Selected Telbivudine (Tyzeka) Studies Presented at the 42nd Annual EASL Meeting

By Ronald Baker, PhD

The U.S. Food and Drug Administration (FDA) approved telbivudine (Tyzeka) for the treatment of adults with chronic hepatitis B virus (HBV) infection in October 2006. Switzerland and the countries of the European Union have also approved telbivudine.

Telbivudine is a new molecular entity, a term used by the FDA to describe a medication containing an active substance that has never before been approved for marketing in any form in the United States.

There were 9 studies involving use of telbivudine for the treatment of chronic hepatitis B presented at the recent 42nd Annual Meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain (April 11-15, 2007).

The focus of these studies included adefovir salvage therapy for telbivudine-treated patients with virological breakthrough, early HBV suppression by telbivudine at 24 weeks, 76-week follow-up of HBeAg positive patients receiving telbivudine, switching to telbivudine versus continued lamivudine (Epivir-HBV), cost-effectiveness of telbivudine versus lamivudine, and efficacy of telbivudine versus lamivudine at 2 years in HBeAg positive patients. Following are selected highlights from these presentations.

HBeAg Positive HBV Patients on Telbivudine and on Lamivudine Experience Off-treatment HBeAg Response [1]

In HBeAg positive patients, seroconversion and HBeAg loss are important therapeutic markers. The Phase III GLOBE trial compared telbivudine versus lamivudine in patients with chronic hepatitis B. This study was the largest registration trial ever conducted for a chronic hepatitis B treatment. The trial included 1367 adults with chronic hepatitis B (921 HBeAg-positive, 446 HBeAg-negative), and was conducted at 112 clinical centers in 20 countries worldwide, including the Czech Republic, France, Germany, Greece, Italy, Poland, Spain, Turkey, and the United Kingdom. GLOBE was also the first international hepatitis B study to include patients in China.

In this trial, participants could stop treatment after a year if they had HBV DNA < 5 log₁₀ copies/mL and had experienced HBeAg loss for at least 24 weeks

134 of 458 patients (29%) receiving telbivudine and 123 of 463 patients receiving lamivudine (27%) were eligible to discontinue treatment, but due to investigator choice, only 59 of 257 (23%) did so.

At week 104, > 80% of both telbivudine and lamivudine recipients exhibited sustained HBeAg responses (Table). The median duration off-treatment was 35.2 weeks for telbivudine and 29.1 weeks for lamivudine.

Table

Adefovir Is Successful Salvage Therapy in Telbivudine-treated Patients with Virological Breakthrough [2]

In the GLOBE trial (described above), patients experiencing virological breakthrough were offered adefovir (Hepsera) to enhance viral suppression. Adefovir is an approved salvage therapy for lamivudine-treated patients with HBV breakthrough.

At EASL, initial outcome data were presented for 22 telbivudine-treated patients with virological breakthrough who started adefovir as salvage therapy, either as follow-on monotherapy (n=17) or in combination with continued telbivudine (n=5).

After 16 weeks of adefovir, HBV DNA levels decreased by a mean of 4.1 log₁₀ copies/mL, and ALT levels were reduced by 93.1 IU/L (Table). HBV DNA levels decreased by a mean of 5.1 log₁₀ copies/mL in the subset of 5 patients who received adefovir in combination with telbivudine, compared to 3.8 log₁₀ copies/mL in the 16 patients who switched from telbivudine to adefovir monotherapy.

Study treatment, including adefovir, was generally well tolerated, and no serious adverse events were reported.

The study authors concluded, “Adefovir salvage therapy, as follow-on monotherapy or in combination with telbivudine, resulted in consistent viral suppression for telbivudine-treated patients experiencing virologic breakthrough.”

After 2 Years of Treatment, Telbivudine Produces Significantly Greater Antiviral and Clinical Efficacy than Lamivudine in HBeAg Positive Patients [3]

There is widespread agreement, as shown in several international treatment guidelines, that treatment is indicated for HBeAg-positive chronic hepatitis B patients with elevated HBV DNA and pretreatment ALT 2 times the upper limit of normal (x ULN).

In the present study, researchers reported 2-year results from the international GLOBE trial (described above) regarding treatment results for HBeAg-positive patients. The trial enrolled 921 patients with HBeAg-positive chronic hepatitis B with baseline HBV DNA >6 log₁₀ copies/mL, ALT 1.3-10 x ULN, and compensated liver disease.

Patients were pre-stratified by pre-treatment ALT (< or = 2 x ULN; ULN of 48 IU/L for males and 37 IU/L for females) and randomized (1:1) to receive oral telbivudine (600 mg/day) or lamivudine (100 mg/day). The population analyzed here included all 580 HBeAg-positive patients with baseline ALT = 2 x ULN (63% of all HBeAg-positive patients in the GLOBE trial)

Results

• As shown in the table below, after 2 years telbivudine was superior to lamivudine for the primary efficacy measure (therapeutic response) and all direct measures of antiviral efficacy (log₁₀ HBV DNA reduction, PCR negativity, protocol defined resistance, and primary treatment failure) (all P<0.05).
• Patients receiving telbivudine were also significantly more likely to achieve HBeAg loss, HBeAg seroconversion, and ALT normalization.

The authors wrote in conclusion, “In 580 HBeAg-positive patients with chronic hepatitis B and baseline ALT = 2 x ULN from the GLOBE trial, a patient population recommended for treatment by international guidelines, telbivudine produced significantly greater antiviral and clinical efficacy than lamivudine.”

After 24 or 52 weeks of Suboptimal Response to Adefovir, Switching to Telbivudine Produces Substantial Additional Reduction of HBV DNA through Week 76 [4]

Researchers learn important information about the efficacy and safety of a drug by comparing it directly with another drug(s) in clinical trials. In the current study, researchers report results of a 1-year randomized trial of telbivudine versus adefovir, followed by 24 weeks of open-label telbivudine.

The randomized active-controlled study enrolled 135 adults with HBeAg-positive chronic hepatitis B with HBV DNA > 6 log₁₀ copies/mL, serum ALT 1.3-10 x ULN, and compensated liver disease. Patients were initially randomized (2:1) to 10 mg/day adefovir or 600 mg/day telbivudine for 24 weeks, with a secondary randomization (1:1) of adefovir recipients to continue adefovir or switch to telbivudine after week 24.

The primary endpoint was HBV DNA reduction at week 24. After week 52, most patients received telbivudine in an open-label extension trial. The effects of switching from adefovir to telbivudine in patients with suboptimal response to adefovir (HBV DNA >3 log at 24 or 52 weeks) were analyzed.

At week 24, the mean HBV DNA reduction from baseline was significantly greater with telbivudine than with adefovir (–6.30 vs –4.97 log₁₀ copies/mL; P<0.01). Mean viral load decreased sharply in adefovir-treated patients after switching to telbivudine at week 24.

Among the 78% of patients in the adefovir group with suboptimal response at week 24 (HBV DNA >3 log₁₀ copies/mL), those who switched to telbivudine displayed an additional mean 2.1 log₁₀ reduction between week 24 and week 52, vs 0.9 log₁₀ for patients who remained on adefovir.

Based on these results, the study authors concluded, “Telbivudine provided greater and more rapid antiviral effects compared with adefovir through 1 year of treatment.”

They added, “For patients with suboptimal response to adefovir, switching from adefovir to telbivudine after 24 or 52 weeks provided a substantial additional reduction of serum HBV DNA that persisted through week 76.”

Early Virological Response to Telbivudine or Adefovir at 24 WeeksPredicts High Rates of Undetectable HBV DNA and HBeAg Seroconversion at 52 Weeks [5]

In this analysis of the population described in study [4] above, the objective was to evaluate the predictive value of early virological response (EVR), determined by HBV DNA level at 24 weeks, for efficacy responses at 1 year in patients treated with either telbivudine or adefovir.

The investigators analyzed efficacy outcomes at 52 weeks for patients whose HBV DNA levels were below or above 3 log₁₀ copies/mL at week 24.

Results

• At week 24, serum HBV DNA levels were below 3 log₁₀ copies/mL in significantly more telbivudine recipients compared with adefovir recipients (49% vs 22%, P<0.01).
• For all efficacy parameters, results at week 52 correlated with patients’ HBV DNA level at week 24.
• Almost all patients with early virological response (<3 log₁₀ at week 24) had undetectable HBV DNA at 1 year and a high proportion (44%) experienced HBeAg seroconversion.
• In all patients with viral breakthrough at 1 year (2 on telbivudine, 1 on adefovir), HBV DNA levels were > 4 log₁₀ copies/mL at week 24.

The findings of this study show that “serum HBV DNA level after 24 weeks of treatment with anti-HBV nucleosides/nucleotides correlates with efficacy outcomes and viral breakthrough at 1 year. Greater 1-year efficacy is observed with agents that provide the greatest degree of early viral suppression.”

At 24 Weeks, Patients on Lamivudine with Detectable HBV DNA Experience Significantly Greater HBV Suppression by Switching to Telbivudine [6]

Results of Phase II and III studies have demonstrated that telbivudine produces greater virological suppression than lamivudine. Led by R. Safadi of Nazareth, Israel, and Q. Xie of Shanghai, China, this international, multicenter study investigated whether patients receiving lamivudine therapy would benefit from a switch to telbivudine.

Eligible patients had previously received lamivudine for 3-12 months at the time of screening, and were HBsAg-positive or HBsAg-negative, with HBV DNA >3 log₁₀ copies/mL and compensated liver disease. Patients were randomized (1:1) to receive one year of treatment with telbivudine (600 mg/day) or continued lamivudine (100 mg/day), and were stratified by HBeAg status and prior duration of lamivudine therapy (12-24 weeks or 25-52 weeks). The primary efficacy endpoint was HBV DNA reduction at week 24.

Results

• Median baseline HBV DNA was 5.04 and 5.27 log₁₀ copies/mL in the telbivudine (n=122) and lamivudine (n=124) arms, respectively.
• Patients switched to telbivudine showed significantly greater serum HBV DNA reduction at week 24 than patients who continued on lamivudine.
• HBV DNA was suppressed to below 5 log₁₀ copies/mL in 80% of patients switched to telbivudine vs 56% maintained on lamivudine (P<0.001).
• HBV DNA became undetectably by PCR 40% vs 31%, respectively (P=0.14).
• All randomization strata showed similar results.
• 10% and 9% of patients at who were HBeAg-positive at study entry experienced HBeAg loss by week 24 in the telbivudine and lamivudine groups, respectively.
• Both treatments were well tolerated.

The study authors concluded, “[At 24 weeks], patients with detectable HBV DNA during lamivudine therapy experienced significantly improved HBV suppression by switching to telbivudine.”

Cost-effectiveness of Telbivudine versus Lamivudine in Hepatitis B Patients [7]

Cost effectiveness is an important consideration when contemplating taking a drug. In the present analysis, researchers at Tufts-New England Medical Center in Boston, MA, estimated the cost-effectiveness of telbivudine versus lamivudine for HBeAg-positive or HBeAg-negative chronic hepatitis B patients.

Individual patient data (age, sex, virological, serological, and biochemical response, and resistance to telbivudine versus lamivudine) after 104 weeks from 1367 participants in the multinational GLOBE (described in study [1] above) were applied to a Markov cohort simulation to project lifelong clinical and economic outcomes using U.S. data for life expectancy, quality of life, liver transplant survival, and drug cost (telbivudine $18 and lamivudine $7 per pill) with a 3% annual discount rate.

Because of differences in demographic characteristics and response, separate analyses were performed for HBeAg-positive and HBeAg-negative patients.

Results

• At week 104, among HBeAg-positive patients, 56% treated with telbivudine and 38% treated with lamivudine achieved undetectable HBV DNA (p<0.0001).
• Among HBeAg-negative patients, the corresponding rates were 82% with telbivudine and 57% with lamivudine (p<0.0001).
• For HBeAg-positive patients, telbivudine reduced the 10-year relative risk of cirrhosis by 33% (from 14% to 9.6%) and extended life by 3.8 years (4.3 quality-adjusted life years) in the model.
• Telbivudine had an incremental cost-effectiveness ratio of $2500 per discounted quality-adjusted life year (DQALY) gained.
• Because HBV disease progression is more rapid in older patients and in men, incremental cost-effectiveness ratios for telbivudine were $5000 at age 20; $2800 at age 30; $2200 at age 40; and $2700 at age 50 (baseline 74.3% men); and were $1600 for men and $6900 for women (baseline mean age 32.4).
• For HBeAg-negative patients, telbivudine reduced the 10-year relative risk of cirrhosis by 18% (from 12% to 9.9%) and extended life by 0.8 years (0.8 quality-adjusted life years).
• In this group, telbivudine had an incremental cost-effectiveness ratio of $37,800 per DQALY.
• In sensitivity analyses, incremental cost-effectiveness ratios for telbivudine were $59,000 at age 20; $48,900 at age 30; $40,100 at age 40; $33,000 at age 50 (baseline 78.9% men); and were $34,300 for men and $54,200 for women (baseline mean age 42.9).

The authors concluded, “Based on the 104-week GLOBE trial results for patients with chronic hepatitis B, telbivudine may prolong life and should be a cost-effective alternative to lamivudine with an incremental cost-utility ratio falling within the range of other accepted medical interventions.”

04/24/07

References

All references are from the 42 Annual Meeting of the European Association for the Study of the Liver. Barcelona, Spain. April 11-15, 2007.

1. T Poynard, A Chutaputt, S G Hwang, and others. SUSTAINED OFF-TREATMENT HBEAG RESPONSE IN TELBIVUDINE AND LAMIVUDINE TREATED HBEAG-POSITIVE PATIENTS FROM THE GLOBE STUDY.

2. E Gane, C-L La, A Min, and others. ADEFOVIR SALVAGE THERAPY FOR VIROLOGIC BREAKTHROUGH IN TELBIVUDINE-TREATED PATIENTS FROM THE GLOBE STUDY.

3. J Rasenack, T Poynard, C-L Lai, and others. EFFICACY OF TELBIVUDINE VS LAMIVUDINE AT 2 YEARS IN PATIENTS WITH HBEAG-POSITIVE CHRONIC HEPATITIS B WHO ARE ELIGIBLE FOR TREATMENT BASED ON GUIDELINES.

4. P Marcellin, H L Y Chan, C-L Lai, and others. 76 WEEK FOLLOW UP OF HBEAG-POSITIVE CHRONIC HEPATITIS B PATIENTS TREATED WITH TELBIVUDINE, ADEFOVIR OR SWITCHED FROM ADEFOVIR TO TELBIVUDINE.

5. P Marcellin, H L Y Chan, C-L. Lai, and others. IN HEPATITIS B PATIENTS TREATED WITH EITHER ADEFOVIR OR TELBIVUDINE, MAXIMAL EARLY HBV SUPPRESSION AT 24 WEEKS PREDICTS OPTIMAL ONE-YEAR EFFICACY.

6. R Safadi, Q Xie, Y Chen, and others. A RANDOMIZED TRIAL OF SWITCHING TO TELBIVUDINE VERSUS CONTINUED LAMIVUDINE IN ADULTS WITH CHRONIC HEPATITIS B: RESULTS OF THE PRIMARY ANALYSIS AT WEEK 24.

7. J B Wong and S G Pauker. COST-EFFECTIVENESS OF TELBIVUDINE VERSUS LAMIVUDINE FOR CHRONIC HEPATITIS B.

<-----   42nd EASL Main Page

HOME