Drug Profile: Telbivudine (Tyzeka)

Hopkins HIV Report 2007 Jan; 19(1):7,10

Paul A. Pham, Pharm.D. and Chloe Thio, M.D.
Johns Hopkins

Manufacturer: Idenix pharmaceuticals

Class: Synthetic thymidine nucleoside analog with activity against HBV but not HIV.

Formulation/Storage: 600 mg tablet/Store at room temperature

Indication: Treatment of chronic hepatitis B (HBeAg pos, irrespective of e-Ag status) with ongoing viral replication and evidence of transaminase elevation or histologically active disease.

Dose: 600 mg once daily with or without food.

Dosing with renal impairment: GFR >50 mL/min: 600 mg once daily.; GFR 30-49 mL/min: 600 mg every 48 hr; <30 mL/min (no HD): 600 mg every 72 hr; ESRD (HD): 600 mg every 96 hr (on days of HD, dose post-HD).

Dosing with hepatic impairment: 600 mg once daily

Pregnancy Risk: Category B. Telbivudine was not embryotoxic or teratogenic in animal studies. No human data.

Pharmacokinetics: Telbivudine is well absorbed with a mean C_max of 3.69 mcg/mL, AUC 26.1 mcg hr/mL, and C_min 0.2-0.3 mcg/mL on 600 mg/d at steady state. Telbivudine is not metabolized, and is primarily excreted via glomerular filtration with a terminal T1/2 of 40-49 hours.

Drug Interactions: Telbivudine is not a substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. Interactions with PIs or NNRTIs are unlikely. No antagonism was observed with other NRTIs in vitro.

Adverse Drug Reactions: Telbivudine is generally well tolerated with adverse reactions that were similar to lamivudine and adefovir. CK elevation is more common with telbivudine than with lamivudine (9% vs 3%). Cases of reversible myositis have been reported.

Resistance: M204I genotypic substitution accounts for 74%-94% of observed mutations associated with resistance [Bzowej et al. Gastro 2006;130:A765; Standring et al. EASL 2006, Vienna]. Additional mutations that have been reported include L80I/V, A181T, L180M, L229W/V. In a two-year follow-up, resistance, defined as breakthrough viremia with mutations, developed in 8.6% and 21.6% of telbivudine-treated patients who were HBeAg-negative and HBeAg-positive, respectively. Although these resistance rates were high, they were present in only 2-4% of a subset of patients with undetectable viral loads at 24 weeks. The clinical implication of this finding is unclear, but some experts have advocated a treatment strategy of using monotherapy for 24 weeks with “intensification” only if viral load remains detectable.

The efficacy of telbivudine against HBV harboring lamivudine and adefovir resistance remains to be determined. In vitro, telbivudine is active against lamivudine-resistant virus with the M204V mutation alone, but it was not active against lamivudinetreated virus with the L180M/M204V double mutation or the M204I mutation. HBV encoding adefovir resistance associated with A181V mutation showed a 3 to 5-fold reduced susceptibility.

Clinical Study Results: The GLOBE study was a randomized, blinded phase III trial comparing telbivudine (600 mg/d) vs lamivudine (100 mg/d) in 1367 treatment-naïve patients with chronic hepatitis B. Patients had HBV DNA >6 log₁₀ c/mL, an ALT 1.3-10x ULN, and compensated liver disease. Therapeutic response was defined as HBV DNA <5 log₁₀ c/mL with HBeAg loss in those with HBeAg-positive disease or ALT normalization. At week 104, therapeutic response was 61% and 74% of HBeAg-positive (n=921) and HBeAg-negative patients (n=446) treated with telbivudine, respectively. These response rates were higher than those observed in lamivudine-treated patients, which were 47% and 62% of HBeAgpositive and HBeAg-negative patients, respectively. However, in the HBeAg-positive group, HBeAg seroconversion was not different between those who received telbivudine and lamivudine, 29% and 24%, respectively. Tolerability was comparable between the treatment groups. Three cases of reversible myositis were reported in the telbivudine group [Lai CL, et al. AASLD 2006, Abstract 91].

In lamivudine-experienced patients, 256 patients with persistent viremia (HBV DNA >3 log₁₀ c/mL) despite 3-12 months of lamivudine treatment were randomized either to switch to telbivudine or to continue therapy with lamivudine. At the preliminary 24 week evaluation, serum HBV DNA level was suppressed to below 5 log₁₀ c/mL in 80% of patients switched to telbivudine compared to 56% in the lamivudine group, and an undetectable HBV DNA was achieved in 41% and 31%, respectively [Gane E, et al. AASLD 2006, Abstract 1007].

In a multicenter, randomized study involving 135 treatment-naïve patients with compensated liver disease, telbivudine, adefovir, and adefovir-telbivudine (adefovir for the first 24 weeks followed by a switch to telbivudine for 28 weeks) were compared. Patients were HBeAg-positive with a HBV DNA >6 log₁₀ c/mL and an ALT 1.310x ULN. Compared to adefovir, telbivudine-treated patients had a 1.4 log₁₀ c/mL greater HBV DNA decline at 24 weeks (p<0.001). This benefit was maintained at 52 weeks. In addition, undetectable viral load (HBV DNA <300 log₁₀ c/mL) was achieved in 58% and 39% of telbivudine- and adofovir-treated patients, respectively (p=0.14); however, HBeAg loss and ALT normalization were similar to the two groups. In patients who were switched from adefovir to telbivudine at 24 weeks, an additional 1 log₁₀ c/mL drop in HBV DNA was observed following the switch; HBV viral suppression in these patients was similar to that seen in patients who received adefovir for 52 weeks [Bzowej N, et al. AASLD 2006, Abstract 1005].

Comments: In the treatment of chronic hepatitis B, telbivudine offers clinicians a more potent alternative to lamivudine and adefovir. In vitro, it is active against lamivudine-resistant strains with the M204V mutation, but the clinical efficacy against this mutant remains to be determined. Although, the resistance rate to telbivudine is lower and slower to develop than with lamivudine, the rate is still high. making it difficult to determine the optimal use for this agent. In contrast to adefovir, lamivudine, and emtricitabine, telbivudine does not have activity against HIV. Head-tohead comparison with more potent agents (e.g. entecavir), combination therapy studies, and studies evaluating sequencing strategies in the treatment of HBV are needed to establish the exact role of telbivudine.

In HIVHBV co-infected patients who need treatment for both viruses, tenovir/ emtricitabine (Truvada) is a better choice than telbivudine since it treats both viruses and is a dual therapy for HBV perhaps reducing rates of resistance. In the co-infected patients who only need HBV thearpy, the rates of resistance limit its utility.

2007-01-10
HHR-2007-01-04

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