| Comparison of Adefovir Dipivoxil Plus Emtricitabine Combination Therapy vs Adefovir Alone in HBeAg (+) Chronic Hepatitis B
Improvement of treatment response in chronic hepatitis B requires new antiviral regimens and better understanding of viral and host factors associated with sustained control of HBV replication.
The objectives of the current study were (1)To compare the efficacy of a new combination therapy with ADV plus FTC versus ADV alone; (2) To examine early HBV kinetics and virus-specific T-cell reactivity to gain understanding of the mechanisms of successful HBV control.
Thirty treatment na飗e, HBeAg (+) patients (HBV genotype B - 9; genotype C - 21) with ALT> 1.3xULN were randomized to receive ADV 10 mg + FTC 200 mg qd (Group A, n=14) or ADV 10 mg + placebo qd (Group B, n=16) for 48 weeks.
Blood samples were collected at Day 0, 1, 3, 5, 7, 9, 11, 14; Week 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48. HBV DNA was quantitated by Cobas amplicor and by molecular beacons assay (range 3x102 to 109 copies/mL).
Mathematical modeling was employed to determine the patterns of viral kinetics (Beacon). HBV-specific CD4 and CD8+ T-cells were enumerated by IFNγ ELISpot assays and tetramer staining for CD8+ T-cells.
Results
The combination (ADV+FTC) therapy showed greater antiviral activity compared to ADV alone: median log10 reduction of viremia at treatment week 28 (TW28) was 5.04 vs 3.2 (p=0.04); at TW48 5.3 vs. -3.4 (p=0.13), respectively.
HBeAg seroconversion occurred in 3 patients - 2 in Group A and 1 in Group B.
Modeling of early HBV kinetics (baseline to TW12) revealed a 2-phase decay in most patients with the 1st phase t1/2 from 0.5 day to 3.3 days (mean: 1.4 ?0.7 day) and the 2nd phase t1/2 from 3.6 to 112 days (mean: 24.4 ?22.6 days).
The infected cell loss rate (δ) was significantly higher in the combination arm (δ =0.07 day-1) vs monotherapy ( (δ =0.04 day-1 p=0.04).
Early HBV kinetics identified two subsets - patients who cleared the virus (<300 copies/mL) by TW12 (fast responders) and those who did not (slow responders). Fast responders had a larger δ (0.07 day-1) than slow responders (δ =0.03 day-1, p=0.006).
Patients on combination treatment were more likely to be fast responders than those on monotherapy (11/14 vs 5/16,p=0.01).
A fast response was associated with enhanced T-cell reactivity (for T-cell response to HBeAg p=0.05; and to HBsAg p=0.03).
All 3 cases with HBeAg seroconversion were fast responders.
No mutations or safety concerns were observed.
Conclusions
The authors conclude:
ADV plus FTC combination therapy shows faster and greater HBV suppression in comparison with ADV alone; This faster suppression is reflected in the second phase viral kinetic parameters; and Early HBV suppression during therapy is associated with enhanced antiviral immunity.
11/01/04 Reference
G K K Lau and others. ANDOMIZED, DOUBLE-BLIND STUDY COMPARING ADEFOVIR DIPIVOXIL (ADV) PLUS EMTRICITABINE (FTC) COMBINATION THERAPY VERSUS ADV ALONE IN HBEAG (+) CHRONIC HEPATITIS B: EFFICACY AND MECHANISMS OF TREATMENT RESPONSE. Abstract 245 (oral) and Abstract 1155 (poster). 55th AASLD. October 29-November 2, 2004. Boston, MA. | 
发表于 2004-11-3 00:38
