212

PEG IFN ~ 2b 1,0 meg/kg/wk + ribavirin is equally as effective as PEG IFN 2b 1.5 meg/kg/wk + ribavirin: Preliminary, results from a prospective, randomized, controlled, multi-center trial Steven L Flamm Joel Cahan, JeiFey Goldman Greg Nelligan, David Chua, Bradley Shapiro, Rockford Yapp, Edward Jurkovic, Mohammad Bawani Daniel Ganger, Gerald Mmgolelli

BACKGROUND : PEG-iaterferon a 2b (1.5 mcg/kg'wk) + rihavirni (800mgld) is eft~:cnve and approwd for tmatmeat of pts with chronic hepatitis C virus (HCV) inlection. The medications have side effects and frequently require dose reduction or discontinuation. Data cotni)armg PEG-iFN a 2b (1 0 rncg/k~*wk) monothempy yield equivaleat sustained response rates in compariaon to PEGqFN u 2b (15 mcgAg/wk) monotherapy. Sustained response rates and tolerability of PEGqEN u 2b (i.0 mcg/kg/wk) + ribavirin are unknoml. AIM : We sought to determine the efficacy and tolerabihiy of PEGdFN c~ 2b (1.0 mcg/kgAvk vs 15 mcg&g/wk) in combination with ribavmn. We speculate that lower dose PEGqFN 2b may be equally effective and better tolerated than the standard dose METHODS : Pts with chronic HCV (+ HCV RNA) were evaluated withni the context of a prospective, randomized, coatrol/ed, muhi<eater trial comparing low dose (LD) PEG-IFN c~(10 mcg/ kg/wk) + ribavirni (800-1400mg/d) vs. standard dose (SD) PEG-1FN e~ 2b (1.5 mcg/kg/ wk) + rfbavirin (800-1400rag/d). Demographic, serological (ALT), vimlogacal (HCV P, NA level and HCV genotype) and histological data were obtained. Eligible paueats were random- ized to one treatment group. Medications were administered fbr 24 wks (HCV GT non-i) or 48 wks (HCV GT 1). Tolerabflity (side effect profile and drop out rate) was determined. Preliminary 24-wk treauneat response data are reported RESULTS : 246 pts have been enrolled 103 pts (54 in LD and 49 in the SD) have received the medications for at least 24 wks 40154 (74%) in LD are GT1 in comparison to 37/49 (76%) in SD 22/54 (41%) in LD have Eb4 ni companson to 26/49 (53%) in SD There are no significant differences bmween the groups at basehne. 36154 (67%) in LD are HCV RNA - at Wk 24 ~23/40 (58%) GT 1 and 13114 (93%)GT non-l~ in comparison to 25149 (51%) in SD d6/37 (43%) GT I and 9/12 (75%) GT non-l** 13% in LD discontinued the regimen prior to Wk 24 in comparison to 16% in SD There is a trend to fewer adverse eveats in LD (52) in comparison to SD (64). There are no significant differences in 24-wk treatment response rates or medication disvontniuation rates. CONCLUSIONS:l) PEG-IFN ~ 2b (1.0 mcg/kg.~,k) + ribavirin is equally as effective as PEGqFN c~ 1.5 mcge~xg/wk + rihavmn in regards to HCV RNA ~ at Week 24. This is tree in GT 1 and GT non-] pts 2) Medication discontinuation rates were equal between the two groups. 3) There is a trend to tewer adverse events in the LD group.

213

Clinical Significance of Pegylated Interferon Induced Neutropenia: Results from the WIN-R Trial Furqaan Ahined, Ira M. Jacobson, Robert S. Brown Jr , Nezam Afdhal, Raymond Rubin, James Spivey, Bradley Freflich, Fredric Regenstem, David Bemstem Robert Doig, Clifford Brass, Win-R Study Group

Background: Neatropema occurs commonly in patients treated with pegylated iatefl)ron and rfbavmn (Mamrs, hancet 2001;358:958-65). The climcal significance of this neutropenia remains uncertain. Aim: To determine if there is a correlation between the occurrence of neutropenia and the development of serious infections while on combination therapy. Mefnod: We provide data on infectmus serious adverse eveats (SAE) irom the WIN-R Trial, a U.S multiceater study" comparing fixed (800mg) versus weight based (800-1400mg) daily dosing of ribavmn in combination with pegylated interferon alfa-2b (pegintron) 1.5 fig&g/ week We reviewed serious intections and ANC data at weeks 0,2,4,8,12,18,24,30,36.42, and 48. Results: Ot the 4243 patients enrolled in the study', 30 (0.7%) developed infectious SAEs while on therapy. These 16 male and 14 female patients ranged in age from 35-63 years (mean 47 years). The infections included pr~eunmnia (10), UTI (3), cellulitis (3), URTI (2), abscess (4), and one case each of cat scratch disease, salmonella colitis, thruncle, meningitis, appendicitis with perforation tibial hardware nifection, bacteremia, and invasive C. jejuni diarrhea Reviewing available data, 24 patients i~ceived antibiotics, 27 were hospital- ized, and 7 required surgical irnela, eation. One patient died with pneumonia. Complete ANC data was available fnr 25 of the nif?ctious SAE patients. The ANC fell below 1000 at some point in 14 (56%) patients. The overall mean nadir ANC in all patients was 1317 • 822. Ihe mean nadir ANC for the SAE patients was not sigmtficaatly different than that for the rest of the paneats (1198 • 757 vs 1318 • 823, p = 046). The proportion of patients who developed ANC <750 was similar in both groups (20%) in patients with intectious SAEs, the mean ANC prior to infection was significantly higher than the mean nadir ANC(2286 • 1676 vs 1198 • 757, p = 0005). The r~dir and pre-inleetion ANCs were the same in only 15% (3/20) of patients The mean timing of the nadir ANC and the onset of infection were similar (week 18 v~. v``,!ek 16) Additional data regarding this issue ia being accumulated Ccmchisions: (1) Patients who develop serious inteetions whde on combination therapy with pegyiated interferon atfa~2b and ribavinn do not have signitlcaatly lower mean nadir ANCs (2) lniectious SAEs generally did not occur at the time of nadir ANC. (3) Criteria and utility fur dose reduction of peginterferon and the use of granulocyte stimulating factor to treat neutmlx~nia require further assessment

214

Successful Retreatment of Peginterferon Nonresponder Patients With Chronic Hepatitis C With High Dose Consensus Interferon Induction Therapy Stephan Kaiser Holger ttass, Michael Gregor

Treatmem w~th pegyIated mtertemn alia (PEG IFN) and ribavirin has an efficacy in chromc hepatitis C patients with sustanied response rates of about 50%. However, response in genotype I patients with high viral load is considerably lower with SR rates of 29-37%. Furthermore, numerous recent studies with peginterferons have shown only low response rotes of 11 to 36% in the treatment of combiimtton therapy nonmsponders. In contrast,

several recent studies have shown improved response rates using consensus interferon (interferon alIacond, CIFN) in ganotype 1 / high viral load patients as well as previous combination therapy non-responders. In the present stud),, the efficacy of a ClFN induction tberapy fbllowed by a CIFN / ribavirin combination treatment in PEG IFN combination therapy non-responders was evaluated. 23 patients have been included so far All paneats had elevated ALT~values and were viremic, with 22 having genotype 1 Histologic confirmation oI chronic inflammation by liver biopsy was obtained in all patients with grading and staging according to the Knodell-Ishak Score, where 7 patients showed bridging fibrosis or cirrhosis. Patients were either treated with CIFN at a dosage of 9 ug QD for 16 weeks or with CIFN 27 ug QD for 4 weeks, followed by 12 weeks of CIFN 18 ug QD. Thereafter, treatment is continued in all treatment groups with CIFN at a dose of 9 ug QD with rlbavirin (at 10 - 14 mg/kgld) for another 34-56 weeks~ depending when the PCR result becomes negative ensuring a negative PCR result for at least 48 weeks under therapy. Results show that after the initial 16 weeks of CIFN monotherapy, a primary response with undetectable serum HCV-RNA was observed in 36% of patients in the CIFN 9 ug QD group and in 50% in the CIFN high dose 27118/9 ug group. After 24 weeks ot CIFN / rihavirin combination therapy, a negative PCR was observed in 49% in the CiFN 9 ug + ribavirni group, and in 57% of the CIFN 27/18 ug + ribavirni group. Due to side effects the C1FN dose had to be reduced in 2 patients and discontinued in one patient CIFN daily dosing/induction therapy together ``vith subsequent nbavtrin combination therapy thus shows response rates m about half of pre'vious pegmterferon combination fherapy non-responders. If these primary response rates translate into correspondingly strong sustained response rates, an ell~ctive treatment ,,viii be in place fiat this diflicuh-to-treat patient group.

215

The Safety, EITlcacy and Pharmacokinetics of Peginterferon Alfa-2a (40KD) In Children With Chronic Hepatitis C Kathleen B Schwarz, Parvathi Mohan, Michael Narkewicz, Jean P. Molleston, Helen S. Te, Sylvia Hu, Susan Sheridan, Matthew Lamb, Stephen C. Pappas, George Harb

The role of antiviral therapy for chronic hepatitis C (CHC) in children remains unclear Some studies have sho``vr~ the safety and efficacy of standard interfiemn (IFN), with or without ribavirin (RBV), in children witl~ CHC, but no data is available regarding the use of pegylated IFN in this population Objective: To investigate the safety, effica W and pharmacokinetics (PK) of peginterferon alta-2a (40KD) in children with CHC. Methods: This is a muhiceater, open-label study of treatment-nalve children with established CHC Children received pegmterferon alta-2a (40KD) once ``veekly for 48 weeks with a 24-week posttreatment follow-up. The dose was normalized for patient body surface area (BSA) ([180big/i.73 ma)] x patient BSA). Muhiple blood samples were obtained to determine single- dose and multiple-dose PK. Adverse events (AEs) were assessed by clinical exam HCV RNA was measured at weeks 12, 24, 48 and 72 using AMPLICOR MONITOR TM HCV Test v. 2.0 Results: Fourteen patients, 8 males, 6 females, aged 2-8 (median = 3.5) years were enrolled; majority (13/14) were Caucasian and genotype 1 (12/13). CHC was acquired by vertical transmission in 11 patients. After administration of the first peginterfemn alla-2a (40KD) dose, there was rapid and sustained absorption with mean concentrations of 22.3 _+ 8.2 ng/ml and 19.0 • 8.4 ng/ml at 24 and 96 hours postdose. Mean stea@-state trough concentrations were 24.3 -+ 13.7 ng/mL Peginterferon alfa-2a (40KD) concentrations increased 1.5- 2.5-fold before reaching steady state by week 12. At weeks 24, 48, and 72, 57% (8/14), 43% (6/14) and 38% (5/13) of patients, respectively', were HCV RNA negative Most frequently reported AEs were pyrexia, headache, vomiting, anorexia and abdominal pain; no serious AEs were observed. The majority, of these AEs were mild in intensity. Four patients were withdrawn from therapy (1 due to lack of viral response at week 24; 2 due to elevated transaminases; 1 due to exacerbation of baseline hypertnglyceridemia). Five patients required dose reductions due to neutropema. Conclusmns: Peginterferon alfa-2a (40KD) was wdl-tderated. Exposure to peginterferon alfa-2a (40KD) in pediatrics is slightly higher than in adults following a fixed 180 ~tg dose The efhcacy of peginterferon alfa-2a (40KD) monotherapy in children appears higher than that reported for adults and approaches that for standard IFN + RBV in children. These resnhs support further stud?, of pegiatefferon alfa-2a (40KD), with and without RBV, m children with CHC.

216

Aggressive Psychiatric Intervention Based on Clinical Suspicion, Not Standardized Depression Scores, Increases Adherence to Pegylated Interferon and Ribavirin Therapy for Hepatitis C Jennifer Moss, Anshu Cbandra, Paul Gaglio, Sil'ia Hafiiger, Lorna Dove, Steve Lobritto, Ira Jacobson, Robert Brown

introduction: Neuropsychiatric side efli::cts of pegylated interferon often limit therapy for HCV. Depression is the most common reason for treatmeat discoatinuation. Early' treatment of depression may increase the efhcacy of interferon-based therapy. Aim: To investigate the utility of standard depression scores (Beck Depression Index (BDI) and Center for Epidemiologic Stu&es-Depression (CES-D) for predicting depression and of early psychiatric mterveation on adherence to pegylated interteron and ribavirin therapy. Methods: 55 treat- ment naive HCV patients at one site were entered into WlNR-R, a study comparing standard ribavirm 800rag qd to weight based nbavirin, 800-1400mg qd, both with PEGqmron 15 ug/kg q wk. We report on 39 patients with complete follow-up. BDI and CES-D surveys were completed at weeks 0,4,12,24,48 and 24 weeks postIherapy; investigators were blinded to results. Psychiatric evaluation was performed by 1 psychiatrist if there was current (+ ad, n = 6) or prior ( + hx, n = 8) depression, or if they reported depression on matme questioning Data on psychotropic medication and outcomes was collected. Results: 30 of 39 patients completed surveys. During therapy, 40 (20% at entry), 30, and 6% used antidepressants, sleeping medications and benzodiazepines respectively. 30% used no psychotmpic medica- tions. There were no dose reductions for psychiatric side effects. The 2 surveys were analyzed nidividually, and were normalized to produce 1 data set Patients requiring antidepressants had mean maximum scores of 19 (BDI), 27 (CES-D), and 12 (normalized) compared to 10, 13, and 6 mspectivdy for those not requirnig antidepressants(p<0 05). Mean scores for patient groups are shown in the figure BDI and CES-D scores in~reased at wk 4. were

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