Virologic Response
On intention-to-treat analysis, 30 of 50 patients (60%) in the combination treatment group and 14 of 50 patients (28%) in the lamivudine monotherapy group showed virologic response at the end of treatment (absolute difference, 32 percentage points [95% CI, 14 to 50 percentage points]; P = 0.001). After adjustment for baseline ALT levels, the absolute difference in predicted probabilities of combination treatment and lamivudine monotherapy for end-of-treatment response was 31 percentage points (CI, 10 to 49 percentage points; P = 0.003). All patients who had lost HBeAg developed antibodies to HBeAg. One patient receiving combination treatment had lost HBsAg by the end of treatment. No patient receiving lamivudine monotherapy became HBsAg-negative. Five patients receiving combination therapy and 2 patients receiving lamivudine monotherapy became HBV DNA--negative by polymerase chain reaction assay. Among patients with baseline ALT levels less than 5 times the upper limit of normal, the end-of-treatment virologic response of the combination treatment group was still statistically significantly higher than the response of the lamivudine monotherapy group (25 of 42 [60%] patients vs. 12 of 44 [27%] patients [absolute difference, 32 percentage points (CI, 12 to 52 percentage points)]).
At the end of treatment, the median reduction in HBV DNA of patients who completed combination treatment and lamivudine monotherapy was 3.89 log10 copies/mL (range, 1.59 to 6.35 log10 copies/mL) and 2.74 log10 copies/mL (range, --0.10 to 5.68 log10 copies/mL), respectively (median difference, 1.24 log10 copies/mL [CI, 0.78 to 1.66 log10 copies/mL]). Since the treatment duration in the combination treatment group was 8 weeks longer than the duration of treatment in the lamivudine monotherapy group, we also compared the changes in HBV DNA levels when patients in both groups finished 48 weeks of treatment. At 48 weeks, the reduction in HBV DNA level among patients receiving combination treatment and lamivudine monotherapy was 4.65 log10 copies/mL (range, --0.84 to 7.83 log10 copies/mL) and 3.62 log10 copies/mL (range, 1.32 to 7.33 log10 copies/mL), respectively (median difference, 1.10 log10 copies/mL [CI, 0.55 to 1.65 log10 copies/mL]). Fifty percent of the patients receiving combination treatment and 28% of those receiving lamivudine monotherapy had virologic response at week 48 (absolute difference, 22 percentage points [CI, 3 to 41 percentage points]), although all HBeAg seroconversion in lamivudine monotherapy group occurred on or before week 40.
Nine patients in the combination treatment group had HBeAg seroconversion at week 8 before the commencement of lamivudine therapy. After 24 weeks of lamivudine treatment in both groups, 11 additional patients receiving combination treatment and 11 patients receiving lamivudine monotherapy had HBeAg seroconversion. More patients in the combination treatment group had HBeAg seroconversion in the last 28 weeks of extended lamivudine treatment (10 of 30 [33%] remaining patients) than in the lamivudine monotherapy group (3 of 39 [8%] remaining patients) (absolute difference, 25 percentage points [CI, 7 to 45 percentage points]). Among patients who developed HBeAg seroconversion during treatment, the median time for HBeAg seroconversion after commencement of treatment was 24 weeks (range, 8 to 60 weeks) in the combination treatment group and 24 weeks (range, 0 to 40 weeks) in the lamivudine monotherapy group (P = 0.13).
At 24 weeks after treatment, 18 patients (36%) in the combination treatment group and 7 patients (14%) in the lamivudine monotherapy group had sustained virologic response (absolute difference, 22 percentage points [CI, 6 to 38 percentage points]; P = 0.011). After adjustment for the baseline ALT levels, the absolute difference in predicted probabilities of combination treatment and lamivudine monotherapy for sustained virologic response was 22 percentage points (CI, 3 to 47 percentage points; P = 0.015). Among the subgroup of patients with baseline ALT levels less than 5 times the upper limit of normal, the predicted probability for sustained virologic response was still higher in the combination treatment group (15 of 42 patients [36% (CI, 21% to 50%)]) than in the lamivudine monotherapy group (6 of 44 patients [14% (CI, 4% to 24%)]) (absolute difference, 22 percentage points [CI, 4 to 40 percentage points]). Twelve of 30 (40%) patients who received combination treatment and 7 of 14 (50%) patients who received lamivudine monotherapy developed post-treatment viral relapse after an initial end-of-treatment response. Three patients receiving combination treatment and 2 patients receiving lamivudine treatment were negative for HBV DNA by polymerase chain reaction assay at 24 weeks after treatment.
Biochemical Response
At the end of treatment, 45 patients (90%) receiving combination treatment and 39 patients (78%) receiving lamivudine monotherapy had normalization of ALT levels (absolute difference, 12 percentage points [CI, --2 to 26 percentage points]). At 24 weeks after treatment, more patients receiving combination treatment had sustained ALT level normalization compared with those receiving lamivudine monotherapy (50% vs. 30% [absolute difference, 20 percentage points (CI, 1 to 39 percentage points)]). Among those with sustained virologic response, all except 1 patient who received combination treatment had sustained normalization of ALT levels (ALT level 1.1 times the upper limit of normal).
Histologic Response
Paired liver biopsy specimens were available in 40 patients receiving combination treatment and 44 patients receiving lamivudine monotherapy. Eight patients had insufficient liver tissue for accurate grading in 1 of the paired biopsy specimens (7 patients at baseline and 1 patient at week 52), 3 patients declined liver biopsy after treatment because of personal reasons, 4 patients withdrew prematurely from the study (1 patient also had insufficient liver tissue at baseline biopsy), and 2 post-treatment liver biopsies were cancelled because of the hospital outbreak of severe acute respiratory syndrome in March 2003. Among the 16 patients without evaluable paired liver biopsy specimens, 6 patients (4 receiving combination treatment and 2 receiving lamivudine monotherapy) had end-of-treatment virologic response and 2 patients (both receiving combination treatment) had sustained virologic response.
Twenty-four (60%) patients receiving combination treatment and 26 (59%) patients receiving lamivudine monotherapy had at least a 2-point increase in necroinflammatory score (absolute difference, 1 percentage point [CI, --20 to 22 percentage points]). Four (10%) patients receiving combination treatment and 4 (9%) receiving lamivudine monotherapy had at least a 2-point decrease in necroinflammatory score. Six (15%) and 4 (9%) patients receiving combination therapy and lamivudine monotherapy, respectively, had at least a 2-point increase in fibrosis scores (absolute difference, 6 percentage points [CI, --8 to 20 percentage points]), while 4 (10%) and 2 (5%) patients, respectively, had at least a 2-point decrease in fibrosis scores (absolute difference, 5 percentage points [CI, --6 to 17 percentage points]).
Drug-Resistant Mutants
At the end of treatment, a higher proportion of patients receiving lamivudine monotherapy developed a lamivudine-resistant mutant (19 of 48 [40%] patients) than did those receiving combination treatment (10 of 48 [21%] patients) (absolute difference, 19 percentage points [CI, 8 to 37 percentage points]). Among patients receiving monotherapy, 7 had a lamivudine-resistant mutant and 12 had both wide-type and lamivudine-resistant mutants. Among patients receiving combination therapy, 5 had a resistant mutant and 5 had mixed wide-type and resistant mutants. Patients who developed lamivudine resistance tended to have higher pretreatment HBV DNA (Table 2). A higher proportion of patients who developed lamivudine resistance (9 of 29 [31%] patients) had HBV DNA greater than 500 000 copies/mL at the end of treatment than those who did not develop lamivudine resistance (7 of 67 [10%] patients) (absolute difference, 21 percentage points [CI, 2 to 39 percentage points]). However, the development of lamivudine resistance did not seem to mitigate the virologic, biochemical, and histologic response.
Safety
Most adverse symptoms and events were transient and were related to the use of pegylated interferon-{alpha}2b. Four (8%) patients receiving combination treatment had serious adverse events. One patient developed bipolar disorder requiring antidepressant therapy (week 21), 1 developed pulmonary tuberculosis with right pleural effusion requiring antituberculosis treatment (week 11), 1 developed thyrotoxicosis requiring propyluracil treatment (week 17), and 1 developed severe local reaction at the injection sites (week 8) that resolved spontaneously. Pegylated interferon-{alpha}2b treatment was stopped in all 4 cases. Lamivudine treatment was continued in the first 3 cases until week 60, and we evaluated the treatment responses as per protocol. The fourth patient, who had received only 7 doses of pegylated interferon, withdrew from the study and was considered to have treatment failure. Five (10%) patients required reduction of dosage of pegylated interferon-{alpha}2b to 50 µg per week (if body weight > 65 kg) or 1.0 µg/kg per week (if body weight < 65 kg) as per protocol because of anemia (1 patient), neutropenia (3 patients), and/or thrombocytopenia (4 patients). One patient had pegylated interferon withheld for 2 doses at weeks 4 and 5 because of severe hepatitis flare-up (ALT level, 1762 U/L) and resumed at full dose at week 6 when ALT level decreased to a lower level (242 U/L). No patient who received lamivudine monotherapy developed serious adverse event during treatment, and no patient had dosage adjustment for lamivudine.
Five (10%) patients in the combination group and 11 (23%) patients in the lamivudine monotherapy group developed severe post-treatment relapse of chronic hepatitis B (absolute difference, --13 percentage points [CI, --27 to 2 percentage points]). Two patients in lamivudine monotherapy group had post-treatment relapse leading to elevation of serum bilirubin levels to 82 µmol/L (4.8 mg/dL) and 153 µmol/L (9.0 mg/dL), respectively. Lamivudine treatment was resumed, and all patients responded. No patient died or required liver transplantation.
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