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Telbivudine in chronic hepatitis B


With available treatments aimed at reducing hepatitis B viral load bringing side-effects or drug resistance, new oral antiviral telbivudine – now approved in the USA and Europe – could be a valuable option

Giovanni Battista Gaeta

Chair, Infectious Diseases

Gianfranca Stornaiuolo

Clinical and Research Assistant

Viral Hepatitis Unit
University of Naples 2

Chronic hepatitis B is a major cause of liver disease and hepatocellular carcinoma worldwide. The clinical course of hepatitis B virus (HBV) infection is complex and can be influenced by various factors; overall, chronic HBV infection may progress to end-stage liver disease in approximately 15–40% of

The maintenance of necroinflammation and the progression of fibrosis is directly related to viral load. In a review of 26 prospective studies, there was a statistically significant correlation between serum HBV-DNA levels, the histological activity index, and the biochemical and serological responses.[2] In a prospective population-based study, a cohort of 3,582 untreated patients with HBV infection was followed up for a mean of 11 years.[3] The cumulative incidence of cirrhosis increased significantly from 4.5% for patients with the lowest
viral load at baseline, to 36.2% for those with the highest level of viral replication. Similarly, increasing baseline serum HBV levels were associated with increasing incidence of hepatocellular carcinoma.[4]

The primary aim of treatment should be to durably reduce viral replication and possibly suppress serum HBV-DNA to undetectable levels using sensitive polymerase chain reaction (PCR) assays, histological improvement and normalisation of alanine aminotransferase levels.

In hepatitis B e-antigen-positive patients, the loss of this antigen (HBeAg), with seroconversion to anti-HBe, is a durable endpoint. Loss of hepatitis B surface antigen (HBsAg) is desirable but seldom occurs.

Antiviral therapy with oral nucleosides/nucleotides provides a course of treatment of indefinite duration and is well tolerated and easily administered (oral therapy). Four nucleoside/nucleotide analogues are currently licensed for treatment of chronic hepatitis B: lamivudine, adefovir, entecavir and, more recently, telbivudine.

The major limitation on antiviral agents is the emergence of viral resistance, which is followed by the loss of biochemical and histological response. For example, lamivudine causes resistance in 20% of patients per year[5], and adefovir in 29% of patients after five years[6]. Entecavir resistance is rare in naive patients (about 1% at four years) but increases over time in lamivudineresistant patients (43% after four years).

Telbivudine (LdT) is a β-L-nucleoside analogue that is very potent and rapid in reducing HBV-DNA levels in both HBeAg-positive and HBeAg-negative patients. In preclinical studies, telbivudine rapidly reduced HBV-DNA load and showed no adverse effects or mitochondrial toxicity,[7,8] with an excellent safety profile and a favourable pharmacokinetic profile.[9,10] A large, multicentre randomised study (the GLOBE trial) compared telbivudine 600mg/day vs lamivudine 100mg/day in a population of 1,367 patients with HBeAg-positive or HBeAg-negative chronic hepatitis B.[11–13] After 104 weeks of treatment, an intention-to-treat analysis showed that 61% of HBeAg-positive patients and 82% of HBeAg-negative patients treated with telbivudine had undetectable serum HBV-DNA at PCR assay. These figures were significantly higher than those achieved with lamivudine (39% and 57%, respectively).

Interestingly, in patients with basal viraemia lower than 9log10/ copies for HBeAg-positive patients and lower than 7log10/ copies for HBeAg-negative patients, viral clearance was achieved in 77.5% and 89%, respectively. Moreover, the GLOBE study introduced the concept of the assessment of HBV-DNA response at week 24. For those patients with low viraemia at
baseline who achieved HBV-DNA undetectability at that time, response rates at week 104 were 89% for HBeAg-positive and 91% for HBeAg-negative patients (see Figure 1). Anti-HBe seroconversion was obtained in 52% of HBeAg-positive patients.

Resistance to telbivudine rarely emerged; in particular, only 2% of HBeAg-negative and 4% of HBeAg-positive patients, who were PCR-negative at week 24, harboured resistant HBV variants over two years. Importantly, the only resistance mutation described so far was the substitution M204I, with
some secondary mutations not causing resistance.

Patients undergoing treatment with lamivudine or adefovir can be switched to telbivudine, achieving a significantly greater reduction in HBV-DNA levels than those who continued the treatment.[14,15]

The available treatment options aimed at reducing viral load and hence improving outcome are either based on IFNs or on nucleoside/nucleotide analogue antiviral agents, which inhibit HBV-DNA replication. IFNs have a unique mechanism of action and are effective in reducing viral load in some 30% of eligible
patients after 48 weeks of treatment. However, their use for longer periods is limited by their side-effects. The antiviral agents have much more acceptable side-effect profiles and higher antiviral potency, and telbivudine and entecavir, the newest antivirals, have so far not been associated with a clinically important rate of resistance, fulfilling the main aims of anti-HBV therapy. Current guidelines do not recommend lamivudine as first-line therapy for chronic hepatitis B.[16]

Available data indicate that telbivudine is a valuable option for patients with HBV-DNA levels below 9 or 7 log10/ copies for HBeAg-positive andHBeAg-negative chronic hepatitis, respectively.[17] Entecavir should be used for patients with higher viraemia levels.


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12. Lai CL, et al. Two-year results from the GLOBE trial in
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14. Safadi R, et al. A randomized trial of switching to telbivudine versus continued lamivudine in adults with chronic hepatitis B. J Hepatol 2007;46(S1):196A.
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16. Lok ASF, et al. Chronic hepatitis B. Hepatology 2007;45:507-39.
17. Gaeta GB, et al. Therapy of chronic hepatitis B. Dig Liver Dis 2007;39(S3):372-8.

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