Long-term safety beyond 48 weeks of adefovir dipivoxil (ADV) 10 Mg once daily for chronic hepatitis B (CHB): An integrated analysis of two phase III studies

339

groups Liver histology tbllow up was available m 95 of these patients Liver histology was not ditferent in the two groups at the two-year follow-up. Subgroup analysis to assess the response in patients by randomization strata as well as baseline severity of disease failed to disclose any treatment benefit in these subgroups. SUMi',s UDGA in a dose of 13-15 mg/kg/day w?s *lot agsociated with improved liver biochemistries or liver histology in patients with nonalcoholic steatohepatitis when compared to placebo CONCLUSION: Ursodeoxycholic acid, ahhough safe and well tolerated at a dose of 13-15 mg/kg/day, is not an effective therapy for patients ~ylth nonalcoholic steatohepatitls

Comparison of Viral Replication Fitness of Wild-Type and Lamivudine-Resistant HBV in Patients William Delaney Iv, Christopher Westland, Hinling Yang, Humid Namini, Vincent Thibault, Yves Benhamou, Carol BrosgarL Craig Gibbs, Michael Miller, Shelly Xiong Background: Lamivudine-resistant HBV has been described as replication defective based on early clinical observations and in ,dtro data for single mutations of M204V or M2041 in the YMDD motif of HBV polymerase. However, recent data suggests that compensatory mutations also emerge and patients with long-term lamivudine resistance undergo disease progression. Aims: To compare levels of serum HBV DNA and ALT in patients with lamiw~dine-resistant and wild-t),~ HBV To determine the prevalence of compensatory mutations in YMDD-mutants and their contributions to replication fitness. Methods: Patients analyzed were enrolled in trials of adefovir dipivoxil for the treatment of wild-type (2 trials, n = 695) or lamivradine-resistant HBV (3 trials, n = 203). Patients were required to have serum HBV DNA levels ->5 logl0 copies/mL at entry'. Serum HBV DNA was measured by Roche Ampiieor PCR. DNA sequencing was used to identify resistance mutatimrs at baseline. Results: At baseline, patients with lamivudine-resistant HBV had similar serum HBV DNA (medians 7.7, 8. I, and 8.8 logl 0 copies/roD compared to patients with wild-type HBV (medians 7.1 and 8.4 logl0 copies/mL); median ALT levels were 79-82 IU/L in lamivudine-resistant and 94-98 IU/L in wild-type patients. Compensatory mutations (V173L, L180M) that enhance the replication of YMDD-rmatant HBV in vitro were found in the majority (88%) of lamiv~dine-resistant patients. At baseline, four major mutational patterns were identified in patients vdth tamivudine-resistant FtBV (L180M+M204V [58%], V1731.+LI80M+M204V [17%], M204I [12%L L180M+M204I {11%]); serum HBV DNA did not vary sigmficantly across the different mutational patterns. Conclusions: Lamivudine-resistant HBV is capable of replicating to levels comparable to wilddype HBV and causing abnormally high ALT. Exclusion of patients with lower serum HBV DNA leveIs from eligibility preclude an assessment across a greater spectrum of viral load The four patterns of lamivudine resistance mutanons all had similar levels of serum HBV DNA

337 A Dose Escalating.Trial Evaluating the Safety and Antiviral Activity of Clevudine in Patie'/jts with Chronic HBu Infection Patrick Mareellin, S{~yg Sacks~ George Kk Lau, Herve Mommeja-Marin, Dominique 5ereni, Jean-Pierre Fr~?novacki, Brian Conway, Christian Trepo, Elsa Mondou, Andrea Snow, B C, ~'oo; HIaS Lee, Franck Rousseau Background: Cle~'udihe (CLV, 1.-FMAU) is a potent inhibitor of HBV replication in vitro. in woodchnaks, CLV. produced a potent and sustained viral suppression following a 12 weeks closing periodc Methods: This was a multicenter, open-labd, dose escalation study evaluating 10, 50:100 and 200 mg CLV QD for 28 days (n=5, 10, i0 and 71arm, respectively). Patients were followed post-treatment for 24 weeks. Eligible patients had chronic EIBV intection, Baseline HBV DNA levels (~q_)->3x106 copies/mL, were nucleoside treatment naive and without H1V or FtCV co-inti.ctinn. VL was assayed using Digene Hybrid Capture II (wuh a lower limit of detection of 4700 c/roD and genotype by" di-deoxy sequencing Resuhs: 32 patients were enrolled 81% were male, 81% Asian, 88% HBeAg positive At Baseline, median VLs were 73, 8,0, 8 8 and 8.4 logl0 c/mL and median ALTs were 55, 119, i06 and 64 1U/L in the 10, 50, 100 and 204) mg QD cohorts, respectively. Afier 28 days of dosing, the median log10 VL cMnge from Baseline was -2.5, Q.7, -3,0 and ~2.6 and median change in ALT flom Baseline was -13, -14.5, +37 and -14 U/L, in the 10, 50,100 and 200rag cohorts, respeclively. At 6 months post-dose, sustained biochemical and virologic responses were observed: 71% of the patients overall had normal ALl" levels and median log10 VL ctmnges from Baseline were -1.2, -L4, -2.7 and -L6 in the 10, 50, 100 and 200rag arms, respecnvely. During the study, 8 patients lost HBeAg (30%) of whom 5 seroconverted to HBeAb (119%). CLV was well tolerated, without dose related adverse events. A transient increase in ALT was observed in the 100 mg cohort but not in the 200 mg group. The phannacokinetics of CLV were dose proportional with a long plasma balghfe supporting a once daily regimen No treatment emergent mutations in the HBV DNA pol domain were observed 5 months after treatment. Conclusion: These msuhs confirm die antiviral activity of once daily clevndine and further demortstrate, in humans the uniquely sustained postdreatmem antiviral effect seen prevmudy in woodchucks. Despite the short (4 weeks) duration of therapy very" favor:able rates of HBeAg loss and serocouversion were observed without evidence to date of acquired resistance on CLV therapy,

340 Long-Term Safety Beyond 48 Weeks Of Adefovir Dipivoxil (ADV) 10 Mg Once Daily For Chronic Hepatitis B (CHB): An Integrated Analysis Of Two Phase III Studies M. Tong, M. Shiffman, j. Heathcote, R Gish, k Jeffers, S Sacks, K Kaita, R Fallis, M. Wollman, C. James, S. Van Doren, J. Fry, S. S. Chert, C Brosgart Background: ADV is a nucleotide analog with activity against wild-type, precore and lamivudine-resistam hepatitis B virus (HBV) resulting in significant histological, serological, and biochemical improvement. Objective: To report safety results of treatment with ADV 10 mg qd for up to 109 weeks in compensated HBeAg+ or HBeAg- CHB patients. Methods: Data fi'om two phase Iii studies were integrated Clinical and laboratory adverse events (AEs) from 492 patients receiving ADV 10 mg qd were analyzed. Results: Patients were 78% male, 48% Caucasian, 47% Asian, median age 40 years (range 16 to 67 years); median ADV exposure: 49 weeks (range 0.4-1094 weeks) Frequency and nature of AEs was similar to that seen with ADV and placebo m the first 48 weeks. AEs leading to drag discontinuation in 3% of patients and Serious AEs were reported in 5% of patmnts. No single SAE occurred in > 2 patients (< 1% each) One unrelated death was reported. Two patients (<1%) had a confirmed serum creatinine increase -> 0 5 mg/dL from baseline; both resolved. Of 111 patients who sv~tched from ADV to placebo in the second 48 weeks, 25% had ALT elevations > 10 x ULN; none experienced liver decompensation. Conclusinn: ADV 10 mg once daily w~s well tolerated in up to 109 weeks of dosing. Serum creatinine elevation was rare. Patients who discontinue HBV therapy', including ADV, should be closely monitored for ALT flares.

338 Predictors of Virologic Response after Lamivudine Treatment in Children with Chronic Hepatitis B Xenia Horn, Nancy R, Little Maureen M. jonas Background: kamivudine is a therapeutic option for children with chronic hepatitis B (HBV). in adults, pretreatment ALT andJor histologic activW predict HBeAg loss with treatment. Aim To ident@ the pretreatment variables that predict virologic' response (VR)(defined as loss of HBeAg and undetectable HBV DNA in serum after 1 year of treatment) to lamivudine in children. Methods: A randomized, placebo-contrulled tnal of lamivudme (52 wks) has been completed in 288 children (Jonas et al, NEJM 2002;346:1706-13). Exploratory" analyses with prospectively defined baseline covariates of interest were used to evaluate potential predictors of 'v~ These included age, gen&r, race, weight, body mass index (BMI), ALT, HBV DNA, and ttistoiogic Activity Index (HAl) scme, lintially, umvariate analyses were conducted using ]ogistic regression. Next, multivariate analysis was used to Investigate the pattern ot covariation of multiple factors with response (step-wise logistic model). Subgroup analyses were then pertbrmed to show response rates across different levels of baseline characteristics (Mantei-Haenszel test) Results: In the umvariate model, there was no difference in rate of VR by" age, gender, race (.asian vs non-Asian), weight, BMI, or previous interferon therapy afier adjusting for treatment. Basdine ALT level (table) and HAI scores ~Odds Ratio of VR was 177 (95%CI 09%3.29) for HAl scores 5-9 and 2.57 (95%C1 0,818.17) for HAl scores 10-14 as compai~d to scores 0-2 ( P = 0 0 0 2 ) . were both strong predictors of VR and 1-1BeAgseroconversion. Conclusions: As in adults, baseline ALT and HAI scores are inlportant predictors of VR to lamivudine in children, The likelihood of response was not sigmficantly affected by" patient age or race,

341 Rescue Treatment with Adefovir Dipivoxil for Lamivudine Resistant Patients pre- and post- Liver Transplantation Pietro kampertico, Mauro Vigano, Chiara Seletti, Massimo lavarone, Ersifio Del Ninno, Nicole Lama, Massimo Colombo Background and Aim. Candidates for liver transplantation who develop lamivaldine resistant strains of HBV are at increased risk of hepatic decompensatmn and recurrence of hepatitls B after lwer transplantation. The aim of the study was to assess the efficacy and safety of adefovlr dipivoxil 10 mg once daily" to treat patients with lamiwadine-reslstant hepatitis B (HB\0 Material and Methods. 14 patients (12 men, 5I years old, 4 HBeAg positive) with lamivudine-resistartt HBV, i.e. devated ALT, HBV-DNA > 102',6 copies/mL by HBV Roche Ampficor Monitor, YMDD mutants, either waiting for liver transplantation (n = I0) or with hepatitis B recurrence post-transplantation (n = 4), were treated with adefo~ar 10 mg once daily (Gilead Sciences) for 2-21 months (median 6 months) added to ongoing lamiv'udine treatment. Results. HBV-DNA levels decreased from a median of 2x10/',7 copies/ml (rangel0A6-10A9) at enrolment to 3x10AS, 5x10/\4, 4x10/\4, and 2x10/\4 copies/ml at month I, 2, 3 and 6 of treatment, respectively. By month 3, 9 patients had at least a 3 log reduction of serum HBV-DNA, 4 patients had a 2 log decrease and 1 patient had a I log decrease. By month 6, HBV-DNA became undetectable by PCR (<200 copies/ml) in 5 of 6 patients with pre-treatment HBV-DNA <10/\8 copies/m1 compared to 0 of the 4 with >10A8 copies/nil, in 2 of 3 patients with HBV-DNA levels between 10/\5-10/\6 copies/ ml at month 6, contmuons treatment with ADV up to month 12 did not significantly decrease viremia thrther. ALT levels progressively decreased dumlg treatment: 7 (50%) patients had normal ALT by month 3 and 10 (74%) by month 6. Child-Pugh score improved by at least 2 points in 6 of 8 Child-Pugh B/C patients. Liver transplantation was performed in 2 patients with HCC and pre-OLT HBV-DNA levels of 4xl0A,2 and 4x10/'\4 copies/ml, respectively: none had HBV recurrence after 12 months of Mlow-up (both were treated also with HBIg). None of the patients had adefo'ar-related side effects or significam changes of renal f:anction. Conclusions. Treatment with adefovir dipivoxil resulted in a rapid and significant reduction

,

vi~og!c Respo,tse H B ~ Seroconver~on (3.comp~ Placebo Lamlvudine Ptacebo Lamlvudine (n=~5) (n=191) (n---95) (n=191) <=1 1/7(14%) 1/8(13%) 1/7(14%) 1/8(13%} 9,:'1.,:=2 2/30 (7%) 10/86 (12%} 2/30 (7%) 10/86 (12%} >2-5 5/41 (12%) 25/81 (31%) 5/41 (12%) 23/81 (28%) >5 4/11 (24%) 8/16 (50%) 4/17 (24%) 8/16 (50'4) Overall 1~95 (13%) 44/191(23%) 12/95 (13%) 42/191 (22%) P-value' 0,111 0,001 0,111 0.001 9P-value based on Mantet-Haenszel test comping responsehloresponseby baselineALl" category,excludingpts with r,)rmal ALT #De~ned as HBeAg-veh.IBeAbwe/HBVDNA-ve ALT

(x ULN)

A-709

AASLD Abstracts