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Entecavir Therapy for up to 96 Weeks in Patients With HBeAg-Positive Chronic Hepatitis B
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Gastroenterology Nov 2007
Presented in part at the 56th annual meeting of the American Association for the Study of Liver Diseases, November 11-15, 2005.
Robert G. Gish, Anna S. Lok, Ting-Tsung Chang, Robert A. de Man, Adrian Gadano, Jose Sollano#, Kwang-Hyub Han, You-Chen Chao, Shou-Dong Lee, Melissa Harris, Joanna Yang, Richard Colonno, Helena Brett-Smith
ABSTRACT
Background & Aims: Entecavir demonstrated superior benefit to lamivudine at 48 weeks in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). We evaluated continued entecavir and lamivudine treatment through 96 weeks.
Methods: 709 HBeAg-positive CHB patients were randomized to entecavir 0.5 mg (n = 354) or lamivudine 100 mg (n = 355) once daily. At week 52, protocol-defined virologic responders could continue blinded treatment for up to 96 weeks. Patients continuing in year 2 (entecavir, n = 243; lamivudine, n = 164) were assessed for serum hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT) normalization, HBeAg seroconversion, and safety. Cumulative confirmed proportions of all treated patients who achieved these responses were also analyzed.
Results: Among patients treated in year 2, 74% of entecavir-treated versus 37% of lamivudine-treated patients achieved HBV DNA <300 copies/mL by polymerase chain reaction (PCR), and 79% of entecavir-treated versus 68% of lamivudine-treated patients normalized ALT levels. Similar proportions of entecavir-treated and lamivudine-treated patients achieved HBeAg seroconversion (11% vs 12%, respectively). Higher proportions of entecavir-treated than lamivudine-treated patients achieved cumulative confirmed HBV DNA <300 copies/mL by PCR (80% vs 39%; P < .0001) and ALT normalization (87% vs 79%; P = .0056) through 96 weeks. Cumulative confirmed HBeAg seroconversion occurred in 31% of entecavir-treated versus 25% of lamivudine-treated patients (P = NS). Through 96 weeks, no patient experienced virologic breakthrough due to entecavir resistance. The safety profile was comparable in both groups.
Conclusions: Entecavir treatment through 96 weeks results in continued benefit for patients with HBeAg-positive CHB.
Results
Study Population
Of the 709 patients randomized and treated in the first year of the study (entecavir, 354; lamivudine, 355), 74 entecavir-treated patients (21%) and 67 lamivudine-treated patients (19%) achieved response at week 48, discontinued therapy after week 52, and were followed for up to 24 weeks off-treatment.22 Nineteen entecavir-treated patients (5%) and 94 lamivudine-treated patients (26%) had nonresponse at week 48 and were to discontinue therapy at week 52. A total of 247 entecavir-treated patients (70%) and 165 lamivudine-treated patients (46%) achieved virologic response at week 48 and were eligible to continue blinded therapy for a second year. Of these, 243 entecavir-treated and 164 lamivudine-treated patients continued to a second year of blinded dosing (Figure 1).
During the second year, fewer entecavir-treated (16) than lamivudine-treated patients (45) discontinued blinded therapy. Reasons for treatment discontinuation included lack of efficacy (entecavir, 3; lamivudine, 40), withdrawal of consent (entecavir, 7; lamivudine, 2), loss to follow-up (entecavir, 3; lamivudine, 1), noncompliance (entecavir, 1), pregnancy (entecavir, 2; lamivudine, 1), and adverse event (lamivudine, 1). The mean time on therapy was 80.8 weeks for entecavir (range, 0.1-134.4) and 67.7 weeks for lamivudine (range, 0.1-104.6 weeks), with 182 of 243 entecavir-treated patients (75%) and 86 of 164 lamivudine-treated patients (52%) remaining on therapy through week 96.
The 2 treatment groups were well balanced at baseline (pretreatment) for disease and demographic characteristics, as reported previously.22 Patients who continued in the second-year treatment cohort had a baseline mean HBV DNA level of 9.8 log10 copies/mL (1.2 X 109 IU/mL) and 9.4 log10 copies/mL (4.8 X 108 IU/mL) for entecavir and lamivudine, respectively. Most patients in the second-year treatment cohort demonstrated ALT levels >1X the ULN at baseline (entecavir, 95% [232/243]; lamivudine, 96% [157/164]).
Virologic Response
Figure 1 indicates cohorts assessed for efficacy end points. At week 48, 64% (156/243) of entecavir-treated and 40% (66/164) of lamivudine-treated patients had already achieved HBV DNA levels <300 copies/mL by PCR assay before continuing to a second year of therapy (Figure 2 and Table 1). At the end of the first year, 0% of entecavir-treated versus 10% of lamivudine-treated patients in the second-year treatment cohort demonstrated HBV DNA levels ≥105 copies/mL.
By the end of dosing during the second year, 74% (180/243) of entecavir-treated and 37% (60/164) of lamivudine-treated patients in this cohort achieved HBV DNA levels <300 copies/mL by PCR. End-of-dosing HBV DNA level was not available in 24 of 243 entecavir-treated patients and in 23 of 164 lamivudine-treated patients, and these patients were therefore considered treatment failures. Fewer entecavir-treated (2%; 6/243) than lamivudine-treated (26%; 43/164) patients demonstrated HBV DNA levels ≥105 copies/mL at the end of dosing during the second year (Figure 2). For all treated patients, the cumulative analysis showed that a higher proportion of entecavir-treated than lamivudine-treated patients achieved confirmed HBV DNA levels <300 copies/mL by PCR assay through 96 weeks of treatment (entecavir, 284/354 [80%]; lamivudine, 137/355 [39%]; P < .0001; Table 2).
Biochemical Response
In the second-year treatment cohort, 66% (161/243) of entecavir-treated and 71% (116/164) of lamivudine-treated patients had already achieved normalization of ALT levels (ALT level 1X the ULN) at week 48 (Table 1). By the end of dosing during the second year, the proportion of patients achieving normalization of ALT levels increased to 79% (193/243) for entecavir-treated patients and decreased to 68% (112/164) for lamivudine-treated patients. Through 96 weeks of therapy, for all treated patients, a higher cumulative proportion of entecavir-treated (87%) than lamivudine-treated (79%) patients achieved confirmed normalization of ALT levels (P = .0056; Table 2).
HBeAg and HBsAg Serologic Responses
As defined in the study protocol, none of the virologic responders had lost HBeAg at week 48. Twenty-six of 243 (11%) entecavir-treated and 20 of 164 (12%) lamivudine-treated patients who continued in the second year of therapy seroconverted to anti-HBe by the end of dosing. Among all treated patients through 96 weeks and 6 months of post-treatment follow-up, the proportions of patients who ever achieved a confirmed HBeAg seroconversion to anti-HBe were comparable in the 2 treatment groups (entecavir, 110/354 [31%]; lamivudine, 92/355 [26%]; P = NS; Table 2). Through 96 weeks of treatment and 6 months of post-treatment follow-up, 5% (n = 18) of entecavir-treated and 3% (n = 10) of lamivudine-treated patients achieved confirmed HBsAg loss, and 2% (entecavir, n = 6; lamivudine, n = 8) of patients in both treatment groups achieved seroconversion to antibody to hepatitis B surface antigen.
Protocol-Defined Patient Management Outcomes Through Year 2
During the second year of therapy, an additional 37 of 243 (15%) entecavir-treated and 26 of 164 (16%) lamivudine-treated patients achieved protocol-defined response (HBeAg loss and HBV DNA level <0.7 MEq/mL). Over the course of 2 years of treatment, a total of 111 of 354 patients (31%) on entecavir (74 at week 48, plus 37 during the second year) versus a total of 93 of 355 patients (26%) on lamivudine (67 at week 48, plus 26 during the second year) became responders (Figure 1). Fewer entecavir-treated (27/354 [8%]) than lamivudine-treated (147/355 [41%]) patients were nonresponders during this 96-week period.
Off-Treatment Results
At the end of year 1, 74 patients in the entecavir group and 67 in the lamivudine group met the protocol-defined management criteria of response (HBV DNA level <0.7 MEq/mL and HBeAg loss) and discontinued therapy. At week 48, 71 entecavir-treated patients had HBV DNA levels <300 copies/mL, 63 had normalization of ALT levels, and 70 achieved HBeAg seroconversion. These results were sustained in 37%, 79%, and 77%, respectively, at 24 weeks off-treatment (Table 3). At week 48, among lamivudine-treated patients with a protocol-defined response (HBV DNA level <0.7 MEq/mL and HBeAg loss) who discontinued therapy, 58 had HBV DNA levels <300 copies/mL, 59 had normalization of ALT levels, and 61 had achieved HBeAg seroconversion. By the end of follow-up, these responses were sustained in 34%, 64%, and 72%, respectively (Table 3).
Of the 243 and 164 patients treated in the second year, 37 patients in the entecavir group and 26 in the lamivudine group met the protocol-defined management criteria of response (HBV DNA level <0.7 MEq/mL and HBeAg loss) who discontinued therapy. The results for these patients at the end of follow-up can be seen in Table 3. During the second year of treatment (weeks 52-96), patients discontinued therapy once response was identified; thus, most of these individuals did not receive consolidation treatment.
Resistance and Virologic Breakthrough
Among all entecavir-treated patients (n = 354), 13 patients had virologic breakthrough during the 2 years of study observation.23 Sequencing and susceptibility testing for these 13 patients showed that 1 patient had lamivudine resistance substitutions and none had entecavir resistance substitutions. None of the patients with virologic breakthrough had decreased phenotypic susceptibility at the time of breakthrough. In addition to patients with virologic breakthrough, all paired samples available from patients with HBV DNA levels ≥300 copies/mL were sequenced, which resulted in the identification of 3 additional patients with lamivudine resistance substitutions, all detectable at baseline, and 1 patient with emerging lamivudine and entecavir substitutions; none of these 4 patients had virologic breakthrough through 96 weeks of therapy. In the 1 entecavir-resistant patient, lamivudine (M204V and L180M) and entecavir (S202G) and Y54H substitutions emerged at week 84 that were not detectable at baseline.23
Safety
Mean exposure to study therapy for all treated patients was 80.8 weeks (range, 0.1-134.4 weeks) for entecavir and 67.7 weeks (range, 0.1-104.6 weeks) for lamivudine. For all 709 patients treated with entecavir or lamivudine up to 96 weeks, the frequency of on-treatment adverse events was comparable (entecavir, 87%; lamivudine, 84%). Serious adverse events on-treatment occurred in 8% of patients in both treatment groups. On-treatment adverse events attributed to study therapy and reported for ≥5% of patients in either treatment group were fatigue (entecavir, 6%; lamivudine, 5%), increased ALT levels (entecavir, 4%; lamivudine, 7%), and headache (entecavir, 10%; lamivudine, 8%). Fewer discontinuations due to adverse events occurred among entecavir-treated (n = 1) than among lamivudine-treated (n = 9) patients.
Through 96 weeks, on-treatment ALT flares (ALT levels >2X baseline and >10X the ULN) were observed less frequently among entecavir-treated than among lamivudine-treated patients (entecavir, 3%; lamivudine, 7%). In the entecavir group, the majority (11/12) of ALT flares were associated with at least a 2-log10 reduction in HBV DNA by bDNA assay that was maintained for the duration of the treatment period and through the resolution of the flare. Eleven of 12 ALT flares in the entecavir group resolved within 1-7 weeks on continued treatment. The remaining patient discontinued entecavir at study week 4, and the ALT flare resolved 4 weeks later. No entecavir-treated patient experienced hepatic decompensation.
In the lamivudine group, approximately one half (11/23) of the on-treatment ALT flares were associated with increasing HBV DNA levels that preceded or coincided with the flare. The majority (8/11) of these flares persisted up to treatment discontinuation, consistent with treatment failure. One lamivudine-treated patient experienced an on-treatment ALT flare complicated by hepatic decompensation and subsequently died during follow-up. This case is described in more detail in the following text.
A total of 334 patients (entecavir, 183; lamivudine, 151) entered an off-treatment follow-up period. During off-treatment follow-up, the frequency of adverse events in each treatment group was comparable (entecavir, 50%; lamivudine, 56%). Serious adverse events off-treatment occurred with comparable frequency in the 2 treatment groups (entecavir, 5%; lamivudine, 7%). Fewer off-treatment ALT flares (ALT level >2X reference and >10X ULN, where the reference value was the lesser of the baseline and the end-of-dosing ALT values) occurred in entecavir-treated patients (entecavir, 2%; lamivudine, 9%). Most off-treatment ALT flares occurred in association with a return of serum HBV DNA levels toward baseline, and no off-treatment ALT flare was associated with hepatic decompensation.
Six deaths (entecavir, 2; lamivudine, 4) were reported during the study; none were attributed to study medication. Two deaths occurred on-treatment, both in the lamivudine group: one patient died of sudden dyspnea at week 27, and one patient died at week 37 of an undetermined cause. Four deaths occurred during the follow-up period (lamivudine: metastatic malignancy [1], hepatorenal syndrome following an on-treatment ALT flare [1]; entecavir: HCC, diagnosed at study week 51 [1]; squamous cell carcinoma of the esophagus [1]).
Discussion
The current study provided controlled data documenting the efficacy of entecavir compared with lamivudine, when each was continued for up to 96 weeks. Within the second-year treatment cohort (virologic responders at week 48), response rates to entecavir continued to improve during extended treatment. The proportion of patients achieving an undetectable HBV DNA level (<300 copies/mL) increased from 64% at week 48 to 74% at the end of dosing. This 10% increment in virologic response was accompanied by a 13% incremental increase in normalization of ALT levels (79% at end of dosing) and by an additional 11% of patients experiencing HBeAg seroconversion. Among patients randomized to lamivudine, the patterns of response with extended therapy were less favorable, with only 37% reaching an undetectable level of HBV DNA and 26% of patients demonstrating HBV DNA levels ≥105 copies/mL at the end of dosing.
The findings in the second-year cohort confirmed that extended treatment with entecavir provided continued viral suppression and normalization of ALT levels through 96 weeks. Continued monitoring for resistance in year 2 among those with detectable HBV DNA levels or virologic breakthrough confirmed that entecavir resistance through 96 weeks is rare.
Over this 2-year experience, entecavir maintained a safety and tolerability profile that was comparable to that for lamivudine. Fewer ALT flares were observed in entecavir-treated patients both on- and off-treatment. Long-term surveillance of entecavir safety continues.
Current treatment strategies for patients with HBeAg-positive CHB continue to evolve. The design of this 2-year study is of interest because it followed the existing pattern of clinical practice in which individual patients discontinue treatment after they have attained predetermined clinical end points. However, this aspect of the design also presents certain challenges. First, the specified response criteria that led to treatment discontinuation were selected more than 5 years ago and no longer reflect current practice. During the conduct of this study, the bDNA assay was replaced by PCR assays. Also, the use of HBeAg loss rather than seroconversion and the absence of a period of consolidation treatment before discontinuation were less stringent criteria than in current practice. Therefore, it is possible that the off-treatment results in this study may represent an underestimate of the durability of HBeAg seroconversion that would be observed if current criteria had been used. Still, 77% of entecavir-treated patients who achieved HBeAg seroconversion at week 52 sustained this response after 24 weeks off-treatment follow-up. These results are consistent with those reported for other treatment strategies.25, 26
The study was designed to evaluate the possibility of discontinuing treatment after meeting prespecified patient management criteria at week 52; therefore, the protocol specified that responders and nonresponders should discontinue treatment at or after week 52. As a result, another challenge when interpreting the second-year results derives from the absence of a cross-sectional presentation of response rates at week 96. After week 52, it is not possible to provide an assessment in which all patients who originally started treatment are accounted for at a single time point under uniform treatment conditions. Therefore, the results from this study cannot be compared directly with other studies that evaluate continuous treatment in all patients through 2 years, regardless of clinical course.
The cumulative confirmed analysis was developed as an approach that addresses the need to integrate response data across all patients who initiated treatment; however, it does not reflect the possibility of relapse after treatment discontinuation. The strength of the cumulative analysis is that it allows a clinician to assess, at the start of therapy, the probability that patients can reach a particular clinical end point while on treatment. It is complemented by analyses for the second-year treatment cohort, because these provide an assessment of the incremental benefit accrued through continued treatment for those who are eligible. These 2 analyses provide consistent results; 80% of all entecavir-treated patients achieved an undetectable HBV DNA level by the cumulative confirmed analysis, while 74% of the second-year treatment cohort achieved an undetectable HBV DNA level at week 96.
Durable suppression of HBV replication to below the limit of assay detection has become a principal goal of therapy.27, 28, 29 Sustained suppression of HBV DNA levels is linked to improved clinical treatment outcomes,15 and successful antiviral treatment is correlated with reduction of long-term risks of cirrhosis and HCC in patients with advanced disease.16 The recently published REVEAL studies suggest a link between rising HBV viremia and increased risk of cirrhosis and HCC among untreated patients observed in Taiwan.5, 6 It is increasingly evident that substantial proportions of patients with chronic HBV infection, including those with HBeAg-positive disease, will require long-term suppressive antiviral therapy. This approach requires agents that are highly potent against HBV and that have a high barrier to viral resistance. The data presented here for treatment with entecavir through 96 weeks provide a favorable clinical profile and suggest that this therapeutic agent represents an important advance in the management of CHB in nucleoside-naive HBeAg-positive patients.
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