HEPATOLOGY Vol. 34, NO. 4, Pt. 2, 2001 A A S L D A B S T R A C T S 6 2 9 A

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SERUM ALANINE AMINOTRANSFERASE FLARES DURING INTER- FERON (IFN) TREATMENT OF CHRONIC HEPATITIS B(HBV): IS SUS- TAINED CLEARANCE OF HBV DNA DEPENDENT ON LEVELS OF PRE- TREATMENT VIREMIA?. Satheesh Nair , Rober t P Perri l lo, O c h s n e r Clinic, N e w Or leans , LA

Background: During IFN treatment of HBV, an ALT flare may herald a sustained loss of viral replication, but the relationship between a virologic response, the extent of a flare, and pre- treatment HBV DNA level has not been defined. Aim: to determine the relationship between the effect of ALT flares on sustained virologic response according to baseline viremia (HBV DNA) in chronic HBV infection. Methods: We performed a retrospective review of the database of a multi- center trial of IFN alfa-2b in chronic HBV (N Engl J Med 1990,323:295). All patients were HBeAg and HB¥ DNA positive before treatment. "fhe impact of an ALT flare on sustained virologic response was determined in patients with low (< 100 pg/mL) and high level (>100 pg/ml) HBV DNA at baseline as determined by the solution hybridization method. The study included 121 IFN-treated patients as follows: low dose IFN (n = 41), high dose IFN (n = 38), and six week course of prednisone followed by high dose IFN (11 = 42). Forty-two untreated patients served as controls. The degree of ALT flare was classified as mild [increase in ALT of 86-171 IU from baselinel, moderate (increase of 172-343 IU from baseline) and severe (--> 344 IU from baseline). Results: In patients having a flare, undetectable serum HBV DNA and HBeAg loss were significantly more likely at the end of follow-up (50% vs. 22%, p =0.0001 and 40% vs. 15%, p = 8.001, respectively). In the high viremia group, a proportionate increase in virologic response was ob- served as the degree of flare increased: HBV DNA loss 9%(no flare)--~25%(mildflare)-->36%( moderate flare) --+50%(severe flare) and HBeAg loss 6%--*16%--+29%--~35%; see table). In con- trast, an association between the degree of flare and virologic response was not observed in the low viremic group. By muhivariate analysis, high baseline HBV DNA, high pretreatment ALT, and both moderate and severe ALT flare were independently predictive of a virologic response with severe flare being the most powerful predic tot for a sustained loss of serum HBV DNA (odds ratio 5.3, p = 0.004). However, severe flare was predictive of a virologic response (odds ratio 7.2 p value 0.02) in the high but not low viremia group. Severe flare was also associated with a higher HBsAg loss (21%) when compared to the no flare group (2.4%, p value = 0.01). Conclusions: In patients with high level viremia, a virologic response is dependent upon the degree of ALT flare. Induction of a robust flare may enhance virologic response when high level viremia is detected.

Virological Response and Degree of Flare in Low and High Level Viremia

Low viremia ( n=78 ) High virem!a ( n= 8.5.)

No Flare(n= 85) e=40 n=45 HBV DNA less 15 (38%) 4 (9%) HBeAg loss 10 (25%) 3 (6%) Mild Flare ( n=25 ) n = 13 n = 12 HIBV DNA loss 6 (46%} 3 (25%) HBeAg loss 3 (23%) 2 (16%) Moderate Flare (n=29) n = 15 n= 14 HBV ONA loss ~ ~ (73%) 5 (36%) HBe Ag loss 10 (66%) 4 (29%) Severe Flare ( rl=24 ) n=10 n = i4 HBV DNA loss 7 (70%) 7 (50%)

_HHBeA 9 loss 6 (60%) 5 (35%)

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PHASE I DOSE-ESCALATION PHARMACOKINETICS OF L-DEOXYTHY- MIDINE (LDT) IN PATIENTS WITH CHRONIC HEPATITIS B VIRUS (CHB) INFECTION. Xiao-Jian Zhou, Nov i r io Pharmaceui tca l s , Cambr idge , MA; Seng-Gee Lira, Na t iona l U n i v H o s p Singapore; C h i n g - L u n g Lai, U n i v of H o n g Kong, P o k - F u I . am H o n g Kong; Rober t L M ur phy , N o r t h w e s t e r n Univ , Chicago, IL; D e bo r a h M Pow, M a u r e e n W Myers , Nov i r io Pharmaceut ica l s , Cambr idge , MA

Background: LdT, a 13-L-configured t h)nnidine analog, has demonstrated potent and specific HBV activity irt vitro and in vivo. In an ongoing phase I/II dose escalation clinical trial in subjects with CHB, dose- dependent viral suppression without significant toxicity was noted. Methods: Six subjects per cohort were randomized to LdT 25, 50,100, 200, and 400 mg QD. Plasma pharmacokinetics of LdT were evaluated after the first administration and at steady state (week 3-4). Serial blood samples were obtained up to 8 hours post administration. Plasma concentrations of LdT were assessed by a validated HPLC method with a lower limit of quantification of 0.1 /~g/ml and were used for model-independent pharmacokinetic analyses. Results: LdT was rapidly absorbed witb a mean time to maximum concentration (Cmax, Tin.x) ranging from 0.75 to 2.67 h. Cmax, after first administration and at steady state, increased linearly with administered doses (r2>0.83, p<0.00001 ). Cmax at steady s rata was higher than after the first dose (p = 0.01 with a mean steady state:first dose ratio of 1.31. Accordingly, area under the plasma concentration curve (AUC) increased linearly with dose (r2>0.82, p<0.0n001) and at steady state was greater than after the first administration (p=0.04) with a mean steady state:first dose ratio of 1.47. Plasma decay of LdY was monophasic up to 8 b with mean observed half-life (t m) ranging from 2.54-6.24 h. Plasma tl/z was comparable after first dose and at steady state and was independent of dose. Substantial pre-dose druglevels (range 0.10-0.26 bL~mi) were observed at steady state for doses ~ I00 my, indicative of a slower second elimination phase of the drug. Conclusions: tAT exhibits linear plasma pharmacokinetics with respect to Cmax, AUC and tuz over the doses studied. The slight accumulation of drug at steady state indicates a sustained exposure of the drug and justifies the selection of a QD regimen. Higher drug levels at steady state were not due to alteration in LdT elimination processes as evidenced by no change in tl/2 over time. These findings, in conjunction with the reported dose-dependent antiviral effects and favorable safety profile, justify exploration of higher doses of tAr.

O rio IOO 160 2~0 Y~ S~3 360 400

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TIIYMOSIN-od INCREASES INTRAHEPATIC NATURAL KILLER T CELLS AND CYTOTOXIC T LYMPHOCYTES IN THE PATIENTS W I T H CHRONIC HEPATITIS B. Satoshi Sugahara , T a k a f u m i Ichida, Satoshi Yam- agJLwa, H i r o k a z u Uehara , T o r u I sh ikawa, Yuhei Yoshida, H i s a m i Watanabe , T o m Abo, H i tosh i Asakura , Ni iga ta Univers i ty , Ni iga ta Ci ty J a p a n

B a c k g r o u n d & Aims : Thymosin-c~l ( T - M ) is a i m m u n e modi f i e r that influ- ences T-cell ma tu ra t ion , p roduc t i on of na t ive in te r fe rons ( IFN) and cy tok ines s u e h as in te r leukin-2 , and ac t iv i ty of na tu ra l ki l ler (NK) ce l l -media ted cyto- toxicity. Clinically, i t is r epo r t ed that T - c d can decrease s e r u m a lan ine a m i n o - t ransferase (ALT) level a n d ach ieve s e r u m HBV D N A clearance in the m a j o r i t y of HBeAg-pos i t ive pa t ients w i t h ch ron ic hepat i t i s B (CHB). To evaluate w h a t k i n d of l y m p h o c y t e s con t r ibu te to the r educ t ion in v i ra l load, the au tho r s inves t iga ted a change of T h l / T h 2 balance in per iphera l b lood l ymphocy te s (PBL) and in t rahepa t ic N K T cell d i s t r ibu t ions by T - ~ I t rea tment . Pat ients & Methods : Seven pa t ien ts w i t h CHB w e r e t rea ted w i t h 0.8 or 1.6 m y / d a y of T-c~l for 24 weeks . PBL and in t rahepa t ic lyrnphocytes were ana lyzed by f lowcytom- etry, before and af ter T - ~ I t rea tment . S e r u m cy tok ines were m e a s u r e d by ELISA. Resuhs : T w e n t y - f o u r w e e k s af ter T - c d t rea tment , s e r u m ALT was im- p r o v e d to a lmos t n o r m a l r ange and HBV D N A level decreased. Comple te re- sponse (no rma l i za t ion of s e r u m ALT and d i sappea r ing s e r u m HBV DNA) rate was 40 %. A l t h o u g h s e r u m I F N - y level d id no t increase, T h l - t y p e cells in- c reased a n d Th2- type cells dec reased in PBL. C D 5 6 + N K T cells in PBL in- c reased d u r i n g T - ~ I t rea tment , and then it r educed to p r e - t r e a tmen t level at the end of t rea tment . But C D 5 6 + N K T cells in the l iver r e m a i n e d s igni f icant ly a u g m e n t a t i v e even at the e n d of t r e a t m e n t ( p < 0 . 0 5 ) . C D 5 7 + N K T cells s l ight ly inc reased bo th in PBL and the liver. C D 8 + T cells also increased. T - ~ I d id no t in f luenced in e i ther doub le -pos i t ive C D 4 + C D 8 + or doub le -nega t ive CD3+CD4-CD8"cel l subsets . Conc lus ion : These resul ts ind ica ted that T - ~ I inc reased tFN-3 ,+ T h l - t y p e l y m p h o c y t e s a n d s t imu la t ed in t rahepa t ic l y m p h o - cytes, s u c h as N K T and C D 8 + T cells. It is s u g g e s t e d that the a u g m e n t a t i o n of N K T cells a n d cy to toxie T l y m p h o c y t e s in the l iver by T-c~l cont r ibu tes to the exc lus ion of HBV infec ted hepatocytes .

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HBV DNA BREAKTHROUGH DURING LAMIVUDINE TREATMENT IS MORE COMMON IN THE PATIENTS WITH PRETREATMENT ALT BE- LOW 5 TIMES LEVEL OF UPPER NORMAL LIMIT. Sang-Jong Park , Pun- dang J e s a e n g Genera l Hospital , S u n g n a m South Korea; Seung W o o n Paik, Byeong H o o n Ahn, M o o n Seok Choi , J o o n H y e o k Lee, K w a n g Cheol Koh, S a m s u n g Medical Center , Seoul South Korea

B a c k g r o u n d : L a m i v u d i n e t r ea tmen t in the pa t ients w i t h hepat i t i s B h a p p e n s to b r ing about hepat i t i s f lare-up due to the e m e r g e n c e of l amivud ine res is tan t strains. The a i m s of this s tudy w e r e to evaluate the clinical features of HBV D N A b r e a k t h r o u g h (BT) d u r i n g l amivud ine t r ea tmen t and to f ind the r i sk factors related to the b reak th rough . Subjects & Methods : The clinical course of 173 hepat i t i s B pat ients w i t h detectable s e r u m HBV D N A by hybr id cap ture assay was r ev i ewed re t rospect ively . The pa t ien ts w i t h hepat i t i s C, hepatocel - lular ca rc inoma , h is tory of i m m u n o s u p p r e s s i v e t r ea tmen t and w h o rece ived l a m i v u d i n e for less than 3 m o n t h s w e r e excluded. S e r u m HBV D N A and HBeAg/Ab w e r e c he c ke d eve ry 1-3 moths . Male to female rat io was 138 to 35 and their m e a n age was 4 0 . 3 + 9 . 9 years . 23 subjects had rece ived pr ior inter- fe ron therapy. The m e d i a n fol low-up was 15.5 m o n t h s (4 .2 -49 .2)and the me- d ian dura t ion of l a mivud ine t r ea tmen t was 15.2 m o n t h s (4.1-48.5). Mean p r e t r e a tmen t ALT was 2 8 7 . 7 + 3 5 9 . 1 IU/L and m e a n HBV D N A was 746.8 + 1202.9 pg/ml. Hepat i t i s f lare-up was def ined as the case of ALT eleva- t ion over 5 t imes level of u p p e r n o r m a l l imi t (UNL) or 2 t imes of p r e t r e a t m e n t level. Results: Nega t ive s e roconve r s ion of HBeAg deve loped in 39 subjects (22.5%) and ant i -HBe was also obse rved in 26 subjects . BT deve loped in 61 subjects (35.3%) after m e d i a n 13.1 m o n t h s (3.0-34.7) of l amivud ine treat- ment . After BT, ALT was e levated ove r 2 t imes level of U N L in 33 subjects . 21 subjec ts (34.3%) s h o w e d acute hepat i t i s f lare-up and b i l i rub in was e levated in 7 subjects . Sex, h i s tory of p r ior in te r fe ron t rea tment , and presence of c i r rhos is m a d e no s igni f icant di f ferences in the d e v e l o p m e n t of BT. But 46.4% s h o w e d BT out o f 97 subjec ts w i t h p r e t r ea tme n t ALT < 5 t imes of UNL, whereas 21.1% s h o w e d BT out of 76 subjec ts w i t h p r e t r ea tme n t ALT ~ 5 t imes of U N L ( p = 0 . 0 0 1 , OR 3.245, 95% CI; 1.643 - 6.410). In BT group , p r e t r e a t m e n t HBV D N A was 1 0 8 4 . 9 z 1 4 2 4 . 4 pg /ml and in no BT group , 562.7_+1023.9 pg / m l ( p = 0 . 0 1 3 ) . The m e a n dura t ion to the ALT norma l i za t ion af ter l a m i v u d i n e t r ea tmen t was 5.0-+2.8 m o n t h s in BT g roup and 4 . 0 ± 2 . 5 m o n t h s in no BT g roup ( p = 0 . 0 2 2 ) . BT deve loped in 12.8% of 39 HBeAg se roconve r t ed subjec ts bu t in 41.8% of 134 n o n c o n v e r t e d subjec ts (p = 0.001). Conc lus ions :HBV D N A b r e a k t h r o u g h after l amivud ine t r ea tmen t in the pa t ients w i t h hepat i t i s B de- ve loped m o r e c o m m o n l y in the pa t ien ts w i t h p r e t r e a t m e n t ALl" b e l o w 5 t imes level o f UNL, h i g h p r e t r ea tme n t HBV DNA, no HBeAg se roconvers ion , and longer du ra t ion to A L T normal iza t ion .