Randomized, controlled trial with interferon-α (IFN-α) combined with ribavirin with and without amantadinsulfat in primary IFN-α non-responders with chronic hepatitis C

1953

1955

Intensive Daily High Dose Interferon Does Not Overcome Autiviral Resistance in African Americans with Chronic Hepatitis C. Dickens Theodore, Univ of North Carolina, Chapel Hill, NC; Mitchell L. Shiffman, Richard K. Sterling, Medical Coil of Virginia, Richmond, VA; Christine J. Bruno, Emory Univ, Atlanta, GA; Jeffrey Weinstein, Jeffrey Crippin, Baylor Univ, Dallas, TX; Gabriel Garcia, Stanford Univ, Polo Alto, CA; Teresa L Wright, Univ of CA, San Francisco, CA; Had S. Conjeavaram, Univ of Chicago, Chicago, IL; Rajender K. Reddy, Univ of Miami, Miami, FL; Frederick S. Noite, Emory Univ, Atlanta, GA; Michael W. Fried, Univ of North Carolina, Chapel Hill, NC

Randomized, Controlled Trial With Interferon-or(IFN-a) Combined With Ribavirin With And Without Amantadinsulfat In Primary IFN-a Non-ResponderaWith Chronic Hepatitis C Gedinde Teuber, Univ Hosp, Frankfurt Germany; Thomas Berg, Univ Hosp, Berlin Germany; Manfred Lafrenz, Univ Hosp, Rostock Germany; Hans Weidenbach, Univ Hosp, UIm Germany; Juergen Schoelmerich, Univ Hosp, RegensburgGermany; Perdita Wietzke-Braun, Univ Hosp, GoettingenGermany; Juergen Pausch, Medical Hosp, Kassel Germany; Rudolf Arnold, Univ Hosp, Marburg Germany; Guntram Lock, Univ Hosp, RegensburgGermany; Hopf Uric, Univ Hosp, Berlin Germany; Stefan Zeuzem, Univ Hosp, Frankfurt Germany

Recent studies have suggested that African American (AA) patients with chronic HCV have a lower rate of response to interferon (IFN) therapy than Caucasians(Ca). To date, patients in these studies have all been treated with similar regimens of interferon (3MU TIW or 9 mics TIW) alone or in combination with ribavirin. It is not known if a more aggressive IFN regimen would improve response rates among AA. Aim: To determine if an intensive regimen of daily, high dose IFN would improve the initial response rates to therapy for hepatitis C among AA patients compared to Ca patients. Methods: We have previously reported that treatment with daily, high dose IFN significantly improves initial and end-treatment response rates (Amer J Gastro 2000; 95:3225-3229) comparedto standard doses of thrice weekly IFN. In this trial, conducted between 10195 and 6/97, 104 patients were randomizedto 24 wks of therapy with IFN alfa-2b at either 5 MU daily or 3 MU TIW. Treatmentgroups were prospectively stratified by HCV genotype and pretreatment HCV RNA levels (Amplicor Monitor). Treatment was discontinued at week 12 of therapy for patients who remained HCV RNA positive. In a retrospective analysis of this database which included a high percentage of AA, we have evaluatedthe effect of IFN dose and raceon initial treatment responsein subjects w/genotype 1. Results: Of 104 patients, AA: n= 21 (20%) and Ca: n=78 (75%). Genotype 1 was significantly more common among AA than Ca [20121 (95%) vs 64/78 (69%); p < 0.02]. The response rates at wk 12 among AA or Ca for two IFN regimens are shown in Table 1. Levels of HCV RNA decreased more slowly dudng the first 12 wks of therapy among AA, regardless of IFN dose, than in Ca (data not shown). Conclusions: AA respond poorly to standard doses of IFN. Treatment with an intensive high dose regimen improved the initial response for Caucasians but had little effect on response in African Americans. Increasing dose of IFN does not overcome the antiviral resistance in African Americans.

Recent pilot studies suggested a beneficial effect of triple therapy with IFN-~ combined with ribavirin and amantadine in primary IFN-a non-responders with chronic hepatitis C (1). The aims of the present study were to evaluateefficacy and safety of IFN-~ribavirin retreatment with or without amantadine sulfate in a large cohort of IFN-~ non-responsive patients. 134 consecutive IFN-a non-responderswere enroged. Patients received IFN-a 2b 5 MU daily for 4 weeks, 5 MU tiw for 20 weeks,followed by 3 MU tiw for additional 24 weeks in combination with ribavirin 1000-1200 mg/d (n = 70) or with IFN-od'dbavirinplus amantadine sulfate 100 mg bid for 48 weeks (n=64). Treatmentwas discontinued in patients with detectableserum HCV-RNA after treatment week 24. An overall sustained virologic response with undectable serum HCV-RNAlevels was observed in 271134 patients (20.1%). Despite a trend towards a higher sustained virologic response rate in patients receiving triple retreatment compared with those treated with IFN-~ribavirn alone (23.4% vs. 17.1%), the observed differences between the two treatment arms were not significant (p=n.s.). Irrespective of treatment, patients infectedwith HCV-genotypenon-1 were more likely to respondto antiviral retreatment than patients infected with HCV-genotype1 (38.8% vs. 172%, p=0.013). In conclusion, the present study does not confirm an antiviral effect of amantadine in combination with IFN-a and ribavidn. The observed relatively high overall sustained virologic response rate may be relatedto intensified interferon retreatmentin combination with dbavirin comparedto standard regimens. (1) Brillanti, S. et al: Hepatology 2000; 32: 630-4. 1956

Responseratesat wk 12: AA vs Ca IFN Dose 5 MU Daily 3 MU TIW

AA 2/8 (25%), 1/12(8%)c p=ns(~c)

Ca 18/24(75%)b 9•30 (30%o)d p<.01 ~a)

Hepatitis C Virus Genotype 4 Infection in the United States; Clinical Features and Response to Therapy Sunil Ramrakhiani, Bruce R. Bacon, SreelathaC. Varma, Sanjay Ramrakhiani, Adrian M. Di Bisceglie, Saint Louis LJnivSch of Med, St. Louis, MO

p=.O3(,,~b) p=ns(c~d)

Background: HCV genotype is a useful epidemiological marker of HCV infection and an important determinant of responseto antiviral therapy. Genotype 1 accounts for about 70% of infections in the U.S. while genotype 4 accounts for less than 2%. HCV genotype 4 is the predominant strain in the Middle East and Africa, where it is associated with severe fiver diseaseand poor responserate to interferon therapy. Aims: To study the epidemiology,clinical charecterietics and response rate to interferon and ribavidn of patients with HCV genotype 4 infection in the U.S. Patients and Methods: Fifteen patients with HCV genotype 4 infection, treated at St. Louis Univ., were identified and evaluated. Retrospective chart review was performed to know demographics, risk factors for acquisition of infection, baselinelaboratory studies and response to combination therapy. HCV genotype was determined by various methods (RFLPanalysis 7, DNA sequencingwith phylogeneticanalysis 6 and unspecified 2). Liver biopsy was performed for assessment of hietolooic grade and stage. HCV RNA was measuredby quantitativePCR.Patientswith detectableHCV RNAat 6 months were considered nonresponders and their therapy discontinued. The remainder were treated for an additional 6 months. Sustained biochemical and virological response was defined as normal ALl and undetactable HCV RNA 6 months after completing therapy (i.e. at 18 months). Results: All but one of the 16 patients were born in U.S.; 13 (87%) were Caucasianand 10 (67%) were male. Seven each had HCV subtype 4a and 4b/c while I had 4e. Eight patients (63%) had history of injection drug use, 1 (7%) used intranasal cocaine, 3 (20%) had normal serum ALT values (mean ALT 112 U/L, range 15-502). All had detectableHCV RNA (mean 434,097 copies/ml, range 14,000-1,000,000). Only 1 had cirrhosis (stage 1, 27%; stage 2, 60%; stage 3, 6.5%; stage 4, 6.5%). Eleven patients were treated with interferon and ribavirin (9 have completed and 2 are still on treatment). Nine of these 11 (82%) had undetectableHCV RNA after 6 months of therapy and 6 of 9 (67%) who have completed therapy had undetectable HCV RNA6 months after completion of treatment (sustained response).Conclusions:Infection with HCV genotype 4 is commonly associatedwith a history of illicit drug use. Most patients with HCV genotype 4 have mild liver disease.Patients infected with HCV genotype4 respond well to 12-month course of combination antiviral therapy.

1954 Continuous Combination Therapy Has Superior Viral Clearance ComparedTo Standard Combination Therapy-A Multicenter, RandomizedTrial Eric J. Lawitz, Shailesh C. Kadakia,Brooke Army Medical Ctr, San Antonio, TX; Mark Jeffries, Wiitord Hall Air Force Medical Ctr, San Antonio, TX; Avanish Aggarwal, Bahri Bilir, Edward A. Galen, Kenneth Diamond, David James, John Jolley, Harry Matossian, Thaun Nguyen, Paul Warfield Background:The current standard combinationtherapy for hepatitis C, interferon alfa 2b (IFN) 3 million units three times per week and daily ribavirin 1000 or 1200mg, provides a sustained response rate of 35-45%. Viral kinetics studies show an initial dose dependent HCV-RNA clearance.Twenty-Igorhours after a single dose of IFN viral reboundbeginsto occur. Sustained responseratesmay be optimized by the use of induction dosing, followed by daily combination therapy (continuous combinationtherapy). Aim: To comparethe efficacy of continuous combination therapy with standard combination therapy. Methods: Participants were randomized to receive either standard combination therapy for 48 weeks or 5 million units of IFN daily + 1000-1200mg ribavirin daily for 4 weeks followed by 3 million units of IFN daily + 10001200mg ribavirin for 44 weeks. HCV-RNAwas measured at week O, 12, & 48 of treatment and 24 weeks post treatment. Results: Two hundred and twenty-five adult participants with compensated liver diseasewere randomized,132 participants have completed 12 weeks and 66 havecompletedtherapy. Baselinedemographics,virology, & histology were similar. Results are seen in the chart below. Conclusion:Continuous combinationtherapy results in a superior viral clearancecompared to standard combination therapy at 12 and 48 weeks. Benefits are most evident in patientswith genotype1, higher viral loads, & advancedhistology. Completion of this study will discern whether this encouraging interim analysis will translate to an improved sustainedviral response. Partial sustained responseresults will be availablefor the annual meeting.

HCV-RNA Clearance Genotype 1 HCV-RNA>

STANDARD 12 weeks

DALLY 12 weeks

STANDARD 48 weeks

DALLY 48 weeks

42% (29/68)

75% (48164)

30% (12/40)

73% (19/26)

35% (19154) 30% (11/38)

70% (28140) 65% (22/34)

25% (8/32) 21% (6•28)

68% (13119) 60% (9/15)

32% (7/22)

75% (12/16)

11% (1/9)

57% (4/7)

1957 A Phase II Study of the Combination of Histamine Dihydrochloride and Interferan alpho-2b (IFN-~2B) as Initial Therapy in Chronic Hepatitis C (HCV) Patients: 48week Results Yoav Lude, Kapian Medical Ctr, Rehovut Israel; Sandy Hyle, Kurt R. Gehlsen, Maxim Pharmaceuticals, San Diego, CA Histaminedihydrochloddemay potentiateimmune-basedtherapiesby inhibiting the production and releaseof free radicals from phagocytic cells in the liver and thus may protect NK cells and T cells from free radical-inducedapoptosis. Histamine dihydrochlodde was studied as a potential immunoenhancer of interferon (IFN) therapy in HCV. Objective: To examine the efficacy, safety and optimal dose of histamine as combination therapy with standard IFN-~ 2b therapy in chronic HCV. Design: 129 naive patients ages -> 18 years with chronic HCV were enrolled in an international, muiticenter, open label, randomized phase II study. All patients received IFN-~-2b (3 MIU, sc, TIW) and were randomizedto one of four doses of histamine including 3, 5, 6, or 10 mg histamine dihydrochloride per week (1 mg, sc (TIW; QD 5 x W; bid TIW; or bid QD 5 x W)). Patients were treated for 12 weeks, and 118 patients with a virological complete or partial responsewere enteredinto an extensionprotocol, treated for an additional 36 weeks, and followed-up at 72 weeks. HCV RNA levels were determined by the Cobas Amplicor HCV monitor test v2.0 (Roche). Results: Pretreatment baseline

2x106

Stage3-4

TM

A-381