5 9 8 A AASLD ABSTRACTS HEPATOLOGY O c t o b e r 2001

1703

INTERFERON DOSE INCREASE FOR EARLY (WEEK 12) NON-RE- SPONDERS TO INTERFERON ALFA-2B + RIBAVIRIN THERAPY FOR CHRONIC HEPATITIS C DOES NOT LEAD TO A VIRAL RESPONSE AT 4 8 WEEKS. Norber t Bran, Peiying Xiao, Douglas A Finch, Charles S Lieber, Bronx VA Medical Ctr and Moun t Sinai School of Medicine, Bronx, NY

BACKGROUND: At the end of treatment with interferon alfa-2b (IFN) and ribavirin (RBV) for chronic hepatitis C, the viral response rate (HCV RNA <100 copies/ml) is only 50%. Patients who have a poor response at treatment week 12 typically have a low treatment response. This study examined whether in such patients a dose increase of interferon can lead to a better outcome. METHODS: An open-label non-randomized parallel-group dose increase study was conducted in which patients with chronic hepatitis C (HCV RNA + ) were begun on standard dose combination therapy (IFN 3MU TIW + RBV I000 mg QD) for a total of 48 weeks. Patients were either treatment naive or had prior unsuccessful treatment with IFN monotherapy. Patients were considered early non-respunders, if at treatment week 12 HCV RNA was reduced by less than 50% from baseline or ALT was elevated. These early non-responders were continued at treatment week 16 with an increased iFN dose of 5 MU TIW. Early responders were continued at the same IFN dose of 3 MU TIW. RBV dose remained unchanged. Primary endpoint was sustained viral response (HCV RNA < 100 copies/ml) at post-treatment Week 24 (SVR). Secondary endpoints were viral response at end of treatment and post-treatment week 48. Analysis was by intention-to-treat. RESULTS: Fifty-five patients were enrolled in the study, of whom 8 discontinued from the study before week 16. The remaining 47 patients continued at week 16 with an IFN dose of either 3 MU (n=37) or 5 MU T1W (n= 11) and are used for this analysis. Both groups were similar in HCV genotype ( 1 = 87.5% 2+3 = 12.5%), baseline HCV viral load (median 3.4 M copies/ml), prior treatment vs. naive, and demographics. Among the 47 subjects, 3 were lost to follow-up and were considered end of treatment non-responders. One patient in the 5 MU group had HCV RNA <100 copies/ml at weeks 12, 48, 72, and 96 with abnormal ALT throughout due to Parkinson medication rather than hepatitis C. He was reclassified as early respondar. The results of viral response and early discontinuation in each group are displayed in table 1. No early non-responder had a response to' treatment with increased IFN dose of 5 MU T1W + RBV 1000 mg/d. By contrast, early responders had a significantly higher rate of SVR of 29.7%. Afl 11 sustained viral responders remained HCV RNA negative at follow-up week 48. CONCLUSION: Increasing the IFN dose from 5MU T1W at week 16 for early non-responders to IFN 3 MU TIW + RBV 1000 mg/d does not lead to a viral response at the end of 48 weeks of treatment. It may lead to more treatment discontinuation due to side effects. A sustained viral response at follow-up week 24 remains sustained at week 48.

Table 1! Viral re_r~.p_onse and early discontinuation

Treatment N group

Early 37 responders Early non- 10 responders p value (Fisher's exact test)

Viral Viral Viral reap. SVR SVR resp.

response post-Rx post,Rx genotype genotype EadyD/C end Rx wk 24 1 s 2+3

(SVR) wk 48

35.1% 29.7% 29.7% 2"L9% 80.0% (n=32) (n=5) 16.2%

0,0% 0.0% 0,0% 0.0% 0,0% 30,0%

0.025 0.049 0,049 0.15 0.33 0,29

1 7 0 4

POOR EFFECTIVENESS OF INTERFERON ALPHA MONOTHERAPY FOR THE TREATMENT OF CHRONIC HEPATITIS C IN H U M A N I M M U N O - D E F I C I E N C Y VIRUS COINFECTION. Mass imo Puoti , S Zaltron, Un iv of Brescia AO Spedali Civili, Brescia Italy, P Delle Foglie, Ospedale di Tren to , Tren to Italy; P Quinzan , Ospedal i Riuniti, Bergamo Japan; P Costa, Ospedale Carlo Poma , Mantova Italy; R Mar ino , Ospedale di Vibo Valentia, Vibo Valentia Italy; M Andreoni , Ospedale di Biella, Biella Italy; G Stagni, Un iv di Perugia Italy; C P Corosi, Un iv of Brescia Italy

AIMS: To assess efficacy, tolerability and impac t on HIV infect ion of In te r fe ron alpha m o n o t h e r a p y in HIV-HCV coinfected patients. DESIGN: Muhicent re , opena, r andomized , control led trial a imed to c o m p a r e In ter feron a 2a 6 MIU tw wi th no t r ea tmen t for HCV coinfection. METHODS. Inc lus ion criteria were: chronic hepat i t is C as the only cause of l iver damage , no contra indica t ions to interferon, compensa t ed l iver disease and stable HIV disease w i th CD4 con- s tant ly above 3 0 0 / m m c in the last 6 mo. Three pat ients were cirrhotics, 53% were infected by genotype 1; all we re m o n i t o r e d m o n t h l y w i th b iochemis t ry , comple te b lood counts and thr imes t ra ly w i th Ampl ico re HCV 2.0, thyroid h o r m o n e s , HIVRNA and CD4. In ter feron was s topped in the presence of W H O class II1 adverse event. P r imary response and sus ta ined response were defined as ALT normal iza t ion and undetec tab le HCVRNA respect ively at the end of t r ea tmen t and 6 m o n t h s after therapy w i t h d r a w a l RESULTS. Eighty four pe r cent of pat ients were males , 84% have had his tory of IDU, aged 34+ / -5 . Fifty pe r cent of the pat ients were on t r ea tmen t w i th HAART at baseline. For ty one pat ients were ass igned to the t r ea tmen t g roup and 43 were identified as con- trois; they were r a n d o m i z e d f r o m Janua ry 1998 to J anua ry 2000. End of treat- m e n t response was observed in 16% of t reated pat ients ( p = 0.05 vs. un t rea ted) and a sus ta ined response was observed in 7% of t reated pat ients ( p > 0 . 0 5 vs, n o n treated) . N o n e of the un t rea ted pat ient s h o w e d bo th and end of t r ea tmen t or sus ta ined response. One pat ient in the t reated group d ied for abdomina l lympf ioma. Two pat ients in the t reated g roup s h o w e d an HIV-1RNA increase greater than 0.5 log/m; h o w e v e r HIV-1 RNA levels and m e a n CD4 counts were similar in the two groups at all t ime point . HAART failure occur red in 2 pat ients f rom each group . CONCLUSION Even if a lpha in terferon m o n o - the rapy can be conduc ted wi thou t severe side effects, its efficacy and cost- effectiveness remains questionable. Combina t ion therapy will p robably be n e e d e d to t reat HCV coinfect ion also in HIV infected patients.

1 7 0 5

VIRAL LOAD DEPENDENT DOSING OF INTERFERON: 3 VS 5 M I L L I O N U N I T S WITH RIBAVIRIN. Lawrence B Stein, Wi l l i am C Sloan, Carl B Wallach, Za lman R Schrader , Michael A Samach, Robert W Schuman , Ellen J Rosen, Brian T Kloss, Angela Novack , Michael Oros, Affiliates in Gas t roenter - ology, F l o r h a m Park, NJ

PURPOSE: In te r fe ron (IFN) and Ribavirin (RIB) in combina t ion have been s h o w n to be m o r e effective in e l iminat ing hepati t is C v i rus (HCV) at end of t r ea tmen t (ETR) and after cessat ion of t r e a tmen t (sus ta ined virologic response - SVR) than IFN alone. Nonetheless , there are groups of pat ients that r e spond less well; i.e. those w i th geno type 1 and HCV viral levels > 2 mil l ion/mL. W e s tudied pat ients w i th CHCV w h o were na ive to t r ea tmen t us ing 3MU of IFN in pat ients w i th viral loads < 3 mi l l ion and 5MU of IFN in pat iens w i th viral loads > 3 mill ion. All rece ived s tandard we igh t -based RIB doses. METHODS: Eighty- eight t r ea tmen t na ive pat ients w i th PCR detectable HCV and a b n o r m a l ALTs were studied. A liver b iopsy was done in pat ients suspec ted of be ing H C V posit ive > 5 years, none had cirrhosis and all agreed to par t ic ipate after in- fo rmed consent . T r e a t m e n t was ini t iated and con t inued for 48 weeks in all b u t one pat ient w h o was geno type non -one and was therefore t reated for 24 weeks. T r e a t m e n t was con t inued unless side effects or noncompl i ance wa r r an t ed dis- cont inuat ion . Patients were fol lowed accord ing to a pescr ibed p r o t o c o l Re- sponse was m e a s u r e d us ing viral c learance as an end po in t and analysis in- d u d e s those pat ients w h o have ei ther r eached the 24 -week m a r k or have d i scont inued the s tudy. Those no t yet at 24 weeks have no t been inc luded in the analysis. RESULTS: Eighty-e ight pat ients began t rea tment : 4 d/c because of non-compl i ance , 6 because of side effects (2 psychiatr ic , 1 hemato logic , 1 GI, 1 dermatologic , 1 fatigue) and 3 for reasons no t s tudy related. Current ly , fifty-eight pat ients are enro led in the 3MU group and thir ty are in the 5MU group; a total of five pat ients are early in t r ea tmen t and are no t ye t at w e e k 24. Data collect ion and analysis is ongoing. Ten pat ients r equ i red dose r educ t ion of RIB due to a n e m i a and five pat ients r educ t ion of IFN due to leukopenia . The re was no significant difference in side effects be tween the two groups. CONCLUSION: A l though the n u m b e r s are smal l and the data pre l iminary , the response rates in the two groups suggest that h igher dose in ter feron increases the l ikel ihood of SVR in those pat ients w i th h igher viral loads. Research sup- por t ed f rom an unres t r ic ted g ran t f r o m In tegra ted Therapeut ics .

Responses to Treatmen t Dose ,,, Week,,24 ErR SVR

"3 MU 19153 = 36% 17f50 = 34% ........ t 1/45 = 24% 5 MU 22/30 = 74% 17/29 = 59% I1/26 = 42%

1 7 0 6

ADMINISTRATION OF RIBAVIR1N WITH FOOD RESULTS IN HIGHER AND LESS VARIABLE RIBAVIRIN PLASMA CONCENTRATIONS. Ian M Marks , Ma t thew W Lamb, Roche Laborator ies Inc, Nutley, NJ; Michael W Fried, David Halajko, Susan Pusek, Steven Zacks, Dickens Theodore , Roshan Shrestha, Univers i ty of Nor th Carolina, Chapel Hill, NC; Mar lene W Modi, Hof fmann-La Roche Inc, Nutley, NJ

Background: Ribavirin in combination with standard interferon has become the standard of care fur the treatment of chronic hepatitis C. Oral doses of ribavirin are rapidly and extensively ab- sorbed. The effect of food on the pharmacokinetics of ribavirin has not been well studied. It has been reported that ribavirin bioavailabifity increases if taken with a high-fat meal; one study reported a 16% increase in C~x and a 4% increase in AUC0.2~h, while another reported a 70% increase in both Cmax and AUC0.hst for ribavirin capsules. In the same studies, ribavirin absorption was slowed following a high-fat meal (33% and 145% increase in t~x, respectively). With these disparate results, we conducted a 2-way crossover design study to better characterize the effect of food on the pharmacokinetics of ribavirin when administered as tablets. Objective: To assess the effect of food on the pharmacokinetic properties of ribavirin after oral administration of Roche ribavirin tablets. Methods: Forty-six individuals with current or previous CHC infection who met entry criteria were randomized to receive a single oral dose (600 rag) of ribavirin under fed (with food) or fasted conditions on 2 occasions separated by a 7- to 10-day washout period following the last blood sample. Serial blood samples were collected for the determination of ribavirin plasma concentrations up to 192 hours postdose. Noncompartmental and compartmental pharmacoki- netic analyses were performed and a statistical evaluation was completed to determine the effect of food on ribavirin pharmacokinetics when givenin tablet formulation. Results: The effect of food on the pharmacokinetics of ribavirin in subjects who successfully completed the 2-way crossover was evaluated after a high-caloric, high-fat meal. The ratio of the least-square geometric treatment means (fed/fasted) for AUC0-t92h and C~x was 1.42 and 1.66, respectively. This may be due to enhanced absorption or a reduction in pre-systemic metabolism when ribavirin is given with food. There was a 2-hour delay in tmax (4 vs 2 hours) and AUC0_i~r increased by 38% following the fed treatment. The terminal half-life was similar for both groups. The oral clearance was decreased by 25% following the fed treatment and is reflected by the increase in AUC0 i,f- The intra-subject variability was approximately 18% for AUC019~h and 26% for C ~ . The inter-subject variability for most pharmacokinetic parameters was less during the fed treatment. Conclusions: Our results are consistent with previous reports demonstrating increased systemic exposure ff ribavirin is taken with food. However, the magnitude of the food effect with the Roche ribavirin tablet is less than that reported for ribavirin capsules. Since variability in ribavirin concentrations is reduced with food, it is recommended that patients take ribavirin with food. When ribavirin is taken with food, patients will have higher but less variable plasma concentrations. This may translate into a more consistent therapeutic effect.

Mean (%CV) P,harmacokinet,!c Parameters . . . . . . . . . . . . . . . . . . . . AUCe4s~ C..= " AUCoi~.f

Treatment (~9.h/mL) (ng/mL) t~= 1 (h) (p~.hlmL I ttt2 (h) Cl/F (LJh)

1172.5 4,0(39,8) 40.72(31,9) 167(34.5) 16.29(33,3) Fed 26,58 (30.5) (34.9)

Fasted .... 18,~8,5(32,~3), 731.8(43.7) 2.0(68.3) 31,21(37.9) 158(29,9) 2 2 ~ Median values