Entecavir Therapy for up to 96 Weeks in Patients With HBeAg-Positive Chronic Hepatitis B
Article Outline
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.
Abbreviations used in this paper: bDNA, branched DNA, CHB, chronic hepatitis B, PCR, polymerase chain reaction, ULN, upper limit of normal
See CME quiz on page 1691; See editorial on page 1718.
Chronic hepatitis B (CHB) is one of the most common infectious diseases in the world, affecting approximately 400 million people.1, 2 Individuals with CHB are at significantly increased risk for developing cirrhosis and hepatocellular carcinoma (HCC). Approximately 1 million deaths worldwide are caused by CHB-related liver disease each year.3, 4 Chronically infected patients with persistently high serum hepatitis B virus (HBV) DNA levels are at higher risk of progressive liver disease, cirrhosis, hepatic decompensation, HCC, and death.5, 6, 7, 8
A goal of treatment for CHB is to suppress HBV replication, thus decreasing the hepatic necroinflammatory response and arresting or reversing progression of liver disease.9, 10, 11, 12 Maintenance of virologic suppression has been associated with improved liver histology in hepatitis B e antigen (HBeAg)-positive patients treated with nucleoside analogues.13, 14, 15 Liaw et al showed that long-term lamivudine therapy reduced rates of hepatic decompensation and HCC among patients with HBV-related compensated cirrhosis or advanced fibrosis who were HBeAg positive or had serum HBV DNA levels greater than 0.7 MEq/mL.16 In that study, poorer long-term outcomes were observed in patients who had viral breakthrough and harbored HBV with emerging lamivudine resistance substitutions versus those who did not, suggesting that long-term clinical benefit is mediated by continued suppression of viral replication. Maintained normalization of alanine aminotransferase (ALT) levels has also been associated with longer survival without hepatic decompensation and decreased rates of HCC development.17, 18, 19 Conversely, patients with persistently high HBV DNA and serum ALT levels have been shown to have higher rates of progression to cirrhosis and HCC.6, 8, 20
Entecavir is a potent inhibitor of HBV DNA polymerase.21 In a large randomized study of HBeAg-positive CHB (www.clinicaltrials.gov identifier: NCT00036608), entecavir demonstrated superior histologic, virologic, and biochemical responses compared with lamivudine at 48 weeks, as reported previously.22 The present analysis investigates the efficacy and cumulative safety of entecavir versus lamivudine for up to 96 weeks of blinded treatment, and through 24 weeks of off-treatment observation, in patients with HBeAg-positive CHB who had not previously received a nucleoside analogue.
Patients and Methods
Study Design
This study was a double-blind, double-dummy, randomized, controlled trial comparing the safety and efficacy of entecavir 0.5 mg once daily and lamivudine 100 mg once daily in patients with HBeAg-positive CHB. The study had a 52-week blinded treatment phase, followed by an extended blinded treatment phase for up to 44 additional weeks (96 weeks total). A total of 715 patients were recruited into the first year of the study between December 2001 and September 2002 from 137 centers worldwide.
At the end of 52 weeks of treatment, patients either stopped therapy or continued blinded treatment according to protocol-defined patient management criteria. This design intended to test the hypothesis that finite antiviral therapy was possible when certain treatment end points were achieved. Individualized patient management criteria were based on week 48 results for HBV DNA by branched DNA (bDNA) assay and HBeAg status. The bDNA assay was used for the patient management criteria because this was the approved assay at the time of protocol development.
Patients who achieved HBV DNA levels <0.7 MEq/mL (approximately 700,000 copies/mL) and loss of HBeAg were considered “responders” and were to discontinue therapy at week 52 with off-treatment follow-up for 24 weeks. Patients whose HBV DNA level was ≥0.7 MEq/mL were labeled as “nonresponders” and were also to discontinue therapy. They were offered alternative anti-HBV therapy or enrollment in an entecavir rollover protocol. Patients who achieved HBV DNA levels <0.7 MEq/mL but did not lose HBeAg were classified as “virologic responders” and were eligible to continue into year 2 to receive blinded treatment up to week 96. During the second year of treatment (weeks 52–96), virologic responders who became responders or nonresponders discontinued therapy once response or nonresponse was identified. The patient management criteria described here are distinct from the efficacy analyses described in the following text, which focus on the end points currently assessed in clinical practice.
Assay Methodology
Serum HBV DNA was quantified using the Roche COBAS Amplicor Monitor PCR assay (version 2.0; lower limit of quantification, 300 copies/mL [57 IU/mL]; Pleasanton, CA) and the Quantiplex bDNA assay (lower limit of quantification, 0.7 MEq/mL; Bayer Diagnostics, formerly Chiron Diagnostics, Emeryville, CA). HBV serologies (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody, HBeAg, antibody to hepatitis B e antigen [anti-HBe]) were measured using the Abbott AxSYM microparticle enzyme immunoassay (Abbott Laboratories, North Chicago, IL) and DiaSorin enzyme immunoassay methods. Serum ALT level was quantified by local laboratories at each site.
Efficacy Analyses
For virologic responders continuing in the second year of treatment (second-year treatment cohort), efficacy analyses included proportions of patients with HBV DNA levels <300 copies/mL by polymerase chain reaction (PCR), normalization of ALT levels (≤1.0 times the upper limit of normal [ULN]), and HBeAg seroconversion (loss of HBeAg and appearance of anti-HBe) at the end of dosing (up to 96 weeks).
A second efficacy analysis using on-treatment data for all treated patients (entecavir, n = 354; lamivudine, n = 355) is also presented. The value of this analysis is to provide the cumulative probability of achieving a confirmed end point among patients who received entecavir or lamivudine for up to 2 years. A confirmed end point on-treatment was defined as 2 sequential measurements, or last on-treatment measurement meeting the success criteria. The cumulative confirmed results do not imply maintenance of the response at week 96 or during off-treatment follow-up. These analyses are presented for the proportion of patients with HBV DNA levels <300 copies/mL by PCR and the proportion with normalization of ALT levels. Similar analyses are provided for HBeAg seroconversion through last observation (on-treatment and 6 months post-treatment).
Off-treatment efficacy was evaluated among patients who, according to protocol-defined patient management criteria, achieved a response (HBV DNA level by bDNA <0.7 MEq/mL and HBeAg loss) at week 48 or through year 2 and discontinued treatment. Efficacy analyses evaluated the proportions of patients who sustained HBV DNA levels <300 copies/mL by PCR, normalization of ALT levels, and HBeAg seroconversion at 24 weeks off-treatment among responders who met these end points at week 48 or at end of dosing during year 2. Because treatment discontinuation was based on the protocol-defined patient management criteria of HBeAg loss and HBV DNA level <0.7 MEq/mL, not all patients had achieved HBV DNA levels <300 copies/mL by PCR, normalization of ALT levels, or HBeAg seroconversion at the time of treatment discontinuation.
Safety analyses included adverse events, serious adverse events, discontinuations due to adverse events, and deaths. On-treatment safety analyses included cumulative data for all 709 treated patients during dosing. On-treatment hepatic flares were defined as ALT elevations >2× baseline and >10× the ULN. Off-treatment safety analyses describe safety information for the 24-week follow-up period during which no alternative anti-HBV therapy was initiated. Off-treatment hepatic flares were defined as ALT elevations >2× reference and >10× the ULN, where the reference value was defined as the baseline or end-of-dosing ALT value, whichever was lower.
Resistance Analysis
A comprehensive resistance monitoring program was undertaken to monitor genotypic markers of entecavir resistance. As reported elsewhere,23, 24 this analysis included sequencing paired baseline and on-treatment samples from all entecavir-treated patients with detectable HBV DNA (≥300 copies/mL) at week 48, week 96, or end of dosing and phenotyping all novel emerging substitutions. In addition, all patients experiencing a confirmed virologic breakthrough (≥1 log10 increase in HBV DNA level above nadir by PCR, as determined by 2 sequential measurements or last on-treatment measurement) were also phenotyped, including those with no observed genotypic changes.
Data Analysis and Statistics
Confidence intervals and P values for differences in proportions are based on the normal approximation to the binomial distribution, with unpooled proportions used in the computation of the standard error of the difference. P values are based on 2-sided tests.
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).
Figure 1.
Study design and protocol-defined outcomes through 96 weeks. Patients entered the second year of treatment at week 52, based on the results of week 48 HBV DNA by bDNA assay and HBeAg status. ETV, entecavir; LVD, lamivudine; R, responder (HBV DNA level <0.7 MEq/mL and HBeAg negative); VR, virologic responder (HBV DNA level <0.7 MEq/mL and HBeAg positive); NR, nonresponder (HBV DNA level ≥0.7 MEq/mL). Only VRs were to continue blinded therapy into the second year.
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 × 109 IU/mL) and 9.4 log10 copies/mL (4.8 × 108 IU/mL) for entecavir and lamivudine, respectively. Most patients in the second-year treatment cohort demonstrated ALT levels >1× 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.
Figure 2.
Distribution of HBV DNA levels through week 96 in the second-year treatment cohort (entecavir [ETV], 243; lamivudine [LVD], 164). Circle diameters are proportional to the percent of patients at the specified HBV DNA level, with the circles in each column totaling 100%. EOD (end of dosing) is defined as the last observation on-treatment.
Table 1. Proportions Achieving Virologic, Biochemical, and Serologic End Points in the Second-Year Treatment Cohort
| End point | Entecavir (n = 243) | Lamivudine (n = 164) |
|---|---|---|
| Virologic end point | ||
 HBV DNA level <300 copies/mL (57 IU/mL) by PCR assay | ||
| Week 48 | 156(64) | 66(40) |
| End of dosinga | 180(74) | 60(37) |
| Biochemical end point | ||
| Normalization of ALT levels (≤1× ULNb) | ||
| Week 48 | 161(66) | 116(71) |
| End of dosing | 193(79) | 112(68) |
| Serologic end point | ||
| HBeAg seroconversion | ||
| End of dosing | 26(11) | 20(12) |
aEnd-of-dosing HBV DNA data was not available for 24 entecavir-treated and 23 lamivudine-treated patients. |
bALT measurements were performed in local laboratories. Median ULN was 41, with a range of 15–80. |
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).
Table 2. Cumulative Confirmed Proportions Achieving Virologic, Biochemical, and Serologic End Points Through Week 96 in All Treated Patients
| End point | Entecavir (n = 354) | Lamivudine (n = 355) |
|---|---|---|
| Virologic end point | ||
| HBV DNA level <300 copies/mL (57 IU/mL) by PCR assay, n (%) | 284(80) | 137(39) |
| P value | <.0001 | |
| Biochemical end point | ||
| Normalization of ALT levels (≤1× ULNa), n (%) | 307(87) | 280(79) |
| P value | .0056 | |
| Serologic end points | ||
| HBeAg seroconversionb, n (%) | 110(31) | 92(26) |
| P value | NS | |
| HBsAg lossb, n (%) | 18(5) | 10(3) |
| P value | NS | |
| HBsAg seroconversionb, n (%) | 6(2) | 8(2) |
| P value | NS | |
aALT measurements were performed in local laboratories. Median ULN was 41, with a range of 15–80. |
bThrough last observation (on-treatment and 6 months post-treatment). |
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 ≤1× 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).
Table 3. Proportions of Responders Who Sustained Virologic, Biochemical, and Serologic End Points Through 24 Weeks Off-Treatment
| 24 weeks off-treatment | ||
|---|---|---|
| Responders (HBV DNA level <0.7 MEq/mL and loss of HBeAg) in year 1 | Entecavir | Lamivudine |
| HBeAg seroconversion | 54/70(77) | 44/61(72) |
| Normalization of ALT levels (≤1× ULN)a | 50/63(79) | 38/59(64) |
| HBV DNA level <300 copies/mL by PCR assay | 26/71(37) | 20/58(34) |
| Responders (HBV DNA <0.7 MEq/mL and loss of HBeAg) in year 2 | ||
| HBeAg seroconversion | 19/26(73) | 14/20(70) |
| Normalization of ALT levels (≤1× ULN)a | 23/33(70) | 18/25(72) |
| HBV DNA level <300 copies/mL by PCR assay | 8/35(23) | 5/20(25) |
aALT measurements were performed in local laboratories. Median ULN was 41, with a range of 15–80. |
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 >2× baseline and >10× 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 >2× reference and >10× 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.
The authors thank Ricardo Tamez, MD, Daniel Tenney, PhD, Ronald Rose, PhD, Bruce Kreter, PharmD, and all of Bristol-Myers Squibb for their assistance in preparing the manuscript.
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The study was sponsored by Bristol-Myers Squibb. The sponsor designed the study in collaboration with expert hepatologists. The sponsor also collected the data, monitored study conduct, performed the statistical analyses, and coordinated writing of the manuscript with all authors. The study was conducted in accordance with the ethics principles of the Declaration of Helsinki and in line with Good Clinical Practice guidelines and applicable local regulatory requirements. Written informed consent was obtained from all participants, and financial disclosures were documented and submitted to the U.S. Food and Drug Administration. Statistical analyses were performed in accordance with the Good Clinical Practice guidelines, and the product was subsequently approved by the U.S. Food and Drug Administration. R.G.G. had full access to all the data and accepts full responsibility for the veracity of the data and analysis.
The authors declare the following conflicts of interest: R.G.G. received a research grant from, and is an advisor to, Bristol-Myers Squibb, A.S.L. received a research grant from Bristol-Myers Squibb, A.S.L., A.G., and K.-H.H. are advisors for Bristol-Myers Squibb, and M.H., J.Y., R.C., H.B.-S. are employees of Bristol-Myers Squibb. T.-T.C., R.A.D., J.S., Y.-C.C., and S.-D.L. have no financial arrangements to disclose.
PII: S0016-5085(07)01482-5
doi:10.1053/j.gastro.2007.08.025
© 2007 AGA Institute. Published by Elsevier Inc. All rights reserved.
Refers to article:
- Continuing Medical Education Exam 2: November 2007
- Hepatitis B: Explosion of New Knowledge