New Oral Treatment for Chronic Hepatitis B: Telbivudine
Special Report
By Nam Do and Jessica C. Song, Nam Do is a pharmacy resident, Santa Clara Valley Medical Center, and Jessica C. Song, MA, PharmD, is Pharmacy Residency Coordinator, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Nam Do and Jessica C. Song report no financial relationships relevant to this field of study.
Treatment of chronic Hepatitis B is directed at suppressing viral replication, reducing hepatitis (necroinflammatory) activity, slowing progression of fibrotic disease, inducing loss of HBeAg with seroconversion to anti-HBe, and rendering patients noninfectious.1 At present, 4 oral antiviral agents, entecavir, adefovir dipivoxil, lamivudine, and telbivudine are FDA (Food and Drug Administration)-approved for the treatment of chronic hepatitis B, with telbivudine receiving FDA approval in October 2006.2 This article will: (1) review the pharmacology, pharmacokinetics, and FDA indications of telbivudine, (2) review the safety and efficacy of telbivudine, and (3) review the drug interactions and dosage of this new nucleoside analog.
Pharmacologic Properties
Telbivudine is a thymidine nucleoside analog with activity against hepatitis B virus (HBV) DNA polymerase that undergoes phosphorylation to the active triphosphate form.3 Telbivudine 5'-triphosphate competes with the natural substrate thymidine 5'-triphosphate and therefore inhibits HBV DNA Polymerase. Inhibition of HBV viral replication occurs following incorporation of telbivudine 5'-triphosphate into viral DNA.
Telbivudine undergoes minimal metabolism, as the majority of the drug is eliminated unchanged in urine by passive diffusion, with the renal clearance of this drug approaching HBeAg (+) (-) glomerular filtration rate.3 Telbivudine is indicated for the treatment HBeAg (+) and HBeAg(-) patients with treatment-naïve chronic HBV, who have evidence of histologically active disease or persistent elevations in serum aminotransferases, and with evidence of viral replication.3
Telbivudine is generally well-tolerated, with the following adverse events occurring in ≥ 9% of patients taking this drug: upper respiratory tract infection (14%), fatigue/malaise (12%), abdominal pain (12%), nasopharyngitis (11%), headache (11%), and elevated blood creatine phosphokinase (CPK; 9%).3 Since severe lactic acidosis (± hepatomegaly with steatosis) and severe acute exacerbations of HBV following product discontinuation have been reported with the use of multiple nucleoside analogs,4-6 the FDA mandated the manufacturer of telbivudine to place black-box warnings in the monograph of this agent.3
The potential for CYP450 (Cytochrome p450) - mediated interactions is low for telbivudine, as it does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP2E1, or CYP3A4. Moreover, telbivudine is not a substrate of any of the commonly seen CYP isoenzymes (refer to above). However, the manufacturer advises precautions with concurrent use of this agent with known nephrotoxic drugs.3 Table 1 summarizes the key pharmacologic properties of telbivudine.
Resistance Patterns,Clinical Efficacy for Treatment of HBV
At present, 4 oral drugs (telbivudine, entecavir, adefovir dipivoxil, lamivudine) and one pegylated interferon product (peginterferon alfa-2a) have been approved by the FDA for use in the management of chronic HBV infection.1 Emergence of resistance (via YMDD mutation) has been associated with lamivudine therapy, developing in 14% of patients after one year of therapy and in up to 69% of patients after 5 years of therapy.1 Viral resistance appears to be less likely to develop during adefovir dipivoxil therapy, as mutant rtN236T (or rtA181V/T) has been identified in up to 29% of patients after 5 years of therapy. To date, the emergence of entecavir resistance among treatment-naïve HBV patients has been shown to be a rare occurrence, as one study showed that none of the patients exhibited resistance during 2 years of treatment.7 However, the incidence of entecavir resistance among lamivudine-refractory patients is estimated to be nearly 10% after 2 years of therapy.7 The incidence of resistance associated with telbivudine therapy has not been established, but a Phase III clinical trial (GLOBE) showed that 2% of HBeAg(-) patients and 3% of HBeAg(+) patients became resistant to this drug after 52 weeks of therapy.8
Recently, an updated HBV treatment algorithm was developed by a panel of U.S. hepatologists and was published in 2006.1 The panel of hepatologists recommended the use of adefovir, entecavir, or peginterferon alfa-2a as initial therapy of HBeAg (+) and HBeAg(-) patients with elevated HBV DNA and elevated serum aminotransferase levels. The addition of adefovir to lamivudine therapy was recommended for lamivudine-resistant HBV patients, whereas the addition of lamivudine or a switch to entecavir were considered the best treatment options for adefovir-resistant HBV patients. Table 2 summarizes the expert panel's treatment recommendations and Table 3 provides key highlights from clinical trials of peginterferon alfa-2a, lamivudine, entecavir, and adefovir dipivoxil in HBeAg (+) chronic HBV patients.1
Clinical trials of telbivudine have primarily included chronic HBV patients with compensated liver disease and HBeAg (+) patients (2 of 3 studies). Reductions in HBV DNA levels after 24 to 76 weeks of telbivudine therapy have ranged from 6.06 log10 copies/mL to 6.60 log10 copies/mL for HBeAg (+) patients. Of note, telbivudine was shown to be superior to lamivudine8 and to adefovir9 in lowering HBV DNA levels in HBeAg (+) patients. In contrast, no difference in the abilities of telbivudine and lamivudine to decrease HBV DNA levels in HBeAg (-) patients were reported in a Phase III study.8 One Phase III clinical trial showed the superior efficacy of telbivudine compared with that of lamivudine in regards to improvement of the proportion of HBeAg (+) patients achieving ALT normalization and the percentage of patients exhibiting HBeAg loss. However, in HBeAg (-) patients, no difference in efficacy for ALT normalization was observed between telbivudine and lamivudine at 76 weeks.
Interestingly, Phase III clinical trials have shown the superior efficacy of entecavir compared with that of lamivudine in HBeAg (-) and in HBeAg (+) patients when evaluating DNA reduction and ALT normalization.
The rates of HBeAg loss and ALT normalization have been shown to be similar for telbivudine- and adefovir-treated patients after 24 weeks of therapy.9 In addition, telbivudine has not been studied in patients with decompensated liver disease, or in lamivudine-, entecavir-, and adefovir-resistant patients.3 Table 4 summarizes the results from clinical trials that evaluated the efficacy of telbivudine in the management of chronic HBV infection.
Conclusion
There is a crucial need for the development of new, well-tolerated agents that are effective for the management of chronic HBV patients, as resistance to certain medications has emerged in recent years. Currently, 4 oral agents, telbivudine, entecavir, adefovir dipivoxil, and lamivudine are available for use in the treatment of chronic HBV infections. Telbivudine has not been studied in patients with decompensated liver disease, whereas adefovir represents the best-studied agent in patients with compensated/decompensated cirrhosis patients.1,5 In addition, the efficacy of telbivudine in the treatment of adefovir-, entecavir-, and lamivudine-resistant chronic HBV patients has not been established. Recent studies have confirmed the superior efficacy of telbivudine compared with that of lamivudine in regards to DNA reduction, proportion of patients achieving ALT normalization, and the rate of HBeAg loss in HBeAg (+) patients. The clinical efficacy of telbivudine is less convincing in HBeAg (-) patients, as no difference in efficacy was found between telbivudine and lamivudine after 76 weeks of therapy. In contrast, entecavir has been shown to be superior to lamivudine in reducing HBV DNA levels and in normalizing ALT levels in HBeAg (-) patients and in HBeAg (+) patients. Although early results from clinical trials are promising, future clinical trials will help further define the potential role of telbivudine in the management of chronic HBV patients.
References
- Keefe EB, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962.
- Medcompare Medical News. Tyzeka (telbivudine) approved by U.S. Food and Drug Administration (FDA) as a new treatment for patients with chronic hepatitis B. Accessed on January 17, 2007: Medcompare - Medical News : TYZEKA™ (telbivudine) Approved By U.S. Food And Drug Administration (FDA) As A New Treatment For Patients With Chronic Hepatitis B.
- Tyzeka (telbivudine) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2006.
- Entecavir (Baraclude) prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; December 2005.
- Adefovir dipivoxil (Hepsera) prescribing information. Foster City, CA: Gilead Sciences, Inc; October 2006.
- Lamivudine (Epivir-HBV) prescribing information. Research Triangle Park, NC: GlaxoSmithKline; December 2004.
- Colonno R, et al. Entecavir 2 year resistance update: no resistance observed in nucleoside naive patients and low-frequency resistance emergence in lamivudine refractory patients (abstr). Hepatology. 2005;42:573A-574A.
- Bzowej N, et al. Phase III comparison of telbivudine vs lamivudine in patients with chronic hepatitis B: efficacy safety and predictors of response at one year. DDW. 2006. May 20-35. Los Angeles, CA.
- Heathcote E, et al. A randomized trial of telbivudine (LdT) vs adefovir for HBeAg-positive chronic hepatitis B: results of the primary week 24 analysis. DDW. 2006;May 20-35, 2006. Los Angeles, CA.
- Lai CL, et al. A 1-year trial of telbivudine, lamivudine and the combination with hepatitis B e antigen — positive chronic hepatitis B. Gastroenterology. 2005;129:528-536.
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