Potential conflict of interest: Dr. Lai is a consultant for, advises, and is on the speakers' bureau of Bristol-Myers Squibb. Dr. S. Han is on the speakers' bureau of and received grants from Bristol-Myers Squibb. Dr. K. Han advises Bristol-Myers Squibb. Dr. Sievert is on the speakers' bureau of Bristol-Myers Squibb. Drs. Xu and Neo own stock in Bristol-Myers Squibb. Dr. Chang received grants from Bristol-Myers Squibb.
Current guidelines for management of chronic hepatitis B recommend treatment for patients presenting with elevated hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) or histological evidence of liver disease. Retrospective analyses have demonstrated that significant hepatic necroinflammation and fibrosis were present in a substantial proportion of patients with ALT 1 to 2 × ULN. To assess therapeutic efficacy in this clinical setting, we retrospectively examined treatment endpoints among the subset of nucleoside-naïve chronic hepatitis B (CHB) patients treated in phase 3 clinical trials of entecavir who had both screening and baseline serum ALT 1.3 to 2 × ULN. A total of 1347 patients were randomized to treatment with entecavir or lamivudine. Three hundred thirty-six patients, constituting 25% of the total study population, had screening and baseline ALT 1.3 to 2 × ULN. Clinically significant necroinflammation (Knodell necroinflammation score ≥7) was observed in 60% and 72% of hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients, respectively, whereas marked fibrosis (Ishak fibrosis score ≥4) was observed in 8% and 15% of HBeAg-positive and HBeAg-negative patients, respectively. Among entecavir-treated HBeAg-negative patients, the proportions of patients achieving histological improvement, HBV DNA <300 copies/mL, and ALT normalization were similar between patients with mildly elevated ALT and those with ALT >2 × ULN. However, entecavir-treated HBeAg-positive patients with mildly elevated ALT had lower response rates for histological improvement, HBV DNA less than 300 copies/mL, ALT normalization, and HBeAg seroconversion than those with ALT greater than 2 × ULN. Conclusion: This retrospective analysis demonstrated that HBeAg-negative CHB patients treated with entecavir responded similarly irrespective of baseline ALT level. However, HBeAg-positive patients with mildly elevated ALT responded less well to treatment with entecavir than did those with ALT greater than 2 × ULN. (HEPATOLOGY 2010.)
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Current guidelines for the management of noncirrhotic chronic hepatitis B (CHB) recommend that treatment should be initiated for patients who are hepatitis B e antigen (HBeAg)-positive if their hepatitis B virus (HBV) DNA levels are at least 105 copies/mL (≥104 copies/mL for HBeAg-negative patients) and their alanine aminotransferase (ALT) levels are greater than 2 × upper limit of normal (ULN).1–3 According to American Association for the Study of Liver Diseases and Asian Pacific Associtation for the Study of the Liver guidelines, biopsy-confirmed liver disease is a key requisite for initiating treatment in patients older than 40 years of age with serum ALT levels between 1 and 2 × ULN.1, 2, 4 The US treatment algorithm advocates the initiation of treatment regardless of biopsy-confirmed liver disease for patients with elevated HBV DNA and ALT greater than 1 × ULN.3 In light of reports that liver-related mortality and complications were greater in patients with ALT levels between 0.5 and 1 × ULN than in those with ALT levels less than 0.5 × ULN,5, 6 revision of the ULN for patients with CHB is recommended by some guidelines.3, 7–9 Nevertheless, the proposal for lowering the ALT “normal” values when assessing CHB patients has not been widely adopted in clinical practice.
Serum ALT level correlates poorly with the degree of liver disease in CHB, and ALT measurements may fail to identify patients with necroinflammatory activity or fibrosis.3, 10–12 HBV-infected patients with borderline normal or mildly elevated (1-2 × ULN) serum ALT levels—particularly those over the age of 35 to 40 years—can show significant necroinflammation and fibrosis on biopsy12–14 and are at increased risk of liver-related mortality.1, 6 HBV-infected patients with mildly elevated serum ALT levels (1-2 × ULN) are at similar risk for the development of complications as compared with those with greater elevations in serum ALT levels (2–6 × ULN).6
Retrospective analyses of HBeAg-positive CHB patients with mildly elevated ALT treated with lamivudine or interferon have demonstrated that these antiviral agents have lower efficacy in this population compared with those with ALT levels greater than 2 × ULN.15, 16 Entecavir is a nucleoside analog with high antiviral potency and a high genetic barrier to the development of viral resistance.17 Phase 3 clinical trials have demonstrated that entecavir is superior to lamivudine in improving virological, histological, and biochemical endpoints in patients with CHB.18–20 The current post-hoc analysis was undertaken to determine treatment outcome in the subset of nucleoside-naïve CHB patients with mildly elevated serum ALT (1.3-2 × ULN) enrolled in phase 3 clinical trials of entecavir.
ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ULN, upper limit of normal.
Patients and Methods
The phase 3 randomized, double-blind trials ETV-022 (HBeAg-positive) and ETV-027 (HBeAg-negative) compared the 48-week efficacy, tolerability, and safety of entecavir (0.5 mg once daily) and lamivudine (100 mg once daily) in nucleoside-naïve CHB patients.18, 19 For study inclusion, patients were required to have baseline (pretreatment) serum HBV DNA levels of at least 3 MEq/mL (HBeAg-positive patients) or at least 0.7 MEq/mL (HBeAg-negative patients) by branched-chain DNA assay, serum ALT levels 1.3 to 10 × ULN, evidence of chronic hepatitis on liver biopsy, and compensated hepatic function. The primary efficacy endpoint in both studies was the proportion of patients with histological improvement (at least 2-point improvement in Knodell necroinflammatory score and no worsening in Knodell fibrosis score at week 48, relative to baseline). Liver biopsy samples were obtained (biopsies were required to be ≥2 cm in length and to include >5 portal areas) for assessment of inflammation and fibrosis. Secondary efficacy endpoints at week 48 included the proportions of patients with: (1) HBV DNA less than 300 copies/mL (Roche COBAS Amplicor PCR assay, version 2.0); (2) normalization of serum ALT (≤1 × ULN); (3) HBeAg seroconversion (HBeAg loss and appearance of anti-HBe [study ETV-022 only]). We performed a retrospective analysis of histological, virological, biochemical, and HBeAg serological efficacy endpoints in the subset of patients with both screening and baseline serum ALT 1.3 to 2 × ULN. According to the study inclusion criteria, patients enrolling in both studies were also required to have had at least one previously documented ALT level between 1.3 and 2 × ULN in the previous 12 weeks before screening. Because ALT levels often fluctuate during the course of CHB infection, the requirement that ALT 1.3 to 2 × ULN be present at both screening and baseline was intended to increase the likelihood that the sample analyzed consisted of patients with persistently mildly elevated ALT. All results are descriptive. Significance testing was not performed in this post hoc analysis.
A total of 1347 patients were randomized to treatment with entecavir (n = 679) or lamivudine (n = 668) in the two trials. Three hundred thirty-six patients (190 HBeAg-positive and 146 HBeAg-negative), constituting 25% of the total population (27% and 23% of the HBeAg-positive and HBeAg-negative patients, respectively), had screening and baseline serum ALT levels 1.3 to 2 × ULN (Table 1). The HBeAg-positive patients with mildly elevated ALT (1.3-2 × ULN) (n = 190) were predominantly male (70%), with a mean age of 35 years, and a mean HBV DNA level of 9.6 log10 copies/mL. The HBeAg-negative patients with mildly elevated ALT (n = 146) were predominantly male (72%), with a mean age of 46 years, and a mean HBV DNA level of 6.9 log10 copies/mL. Clinically significant necroinflammation (Knodell necroinflammation score ≥7) was present in 60% of HBeAg-positive and 72% of HBeAg-negative patients with mildly elevated ALT. Marked fibrosis (Ishak fibrosis score ≥4) was observed in 8% of HBeAg-positive and 15% of HBeAg-negative patients with mildly elevated ALT at baseline (Table 1).
Table 1. Baseline Characteristics and Incidence of Clinically Significant Necroinflammation and Fibrosis in Nucleoside-Naïve CHB Patients with Serum ALT Levels 1.3-2× ULN* Participating in Phase 3 Trials of Entecavir
Entecavir treatment in patients with serum ALT levels less than 2 × ULN resulted in substantial proportions of patients achieving histological improvement, ALT normalization, and HBV DNA less than 300 copies/mL regardless of HBeAg status (Table 2; Fig. 1). Among HBeAg-negative patients, the proportions of entecavir-treated patients with serum ALT less than 2 × ULN who achieved histological improvement, HBV DNA less than 300 copies/mL and ALT normalization were high (66%, 86%, and 76%, respectively), and HBV DNA response for entecavir-treated patients exceeded those in the equivalent lamivudine-treated population. Entecavir-treated HBeAg-positive patients with ALT less than 2 × ULN at screening and baseline also responded well with regard to histological improvement, HBV DNA less than 300 copies/mL, and ALT normalization (62%, 48%, and 55%, respectively). HBV DNA response was higher in the entecavir-treated subgroup with ALT less than 2 × ULN than in the equivalent lamivudine-treated subgroup. As expected, the proportions of patients who seroconverted in the ALT less than 2 × ULN subgroups were lower than those seen in the total population for each treatment arm.
Table 2. Efficacy Endpoints in Nucleoside-Naïve CHB Patients with Serum ALT Levels 1.3-2 × ULN and ≥2 × ULN
Study ETV-022: HBeAg-Positive Patients
ALT 1.3-2 × ULN
ALT ≥2 × ULN
Patients with evaluable biopsies: n = 628 (ETV: 314, LVD: 314); of them, 154 had ALT 1.3-2 × ULN at both screening and baseline.
Patients with evaluable biopsies: n= 583 (ETV: 296, LVD: 287) of whom 128 had ALT 1.3-2 × ULN at both screening and baseline
Current management guidelines for noncirrhotic CHB patients with high viral load emphasize that treatment should be initiated when serum ALT exceeds 2 × ULN or there is evidence of histological damage, on the basis that histological damage and ALT elevation are established prognostic factors for disease progression.1–3, 21 For patients with ALT levels between 1 and 2 × ULN, guidelines recommend that treatment should be initiated in patients with biopsy-confirmed liver disease.1, 2 Because liver biopsy is not always acceptable to patients, it is possible that stringent adherence to the serum ALT threshold of 2 × ULN could exclude from treatment patients with significant underlying hepatic disease.12–14
The case for initiating treatment in patients with mildly elevated ALT is tempered by concerns about the consequences of early and prolonged antiviral therapy—adverse drug reactions and development of HBV resistance—and the perception of low treatment efficacy in this clinical setting. In the past, physicians tended to rely on serological markers as surrogates of treatment efficacy in CHB. Because HBeAg seroconversion was the dominant treatment endpoint, CHB patients with lower baseline ALT levels were deemed to benefit less from treatment with HBV antiviral agents than patients with higher baseline ALT levels. The post-hoc analysis of studies ETV-022 and ETV-027 offered an opportunity to show the 48-week efficacy of antiviral treatment in patients with mildly elevated ALT (1.3-2 × ULN), and to compare this with efficacy in patients with higher ALT levels (>2 × ULN). All patients in the current analysis had biopsy-proven histological damage at baseline.18, 19
Among HBeAg-negative patients, similar treatment responses were observed between patients with mildly elevated ALT and those with ALT greater than 2 × ULN. The high rates of HBV DNA less than 300 copies/mL are likely attributable to the lower baseline HBV DNA in these patients, as lower baseline HBV DNA consistently predicts for a higher rate of virological response across treatment studies using nucleos(t)ide analogs; however, similar histological improvement and biochemical responses were also observed for both groups. This suggests that ALT levels are less important when considering treatment initiation in HBeAg-negative patients with abnormal ALT levels and that treatment decisions should be based on virological and histological parameters.
For entecavir-treated HBeAg-positive patients with mildly elevated ALT, histological improvement, HBV DNA less than 300 copies/mL, and HBeAg seroconversion were achieved by 62%, 48%, and 8% of patients, respectively. Antiviral therapy with either entecavir or lamivudine was less effective in HBeAg-positive patients with mildly elevated ALT than in those with ALT greater than 2 × ULN. This observation is consistent with results from previous analyses in lamivudine-treated patients.15, 16 Although the inclusion criteria made it unlikely that many HBeAg-positive patients with ALT 1.3 to 2 × ULN and biopsy-proven histological disease in this study were in the immune-tolerant phase,22–24 the probability that some patients may have been in the early stage of the immune clearance phase at the time of treatment initiation cannot be excluded. Because low rates of HBeAg seroconversion would necessitate long-term treatment, when HBeAg-positive patients with mildly elevated ALT receive antiviral therapy, initiation of treatment with drugs that have the most potent antiviral effect and the lowest resistance rates is mandatory; regular HBV DNA monitoring is also critical.1, 3, 25
One limitation of this study is that the data are derived from registration studies that required patients to have ALT levels 1.3 to 10 × ULN and biopsy-proven histological disease. In addition, this was a retrospective analysis of a subset of patients who not only had ALT values between 1.3 and 2 × ULN at both screening and baseline, but who had also had at least one previously documented elevated ALT between 1.3 and 10 × ULN up to 12 weeks before screening. Therefore, results for the subset of patients described here may not be generalizable to the full range of patients seen in the usual course of clinical care who are assessed as having mildly elevated ALT.
In conclusion, HBeAg-negative patients with mildly elevated ALT have treatment responses to entecavir that are similar to the responses for those with ALT greater than 2 × ULN. For HBeAg-positive patients with mildly elevated ALT, entecavir had lower efficacy than for those with ALT greater than 2 × ULN. The findings from this analysis of CHB patients with mildly elevated ALT and biopsy-proven histological damage demonstrate the treatment responses that can be expected should clinicians choose to initiate entecavir treatment in accordance with the current treatment guidelines. A prospective study is required to fully evaluate and guide future treatment options for patients with fluctuating ALT levels or those with persistently mildly elevated ALT levels.