Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
600 mg tablets
Approved indication: chronic hepatitis B
Australian Medicines Handbook section 5.3
Worldwide, hepatitis B is the most common form of viral hepatitis. Some people who are infected develop chronic hepatitis B which may lead to serious liver disease such as cirrhosis and hepatocellular carcinoma. Chronic hepatitis B infection is usually diagnosed by detecting viral antigens and their corresponding antibodies, and viral DNA in serum.1 Current drugs used to treat chronic hepatitis B include interferons and nucleotide/nucleoside analogues (lamivudine, adefovir and entecavir).
Telbivudine is a synthetic thymidine analogue which inhibits the replication of hepatitis B virus by binding to its DNA polymerase and causing DNA chain termination. It is indicated for chronic hepatitis B (irrespective of whether the patient has the hepatitis B e antigen (HBeAg) or not) in patients who have compensated liver disease, evidence of viral replication and liver inflammation and who have not previously been treated with another nucleoside analogue such as lamivudine.
Following oral administration of telbivudine (600 mg), peak plasma concentrations occur within 1–4 hours. Telbivudine has an overall terminal half-life of around 42 hours and is eliminated mainly unchanged in urine. Patients with impaired renal function may need a dose interval adjustment.
In a phase I placebo-controlled trial, the safety, antiviral activity and pharmacokinetics of telbivudine were assessed in 43 adults with HBeAg-positive chronic hepatitis B. Patients were given one of six different daily doses of telbivudine for four weeks and were followed up for 12 weeks after treatment. The antiviral activity of telbivudine, measured by quantifying serum viral DNA (using the polymerase chain reaction), appeared to be higher at doses of 400 mg or above.2
A subsequent phase II trial compared the safety and efficacy of telbivudine (400 or 600 mg/day) and lamivudine (100 mg/day) alone or in combination, in 104 patients with HBeAg-positive chronic hepatitis B. At week 52, there was no detectable viral DNA in 61% of patients on telbivudine monotherapy compared to 32% of patients on lamivudine monotherapy (p<0.05). Likewise, a greater proportion of patients taking telbivudine monotherapy had improved liver function (normalisation of alanine transferase) compared to those taking lamivudine monotherapy (86% vs 63%, p<0.05). Combination treatments with telbivudine were no more effective than telbivudine alone.3
Results of a two-year multi centre phase III trial comparing telbivudine (600 mg/day) and lamivudine (100 mg/day) are currently unpublished. This trial included approximately 1300 patients with HBeAg-positive or -negative chronic hepatitis B. Interim results suggest that viral suppression was greater in patients treated with telbivudine than in those treated with lamivudine. Improvements in liver function were not statistically different between the two treatments.
The efficacy of telbivudine has also been compared to adefovir in an open-label trial of 136 HBeAg-positive patients. After a year of treatment, there seemed to be greater viral suppression with telbivudine than with adefovir.4
In the phase II and III trials, genetic evidence of viral resistance was found following viral breakthrough in some patients.3 In in vitrostudies, some viral strains that showed resistance to other nucleotide/nucleoside analogues, such as lamivudine or adefovir, also had reduced susceptibility to telbivudine.
The safety profiles of telbivudine and lamivudine were comparable in the phase III trial, with muscle-related symptoms being the most common treatment-emergent clinical adverse events, occurring in 2% of all patients. Creatine kinase elevations occurred in 9% of telbuvidine-treated patients and 3% of lamivudine-treated patients.
Telbivudine comes with a warning about the risk of myopathy. Patients taking telbivudine should therefore be advised to report any unexplained muscle aches, pain, tenderness or weakness. Treatment should be stopped if myopathy is diagnosed.
Health professionals should also be aware that discontinuing telbivudine treatment may lead to severe acute exacerbations of hepatitis B infection. Hepatic function should be monitored for a minimum of several months once therapy has been stopped. When monitoring hepatic function in patients taking telbivudine, check for flares in alanine transferase.
Telbivudine offers a new therapy for patients diagnosed with chronic hepatitis B infection. While telbivudine seems to be effective at reducing viral loads, we do not know if viral resistance will become a problem. It is not known if this drug will reduce the long-term complications associated with chronic hepatitis B.
The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
Note on references
At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).
- Nicholson S, Gust I, Siebert D, Locarnini SA. Updated by Bowden DS, Locarnini SA. Hepatitis B: laboratory diagnosis and vaccination. In: Kellerman G, ed. Abnormal laboratory results. Sydney: McGraw-Hill; 2006.
- Lai CL, Lim SG, Brown NA, Zhou XJ, Lloyd DM, Lee YM et al. A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection. Hepatology 2004; 40:19-26.
- Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005;129:528-36.
- Chan HLY, Heathcote EJ, Marcellin P, Lai CL, Cho M, Moon YM, et al. Treatment of hepatitis B e antigen-positive chronic hepatitis with telbivudine or adefovir: a randomised trial. Ann Intern Med. In press 2007.