icon-folder.gif   Conference Reports for NATAP  
  AASLD (American Association for the Study of Liver Diseases)
Nov 2-5, 2002, Boston, MA
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Treatment for Hepatitis B Looks Promising
Reported by Jules Levin
  It looks like hepatitis B will become manageable because there are a number of drugs for HBV. Adefovir is approved for HBV treatment and lamivudine has been available for HBV treatment for a longer period of time. Many HBV or HIV infected individuals have lamivudine (3TC) resistance. It's been reported that the incidence of lamivudine resistance increases from 15-32% at one year, 32% after two years, and to 67% at 4 years of therapy. Studies reported below from AASLD examine adefovir and entecavir in patients with lamivudine resistance. The status of fibrosis is explored after 48 weeks of treatment with adefovir and is reported below. LDT and ACH-126,443 for HBV are in early stages of development and study data in HBV treatment-naive patients were reported at AASLD. As well, results were reported from treatment of HBV with Pegasys for 24 weeks with a 24 week followup period.
Entecavir in Patients with Lamivudine Resistance
Ting-Tsung Chang, reported results from a 48 week study of entecavir in 181 lamivudine resistant patients. In early study of treatment-naive using 0.5 mg once daily HBV DNA was reduced about 5 log after 24 weeks therapy compared to a 3 log reduction in patients receiving 100 mg of lamivudine 100mg per day. In this study, 45% had prior interferon therapy for HBV. 87% of patients in study had TMDD lamivudine mutations. 67% of patients were HbeAg positive. Mean HBV DNA 8.1 log. Patients were randomized to 1 or 3 entecavir doses (0.1, 0.5, or 1.0 mg once daily) or to continue on lamivudine.
After 48 weeks of therapy the high dose of 1.0 mg per day of entecavir showed a mean 5.11 log reduction in HBV DNA. The 0.5 mg dose of entecavir ahowed a 4.46 log reduction. 26% of patients receiving either dose had undetectable HBV DNA. Mean viral load was still declining at week 48 so presumably some patients will achieve greater than 5 log reductions. From speaking to study investigators, it appears that some patients saw up to 8 log reductions in viral load in this study. The percent of patients with abnormal ALT at baseline who had normal ALT at week 48 of entecavir was 59% for patients receiving 0.5 mg dose and 68% for patients receiving 1.0 mg dose.
Investigators reported they did not see any entecavir resistance and there was no breakthrough viremia occurring in the 1.0 mg dosing group. The incidence of clinical adverse events, serious adverse events, and discontinuations due to adverse eventswere comparable among the entecavir treatment arms and the lamivudine arm. The most common reported adverse events were headache, rhinitis, fatigue, and abdominal pain. 80% of patients reported any adverse event, 12% reported serious adverse events. 7% reported discontinuation due to adverse event or lab abnormality. The investigator reported that the majority of HBV DNA reduction occurred rapidly, but HBV DNA continued to fall through 48 weeks. Few patients lost HbeAg or sewroconverted during 48 weeks therapy. The investigators concluded that entecavir was safe and highly effective in reducing viral load and normalizing ALT for patients who failed previous lamivudine therapy. Phase III studies are ongoing in nucleoside naive and lamivudine resistant patients with results expected to be reported in 2003. It appears the 1.0 mg dose of entecavir will be used in future studies of patients who failed lamivudine therapy.
Adefovir in Patients with Lamivudine Resistance
This study presented at AASLD by Eugene Schiff evaluated the safety and efficacy of adefovir (ADV) 10 mg in an open-label study of pre- and post-OLT patients with lamivudine resistance. 196 post-liver transplant (cohort A) and 128 pre-liver transplant (cohort B) patients failing lamivudine enrolled at 75 centers. Patients were further stratified by subcohorts 1 (met all eligibility criteria), 2 (received ADV prior to study entry), and 3 (significant medical and comorbidities). ADV 10 mg daily was added to existing HBV and immunosuppressive therapy. Initial ADV dose was adjusted for patients with baseline renal impairment. All patients were HBsAg and HBV DNA positive, 84% males; median age 52 years, 71% Caucasian. Median duration of ADV therapy was 56 weeks and 19 weeks for cohorts A and B, respectively. HBV DNA declined at week 48 by a median reduction of 4.3 and 4.1 log in cohorts A and B, respectively. Cohort A patients (post transplant), with longer duration of therapy, had reduction in HBV DNA that was sustained at week 96 (median reduction of 4.6 log). Antiviral response was consistent regardless of the pattern of YMDD mutations present at baseline. In patients post-OLT (cohort A), Kaplan-Meier (KM) estimates of patients with HBV DNA < 400 copies/mL (Roche Amplicor PCR assay) by week 48 were 23%, 55%, and 40% in cohorts 1A, 2A, and 3A. By week 96, 62%, 70%, and 50% of cohorts 1A, 2A, and 3A had serum HBV DNA < 400 copies/mL.
In pre-liver transplant patients, KM estimates of patients with serum HBV DNA < 400 copies/mL were 31%, 0%, and 53% in cohorts 1B, 2B, and 3B by week 48. ALT normalization was achieved in 60% of patients at week 48 in cohort A and 61% of patients in cohort B. Improvements in serum bilirubin, albumin and prothrombin time were also observed. KM estimates of survival in patients post-transplant by week 48 were 98%, 100%, and 82% in cohorts 1A, 2A, and 3A, respectively. KM estimates of survival in pre-transplant patients by week 24 (median duration of treatment 20.9 weeks) were 89%, 100%, and 81%.
A low rate of related serious adverse events were reported (5% in cohort A, 4% in cohort B) as well as adverse events leading to drug discontinuation (5% in cohort A, 6% in cohort B). A total of 42 deaths were reported; causes of death were consistent with those seen in patients pre- and post-liver transplant. Serum creatinine elevations were observed in a proportion of patients, all with multiple risk factors at baseline for renal dysfunction including concomitant immunosupressants and other nephrotoxic agents. Most had pre-existing renal impairment (creatinine clearance < 80 mL/min). Most patients continued treatment with dose adjustment; 2% percent of patients discontinued ADV for renal adverse events. New PK data have resulted in ADV dosing guidelines not recommend dose interval adjustment for patients with creatinine clearance <50 mL/min.
The investigators concluded that treatment with ADV 10 mg resulted in significant reduction in serum HBV DNA, clinical and laboratory improvements, and improved survival in pre- and post-liver transplant patients failing lamivudine therapy, regardless of the pattern baseline YMDD mutations and was not associated with treatment limiting toxicity in the majority of patients. HBV DNA suppression was improved over time and sustained up to 96 weeks.
48 weeks of Adefovir Improves Fibrosis and Decreased Progression in HbeAg+ Patients
Year one of a phase 3 placebo-controlled clinical trial of ADV for the treatment of HBeAg+ chronic hepatitis B infection was completed in 2001. Liver biopsies were performed prior to baseline and at 48 weeks of treatment. The primary efficacy endpoint was a two-point improvement in the inflammatory components of the Knodell Histology Activity Index (HAI) with no progression of the fibrosis component. This was achieved by 25% (41/161) placebo treated patients, 53% (89/168) treated with ADV 10 mg QD, and 59% (98/165) treated with ADV 30 mg QD (p=<0.0001 compared to placebo).
The original HAI only allows 3 stages of fibrosis (none, portal, bridging and cirrhosis). The modified HAI, also called the Ishak score (J Hepatol 1995; 22:696-699) has 6 stages of fibrosis, permitting better evaluation of therapy-related changes in fibrosis. The objective of this analysis is to compare changes in fibrosis, as determined by the modified HAI fibrosis score, between the placebo and ADV-treated patients. Possible fibrosis scores with the modified HAI are: 0 = no fibrosis; 1 = fibrous expansion of some portal areas; 2 = fibrous expansion of most portal areas; 3 = occasional bridging fibrosis; 4 = marked bridging fibrosis; 5 = incomplete cirrhosis; 6 = cirrhosis.
In an intent-to-treat analysis, mean modified HAI baseline fibrosis scores were: placebo = 2.47 (62% 0-2, 30% 3-4, 8% 5-6); ADV 10 mg = 2.20 (71% 0-2, 22% 3-4, 7% 5-6); ADV 30 mg = 2.24 (65% 0-2, 30% 3-4, 4% 5-6). After 48 weeks of treatment the mean modified HAI fibrosis scores were: Placebo = 2.55; ADV 10 mg = 1.95 (p=0.0007 compared to baseline); ADV 30 mg = 1.85 (p=<0.0001 compared to baseline). Significant improvement and less worsening of fibrosis occurred in the ADV 10 mg group (p=0.0006) and the ADV 30 mg group (p=<0.0001) as compared to PLB. Improvement by 1 stage occurred in 19% of placebo treated patients, 35% ADV 10 mg and 41% ADV 30 mg. Worsening by 1 stage occurred in 22% of placebo treated patients, 11% ADV 10 mg, and 10% ADV 30 mg.
Adefovir 10 mg Treatment After 48 Weeks
Patrick Marcellin reported at AASLD on the evaluation of the safety and efficacy of treatment with ADV 10 mg beyond 48 weeks in patients with HBeAg+ chronic hepatitis B. Patients with HBeAg+ CHB and serum HBV DNA >=106 copies/mL with ALT 1.2-10 x the upper limit of normal (ULN) were randomized to ADV (10 mg or 30 mg daily) or placebo (PLB).
For this analysis, the median time of additional treatment beyond 48 wk was 16.1 wk (range of 8.1 to 27.3 wk). The median duration of continued treatment with ADV 10 mg was 15.6 wk (range of 7.6 to 24.3 wk). At baseline in the ADV 10 mg group the median HBV DNA was 8.4 log10 copies/mL and the median ALT was 2.3 x ULN and in the PLB group the median HBV DNA was 8.4 log10 copies/mL and ALT 2.4 x ULN. After 48 weks, 21% of ADV 10 mg patients had HBV DNA < 400 copies/mL compared to none receiving PLB. ALT normalized in 48% of the ADV 10 mg group compared to 16% in PLB. At wk 48 12% of ADV 10 mg patients had undergone HBeAg seroconversion compared to 6% of PLB patients.
After week 48, for some patients HBV DNA continued to decline, some patients achieved HbeAg seroconversion and normalized ALT. At week 48 no HBV mutations associated with adefovir resistance in HbeAg patients were observed.
At the time of the interim analysis, patients continuing ADV 10 mg beyond week 48 demonstrated a median decline in serum HBV DNA from the 48 wk baseline (median 5.17 log10 copies/mL) of -0.13 log at wk 60 (n = 54) and -0.21 log at wk 72 (n = 29). Among 71 patients with serum HBV DNA levels > 400 copies/mL at the beginning of the second 48 week treatment period, 15 (21%) on continued ADV 10 mg had serum HBV DNA levels < 400 copies/mL at their last evaluation. Among 74 patients who remained HBeAg positive during the first 48 weeks, an additional 4 (5%) in the ADV group had undergone HBeAg seroconversion. ALT values were > ULN in 41 of 85 patients on ADV 10 mg at wk 48 but normalized in 11 (27%) at the time of the interim analysis.
The authors suggested that the continued improvement after 48 weeks may be due to the absence of resistance. This study will continue for 5 years to evaluate long term safety and efficacy of daily 10mg adefovir and to see if resistance develops.
LDT (telbivudine): new HBV drug in early development
This new drug for hepatitis B from Idenix Pharmaceuticals showed 3-4 log reductions in HBV DNA in phase II study at 400-600mg per day in previously reported study. At AASLD interim data analysis at week 24 was presented from a one year study in which 100 treatment-naive patients received either LDT 400mg per day, LDT 600mg per day, LDT 400mg per day plus lamivudine, LDT 600 mg per day plus lamivudine, or lamivudine. After 24 weeks lamivudine treatment showed about 4.5 log reduction in HBV DNA. All the other treatment arms showed about the same reduction in HBV DNA, about 6 log.
ACH-126,443: new HBV drug in early development
This new drug is in early development for treating HBV by Achillion Pharmaceuticals. Nezam Afdhal reported ACH-126, 443 (L-Fd4C) is an L-nucleoside analog. Early clinical studies showed this drug to be potent against HBV, good oral bioavailability and animal studies showed no significant toxicity when using high doses. In vitro studies show activity against YMDD mutations. 36 treatment-naive individuals participated in multicenter, blinded, placebo-controlled, ascending dose, phase I/II trial designed to evaluate safety, PK, and early antiviral activity of this drug for 14 days in patients with chronic HBV. Participants were randomized to sequentially to dose groups of 1, 5, 10, 20, 50 and 100 mg once daily given orally.
Investigators reported no apparent drug-related adverse events were observed at any dose level. Pharmacokinetic profiles demonstrated peak plasma levels within 1 hour of oral administration ≥20 ng/mL which exceeded the IC50 of wild-type HBV by ≥50-fold with doses of 5 mg daily and above. Mean declines of 1.5 - 3.0 log for HBV DNA, achieved after 14 days of dosing, indicated potent suppression of viral replication in the 5-100 mg daily dose groups (p=0.018 for each active dose group vs placebo). The IC50 of YMDD mutant HBV was reached with a peak plasma drug level of 10 mg daily, and was exceeded by 2 to 20-fold with doses of 20 mg daily and above. A Phase 2 trial in 3TC-failing HBV patients is underway; these data will provide support for evaluation of ACH-126,443 in combination regimens for optimal suppression of viral replication.
Pegasys in HBeAg Chronic Hepatitis B Patients
Cooksley reported traditionally, patients with HBeAg-positive CHB who have high pretreatment HBV DNA levels and low pretreatment ALT values have not responded well to treatment with conventional IFN or lamivudine. 194 adults with HBeAg-positive CHB were randomized to interferon alfa-2a 4.5 MIU tiw or peginterferon alfa-2a (40KD) 90, 180, or 270 mcg once weekly for 24 weeks and were followed up for an additional 24 weeks. Efficacy was assessed by responses to loss of HBeAg, HBV DNA suppression to <500,000 copies/mL (Roche COBAS AMPLICOR HBV MONITORTM Test, sensitivity <200 copies/mL), and ALT normalization.
At the end of follow-up (week 48), the combined response of loss of HBeAg, HBV DNA <500,000 copies/mL, and ALT normalization was achieved by 25% of patients given peginterferon alfa-2a (40KD) and 12% of patients given conventional IFN alfa-2a 4.5 MIU.
Preliminary analyses suggest that some traditional prognostic factors associated with conventional IFN therapy, such as pretreatment ALT values, may be less applicable with the use of peginterferon alfa-2a (40KD). Positive end points for suppression of HBV DNA and loss of HBeAg were achieved by more patients with difficult-to-treat HBV disease who were treated with peginterferon alfa-2a (40KD) compared with IFN alfa-2a: in patients with low pretreatment ALT values (2 x ULN) and high pretreatment HBV DNA levels (≥8 log), suppression of HBV DNA to <500,000 copies/mL was achieved by 25% of peginterferon alfa-2a (40KD) patients compared with 17% of conventional IFN alfa-2a patients. The loss of HBeAg was achieved by 44% of peginterferon alfa-2a (40KD) patients compared with 17% of conventional IFN alfa-2a patients, but the usefulness of a difficult to tolerate interferon therapy will have to be considered in the context of the development of several antiviral drugs for HBV . The authors concluded that peginterferon alfa-2a (40KD) at 180 mcg qw demonstrated substantially higher efficacy than IFN alfa-2a 4.5 MIU tiw.
Is It Possible to Eradicate HBV??
We don't know and perhaps not. But this study reports on test that might evaluate this possibility. Hepatitis B virus (HBV) covalently closed circular (ccc) DNA is a critical intracellular replicative intermediate that is responsible for viral persistence during chronic infection and antiviral therapy. Reducing cccDNA to very low levels may prevent reactivation after stopping therapy.
The aims of these studies were 1) to develop a sensitive and quantitative assay for the detection of HBV cccDNA in biopsy samples from patients with chronic hepatitis B, 2) to determine levels of cccDNA in patients during different phases of the natural history of chronic infection and 3) to determine if levels of cccDNA in patients change during therapy with adefovir dipivoxil (ADV).
48 patients with HBeAg+ chronic hepatitis B, 15 with HBeAg- (presumed pre-core mutant) chronic hepatitis B, 11 inactive carriers (HBsAg+, normal ALT), and 6 patients with HBsAg clearance (anti-HBs+) were included in the natural history study. 24 patients from phase 3 studies of ADV with matching baseline and post-therapy biopsies were also studied (18 treated, 6 placebo).
Average inter-lab variability was assessed using 13 biopsies and found to be less than 2-fold of mean cccDNA values. The limit of detection of the assay was 0.001 copy/cell. Mean levels of cccDNA in HBeAg+ patients (1.0 copies/cell) were 97-fold greater than in HBeAg- patients (0.01 copies/cell) (p<0.0001). Mean levels of total HBV DNA in HBeAg patients (114.9 copies/cell) were 121-fold greater than in HBeAg- patients (0.95 copies/cell) (p<0.0001). Patients with evidence of HBsAg clearance had extremely low mean levels of cccDNA (0.006 copies/cell). ADV therapy resulted in a mean 61-fold decrease in total HBV DNA and a mean 11.5-fold decrease in cccDNA (p=0.002, vs. placebo). In contrast, no significant changes in total and cccDNA were observed in the placebo group during the 48 week trial.
In HBeAg seroconverters, mean baseline cccDNA levels were lower than in non-seroconverters. Following 48 weeks of ADV therapy, mean cccDNA levels in HBeAg seroconverters decreased to levels similar to inactive carriers (0.044 copies/cell).
The investigators concluded that a sensitive assay for the quantification of cccDNA in biopsy samples has been established and may provide a valuable marker for intrahepatic HBV replication. Using this assay we have provided new information on the levels of cccDNA during the natural history of chronic hepatitis B and shown that adefovir dipivoxil therapy results in a significant decrease in hepatic cccDNA. The kinetics of cccDNA loss appear slower than those for serum HBV DNA and total intrahepatic HBV DNA. Further studies are warranted to demonstrate that monitoring cccDNA may provide an indicator of the efficacy of antiviral therapy and an independent predictor of outcome for chronic hepatitis B.