icon-folder.gif   Conference Reports for NATAP  
  HEP DART 2003: Frontiers in drug development for Viral Hepatitis
December 14-18, 2003
Kauai, Hawaii
Back grey_arrow_rt.gif
L-Thymidine (LdT) and Related Compounds
  Reported by Jules Levin
C-L Lai (University of Hong Kong), N Brown, Idenix Pharmaceuticals, and colleagues
The L-nucleoside analogues L-deoxythymidine (LdT; telbivudine) and valyl-L-deoxythymidine (val-LdC;valtorcitabine) are potent inhibitors of HBV replication in vitro and synergistic in the woodchuck model of hepadnavirus infection. Clinical evaluation of both compounds is underway. A completed phase I/II trial of LdT in patients with chronic HBV indicated marked antiviral effects with no identified safety issues. This prompted the present 1-year comparative trial of LdT, LdT+lamivudine, and lamivudine.
This randomized multucenter study compared the 1-year safety and efficacy of LdT 400 or 600 mg/day, and LdT 400 or 600 mg/day combined with lamivudine 100 mg/day, to lamivudine 100 mg/day in adults with HbeAg-positive CHB and baseline ALT>1.3 x ULN. The primary efficacy measure was serum HBV DNA reduction over time, assayed by PCR. Key secondary endpoints included serum ALT normalization, HBeAg response, and safety.
104 patients were enrolled. At week 52, mdian reductions in serum HBV DNA, in log10 copies/ml, for the 5 treatment groups were: 4.66 for lamivudine, 6.43 for LdT 400 mg/day, 6.09 for LdT 600 mg/day, 6.40 for LdT 400 mg/day + lamivudine, and 6.05 for LdT 600 mg/day + lamivudine. All study treatments were well tolerated. Key efficacy results at week 52 for comparisons of treatment type (Lam vs LdT vs Combination) are as follows:
Lamivudine LdT LdT+Lam
Mean HBV DNA 4.57 6.09* 5.99*
HBV DNA-neg by PCR 6/19 (32%) 28/44 (61%)* 20/41 (49%)
ALT Normalization 12/19 (63%) 36/42 (86%)* 31/40 (78%)
HBeAg loss 5/18 (28%) 14/42 (33%) 7/41 (17%)
*p<0.05 vs lamivudine

In exploratory analyses, patient response data were combined, regardless of treatment group, to investigate the possible relationship of early viral suppression to efficacy outcomes. For all efficacy parameters, responses at week 52 were best in patients with the most profound antiviral response at week 24:
Responses at Week 52 (% of Patients)
Serum HBV DNALevel at Week 24 (log10 copies/ml) HBeAg Response HBV DNA-neg by PCR ALT Normalization Viral Breakthrough
Below QL* 43% 100% 90% 0%
QL - 103 35% 62% 88% 0%
103 – 104 10% 23% 71% 19%
>104 7% 7% 56% 26%

The authors concluded that after 1 year of treatment, antiviral efficacy and ALT normalization were significantly greater for LdT compared to lamivudine. Combination with lamivudine appeared to add no benefit to LdT monotherapy. Exploratory analyses suggest that maximal early viral suppression is associated with the highest rates of efficacy responses and the lowest breakthrough rates at week 52.
Note from Jules Levin: very few studies have yet been conducted to explore combination HBV therapy. Since a number of therapy options will soon be available, studies will have to be designed to explore combination therapy. The few studies so far conducted don’t show much benefit to combination therapy from an antiviral effect. But combination therapy may reduce the development of resistance to HBV drugs, as found in study of adefovir+lamivudine. This may have important implications.