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Hepatitis
Figure 1: Proportion of Patients with Hepatitis B Virus Recurrence Table 1: Demographic and Baseline Characteristics of
Study Population
Proportion of patients (%), 95% CI
Characteristic HBIG Historical Control Total
100
85.7
(n=21) (n=14) (n=28)
90
Gender, n (%)
80
Male 17 (81) 13 (93) 30 (86)
Female 4 (19) 1 (7) 5 (14)
70
Race/ethnicity, n (%)
60
Asian 0 7 (50) 7 (20)
50 Caucasian 20 (95) 7 (50) 27 (77)
40
Hispanic 1 (5) 0 1 (3)
Age (years)
30
Mean (standard deviation) 47.6 (9.75) 50.2 (8.91) 48.6 (9.38)
20
Range 31–66 37–68 31–68
5.3
10
MELD score, n (%)
≤9 0 2 (14) 2 (6)
0
HBIG Historical control
10–19 16 (76) 8 (57) 24 (69)
(n=19) (n=14)
20–29 2 (10) 4 (29) 6 (17)
30–39 1 (5) 0 1 (3)
CI = confidence interval; HBIG = hepatitis B immunoglobulin.
≥40 0 0 0
Child-Pugh-Turcotte
When the definition of HBV recurrence was expanded to include the
score, n (%)
development of HBeAg-positivity, an additional patient in the active treatment
5–6 1 (5) 3 (21) 4 (11)
group was determined to have experienced recurrence. Despite inclusion of
7–9 10 (48) 3 (21) 13 (37)
this HBeAg-positive patient in the HBV-recurrence rate (two of 20 patients
10–15 7 (33) 8 (57) 15 (43)
(10.0%); 95% CI 1.2–31.7), differences between the active treatment and Transplant type, n (%)
historical control groups remained statistically significant (p<0.001). Historical
Cadaveric 5 (24) 14 (100) 19 (56)
controls were not consistently tested for HBeAg after transplantation. The
Living 15 (71) 0 15 (44)
seemingly paradoxical finding of HBsAg negativity and HBeAg positivity in one
HBIG = hepatitis B immune globulin, MELD = Model End Stage Liver Disease.
patient was attributed to five indeterminate HBsAg results obtained
throughout the study, three of which corresponded to episodes of severe control group (42.9%; 95% CI 17.7–71.1; p=0.0118; see Figure 3). The
illness. This patient died on day 266 and had an indeterminate HBsAg result median time to death for the control group survivors was 339 days. Causes
and a positive HBeAg finding nine days before death. of death were severe sepsis (one patient in active treatment group), hepatic
failure (four controls), recurrent hepatitis B, respiratory insufficiency, graft
Patients in the active treatment group were tested for anti-HBs serum loss, or duodenal bleeding (one control patient each).
concentrations as a measure of dosing adequacy. Trough anti-HBs levels
less than 500IU/l were considered subtherapeutic. All patients in the Serum aminotranferase activity was measured as a marker of hepatic
active treatment group achieved therapeutic levels within the first few inflammation related to HBV re-infection. The two patients who became
days of treatment. Trough concentrations fell below target levels during HBsAg- or HBeAg-positive had abnormal serum aminotransferase levels that
maintenance phase II in two patients, coinciding with positive HBsAg corresponded with the timing of their positive serology results. It is of note
results in one patient and positive HBeAg results in another. Both patients that the HBeAg-positive patient experienced multi-organ failure. Clinically
had anti-HBs levels <10IU/l at baseline and day 0; the first patient had a significant deterioration in liver tests for the other patients in the active
pre-dose anti-HBs level of 136IU/l on day 364, and the other a pre-dose treatment group occurred at day seven or during maintenance phase I in
anti-HBs level of 145IU/l at day 252. During the first week, the mean conjunction with adverse events, including acute rejection.
trough anti-HBs levels for these patients were 1,337IU/l on day one and
23,003IU/l on day seven. During the maintenance phase I, the mean Safety
trough anti-HBs levels for these patients decreased from 9,277IU/l (day A total of 177 adverse events were reported by the first 14 patients treated
14) to 3,358IU/l (day 84). with HBIG; 13 of these events were classified as serious. The most common
adverse events were headache (9%), diarrhea (8%), and hypertension (7%).
In the secondary efficacy end-point analysis, time to recurrence of HBV Only two events were judged by the investigators to be related to HBIG
infection was defined as the first detectable serum HBsAg finding after LT. administration. These two events, tremor and hypotension, occurred in two
The median time to re-infection in the 12 historical control patients who separate patients during the first week of the study. In each case the adverse
became HBsAg-positive was 88 days post-LT (95% CI 47–125; see Figure 2). event resolved within 24 hours, and did not recur with the subsequent
Only one patient in the active treatment group became HBsAg-positive (day doses of HBIG. The infusion rate in the patient with tremor was reduced
365) and another became HBeAg-positive (day 257). A total of 19 of 20 from 45 minutes to two hours for 10 days, after which the infusion rate was
patients in the active treatment group survived for at least one year after LT returned to 45 minutes with no untoward effects. One patient discontinued
(95.0%; 95% CI 75.1–99.9) compared with six patients in the historical the study due to an adverse event (serious myocardial reperfusion injury),
44 US GASTROENTEROLOGY REVIEW 2007
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