422A AASLD ABSTRACTS HEPATOLOGY O c t o b e r 2001

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COMPARISON O F O U T C O M E S , T R E A T M E N T S E L E C T I O N A N D COM- P L E T I O N IN H E P A T I T I S C P A T I E N T S I N A C A D E M I C A N D C O M M U - N I T Y BASED A M B U L A T O R Y T R E A T M E N T CENTERS. Donald Jensen , Scott Coder , D e p a r t m e n t of Hepato logy, Rush Presbyter ian Saint Luke 's Med- ical Center , Chicago, IL; Goerge Harb , Nick S Poulios, Roche Pharmaceut ica ls , Nutley, NJ; Alicia Shill ington, Ehab Hasan, EPI-Q, Ine, Oakhrook Terrace , IL; Mary Vance, D e p a r t m e n t of Hepato logy, Rush Presbyter ian Sain t Luke ' s Med- ical Center , Chicago, IL

Most published data on antiviral therapy for hepatitis C virus (HCV) infection is derived from controlled trials conducted at academic medical centers. In a large clinical study, 48 weeks of combination therapy with interferon and ribavirin was associated with a 40% sustained response rate and a 20% discontinuation rate for adverse effects (McHutchison et al., N Engl J Med 1998; 339:1485-92). Linle information is available about patient management and treatment outcomes in clinical practice settings. We studied outcomes in interferon (IFN) naive patients with documented HCV infection treated at academic institu- tions and community-based clinics. Charts from 176 patients treated for HCV (74 from 2 academic centers and 102 from 5 community care centers) were retrospectively evaluated to document outcomes, diagnostic utilization, treatment selection, and duration. Included patients were age ->18 years, were anti-HCV sero- positive or had detectable HCV RNA in serum before treatment, initiated treatment 48 weeks prior to inclusion (regardless of treatment completion), and were prescribed either IFN alone, injected subcutane- ously three times weekly, or in combination with daily oral rihavirin. Excluded were those with previous psychiatric disorders, previous organ transplant, prior IFN failure, clinical trial enrollees, decompensatad cirrhosis, or Human lmmunodeficiency Virus (HIV) co-infection. Patients at academic centers (AC) and community-based treatment clinics (CC) were similar with respect to age (43.9 years vs. 45.8), gender (43.2% males vs. 57.8%), and racial/ethnic background (69% Caucasian vs. 71%, 1 I% African American vs. 9%, and 7% Hispanic vs. 4%), respectively. A greater percentage of AC patients underwent genotype testing and liver biopsy (Table I). In addition, biopsies from AC patients had a higher mean grade (2.12 vs. 1.69, p = 0.005) and disease stage (2.0 vs. 1.49, p = 0.01) than CC patients. Of those genotyped, AC patients showed higher incidence of genotype 1 (Table 1), although not statistically significant. Mean 1FN dose at onset of therapy was approximately 3 million units three times weekly, and ribavirin dose was slightly greater than 1000 mg qd regardless of setting. Only 39.8% of all patients completed either 24 or 48 weeks of therapy based upon genotype. Most frequent reasons for treatment dropout included non-response (29.7% AC vs. 30.4% CC), patient non-adherence (6.8% AC vs. 9.9% CC), and adverse events (17.6% AC vs. 23.5% CC), with no significant differences. AC patients received IFN/ribavirin combination therapy, had greater virologic end of treatment (ETVR), and sustained responses (SVR) than CC counterparts (Table 1). Follow-up viral load measurement ranged from 3 - 12 months after treatment cessation but was performed on only 50% of the entire population (n= 88) regardless of setting. Patients with detectable virus at ETVR were considered non-SVR at followup. Among all patients, there is a high rate of dropout prior to completing 24/48 weeks of therapy. Dropout rates are greater and SVR are much lower than reported in clinical trials. Despite apparent increased severity of AC patients, outcomes appear improved compared to CC. AC patients were more likely to achieve non-detectable viral levels than CC counterparts. There are also significant differences between settings concerning diagnostic utilization. These results suggest a role for continuing medical education regarding the treatment of HCV to achieve a consistent standard of care.

Table 1. Liver Bx

Setting performed Academic 89.2% Community 71.6% P value 0.005

Genotyping %genotype %IFNIRBV ETVR SVRHCV performed 1 treatment HCV RNA RNA

78.4% 65.6% 87,0% 83,0% 29.1% 31.4% 50,0% 67,6% 37.5% 14.6% < 0.001 NS 0.02 0,002 0.05

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A F R I C A N AMERICANS HAVE A L O W E R VIRAL CLEARANCE RATE WITH C O M B I N A T I O N I N T E R F E R O N A N D RIBAVIRIN THERAPY FOR HEPATITIS C: RESULTS O F T W O M U L T I - C E N T E R TRIALS. Eric J Lawitz, Matt H e p b u r n , N o r m a S Cantu, Lisa M H e p b u r n , Shailesh C Kadakia, The Alamo Study Group , Brooke A r m y Medical Ctr, SanAntonio, TX

Background: Prior s tudies have sugges ted that African Amer icans have a lower response to in ter feron-based Hepati t is C therapy, bu t race has no t been de- scr ibed as an i ndependen t predic tor of t r ea tmen t o u t c o m e us ing mul t ivar ia te analysis. Aim: To evaluate the viral c learance in Afr ican Aner icans t reated wi th in terferon based therapy. Methods: Data were analyzed f rom two ongoing mul t i - cen te r trials. The first s tudy was a n o n r a n d o m i z e d trial w i th a t r ea tment r eg imen of 5 mil l ion uni ts of In ter feron alfa 2b daily + 1000-1200mg ribavir in daily for 4 weeks fol lowed by 3 mil l ion uni ts of In te r fe ron alfa 2b daily + 1000-1200mg r ibavir in for 44 weeks. In the second s tudy, par t ic ipants were r a n d o m i z e d to receive e i ther s tandard combina t ion therapy for 48 weeks (in- terferon alfa 2b three t imes a w e e k and r ibavir in) or the daily combina t ion therapy as out l ined in the first s tudy. A nega t ive HCV RNA by PCR at twelve weeks was cons idered viral clearance. Subgroup analysis of subjects t reated at Brooke A r m y Medical Center was pe r fo rmed to a t t emp t to control for access to care and income level. These subjects consis ted of mil i tary personnel and beneficiaries, each of w h o m had consis tent access to care and a stable basel ine income. Mult iple logistic regress ion analysis was pe r fo rmed wi th the fol lowing variables to de t e rmine independen t predic tors of viral clearance: age, a lanine aminot ransfe rase (ALT), basel ine HCV-RNA, body mass index, gender , geno- type, l iver b iopsy grade and stage, pr ior in terferon therapy, and race. The same analysis for 70 African Amer icans w h o comple t ed 24 weeks of PEG-In te r fe ron alfa2b and r ibavir in will be available for the annua l meet ing . Results: A total of 659 subjects (49 or 7.5% were African Amer ican) rece ived daily in terferon wi th r ibavir in and 156 subjects (30 or 19.2% were African Amer ican) rece ived s tandard combina t ion therapy. Being African Amer i can was an i ndependen t pred ic tor of failure to achieve viral clearance, w i th an odds ratio of 0 .18 (0.07- 0.46 wi th 95% CI). The lack of therapeut ic response did no t improve whe the r s t andard (OR 0.09, 0 .01-0.96 wi th 95% CI) or daily (OR 0.18, 0.06-0.51 wi th 95% CI) the rapy was given. In subg roup analysis of subjects t reated at Brooke A r m y Medical Center , be ing African Amer i can was an i ndependen t predic tor of failure to achieve vira l c learance (OR 0.09, 0.02-0.49 wi th 95% CI). Con- clusion: Afr ican Amer icans have a decreased viral c learance rate w i th inter- feron and r ibavir in combina t ion the rapy i ndependen t of a mul t i tude of factors that could inf luence t r ea tmen t ou tcome.

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DOSAGE OF RIBAVIRIN I N PATIENTS WITH HEPATITIS C SHOULD BE BASED O N RENAL F U N C T I O N : A P O P U L A T I O N P I t A R M A C O K I N E T I C ANALYSIS. Annet te Bruchfeld, Division of Renal Medicine, Karol inska Insti- tute and H u d d i n g e Un iv Hospital , S tockholm Sweden; Kar in Lindahl , Rober t Schvarcz, Division of Infect ious Diseases, H u d d i n g e U n i v Hospital , S tockholm Sweden; Lars StC*hle, Division of Clinical Pharmacology , Hudd inge Un iv Hos- pital, S tockho lm Sweden

Background: A combina t ion of interferon-alfa and r ibavir in is s t andard therapy for chronic hepati t is C (HCV). Ribavir in dosage is cur ren t ly based on body- weight . The a im of this s tudy was to critically evaluate cu r ren t dosage recom- m e n d a t i o n s on the basis of a popula t ion pha rmacok ine t i c analysis. Methods: 398 r ibavir in p lasma concen t ra t ion samples were collected f rom 63 pat ients unde rgo ing t r ea tmen t for HCV. 44 pat ients had n o r m a l range s e r u m creat inine w i th an es t imated g lomeru la r filtration rate ( G F R = es t imated creat inine clear- ance) of 57-144 mL/m in . Ano the r 19 pat ients had renal i m p a i r m e n t wi th a GFR of 5-57 mL/min . Popula t ion factors were age, gender , body-weigh t , s e r u m creat inine and GFR. A popula t ion pha rmacok ine t i c analysis was pe r fo rmed by non- l inear m i x e d effect model l ing. Results: Ribavir in c learance was found to be l ineari ly d e p e n d a n t on renal func t ion wi th a smal ler non- rena l c learance componen t . Renal funct ion was a significantly be t te r predic tor of r ibavir in c learance than body-we igh t .The v o l u m e of dis tr ibut ion, w h i c h was p ropor - t ional to body weight ( V = 3 5 . 5 x body-weight ) , was large, w h i c h resul ted in a long half-life (100-600 hours depend ing on renal funct ion) and a long t ime to s teady state (2-14 weeks) . The re was an inter- individual variabi l i ty in r ibavir in total clearance. Conclusion: Ribavir in initial dosage should be based on renal func t ion and no t on body weight . A r ibavir in dos ing schedule to reach an in tended target concen t ra t ion is p roposed w h i c h takes GFR into account . Ribavirin mon i to r ing is useful for opt imis ing HCV t r ea tmen t no t only in renal insufficiency, bu t also in o ther pat ients cons ider ing the t ime to s teady state as wel l as the in ter- individual variabil i ty in r ibavir in clearance.

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ORAL A D M I N I S T R A T I O N OF L A C T O F E R R I N L O W E R S SERUM HCV- RNA LEVELS IN PATIENTS WITH GENOTYPE-1B-RELATED CHRONIC HEPATITIS C. Naoki Kumaga i , Satoshi Ysunematsu , Kanji Tsuch imoto , Kita- sato Inst i tute Hospital , Mina to-ku Japan; Koji Yamauchi , S u s u m u Teraguchi , Hiro toshi Hayasawa, Nutr i t ional Science Laboratory, Morinaga Milk Indus t ry CO , LTD, Tokyo Japan; Hide t sugu Saito, H i romasa Ishii, Sch of Medicine, Keio Univ , Tokyo Japan

Background and Aims: In Japan the majority of patients with chronic hepatitis C (CH-C) are infected with HCV genotype lb , which is associated with a significantly lower response rate to interferon o~(IFN) treatment (around 20%). Even in infection with HCV genotype lb, patients with low viremia ( < 100K1U/ml) at baseline show a high long-term complete response rate (over 50%) to IFN treatment. Lactoferrin (LF), which is a milk protein belonging to the iron transport family is known as a primary defense protein against pathogenic microorganisms including viruses. A pilot study has been reported in which LF decreased serum HCV-RNA concentrations in patients with CH-C. In this study, we ex- amined the use of LF in CH-C patients with genotype lb and high viremia to lower serum HCV-RNA levels to < 100 KIU/ml and improve the response rate to IFN treatment. Meth- ods: Fourteen CH-C patients with genotype lb and high viremia (>100 KIU/ml) were given LF at a dose of 600 mg/day. HCV-RNA was assessed by quantitative PCR and biochemical parameters were measured at baseline, 12 and 24 weeks. Thirteen correspond- ing CH-C patients were also followed for 24 weeks without LF treatment. Written informed consent was obtained from all patients. Results: Serum HCV-RNA levels (mean +SD) in the LF group at baseline, 12 and 24 weeks were 505 ---244, 347 ---294 and 366 -+297 KIU/ml, respectively ( baseline vs. 12 weeks p<0.05). Three patients (21%) showed a decrease in serum HCV-RNA to <100KIU/ml at 12 weeks (650 KIU/ml at baseline to 69 KIU/ml at 12 weeks, 240 to 82 KIU/ml, 110 to 30 K1U/ml, respectively) and 4 did so at 24 weeks (750 KIU/ml at baseline to 73 KIU/ml at 24 weeks, 740 to 53 KIU/ml, 650 to 60 KIU/ml, 560 to 78 KIU/ml, respectively; the third case overlapped with the first case at 12 weeks). Six patients (43%) showed low viremia (<100 KlU/ml) at either 12 or 24 weeks during LF administration. In the control group, there was no significant change of serum HCV-RNA levels between baseline and 12 weeks (638 -+232 and 588 -+ 251, respectively). Also, no patient in the control group showed low viremia of <100 KtU/ml at any time. Although there was no significant change of serum ALT levels during LF administration ( 79 +51 IU/ml at base line, 74 +44 at 12 weeks and 63 +31 at 24 weeks), 6 patients with relatively high ALT levels ( >70 IU/ml, which was twice the upper limit of normal) showed a significant decline of ALT levels at 12 weeks compared with baseline (the mean -+ SD of ALT at base line,12 and 24 weeks were 124 + 4 7 , 9 9 -+51 IU/ml and 65 -+30, respectively; baseline vs. 12 weeks p<0.02). There was no significant change of serum ALT levels in the control group. No adverse effect associated with LF administration was observed during the study. Conclusion and Discussion: Oral administration of LF significantly lowered serum HCV-RNA levels in CH-C patients with genotype lb and high viremia. Six out of 14 patients (43%) showed low viremia (< 100 KIU/ml) during the administration. Therefore pretreatment with LF to CH-C patients might improve the response rate to IFN treatment by lowering serum HCV-RNA levels at baseline.