Editorial Board: Emmet B. Keeffe, MD (Chair); Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD
HBV Watch^™
Timely Information for Practicing Physicians

ABSTRACT HIGHLIGHTS OF DIGESTIVE DISEASE WEEK^®

May 14–19, 2005

ENTECAVIR (ETV)

Responses to ETV. Three papers reported responses to ETV, a potent inhibitor of HBV DNA polymerase. In the first study, R.G. Gish and colleagues reported on 709 patients with HBeAg+ chronic hepatitis B (CHB) randomized to receive 48 weeks of treatment with ETV or lamivudine (LVD). Patients who achieved a protocol-defined complete response (CR) (serum HBV DNA <0.7 MEq/mL by bDNA assay plus HBeAg loss) at 48 weeks discontinued therapy and were followed for 24 weeks. CR was achieved by 21% of ETV-treated patients and 19% of LVD-treated patients. At 24 weeks off treatment, 82% of patients in the ETV group and 73% of patients in the LVD group remained in CR. In a second analysis, A.S. Lok et al. evaluated subgroups of patients in 2 large trials that compared ETV to LVD therapy (ETV-022 [HBeAg+ patients] and ETV-027 [HBeAg- patients]). Data were analyzed by baseline HBV DNA (<10⁷ to ³10¹⁰ copies/mL) and baseline serum ALT level (1.0 to >5.0 x ULN). The results showed that ETV therapy achieved consistent histologic and virologic responses in HBeAg+ or HBeAg- patients in all viral load and ALT subgroups. R.S. Brown et al. analyzed these same patients by prior exposure to interferon, geographic region of origin, gender, race, serum ALT at baseline, and HBV genotype. These results also demonstrated that responses to ETV were consistent across baseline subgroups. (Abstracts 321, M934, M913)

PEGINTERFERON ALFA-2a

Effect of previous treatment on sustained response. G.K.K. Lau et al. conducted a partially blinded multicenter study in which 814 HBeAg+ patients with CHB were randomized to peginterferon plus placebo, peginterferon plus lamivudine, or lamivudine alone for 48 weeks. HBeAg seroconversion rates at week 72 were higher in the peginterferon-containing arms than in the lamivudine alone arm regardless of whether patients had previously been treated (with conventional interferon or lamivudine) or not. Seventy-eight percent of patients in the peginterferon arm received ≥90% of the planned total dose of peginterferon. HBeAg seroconversion rates were 28% in patients receiving <90% of the planned peginterferon dose and 33% in those receiving ≥90% of the planned dose. These results showed that patient adherence to the peginterferon dosing schedule was excellent and that peginterferon induced high rates of HBeAg seroconversion despite prior therapies. (Abstract 31) 

Viral suppression does not correlate with HBeAg seroconversion. M.W. Fried and associates evaluated the correlation between virological response and HBeAg seroconversion utilizing data from a large multicenter study in which 814 patients with HBeAg+ CHB were randomized to receive peginterferon plus placebo, peginterferon plus lamivudine, or lamivudine alone for 48 weeks. At week 48 the proportions of patients who achieved undetectable levels of HBV DNA were 25%, 69%, and 40% in the peginterferon alone, peginterferon plus lamivudine, and lamivudine alone arms, respectively. However, the proportion of patients who had developed HBeAg seroconversion at week 72 was 32%, 27%, and 19% in the peginterferon alone, peginterferon plus lamivudine, and lamivudine alone treatment groups, respectively. These findings suggest that greater viral suppression at week 48 does not necessarily translate into increased HBeAg seroconversion rates. (Abstract 488)

Sustained response after a year of follow-up. P. Marcellin et al report the long-term follow-up results (48 weeks after the end of treatment) of 304 patients with HBeAg- CHB treated with peginterferon ± lamivudine or lamivudine alone for 48 weeks. At 24 weeks after the end of treatment, the proportions of patients with normal ALT levels, serum HBV DNA <20,000 copies/mL, and serum HBV DNA <400 copies/mL were significantly higher in the peginterferon-containing arms than in the lamivudine alone arm. At 48 weeks of follow-up after the end of treatment, the rates of biochemical and virological responses were similar to those at 24 weeks of follow-up for all 3 treatment groups. These data demonstrate that 48 weeks of peginterferon induces high rates of sustained biochemical and virologic responses for at least 1 year after discontinuation of therapy. (Abstract 512)

ADEFOVIR DIPIVOXIL (ADV)

Long-term therapy in HBeAg- CHB. ADV 10 mg daily was shown to be safe and effective therapy for patients with HBeAg- CHB in a 96-week randomized, placebo-controlled trial. S. Hadziyannis et al. now report the long-term results of ADV treatment in these patients. Among 79 patients who had been randomized to receive ADV for the first 96 weeks of the study and who then continued open-label ADV, 70 and 67 patients continued ADV treatment for 144 and 192 weeks, respectively. HBV DNA became undetectable in 51 (85%) of 60 evaluable patients. The median decrease in HBV DNA plasma levels was 3.71 log₁₀ copies/mL. Serum ALT normalized in 44 (81%) of 54 evaluable patients and HBsAg seroconversion was observed in 4 patients. The cumulative incidences of ADV resistance at weeks 48, 96, 144, and 192 were 0%, 3%, 11%, and 18%, respectively. Three patients developed transient elevations of serum creatinine. These results demonstrate that ADV therapy results in durable HBV DNA suppression in the majority of patients with low rates of resistance and is tolerated well. (Abstract 492)

Long-term therapy in HBeAg+ CHB. P. Marcellin et al. conducted a double-blind study in which patients with HBeAg+ CHB were randomized to receive ADV 10 mg daily, ADV 30 mg daily, or placebo for 48 weeks. The authors report the results of 171 patients in the ADV 10 mg treatment arm who were eligible to continue open-label ADV therapy. Serum HBV DNA levels were undetectable at weeks 48, 96, and 144 in 28%, 45%, and 56% of patients, respectively. In addition, at weeks 48, 96, and 144; the percentages of patients who developed HBeAg seroconversion were 12%, 29%, and 43%, respectively, and serum ALT normalized in 58%, 71%, and 81% of patients respectively. Two (3.1%) patients developed ADV resistance through the 144 weeks of therapy. ADV was well tolerated. These data show that increasing proportions of patients with HBeAg+ CHB achieved virologic, serologic, and biochemical responses over time with continued ADV 10 mg daily therapy. (Abstract 73)

Incidence and risk factors of resistance. Two studies evaluated the incidence and predictors of resistance in patients with CHB treated with ADV. In the first study by S. Locarnini et al., data from patients enrolled in 5 studies were reviewed. The patient population included 629, 293, 221, and 67 patients who had received ADV for 48, 96, 144, and 192 weeks, respectively. Mutations associated with ADV resistance (N236T and A181V) were found in 22 patients and the cumulative probability for developing ADV resistance (ADV-R) by week 192 was 15%. No ADV-resistant mutations were detected in patients treated with lamivudine plus ADV. Serum HBV DNA rebound occurred in most patients with ADV-resistant mutations. Logistic regression analysis identified only a higher HBV DNA serum level at 48 weeks (median level of 4.2 log) to be a predictor of ADV resistance. In a second study, S.G. Lim and others analyzed data from 183 patients who had received ADV for a median of 147 weeks (range, 15-244 weeks). Nineteen patients developed genotypic ADV resistance (11 patients with N236T, 4 patients with A181V, and 4 patients with dual mutations). Most of these patients had confirmed increases of serum HBV DNA ≥1 log₁₀ copies/mL above the nadir. However, ALT flares (≥5 x ULN) were observed only in 3 of 4 patients with dual mutations. In the 7 patients in whom lamivudine was added to ADV therapy, serum HBV DNA levels fell by approximately 2 log₁₀ copies/mL within 12 weeks of starting lamivudine. These studies indicate that the chance for developing resistance to ADV monotherapy is about 4-fold less than that reported for lamivudine monotherapy. ADV resistance is associated with an increase in serum HBV DNA levels that may often be induced to decrease by the addition of lamivudine. (Abstracts 36 and 508)

CIRRHOSIS

Predictive importance of HBV DNA level. Four analyses of a prospectively followed cohort of 3,851 Taiwanese patients with chronic HBV infection determined that viral load is a strong predictor for the development of cirrhosis in patients with chronic HBV infection. The diagnosis of cirrhosis was based on ultrasonography findings and all cases of cirrhosis diagnosed within 6 months of enrollment were excluded from the analyses. In the first study, U.H. Iloeje et al. observed that 395 cases of new cirrhosis developed and that the incidence of cirrhosis increased significantly in patients with HBV DNA levels ≥10⁶ copies/mL compared to patients with undetectable HBV DNA levels (p < 0.0001). In a second analysis, U.H. Iloeje et al. found that cirrhosis developed in 9.6% of patients with normal ALT levels compared to 24% of patients with elevated ALT levels, and within each ALT strata the risk of cirrhosis was correlated with increasing serum HBV DNA levels. In addition, C.J. Chen and colleagues observed that the risk of cirrhosis in both HBeAg+ and HBeAg- patients in this cohort also correlated with increasing serum HBV DNA levels. Finally, H.I. Yang et al. showed that serum HBV DNA level also strongly predicted progression to decompensated cirrhosis (defined as ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome). (Abstracts 496, 476, 35, and 538)

HEPATOCELLULAR CARCINOMA (HCC)

Viral load is associated with HCC risk. Three analyses found viral load to be a predictor for the development of HCC in patients with chronic HBV infection. In the first study, C.J. Chen and others prospectively followed 3,851 Taiwanese patients with chronic HBV infection. The diagnosis of HCC was made through data linkage with computerized profiles of the National Cancer Registry and Death Certification System in Taiwan. During 43,993 person-years of follow-up, 176 patients were diagnosed to have HCC. Multivariate analysis determined that the risk for developing HCC was associated with serum HBV DNA level in a dose-dependent relationship (p <0.001). In patients with high HBV DNA levels at baseline, the HCC risk was greater in patients with persistent HBV DNA elevation compared to patients in whom HBV DNA was cleared (adjusted relative risk = 6.4 [95%CI: 4.4-9.5]). In addition, U.H. Iloeje et al. found elevated serum HBV DNA levels to be a strong predictor for the development of HCC regardless of serum ALT level in a separate analysis of the same population. G. Chen and coworkers evaluated a cohort of patients with HBeAg+ chronic HBV infection from Haimen City, China over a 10-year period. The authors found the risk for mortality due to either HCC or chronic liver disease was significantly associated with increasing viral load categories (p <0.01). The data from these studies can be used to identify patients at increased risk for serious sequelae due to chronic HBV infection. (Abstracts 35, 495, 477)

DISEASE PROGRESSION

Natural history of disease progression in patients not receiving active therapy. Y.F. Liaw et al. evaluated data from 215 patients with CHB and confirmed advanced fibrosis or cirrhosis who were randomized to the placebo arm in a recent double-blind clinical study. These patients received placebo for median treatment duration of 32 months. Disease progression occurred in 38 patients: 19 (8.8%) experienced an increase in Child-Pugh score, 16 (7.4%) developed HCC, and 3 (1.4%) had bleeding varices. Subgroup analyses showed that disease progression was more likely to occur in patients with higher baseline fibrosis scores and in patients with HBV genotype C. These data demonstrate that HBV patients with advanced disease progress rapidly if left untreated. (Abstract 507)

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