Patient disposition and baseline characteristics.
A total of 163 patients were randomized to either combination treatment with FTC+CLV (n = 82) or monotherapy with FTC (n = 81) and commenced treatment. Overall, 157 patients (96%) completed the study (80 in the FTC+CLV group and 77 in the FTC group), and all patients finished the 24-week treatment phase, except for one patient in the FTC arm who was lost to follow-up (Fig. ). During the 24-week treatment-free follow-up phase, three patients discontinued to initiate commercial therapy to avoid the potential risk of posttreatment exacerbation of hepatitis B in the setting of advanced hepatic fibrosis (two patients in the FTC+CLV group and one patient in the FTC group), and two patients, both in the FTC arm, discontinued due to an episode of posttreatment exacerbation of HBV.
CONSORT diagram for study FTCB-204.
Baseline demographic and disease characteristics are summarized in Table . The treatment arms were well balanced with respect to all parameters, with no statistically significant differences between arms. The median baseline serum HBV DNA level was 6 log10 copies/ml, affording a median measurable change from baseline to the limit of detection of the Digene HBV Hybrid Capture II assay of 2.3 log10 copies/ml. Only three patients had mutations associated with resistance to FTC at baseline (two patients in the FTC+CLV group and one patient in the FTC group).
Baseline demographic and HBV disease characteristics
For the intent-to-treat population, at the end of 24 weeks of treatment, no statistically significant differences between the two treatment arms were observed (Table ). The proportion of patients with serum HBV DNA levels of <4,700 copies/ml was high in both arms: 61/82 (74%) in the FTC+CLV arm and 53/81 (65%) in the FTC monotherapy arm. Using an experimental RT-PCR assay, the proportion of patients with HBV DNA levels of <250 copies/ml was somewhat lower: 46/82 (56%) in the FTC+CLV arm and 37/81 (46%) in the FTC arm (P value was not significant). This lack of a significant difference was also observed in the naïve subgroup analysis and the HBeAg-positive and HBeAg-negative subgroups. Across both assays, the median decrease in serum HBV DNA levels at the end of treatment ranged from 1.8 to 2.3 log10 copies/ml for the FTC+CLV arm and 1.4 to 2.0 log10 copies/ml for the FTC monotherapy arm.
Virologic and biochemical response
There was prolonged antiviral activity through 24 weeks of treatment-free follow-up (48 weeks of study) in the FTC+CLV arm, resulting in 40% of patients versus 23% (FTC) with serum HBV DNA levels of <4,700 copies/ml (P = 0.025) (Fig. and ) and a mean (median) change from baseline of −1.25 (−0.82) log10 copies/ml versus −0.33 (−0.08) log10 copies/ml (P < 0.001). A sustained virologic response, HBV DNA levels of <4,700 copies/ml at week 24 and <105 copies/ml at week 48, was observed in a significantly greater proportion of patients in the FTC+CLV arm than in the FTC monotherapy arm, with 56% and 41%, respectively (P = 0.027) (Table ). The composite endpoint of undetectable serum HBV DNA and normal ALT levels also significantly favored the FTC+CLV arm, with 30% versus 14%, respectively (P = 0.007). Six months after the end of treatment, serum ALT levels were significantly lower (P < 0.001), and the proportion of patients with normal ALT levels was significantly higher (63% versus 42%, respectively) among patients in the FTC+CLV arm (P = 0.002) (Fig. and ).
(a) Proportion of patients with HBV DNA levels of <4,700 copies/ml. (b) Proportion of patients with normal ALT levels.
(a) Mean serum HBV DNA levels (Digene assay) over time (±standard errors). (b) Mean serum ALT levels over time (±standard errors).
There was no significant difference in serologic responses between treatment arms. Among 85 HBeAg-positive patients, 44 in the FTC+CLV arm and 41 in the FTC arm, a loss of HBeAg was observed at week 24 in seven and four patients, respectively, with seroconversion in all but one patient in each treatment arm (14% for the FTC+CLV group and 7% for the FTC group). After 24 weeks of treatment-free follow-up, 8 and 10 patients had a loss of HBeAg in the combination and monotherapy arms, respectively, with seroconversion in 7 (16%) and 10 (24%) patients, respectively.
Mutations associated with FTC resistance, rtM204I/V with or without rtL180M and rtV173L, were identified in sera from 14 patients at week 24. Thus, the 24-week incidence of viremia with FTC resistance mutations not found at baseline was 14/162 (9%) overall and was similar in both treatment arms, occurring in six patients (7%) in the FTC+CLV arm and in eight patients (10%) in the FTC arm. With the exception of one patient in the combination arm who was treatment naïve, all patients with treatment-emergent mutations had prior exposure to FTC for 1 year.
At study FTCB-204 baseline, three patients had resistance mutations (two patients in the FTC+CLV arm and one patient in the FTC arm), and all mutations were L180M plus M204V. After 24 weeks of treatment, neither patient in the FTC+CLV arm responded (serum HBV DNA levels declined 0.5 to 0.6 log10 copies/ml; absolute value, >8 log10 copies/ml). The single patient in the FTC arm experienced a decline in the serum HBV DNA level of 3.53 log10 copies/ml, from 7.2 log10 copies/ml to below the LOD (<4,700 copies/ml). Patients with treatment-emergent mutations identified at week 24 had a median decrease in serum HBV DNA levels of 0.84 log10 copies/ml (FTC+CLV) and 0.51 log10 copies/ml (FTC), and none were below the LOD.
During the treatment period, the incidence of AEs was similar between FTC+CLV and FTC arms, and the most common AEs were headache (10% and 12%, respectively), influenza (9% in both arms), upper respiratory tract infection (9% and 7%, respectively), fatigue (9% and 4%, respectively), upper abdominal pain (7% and 5%, respectively), nausea (6% and 5%, respectively), arthralgia (6% and 4%, respectively), and pharyngolaryngeal pain (6% and 5%, respectively). No patient discontinued treatment due to an AE. A total of nine patients had a SAE during the treatment phase, three (4%) in the FTC+CLV arm and six (7%) in the FTC arm, all of which resolved without treatment interruption. In the FTC+CLV arm, SAEs included gonococcal arthritis (n = 1) and exacerbation of hepatitis B (n = 2), with one case commencing at baseline, initially worsening, and then improving on treatment. In the FTC arm, SAEs included seizure with fever (n = 1), chest pain of musculoskeletal origin (n = 1), fractured vertebrae (n = 1), nonulcer dyspepsia (n = 1), hyperglycemia associated with diabetes mellitus (n = 1), and elevated ALT levels (n = 1). The incidences of grade 3 or 4 laboratory abnormalities were comparable between arms (Table ).
Incidence of grade 3 or 4 laboratory abnormalities during treatment and treatment-free follow-up
During the treatment-free follow-up period, 32 patients in the FTC+CLV arm developed AEs (39%), compared to 41 (51%) in the FTC arm. A total of six patients had a SAE, five patients in the FTC monotherapy arm and one patient in the combination arm, and all were posttreatment exacerbations of hepatitis B. The incidence of laboratory abnormalities of at least grade 3 severity was significantly higher in the FTC (22 [28%]) arm than in the combination (9 [11%]) arm during treatment-free follow-up (P = 0.009), with significantly fewer elevations in ALT, AST, and amylase levels in the FTC+CLV arm (Table ). Higher frequencies of elevations of aminotransferase levels in the FTC arm after the end of treatment corresponded to more frequent posttreatment exacerbations of hepatitis B, which occurred with a higher incidence in the FTC arm (n = 12; 15%) than in the FTC+CLV arm (n = 2; 2%) (P = 0.005) within the confines of the 24-week follow-up period. One patient (FTC arm) developed clinical hepatic decompensation with ascites and coagulopathy in the setting of preexisting cirrhosis that responded to diuretics and lamivudine treatment; all other cases resolved without complications.