected not only by the reduction of viral load but also recovery of viral-specific T-cell immunity. Regulatory T cells (Treg) can suppress the functions of CD4 and CD8 effector cells. The aim of the current study is to investigate the role of Treg in nucleoside/ nucleotide analogue (Nucs)-induced and spontaneous sustained Background/Aim: The effectiveness of hepatitis B virus therapy is reflected not only by the reduction of viral load but also recovery of viral-specific T-cell immunity. Regulatory T cells (Treg) can suppress the functions of CD4 and CD8 effector cells. The aim of the current study is to investigate the role of Treg in nucleoside/ nucleotide analogue (Nucs)-induced and spontaneous sustained remission after HBeAg-seroconversion. Methods: We studied 30 hepatitis B e antigen (HBeAg)-positive patients treated with either adefovir dipivoxil (ADV) monotherapy [n 16] or ADV in combination with emtricitabine [n 14] for 96 weeks followed by ADV monotherapy. Nucs was discontinued 6-months after HBeAgseroconversion and patients followed-up for post-treatment relapse (HBV DNA 10,000 copies/ml with ALT 2 times upper limit of normal). Nine historical control patients with spontaneous HBeAg-seroconversion were recruited for comparison. Serial HBV DNA, Treg (defined as CD4 CD25 CD45RO CTLA-4 ) cell frequency by FACS, FoxP3 mRNA expression level by realtime PCR and intracellular cytokine staining for virus-specific CD8 T-cells by FACS were evaluated every 4-8 weekly. Results: At the time of analysis, 10 of 30 patients (33.3%) had HBeAgseroconversion. All these 10 patients had normal serum ALT and HBV DNA 300 copies/ml at the end-of-treatment (ET). After follow-up of mean 16.1 months, 4 of the 10 patients (40.0%) with Nucs-induced HBeAg-seroconversion had sustained response (SR)and 6 patients (60.0%) had post-treatment relapse. A decline in Treg (mean /- SEM 1.89 /- 0.47 vs. 4.35 /- 1.02 respectively, p 0.01) and FoxP3 (mean /- SEM 14.62 /- 7.48 vs. 48.89 /-24.51 respectively, p 0.002) was detected 8-weeks before HBeAgseroconversion in patients with spontaneous HBeAg-seroconversion when compared with baseline. This decrease in Treg and FoxP3 was sustained until 24 weeks after spontaneous HBeAgseroconversion. No change in Treg was detected in Nucs-induced HBeAg-seroconversion. The 4 patients with SR showed a significantly lower percentage of Treg at ET (mean /- SEM 1.50 /-0.63) when compared with the 6 patients with post-treatment relapse (mean /- SEM 4.41 /- 1.34, p 0.03). Post-treatment relapse was preceded by an increase in Treg and FoxP3. Downregulation of Treg was associated with an increase in virus-specific CD8 T-cells. However, no serum ALT flare was detected during T cell recovery. Conclusion: Downregulation of Treg is associated with spontaneous HBeAg seroconversion and sustained post-treatment remission without cytolytic mediated liver damage. A lower Treg at ET contribute to SR upon withdrawal of nucs after HBeAg-seroconversion

A phase I/II dose escalating trial evaluating safety, tolerability, pharmacokinetics and antiviral activity of clevudine in patients chronically infected with HBV

Abstrac

A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti-hepatitis B virus (HBV) activity in vitro. A multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 × 106 copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log10 copies/mL. After 28 days, the median HBV DNA log10 change from baseline was −2.5, −2.7, −3.0, and −2.6 log10. Six months after dosing, median changes from baseline were −1.2, −1.4, −2.7 and −1.7 log10 in the 10-, 50-, 100-, and 200-mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose-limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study. (HEPATOLOGY 2004;40:140–148.