Effect of IFN-alfa induction treatment on HCV infection of peripheral mononuclear cells (PBMC) and viremia

Viral hepatitis: clinical aspects

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ONE YEAR LAMIVUDINE (LAM) TREATMENT OF "e MINUS" CHRONIC HEPATITIS B (CHB): BIOCHEMICAL, VIROLOGICAL AND HISTOLOGICAL RESULTS R. Fiorino, C. Cursaro, M. Margotti, A. Gramenzi, L. Di Giammarino, E Felline, E. Ferri. M. Hussainl, A.S.E Lock ~, P. Andreone, M. Bernardi Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, University of Bologna, Italy. tUniversity of Michigan and VA Med Ctr, Ann Arbor, USA. Background/A~m: LAM trealmeat seems to 13e effective and safe for pts with CHB, but few data are available in precore mutant hepatitis B virus (HBV) infection. We report here our experience after one ycax c o u r ~ o f LAM (150 ms/daily) in pts with histologically proven "e minus" CHB. Methods: we enrolled 37 pts and to date 22 completed 12 m o o f therapy. Complete response (CR) was defined as normal ALT and negative HBV-DNA by PCR (detection limit 10 copies/ml). Nineteen pts underwent control liver biopsy at the 12th m o o f LAM. Up to now To date the HBV precore and P genes were direetely sequenced in 12 pts. Results: after 12 mo o f treatment, which was well tolerated, 16 pts (73%) normalized ALT, 15 (68%) had undetectable HBV-DNA and 14 (64%) showed a CR. No HBsAg loss was obtained. We observed an important improvenlent in histological activity index according to Knodell (10-a:2.8 vs 7.7=t=3.8, p=0.027) both in necroinfimnm~ory (7.7±2 vs 6-a:3, p=0.047) and fibrosis (2.3=1=1.2 vs 1.6+1.1 p=0.04) scores. HBV polymcrase YMDD mutations all with biochemical and virological relapse were observed in 3 pts (14%). O f thena, one patient also reverted ~ o m A1896 stop codon to wild type ptecore sequence simultaneonsly to YMDD mutation. Conclusions: this trial confirms the usefulness and safety o f LAM also in pts with "e minus" CHB. In fact, LAM induocs a sustained inhibition o f HBV replication in a large proportion o f pts with a significant improvement in liver histology and a low rate o f YMDD resistance.

EARLY HCV-RNA CLEARANCE DURING DALLY ADMINISTRATION OF INTERFERON IN COMBINATION WITH RIBAVIRIN IN NAIVE HCV PATIENTS G. Taliani t, M.C. Badolato 2, C. Pasquazzi~, V. Boddi3, G.B. Gaeta 4, G. Stornaiuolo4, N. Marino 5, EL. Blanc5, C. De Bac2 llnst, of Infect Dis, Univ of Florence, Italy. 2Dept. of Infect and Trop Dis, Univ "La Sapienza", Rome, Italy. 3Dept of Exp Path and Oncol, Univ of Florence, Italy. '*Clinic of Infect Dis, Univ of Neaples, Italy. 5Infect Dis Unit, S Maria Annunziata Hospital, Florence, Italy. In patients with chronic HCV hepatitis, IFN induces HCV-RNA clearance within 12 weeks in virtually all responders.Combination therapy with ribavirin and 3 MU o f IFN t.i.w, reportedly induces a higher rate of HCV-RNA clearance, yet with a delayed response; however, no data are available on viral kinetics during combination therapy with other IFN regimens. We compared viral kinetics in 52 previously untreated patients with chronic hepatitis C, randomly assigned to one of three treatment groups: Group 1 (n=17)-6MU IFN t.i.w.; Group 2 (n=18)-3MU IFN 6 days/week; and Group 3 (n=I7)3MU IFN 6 days/week (defined as daily) plus 1,000-1,200 mg ribavirin daily. HCV-RNA kinetics were grossly similar among these groups. However, the percent of reduction in RNA titer at day 10 was significantly higher for combination therapy compared to daily IFN monotherapy (p=0.04), suggesting that ribavirin enhanced the ability of daily IFN to induce early suppression o f HCV replication. Twentyseven patients achieved complete response (13 in Group I, 6 in Group 2, 8 in Group 3), all within week 12. Unexpectedly, all responders to combination therapy had cleared the virus by week 4. Conclusions: Daily IFN plus ribavirin induces early HCV suppression; thus responders can be recognized early and treatment can be discontinued in non-responders, increasing the cost-benefit ratio without substantially affecting the efficacy.

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EFFECT OF IFN-ALFA INDUCTION TREATMENT ON HCV INFECTION OF PERIPHERAL MONONUCLEAR CELLS (PBMC) AND VIREMIA P. Urbfinek, E. Prochfizkovfi-Francisci, Z. Mare~ek, M. Kahib, R. Bruha, J. Petrt';,1, M. Brodanovfi 1st Dep. of Internal Medicine, 1st Medical Faculty Charles University, Prague. Background: Daily aplication of high doses of interferon-alfa could be cfective ill tim Ireatmcut of clwonieHCV ilffcetion.PBMC were fouud to be possible source of HCV relapses after eessatiou IFN fl~erapy. Active HCV replication was defined as the presence of both ncgalive m~d positive strmld of HCV-RNA in PBMC. Aims of study: i. to evaluate the efficacy of daily aplication of high doses interferon-alfa in elimiuation of HCV ixffeetioqof PBMC 2. to eslablish file efficacy of two phase IFN regimen in the treatment of chronic HCV uffection. Melhods: 20 patiems wilh choonic HCV infcclioa, wilh histologically proved chronic hepatitis of mild or moderate activity were iacludcd into study. Treatmcnl regimen: Plmse A: Imerferon-alfa 2b 10 MU daily for 28 days, Phase B: lnlerfcron-,'flfa2b 3 MU TIW for 12 weeks. PBMC were tested for file prescuce of HCV-RNA by str,'md specific PCR oil days: 0. 5, 29 m~dthereafterevery 4 weeks during the plmse B. Results: HCV-RNA in PBMC was posilivc ou day 0 in 11/20 (55%) pts. Negalive strrmd was detected in 8/11 pts. The same results were oblaincd on &ly 5 . Ou day 29 (end of induction phase) HCV-RNA in PBMC was positive in 4/20 pls. 2/4 samples wcrc positive for uegative smmd of HCV-RNA. All of these 4 pls were clasified as parlial respouders in the cud of induclion Ihefapy. All pts with uondctcetable HCV-RNA iu PBMC on day 29 (16•20) were classified as complele responders. Ulfforhumtcly,during 4-6 weeks of phase B Ireatmcut. 14 pts relapsed - viremia reappeared. This was tile cndpoint of the study. 2 pls who finished fl~c study x~x:restill negative for HCV-RNA in PBMC dnring plmse B and Ihis status slill lasts. These 2 pts arc clasified as sustained respouders. Coaclusions: a) daily application of IFN-alfa is effective mefllod for elinfination of HCV ilffeelion from PBMC b) PBMC seem to be important source of HCV relapses e) 4 weeks al~plicatiou of 10 MU IFN-,'dfilseems Io be short for uutiulaitdng the positive effect of therapy, d) longer iuduction treatment should be evaluated

BILE DUCT LESIONS IN CHRONIC HEPATITIS C: BIOCHEMICAL AND VIROLOGICAL RELATIONSHIPS WITH HISTOLOGICAL DAMAGE E. Giannini, E Botta, A. Fasoli, E Romagnoli, L. Mastacci l, P. Ceppa l, L. Comino 2, A. Pasini2, D. Risso2, R. Testa Gastroenterology Unit, DI.M.I., University of Genoa, Italy. 2Dept. of Human Pathology, University of Genoa, Italy. 3Dept. of Health Sciences, University of Genoa, Italy. Biledua Inims (BIX,)in dxotic l z ~ I s C (Q-¢3 are a c h m n d ~ ~ ies~ Ahnmml le~s of ~ T ~e alsoa mmm~ ~ Wlefl~r liodemiml ~ crv~10oml ~ ~ r , ~ ~ immce of B l ~ mayletp m • e def~im c ~ ~ m~ims~ps ia 0 - ~ T~s sUty e ~ , ~ ~ ~ e ~ m t i ~ ,,,,-~ stub ievds ~ G r , t,3e aads (SBA~ ri.a~ ~ Smsfmse (na3srx rL"V.Rt~ pmam oeI-]b-'V-Rt~md ~e rtesemeo e ~ ia ~ ' y (39 M;21 F. ABe4S* 11~ms) Cr~ paiem (Fs~ m A (~v.<6,,,,-tL) ~ t e ev~m,4 by meresa'emym~ c o b a n ~ test~ ~ ~,a,~u~ AS, Osb, r ~ , w A na3Sa"(~v.501Ufl.,)~ ~1" (1~0~1]~6~. ~ n , ~ n43S1"levels~ee o t m ~ in 16lm, and emmg ~ese 13 ffd mt slxmB I ~ wh'len,GSr v~s alined in only 3 its wi~aB~L HDL ~ na ~ ~ ~ ahnmat S~A ~eves(r~a092~ The s p e a f ~ and ~ ~r -tGT,ane 78% and 73%,respmivdy.C,-.~:-~-~~ cf.rG'T andS~Ahad9 , ~ specilk~ and54°.4s m s i f i ~ i n ~ ~ r ~ , ~ dBD~ We fumdno ~ amm~ stomalevelsOt'.~'T,.x.Gb~,andSBA.FL-'V-RNA ~ a s ' a n e ~ r , ~ o u ~ a n c t s~Smnay, inp~immwi~am)L0,43xt0~+ t,S~0' 5,17x10~+ 1,02x10~).II l~Wa~ FIb'V-RNA+ivc(12%),andnc~had BDI..In

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