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 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. A comprehensive resistance monitoring program was undertaken to monitor genotypic markers of entecavir resistance. As reported elsewhere,23Colonno R.J. Rose R.E. Baldick C.J. et al.Entecavir resistance is rare in nucleoside naïve patients.Hepatology. 2006; 44: 1656-1665Crossref PubMed Scopus (319) Google Scholar, 24Tenney D.J. Levine S.M. Rose R.E. et al.Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine.Antimicrob Agents Chermother. 2004; 48: 3498-3507Crossref PubMed Scopus (493) Google Scholar 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. 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. 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.22Chang T.T. Gish R.G. de Man R.A. et al.A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.N Engl J Med. 2006; 354: 1001-1010Crossref PubMed Scopus (1249) Google Scholar 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.22Chang T.T. Gish R.G. de Man R.A. et al.A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.N Engl J Med. 2006; 354: 1001-1010Crossref PubMed Scopus (1249) Google Scholar 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]). 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 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]). 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.25Dienstag J.L. Cianciara J. Karayalcin S. et al.Durability of serologic response after lamivudine treatment of chronic hepatitis B.Hepatology. 2003; 37: 748-755Crossref PubMed Scopus (212) Google Scholar, 26Chang T.T. Shiffman M.L. Tong M. et al.Durability of HBeAg seroconversion following adefovir dipivoxil treatment of chronic hepatitis B (CHB).J Hepatol. 2006; 44: S187Abstract Full Text PDF Google Scholar 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.27Sherman M. Predicting survival in hepatitis B.Gut. 2005; 54: 1521-1523Crossref PubMed Scopus (21) Google Scholar, 28Keeffe E.B. Dieterich D.T. Han S.H.B. et al.A treatment algorithm for the management of chronic hepatitis B virus infection in the United States.Clin Gastroenterol Hepatol. 2006; 4: 936-962Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 29Yuen M.F. Yuan H.J. Wong D.K.H. et al.Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications.Gut. 2005; 54: 1610-1614Crossref PubMed Scopus (316) Google Scholar Sustained suppression of HBV DNA levels is linked to improved clinical treatment outcomes,15Mommeja-Marin H. Mondou E. Blum M.R. et al.Serum HBV DNA as a marker of efficacy during therapy for CHB infection: analysis and review of the literature.Hepatology. 2003; 37: 1309-1319Crossref PubMed Scopus (251) Google Scholar and successful antiviral treatment is correlated with reduction of long-term risks of cirrhosis and HCC in patients with advanced disease.16Liaw Y.F. Sung J.J.Y. Chow W.C. et al.Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Crossref PubMed Scopus (1984) Google Scholar 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.5Chen C.J. Yang H.I. Su J. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (2508) Google Scholar, 6Iloeje U.H. Yang H.I. Su J. et al.Predicting liver cirrhosis risk based on the level of circulating hepatitis B viral load.Gastroenterology. 2006; 130: 678-686Abstract Full Text Full Text PDF PubMed Scopus (1308) Google Scholar 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. Continuing Medical Education Exam 2: November 2007GastroenterologyVol. 133Issue 5Preview Full-Text PDF Hepatitis B: Explosion of New KnowledgeGastroenterologyVol. 133Issue 5PreviewAs regular readers of Gastroenterology and Clinical Gastroenterology and Hepatology appreciate, a steady flow of publications in both journals continues to expand our knowledge of the natural history and management of chronic hepatitis B virus (HBV) infection. This explosion of new knowledge is appropriate and much needed, because chronic hepatitis B is an important public health problem globally and in the United States. It is estimated that worldwide up to 400 million people have chronic HBV infection,1,2 and treatment options to control active viral replication and disease progression continue to expand. Full-Text PDF This Month in GastroenterologyGastroenterologyVol. 133Issue 5PreviewSimilar to adult gastroenterological practice, the functional gastrointestinal disorders (FGIDs) constitute a major segment of pediatric gastroenterology practice. Among pediatric FGIDs, functional abdominal pain (FAP) and irritable bowel syndrome (IBS) are the most prevalent disorders characterized by abdominal pain. In children, too, the impact of these FGIDs on quality of life is considerable, treatment options are limited, and the long-term outcome is unfavorable in an important subset. In adults, controlled studies have demonstrated that gut-directed hypnotherapy (HT) is effective in the treatment of painful FGIDs, including IBS, functional dyspepsia, and noncardiac chest pain. Full-Text PDF