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Chapter 4.1
180
Table 1. Baseline characteristics
Entecavir 0.05 mg Entecavir 0.1 mg Entecavir 0.5 mg Entecavir 1.0 mg
(n = 3)
(n = 3)
(n = 2)
(n = 2)
Sex (M:F) 1:2 2:1 1:1 2:0
Age (years, range)
Race
23 (20–63) 39 (29–51) 38 (18–58) 27 (19–35)
Asian 0 2 0 1
Caucasian 1 1 1 1
Other 2 0 1 0
Previous
lamivudine therapy
3 3 0 1
HBeAg positivity 3 3 2 2
HBV DNA (geq/ml)
(median, range)
3.11x108 –5.35x109 4.83x108 –1.52x109 1.68x109 –1.5x1010 5.52x107 –3.34x109 ALTxULN
(median, range)
1 (1–1.5) 1.2 (1–3.4) 1.6 (1–2.2) 1.3 (1–1.5)
YVDD, respectively). All patients were positive for HBeAg at the start of therapy. Median
baseline HBV DNA was 1.68 x 109 geq/ml (range 5.52 x 107 –1.50 x 10 10 geq/ml), and
median elevation of ALT at baseline was 1.1 x the upper limit of normal (ULN) (range
1–3.5). Viral decay was determined during 28 days of entecavir therapy (Figure 1). The
median effectiveness of blocking viral replication in all ten patients on entecavir therapy
was 96% (range 87–98%). Turn-over of free virus was 16 h (median; range 12–29 h, n =
10), and turn-over of infected hepatocytes was estimated to be 10.7 days (range 5.2–31.8
days, n = 9). For calculation of the viral decline during the second phase, patient 10 was
excluded. This patient discontinued medication after 1 week due to a serious adverse
event (Table 2). Entecavir was still capable of blocking viral replication in both patients
with detectable lamivudine-induced mutant virus (effectiveness in blocking viral production
of 87 and 98%, respectively).
Rebound of viral replication was followed until 6 months after withdrawal of therapy (n =
9, excluding patient 10) (Table 2, Figure 1). For mathematical description of return of viral
concentration, the inverse of the bi-phasic model for viral decay describes the observed
patient data accurately. The doubling time was 129 h (median; range 62–247 h) and the
slope of the second phase of the rebound in viral concentration approaches zero in all
patients (median 0.0016, range 20.051 to 10.03). The change from the fi rst to the second
phase of viral return was calculated to be at a median of 30 days (range 12–109 days). No
relation between viral load at the moment of withdrawal of entecavir and the fi rst and
second phase of viral rebound with the dose of entecavir could be found. However, the
three patients in the higher dose groups showed a more gradual return of viral replication
to baseline levels than did the six patients in the lower dose groups (p = 0.024).