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We thank Dr. Ozaras and colleagues for their interest in our article. We agree that patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B frequently have low or fluctuating hepatitis B virus (HBV) DNA levels; however, it is clinically desirable for all patients (HBeAg-positive or HBeAg-negative) to quickly achieve undetectable serum HBV DNA levels. The definition of virological response for HBeAg-negative patients in this trial protocol was based on several factors, including American Association for the Study of Liver Diseases (AASLD) guidelines in effect at the time of the trial initiation and similar guidances from the Asia-Pacific Association for the Study of the Liver (APASL) and the European Medicines Evaluation Agency (EMEA). Clinical trial analyses have indicated that, regardless of HBeAg status, most patients with active liver inflammation and elevated alanine aminotransferase (ALT) levels will have serum HBV DNA levels exceeding 5-6 log10 copies/mL.1 Hence, the study enrollment criterion requiring HBV DNA levels greater than 6 log10 at entry was not felt to be too exclusionary for HBeAg-negative patients with active liver disease, and setting the virologic response threshold at 5 log10 copies/mL thereby required a meaningful HBV DNA response of 1 log or more.

In addition, a composite serologic endpoint comprising HBV DNA suppression and ALT normalization has been used in several large clinical trials involving HBeAg-negative patients with chronic hepatitis B.2, 3 The primary efficacy endpoint, Therapeutic Response, conceptually combined both types of composite efficacy endpoints and captured the clinical efficacy desired in hepatitis B patients regardless of HBeAg status. In HBeAg-negative patients, the Therapeutic Response endpoint captures HBV DNA suppression and ALT normalization, the two serum parameters most often monitored in the clinic as measures of response to treatment.1, 2

We agree that with the advent of more sensitive assays, it would be relevant to examine in future trials the definition of virological response for HBeAg-negative patients. We also agree that caution is needed when comparing results from different clinical trials of HBV treatment and in this respect differences in trial designs are particularly relevant. Importantly, telbivudine is the only drug assessed in both HBeAg-positive and HBeAg-negative patient populations for 2 years of continuous treatment, using intention-to-treat analyses.4

References

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  • 1
    Lok AS, McMahon BJ. Chronic hepatitis B. HEPATOLOGY 2001; 34: 1225-1241.
  • 2
    Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. HEPATOLOGY 2001; 34(4 Pt 1): 617-624.
  • 3
    Tassopoulos NC, Volpes R, Pastore G, et al. Efficacy of lamivudine in patients with hepatitis B e antigen- negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B Lamivudine Precore Mutant Study Group. HEPATOLOGY 1999; 29: 889-896.
  • 4
    Lai CL, Gane E, Hsu CW, Thongsawat S, Wang Y, Chen Y, et al. Two-year results from the GLOBE trial in patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine (LdT) vs. lamivudine [Abstract]. HEPATOLOGY 2006; 44(4 Suppl. 1 ): 222A.

Jinlin Hou*, Nathaniel Brown†, JiDong Jia‡, * Department of Infectious Diseases, Nanfang Hospital, Nanfang Medical University, Guangzhou, China, † Idenix Pharmaceuticals, Cambridge, MA, ‡ Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.