HEPATOLOGY Vol. 34, No. 4, Pt. 2, 2001 AASLD ABSTRACTS 625A

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TREATMENT WITH LAMIVUDINE OF VENEZUELAN CHILDREN WITH CHRONIC HEPATITIS B. PRELIMINARY REPORT. Reinaldo Pierre, Hos- pital Agustin Zubillaga, Caracas Venezuela; Carmen Lopez, HospitalJM de Los Rios, Caracas Venezuela; Lisett Rondon~ Hospital Universitario de Caracas, Caracas Venezuela; Irma Machado, Instituto de Inmunologia, Caracas Vene- zuela; Edixa Mendez, Hospital Federico Ozanam, Guatire Venezuela; Keira Leon, Hospital San Juan de Dios, Caracas Venezuela; Alfredo Suarez, Hospital Agustin Zubillaga, Caracas Venezuela; Miguel E Garassini, Hospital Universi- tario de Caracas, Caracas Venezuela

Lamivudine is a nucleoside analogue that has been used for the treatment of adults patients with chronic hepatitis B and recurrent hepatitis B infection after liver transplantation. We report our experience with the use of lamivudine as monotherapy in children with hepatitis B infection. METHODS: 10 patients, 8 male 2 female median age 9,4 years, with chronic hepatitis B: HbeAg and DNA positive with elevated alanine aminotransferase (ALT) were treated with oral lamivudine 4-6mg/Kg for one year. 8 patients had liver biopsy that showed chronic hepatitis B, without cirrhosis. 6 patients had past history of haemato- oncology disease in remission, without treatment. RESULTS: 8 patients low- ered ALT levels, 4 of them to normal levels. 2 patients (20%) had sustained seroconversion during treatment: negative HbeAg, appearance of anti-HbeAg and negative DNA by PCR. One patient became DNA negative but HbeAg persistently positive. 4 patients only showed a reduction in the DNA levels. None of the oncology patients had evidence of seroconversion. Only one pa- tient developed abdominal pain and transient thrombocytopenia during treat- ment that resolved without stopping the medication. CONCLUSION The use of Lamivudine in children with chronic hepatitis B normalized ALT in 40% and produced seroconversion in 20%. The drug was well tolerated without signif- icant side effects. None of the patients with past history of oncology disease responded.

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EFFICACY OF LAMIVUDINE IN PATIENTS WITH CIRRHOSIS DUE TO HEPATITIS B. David N Moskovitz, Les B Lilly, George Tomfinson, Jenny Heathcote, University Health Network, Toronto, ON Canada

Introduction The nncleoside analogue Lamivudine (]-AM) has been shown to be effective in suppressing HBVDNA, normalizing ALT, and improving histo- logical appearances in both HBe positive and negative hepatitis. LAM has also been shown to induce clinical improvement in individuals with decompen- sated hepatitis B. But published trials of LAM therapy have included few pa- tients with cirrhosis. The aim of this study was to examine the efficacy of LAM outside the context of a clinical trial in patients with and without cirrhosis due to hepatitis B. Methods We retrospectively reviewed the charts of all LAM patients given treatment with LAM monotherapy at a single site. Inclusion criteria included presence of HBsAg in serum for at least 6 months with simul- taneous elevation in serum aminotransferase levels and detectable HBVDNA in serum. Pretreatment presence of cirrhotics was confirmed by liver biopsy and/or ultrasound. Response to therapy was defined as ALT in normal range, undetectable HBVDNA, loss of HBsAg, in the HBeAg negative group. Response in the HBeAg positive group was defined as ALT in the normal range, unde- tectable HBVDNA, loss of HBeAg, loss of HBsAg, or the development of anti- HBe. Decompensation was defined as the presence of ascites, hepatic enceph- alopathy, jaundice, or varices. Results There were 99 patients who were treated with LAM for 6 months or more, 78(79%) were male, average age 47 years. The majority 58(59%) were Asian 28(28%), North AmericarffEuropean, and 13(13%) Mediterranean. Fifty-four (54%) were HBeAg positive at baseline. There were 37 (37%) patients with cirrhosis. Response to LAM therapy regard- less of initial HBeAg status was similar regardless of baseline histology (p= 0.67). However evidence of hepatic decompensation despite LAM therapy developed in 12/35 (34%) with cirrhosis diagnosed prior to the introduction of LAM, whereas decompensation occurred in 5/48 (10%) patients without cir- rhosis on pre treatment biopsy (p = 0.017). Conclusion Baseline histology does not influence the antiviral response to LAM therapy, nevertheless hepatic decompensation may occur in the face of continued LAM therapy.

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IS THERE ANY CORRELATION BETWEEN HBV GENOMIC FACTORS AND RESPONSE TO LAMIVUDINE THERAPY IN ANTI-HBE POSITIVE PATIENTS?. Maria Buti, Liver Unit, Hospital General Universitario Valle He- bron, Barcelona Spain; Xose Costa, Montserrat Cotrina, Department of Bio- chemistry, Hospital General Universitario Valle Hebron, Barcelona Spain; Au- ristela Vald¢s, Liver Unit, Hospital General Universitario Valle Hebron, Barcelona Spain; Francisco Rodriguez, Rosendo Jardi, Department of Biochem- istry, Hospital General Universitario Valle Hebron, Barcelona Spain; Rafael Esteban, Jaime Guardia, Liver Unit, Hospital General Universitario Valle He- bron, Barcelona Spain

Background/aims: To evaluate the role of HBV variants in different genomic regions in antiHBe positive patients with chronic hepatitis B treated with lami- vudine. Patients Methods: 20 anti-HBe and HBV-DNA positive patients with elevated ALT levels were treated with lamivudine for more than 3 years. In all cases, at baseline HBV genotype, precore and Basal Core Promoter mutations were studied by PCR and sequencing. HBV-DNA was quantified by bDNA (LLD:7.5xl05copies/ml) and Real Time PCR (LLD:lxl03copies/ml)and YMDD variants by INNO-LiPA at different times during therapy. Response to therapy was defined by bDNA negativity and normal ALT values. Results: Baseline characteristics of these 20 patients were 14 male and 6 female, mean age 43,5 years, mean HBV-DNA 1.5xl06copies/ml, mean ALT 82 UI/L, 30% had liver cirrhosis. HBV genotype: A in 8 cases (40%), D in 10 (50%), Mixed A/D 2 (10%). Pre-core mutations were detected in 14 (70%) cases, Promotor in 15 (75%), and both mutations in 14 cases. Baseline HBV-DNA were lower in patients with pre-core mutants (6.3x100.000 vs 1.9x10.000.000 copies/ml, p<0.04). No statistically significant relationship was detected between viro- logic response to lamivudine and any baseline factor (viral load, HBV geno- type, disease stage, presence/absence of pre-core or core promotor mutations, patients' demography or YMDD variants). Conclusion: In anti-HBe positive patients, biochemical and virologic response decreases when therapy is pro- longed while the proportion of YMDD variants increase. No correlation be- tween any baseline factor and lamivudine response was observed.

YEAR 1 YEAR 2 YEAR 3 No= 20 No= 17 No=tl

Bbchemical response 14 (70%) t 3 (76%) 4 (36%) HBV-DNA by bDNA (-) 18 (90%) 13 (76%) 4 (36%) HBV-DNA by PCR (-) 15 (75%) 8 (47%) 1 (8%) YMDD Variants 5 (25%) 9 (53% / 10 (91%)

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POTENCY AND PHARMACOKINETICS OF ACH-126,443 SUGGEST UTILITY FOR TREATMENT OF LAMIVUDINE-RESISTANT HEPATITIS B INFECTION. Lisa M Dunkle, Scott C Oshana, William G Rice, Achillion Pharmaceuticals, Inc, New Haven, CT

ACH-126,443 (/3-L-Fd4C) is an L-nucleoside analog designed to improve on the anti-HBV and anti-HIV potency of lamivudine while maintaining the safety profile afforded by the protection against mitochondrial toxicity associated with the "unnatural" L-configuration. The ICs0 of ACH-126,443 against wild- type HBV is 0.002/*M (--0.5 ng/mL) compared with 0.01-5.6/.~M (2.3-1300 ng/mL) for lamivudine (3TC). For YMDD mutant strains which are highly 3TC-resistant (IC50>8 p~M), the IC50 for ACH-126,443 is only 0.2 p,M (~50 ng/mL). Objectives: A Phase 1 single dose, ascending dose level, placebo- controlled study was conducted in healthy volunteers to assess whether safety, oral bioavailability and pharmacokinetics of ACH-126,443 support further evaluation for potential utility in the therapy of chronic HBV infection. Meth- ods: Doses of l, 5, 10, 20, 50 and 100 mg were administered to 8 subjects per dose level randomized 6:2 active drug:placebo. Subjects were observed for adverse events and plasma pharmacokinetics for 24 hours and repeat safety evaluations occurred 7 days after dosing. Plasma concentrations were mea- sured using a validated LC/MS assay with a lower limit of detection of I0 ng/mL. Resuhs: No dose- or clearly drug-related clinical or laboratory adverse events were observed. Plasma concentrations were not detected at the 1 mg dose level. At dose levels of 5 mg and above, pharmacokinetics indicated good oral bioavailability with dose-proportional absorption. Maximum plasma con- centrations (Cmax) were achieved at every dose level 60 - 90 minutes after dosing (Tmax). Mean Cmax ranged from 15.8 - 421 ng/mL with coefficients of variability approximating 18 - 36%. The terminal half-life (T1/2) appeared to be approximately 6 - 8 hours and area under the plasma concentration (AUC) curves increased approximately dose-proportionally from 172 - 1935 ngebr/ mL. Conclusions: ACH-126,443 demonstrated good tolerability following sin- gle oral doses up to 100 mg and oral bioavailability appeared to be very prom- ising. Plasma pharmacokinetics, especially total exposure (AUC), suggest that further evaluation for the treatment of both wild-type and 3TC-resistant HBV is clearly warranted.