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FTC for HBV
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"A Double-Blind, Placebo-Controlled Trial of Emtricitabine (FTC) Administerd Once-Daily for Treatment of Chroniv=c Hepatitis B (HBV) Infection"
Reported By Jules Levin
BRIEF SUMMARY: FTC 200 mg once daily improved histologic inflammation & fibrosis & had potent antiviral activity in both HBeAg positive (-4.50 log copies/ml) & negative patients (-2.50 log copies/ml) after 48 weeks therapy. Treatment emergent resistance mutations associated with FTC occurred in 13% of patients. FTC safety & tolerability were similar with placebo, however significantly more ALT & AST elevations were observed in the PLB group on treatment. These results support additional evaluation of FTC for treatment of chronic HBV.
Mitch Shiffman reported this study data at AASLD (Oct 2004). FTC is approved for treatment of HIV & being evaluated for treatment of chronic HBV. FTC is a potent inhibitor of HBV DNA polymerase in vitro (EC50=0.01 to 0.16 uM). Based on results from phase I/II clinical trials in patients with CHB, 200 mg FTC was chosen as the optimal dose to use in phase III HBV studies. A phase III randomized, double-blind placebo-controlled trial in patients with chronic HBV was conducted.
FTCB 301 randomized patients 2:1 to FTC 200 mg (n=167) or placebo (n=81) for 48 weeks therapy, whereupon patients were rolled over into FTCB 204. The primary endpoints were histologic response & tolerability.
BASELINE CHARACTERISTICS
Patients in the two arms were similar: 70% men; 40 yrs median age; 60% Asian; 38% Caucasian; 62% HBeAg positive.
BASELINE DISEASE CHARACTERISTICS
Median ALT (IU/L): 81 for FTC; 92 plac.
Median serum HBV DNA (log copies/ml): 7.7 FTC; 7.4 plac.
Median Knodell Necroinflammatory Score: 9 FTC; 9 plac.
Median Knodell Fibrosis Score: 3 FTC; 3 plac.
Cirrhosis: 12% FTC; 13% plac.
PATIENT DISPOSITION
90% of patients in both arms completed 48 weeks with end of study biopsy. Only 8 in FTC & 6 in PLB arms discontinued prior to week 48. 5 in FTC & 2 in PLB discontinued due to adverse event. 8 in FTC & 2 in PLB did not complete final biopsy.
RESULTS
HISTOLOGIC RESPONSE at WEEK 48 (ITT)
9% missing 48-week biopsy. Defined as 2-point improvement in necroinflammatory Knodell score. Improved fibrosis defined as a 1 point improved Knodell score.
62% taking FTC vs 25% receiving placebo had improvement (p<0.0001)
29% taking FTC vs 66% receiving placebo showed no improvement
Results were similar regardless if patients were HBeAg positive or negative.
KNODELL NECROINFLAMMATORY & FIBROSIS RESPONSE (ITT)
Inflammation improved for 66% taking FTC vs 28% taking placebo (p<0.001).
FTC: 19% no change; 6% worsening
PLB: 44% no change; 19% worsening
Fibrosis improved for 21% taking FTC vs 7% for placebo (p=0.006).
FTC: 63% no change; 7% worsening
PLB: 74% no change; 10% worsening
9% missing 48 week biopsy.
HBV DNA RESPONSE at WEEK 48: proportion of patients with serum HBV DNA < LOD (ITT missing=failure)
Digene Hybrid Capture II, LLQ 4,700 copies/ml
80% taking FTC & HBeAg negative
40% taking FTC & HBeAG+
5% placebo
HBV DNA declined for HBeAg+ from about 8 log at baseline to 3.75 log at week 48, about 4.5 log decline. For HBeAg- patients decline from baseline was from about 6.25 log to 3.75 log, about 2.50 log decline.
BIOCHEMICAL RESPONSE:
ALT declined from about 80 at baseline to about 30 for both HBeAg positive & negative taking FTC. For placebo patients ALT declined from 90 to 70.
About 60% of all patients achieved ALT normalization regardless of being HBeAg positive or negative.
SEROCONVERSION
There was no difference in the proportion of HBeAg positive patients that seroconverted to anti-HBe (12% FTC & 12% PLB).
One patient lost HBsAg & seroconverted to anti-HBs during the 6-month treatment-free followup period.
RESISTANCE
There were 20 patients (13%) with YMDD mutation at week 48:
rtM204V/I -- 1% (n=1)
rtM204V/I + rtL108M -- 11% (n=17)
rtM204V/I + rtL108M + rtV173L -- 1% (n=2)
SAFETY: no difference between FTC & PLB
Grade ¾ AE: 8-9% in both arms
SAE: 8-9& in both arms
Death: 0%
Disct due to AEs: 2-3%
GRADE ¾ LAB ABNORMALITIES
At least 1 G3/4 lab: 19% FTC, 41% PLB
ALT: 7% FTC, 26% PLB
CPK: 5% FTC, 6% PLB
Amylase: 2% FTC, 2% PLB
Glucose: 2% FTC, 6% PLB
AST: 2% FTC, 12% PLB
Lipase: 1% FTC, 0% PLB
Prothrombin time: 0% FTC, 2% PLB
POST-TREATMENT EXACERBATION of HEPATITIS
Defined as ALT or AST >=20 x ULN or >=10 x above the lowest on-study value.
Median time to onset=10 weeks.
Of the 23% with post treatment exacerbation of hepatitis, one patient with bridging fibrosis at study entry developed hepatic failure & underwent orthotopic liver transplantation.
Patients should be closely monitored after discontinuing FTC for risk of exacerbation.
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