Long-term Data Show Telbivudine (Tyzeka) Suppresses HBV Viral Load and Leads to HBeAg Clearance in Chronic Hepatitis B Patients
- Category: HBV Treatment
- Published on Friday, 20 November 2009 00:00
- Written by Liz Highleyman
At the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) this month in Boston, researchers reported 4-year data from the GLOBE study, indicating that the nucleoside analog telbivudine (Tyzeka) continues to provide long-term viral load suppression, ALT normalization, and hepatitis B "e" antigen (HBeAg) seroconversion in chronic hepatitis B patients. Another study showed sustained response up to 2 years after completing telbivudine treatment.
GLOBE was an international Phase 3 trial comparing 600 mg/day telbivudine versus 100 mg/day lamivudine (Epivir-HBV) for 2 years in 1367 chronic hepatitis B patients with compensated liver disease.
As previously reported, at the end of the randomized part of the study, participants taking telbivudine were significantly more likely to experience treatment response than those taking lamivudine, with 63% of HBeAg positive patients and 78% of HBeAg negative patients achieving undetectable HBV DNA.
After completion of the randomized part of the trial, participants were given the option to continue telbivudine treatment for a further 2 years in an open-label extension study to evaluate the drug's long-term safety and efficacy. Y. Wang and colleagues presented 4-year results at the AASLD meeting (abstract 482).
A total of 426 telbivudine recipients (236 HBeAg positive and 190 HBeAg negative) elected to continue in the extension study. None had genotypic resistance to telbivudine at the end of the initial trial. Of these patients, 355 (83%) completed 4 years of therapy. The per-protocol population consisted of 398 patients (213 HBeAg positive and 185 HBeAg-negative).
- Among the 213 HBeAg positive patients who completed 4 years of continuous telbivudine treatment, 79% had undetectable HBV DNA (< 300 copies/mL).
- 86% achieved normal serum ALT levels.
- 55% experienced HBeAg loss and 42% achieved HBeAg seroconversion.
- Patients with undetectable HBV DNA at treatment week 24 in the initial trial were more likely to achieve undetectable viral load (92%) and HBeAg seroconversion (51%) at 4 years.
- Among 185 HBeAg negative patients who received continuous telbivudine, 84% had undetectable HBV DNA at 4 years.
- 91% had normal serum ALT.
- The telbivudine safety profile during the extension study was similar to the 2-year findings, and no new safety signals were observed with continued treatment.
- 16% of patients reported grade 3-4 creatine kinase elevation (a marker of possible muscle damage), 6% experienced grade 3-4 myalgia (muscle pain), and 0.5% each developed serious myopathy (muscle disease) and myositis (muscle inflammation).
- 3% of patients experienced ALT flares (sudden worsening of liver inflammation).
These findings led the investigators to conclude, "In HBeAg positive and HBeAg negative chronic hepatitis B patients, 4 years of telbivudine treatment provides effective viral suppression and ALT normalization with a favorable safety profile."
Moreover, they added, "telbivudine achieves a high seroconversion rate in HBeAg positive patients."
HBsAg as a Predictive Factor
In a related study (abstract 487), German researchers investigated serum hepatitis B surface antigen (HBsAg) levels over 3 years of telbivudine treatment in 162 HBeAg positive and 143 HBeAg negative patients who completed the telbivudine arm of the GLOBE trial, achieved undetectable HBV DNA, and were enrolled in the extension study for at least 52 weeks.
- The researchers observed a significant correlation between baseline serum HBsAg and HBV DNA levels among both HBeAg positive and HBeAg negative patients.
- Telbivudine treatment reduced HBsAg levels from baseline to year 3 in both groups.
- Among HBeAg positive patients, the main HBsAg decline occurred during the first year of treatment.
- In HBeAg negative participants, in contrast, the main HBsAg decline was observed at later time points, between years 2 and 3 of treatment.
At 24 weeks, 3 patterns of HBsAg kinetics were observed:
- Rapid decline > 0.5 log10 IU/mL in 53 HBeAg positive and 11 HBeAg negative patients; consecutive HBsAg loss at year 3 was observed in 7 HBeAg positive patients and 1 HBeAg negative participant.
- Slow decline in 48 HBeAg positive and 59 HBeAg negative patients; consecutive HBsAg loss at year 3 was observed in 2 HBeAg positive patients and 1 HBeAg negative patient;
- Static HBsAg levels in 61 HBeAg positive and 73 HBeAg negative patients.
- A majority of patients with HBsAg loss at year 3 showed rapid decline through week 24.
- Strong HBsAg decline up to week 24 was associated with a significantly higher probability of subsequent HBsAg loss in both HBeAg positive and HBeAg negative participants.
Based on these findings, the investigators concluded, "Baseline serum HBsAg correlates with HBV DNA levels in HBeAg positive and HBeAg negative patients."
"Telbivudine treatment reduces serum HBsAg levels in HBeAg positive and HBeAg negative chronic hepatitis B patients," they continued. "Rapid on-treatment HBsAg decline of > 0.5 log10 IU/mL up to week 24 is highly predictive of future HBsAg clearance."
Finally, Chinese researchers looked at sustained post-treatment outcomes up to 2 years after patients completed treatment with telbivudine (abstract 424).
The analysis included 22 participants (17 HBeAg positive and 5 HBeAg negative) who received 600 mg/day telbivudine for 104 weeks.
Complete response for initially HBeAg positive patients was defined as undetectable HBV DNA, ALT normalization, and HBeAg seroconversion. For initially HBeAg patients, completed response was defined as undetectable HBV DNA and ALT normalization.
Patients who demonstrated complete response for at least 24 weeks could discontinue treatment and were followed for 2 years post-treatment. Serum HBV DNA and HBsAg levels were assessed at baseline, during treatment at weeks 24, 52, and 104, and during post-treatment follow-up.
- At treatment week 104, 50% of participants overall had a complete response and discontinued telbivudine.
- 36% of HBeAg positive patients achieved sustained virological response (SVR), defined as continued undetectable HBV DNA, ALT normalization, and HBeAg seroconversion after 2 years of follow-up.
- A significant positive correlation was observed between on-treatment HBsAg levels and HBV DNA levels.
- Patients who achieved SVR had a greater mean reduction from baseline in HBsAg levels while on treatment than non-sustained-responders.
- An HBsAg level < 2 log10 IU/mL at treatment week 104 was highly predictive of SVR (negative predictive value 100%; positive predictive value 93%).
- An HBsAg decline of 0.8 log10 IU/mL at treatment week 24 also predicted of SVR (negative predictive value 75%; positive predictive value 86%).
- 1 patient with an HBsAg decline > 3 log10 IU/mL at treatment weeks 24, 52, 76, and 104 sero-reverted after completed treatment.
"On-treatment serum HBsAg levels are highly predictive of SVR to telbivudine at 2 years off treatment," the researchers concluded. "Quantitative serum HBsAg levels at treatment weeks 24 and 52 were more predictive of SVR to telbivudine than serum HBV DNA levels in these patients."
Y Wang, S Thongsawat, EJ Gane, and others.
Efficacy and Safety Outcomes After 4 Years of Telbivudine Treatment in Patients with Chronic Hepatitis B (CHB). 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 482.
K Wursthorn, M Jung, MP Manns, and others. Different Kinetics of Serum HBsAg Decline in HBeAg-Positive vs HBeAg-Negative Patients During 3 Years of Telbivudine Treatment in Chronic Hepatitis B (CHB). 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 487.
W Cai, Q Xie, X Zhou, and others.
On-treatment Serum HBsAg Level at 2 Years: Strong Predictor of Sustained Virologic Response to Telbivudine for up to 2 Years Off-treatment in Chronic Hepatitis B Patients. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 424.