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发表于 2003-3-16 12:27
| Experimental Drug Entecavir Is Highly Effective in Reducing Viral Load and ALT levels in HBV Patients Failing Epivir-HBV (lamivudine)
There are currently 3 FDA-approved agents for the treatment of chronic hepatitis B: Epivir-HBV (GlaxoSmithKline), Intron A (Schering-Plough) and Hepsera (Gilead Sciences). A number of new agents are in development for the treatment of hepatitis B.
Entecavir is a promising new experimental nucleoside analog drug from Bristol-Myers Squibb that has entered Phase III clinical trials for efficacy, the final stage of testing prior to FDA evaluation for approval as a prescription drug.
The present study evaluated the effect of entecavir in patients with chronic HBV who had developed resistance to Epivir-HBV. In patients with chronic HBV treated with lamivudine (LVD), up to 24% develop resistance within 1 year, and up to 38% develop resistance within 2 years of therapy.
Entecavir (ETV), a nucleoside analogue with potent, selective anti-HBV activity, has been shown to be superior to lamivudine in reducing HBV DNA and ALT levels in both treatment naive and LVD failure patients after 24 weeks of treatment.
Patients with serum HBV DNA >=10 MEq/mL (Quantiplex bDNA assay) after at least 24 weeks of LVD therapy or with evidence of YMDD mutation and serum ALT <=10 x upper limit of normal (ULN), were randomized 1:1:1:1 to receive ETV 0.1, 0.5, or 1.0 mg, or to continue LVD 100 mg daily for up to 24 weeks in nonresponders, and up to 52 weeks in complete responders.
HBV DNA was recovered from serum samples at baseline, 24 wk and 48 wk by PCR and the polymerase genome encoding amino acids 434 - 680 was sequenced for substitutions conferring viral resistance. Results from 48 weeks of blinded therapy are discussed below.
181 patients started study drug. Treatment groups were similar at baseline for age, weight, race (33% Asian), HBeAg status (67% positive), mean HBV DNA (8.1 log10 copies/mL by PCR assay), median serum ALT (71 u/L) and presence of YMDD mutation (87%). HBV DNA levels by PCR continued to decline on all ETV doses between weeks 24 and 48.
The mean log10 decrease in HBV DNA by PCR from baseline for all 3 ETV doses was superior to LVD at 48 weeks: 2.78 for 0.1 mg, 4.46 for 0.5 mg, and 5.11 for 1.0 mg ETV, compared to 1.41 for LVD (p=0.01 for 0.1 mg vs. LVD; P <0.001 for 0.5 and 1 mg vs. LVD). The percent of patients with undetectable DNA by PCR at week 48 of ETV was 4% for 0.1 mg and 26% each for 0.5 mg, and 1.0 mg, compared with 4% for LVD (p=.005 for both 0.5 and 1.0 mg).
No patient receiving ETV 1.0 mg had breakthrough viremia over 48 weeks, and no novel mutations conferring resistance to ETV were identified during treatment at any ETV dosage. The percent of patients with abnormal ALT at baseline who had normal ALT at week 48 of ETV was 43% for 0.1 mg, 59% for 0.5 mg, and 68% for 1.0 mg, compared with 6% for LVD (p <0.001 for each ETV group vs. LVD).
The incidences of clinical adverse events, SAEs and discontinuations due to AEs were comparable among the ETV treatment arms and between the ETV and LVD arms. The most frequently reported AEs across all groups were headache, rhinitis, fatigue, and abdominal pain.
Conclusion: In patients who previously failed therapy with LVD, ETV given for 48 weeks was safe and highly effective in reducing viral load and in normalizing serum ALT. A greater reduction in DNA (by PCR) was achieved with ETV 1.0 mg than with lower doses, and DNA reduction for all ETV doses was greater at 48 weeks than 24 weeks.
No virologic breakthroughs occurred at the 1.0 mg dose of ETV. Results from this study support the use of ETV at a dose of 1.0 mg in clinical trials involving patients who had failed treatment with LVD.
01/24/03 |
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