A study of contraindications to anti-viral therapy among united states veterans with hepatitis C

of chronic hepatitis C with INF-o~and Ribavirin in psychiatric risk groups compared to controls. Method: In a prospective and controlled study, 77 patients were treated with INF-~ 3x3 Mio U/week and ribavirin(1000-1200 rag/day). Psychiatric patients (n = 16), patients with history of drug addiction (n = 20) or with methadone substition (n = 18) were compared with controls (n = 23). Patients were continuously seen and rated by a psychiatrist for depressivesyndromes according to DSM-IV criterias. Results: Depressive syndromes before and during treatment with INF-o~are shown in table 1. Other frequently observed side effects were aggressiveness and irritability, which occurred in 65% of earlier drug addicts, 78% of methadone patients, 75% of psychiatric patients and 85% of controls. Also other typical symptoms like sleeping disturbances (50-65%) and difficulties in concentration and memory (26-63%) were frequent, but did not differ between treatment groups. In no patient drop-out was due to depression (7 by non-compliance, 3 by severesomatic side effects and 3 by relapse). Beside in psychiatric patients, non-compliance was evenly distributed in all groups. In conclusion, while drug addicts seem to have a slightly increased risk to develop depressive symtoms, we can not confirm an increased risk for psychiatric side effects in patients with severe and chronic psychiatric disorders.

Conb'ol PsychiaL Methadone Earlier Drug Addicts

Depress. Depress. Mild ModerateSevere at during Depress. Baseline IFI~

,~kidll Hictorynf Thoughts Deprwetoo

0% 38% 6%

13% 44% 22%

33% 43% 50%

33% 14% 50%

33% 43% 0%

5% 13% 6%

0% 69% 0%

0%

30%

67%

33%

0%

0%

5%

wks 24 and 72 and f/u wk 24 Pts with detectable HCV RNA at wk 24 are considered nonresponders. Safety assessments: modence of AEs, use of G-CSF and EPO, rate of dose modification and discontinuation. CD4 count and HIV RNA level monitored q12 wks to assess interactions with HIV disease and NRTIs (e.g. ZDV or D4T). Results: As of 12/2000, 165 pts have been randomized (IFN QD. 83 pts / TIW. 82 pts). Baseline characteristics: sex (M, 75%; F, 25%), race (Caucasian, 82 pts; Black, 49 pts; Hispanic, 30 pts; Asian 2 pts), mean age, 43.9 (range 22-66) Hx of IDU, 82 %; depression hx, 32 %; prior 01, 11%. The majority (143 pts; 87.7%) was prescribed ART, including ZDV, 38% and D4T, 37%. The median HIV load was < 400 c/mL (range 0 138,750); 62% had HIV RNA < 400 c/mL. Median CD4 cell count was 528/mm 3(range 71-1532). HCV genotype (available for 83 pts): 1, 75%; 2 or 3, 24%; other 1% Median ALT was 68.0 IU/dL (range 15-622). Results of HCV RNA testing at week 24 will be presented. Conclusions: This is an ongoing, randomized multicanter study to assess the safety and efficacy of interferon alfa-2b plus ribavirin in HCV/HIV co-infected patients. Safetyassessmentsand week 24 virologic response data will be presented. Researchsupported by an unrestricted grant from Schering-Plough

2O97 Aaallofs of lidoderon Sigmal Expression in Hepatitis C Virus-infected Patients' Lympkocyths Takeshi Tanaka, Tokyo Metropolitan Komagome Hosp, Tokyo Japan; Ketsume Asao, Tokyo Metropolitan Institute of Medical Science, Tokyo Japan; Kazuaki Inoue, Kyoko KoharaTsuldyama, Micinori Kohara, Tokyo Metropolitan Inst, Tokyo Japan

Many patients with chronic hepatitis C have have been treated by interferon (IFN). IFN plays an important role for the eradication of hepatitis C virus (HCV). IFN does not have only antiviral action but also immuno-mudulatory effect. However, intracellular expression of IFNrelated molecules in HCV-infected patients remains unclear. Aim: To solve the action of IFN signal in HCV-infectsd patients. Muterial and Method: We quantified IFN signals using real time detection polymerase chain reaction (RTD-PCR) based on Taq-Man chemistry. We examined and messenger RNA (mRNA) level of IFN receptor (IFN-R), double stranded RNAactivated protein kinase (PKR) and 2', 6' oligo-ndenylate synthetase (2-5AS) in peripheral mononuclear cells (PBMC) obtained from chonic hepatitis patients with HCV infection. These patients received IFN treatment. Result: PCR and PCR in-situ hybridization method proved existence of HCV in HCV-infected patients' PBMC. Amount of HCV RNA in PBMC correlates significantly ~ HCV viremia level in patients' sera. IFN-R expression was suppressed in HCV-infected patients' PBMC. Intrinsic 2-5AS mRNA increased but PKR expression was suppressed in HCV-infected patients before IFN therapy. These molecules increased during IFN treatment. IFN-R levelwas relatively lower in IFN non-responder than responder. Conclusion: HCV e)dsted in HCV-infected patients' PBMC. In HCV-infected patients intrinsic 2-5AS was activated but 2-5AS level was not a predictable marker for IFN effect. IFN-resistanceand persistent infection may result from the suppression of IFN-R and PKR.

2895 Changes In Hemoglobin During Therapy With Interferon Alth-2b Plus Rilrovidn In IFN-NaTve And Experienced Patients Linda Brooks, CA Pacific Medical Ctr, San Francisco, CA; Ronald Wasserman, Lisa Ball, Hepatitis Resource Network, Tacoma, WA; Robert G. Gish, CA Pacific Medical Ctr, San Francisco, CA Background: Combination therapy with ribavirin (RBV) is associated with a dose-dependent, hemolytic anemia. Factors associated with significant anemia have not been well described and it is unknown if daily exposure to IFN<+will result in greater anemia. Methods: We retrospectively analyzed treatment-related changes in hemoglobin level in participants of two INF~ plus RBV treatment studies. This 655 patient database included: Study 1,170 IFN-nak'e pts randomized to receive RBV 1000 - 1200 g/d plus IFNe 3 MIU QO or TIW for 48wks and Study 2, 485 IFNa-experiencedpts who were randomized to receive RBV 1000 g/d plus IFN~ 3 MIU OD or TIW for 4 weeks followed by TIW dosing. Per protocol, patients had a Hb level > 12 g/dL for females or > 13 g/d L males at baseline. Pre-treatment clinical and demographic data included gender, age, ethnicity, weight, creatinine, ALT, CBC and liver histology. Hb values were obtained at treatment weeks O, 1, 2, 4, then monthly to week 48 ; and at posttreatment weeks 4, 8,12, 24 and 48). Results: 10.3% (57/551) of pts had a Hb level < lOg/ dL (95% CI 7.9-13.2). However, the incidence of anemia (Hb < lOg/dL) was 5-fold greater in women (20%, 95% CI 13.7 -27.5) than men (4.8%, 95% CI 2.9 -7.5%) [RR 4.6, 95% Ct 2.73 - 7.8]. While Hb decreasesof > 3 g/alL were observed in 56% (308/551) of all patients, the incidence was greater in men (61%) than women (45%) [RR 1.4, 95% CI 1.1- 1.6]. Compared to TIW dosing, QD IFN was not associated with a greater decline in Hb level by wk 4 in Study 1 (- 2.6 g/dL QD vs. 2.6 g/dL TIW, P = .98) or Study 2 (- 2.2 g/dL QD vs, 2.0 o/dL TIW, P = .28) nor at any additional time in Study 1. In a multivariate regression model, significant anemia (decrease > 27% of baseline Hb) was independently associated with age > 49 yrs, higher baseline Hb, and decreased creatinine clearance in the 50 to 99 mL/min range ( estimated by the Cockcroft-Gauit equation which includes age, weight and gender). Conclusions: Women were 5-times more likely to experience a Hb level of < 10 g/ dL during combination therapy and meet criterai for RBV dose reduction. Daily IFN therapy was not associated with an increased risk of significant anemia whereas baseline Hb, age and very small decreases in creatinine clearance were associated with a significantly higher risk of severe anemia. Further research to develop strategies to permit continuation of appropriate RBV dosing (10.6 mg/kg) in pts who develop anemia during HCV therapy, particularly among women.

A Study Of CoofniNIcatious To Anti-Virol Therapy Among United States Veterans

w ~ Hwuu= c.

MJtchel S. Hoffman, Kamal A. Flamed, VA Medical Ctr, Bay Pines, FL

BACKGROUND: Chronic hepatitis C infection affects an estimated 2.7 million individuals in the United States. Treatment is complex and should be reserved for those patients at greatest risk of progressive liver disease. Most hepatologists agree that patients with normal liver function or certain co-morbid conditions should not be treated. However, the proportion of patients with HCV eligible for therapy is not known. OBJECTIVE:To determine the percentage of veterans with HCV antibody eligible for anti-viral with interferon and ribavarin. METHODS: We screened 347 veterans with a positive HCV antibody using ELISA 3.0 (Orfho Diagnostic System). The following were considered contraindications to HCVtherapy: moderate or severe psychiatric disease, recent illicit drug or alcohol use, clinically decompensated liver disease, life-limiting non-hepatic disease,history of non-compliance with clinic visits, inadequatesocial support, or normal ALl. RESULTS: The median age was 48.2 years. One-hundred seventysix (51%) veterans did not have a contraindication to anti-viral therapy. Contraindications to medical therapy were: 59(17%) ongoing excessive alcohol use; 55(16%) psychiatric disease including schizophrenia, depression, or psychosis; 12(3%) recent illicit drug use; 6(2%) noncompliance to clinic visits; 6(2%) severe life-limiting non-hepatic disease; 7(2%) homeless; 10(3%) clinically decompensatedliver disease;and 56(16%) normal ALE level. CONCLUSIONS: In our series, 49% of United States veterans with HCV antibody had contraindications to HCV therapy. Substance abuse and psychiatric disorders were the most common co-morbid conditions associated with HCV. An effective early intervention strategy for diagnosis and treatment to prevent chronic hepatitis C is required.

2896 Multicenter, Randomized, Open-Label Study of the Safety and Efficacy of Interferon (IFN) alfa-2b Plus Ribavirin (RBV) for the Treatment of HCV InfeCtion in HIVInfected Persons Douglas T. Dieterich, Liberty Medical LLP, New York, NY; Mark S. Sulkowski, Johns Hopkins Univ Sch of Medicine, Baltimore, MD; France A B Felizarta, 34th Street Community Health Ctr, Bakersfield, CA; Jihad Slim, Saint Michael's Medical Ctr, Newark, NJ; Ruth E. Berggren, Univ of Texas Southwestern Medical Ctr, Dallas, TX; Cheryl A. Smith, North Gun Hosp, New York, NY; Russell F. Hudnali, Hepatitis Resource Network, Tacoma, WA

2899 InduCtion interferon o~2b5MU Oaily for 4 weeks Followed by Combination Interferen-Ribavirin versos Interferon-Ribavirin Without InduCtionfor Previously Untreated Chronic Hepatitis C Edward Lebovics, Eddy Castillo, Pretam Rampersaud, Jody Hirsch, Ana Casellas, Carol McFadane, New York Medical Coil, Valhalla, NY; Stephen Esposito, New York Hosp Queens, Queens, NY; Hillel Tobias, New York Univ Medical Ctr, New York, NY; Jane Geders, Methodist Hosp, Brooklyn, NY; Ira Jacobsen, New York Heap, New York, NY; Frank Klion, Mount Sinai Medical Ctr, New York, NY; David C. Wolf, New York Medical Coil, Valhalla, NY Combination interferon a2b (IFN) 3MU TIW plus ribavirin (RV) 1000-1200 mg per day for 1 year results in sustained virologic response in 38% of previously untreated chronic hepatitis C (CHC) patients (NEOglJMed 1998; 339:1485). Viral kinetic studies suggest that daily IFN would more effectively clear virus. We aimed to determine if IFN induction improves response. Methods: Adult patients with CHC, HCV RNA PCR+, compensated liver disease, and no other cause of liver injury were randomized to induction(I) IFN 5MU daily for 4 weeks followed by

Background: The progression of HCV-related liver fibrosis is accelerated in HIV-infected persons, leading to increase morbidity and mortality. While strategies to treat HCV-related liver disease are urgently needed, few studies have examined the use of IFN alfa plus RBV for coinfected patients. Objective: To assess the antiviral efficacy and safety of ribavirin with daily (QD) or TIW IFN ~-2b for chronic HCV infection in HIV-infected parsons. Methods: Open-label, randomized, multi-center (67 site) clinical trial comparing IFN alfa-2b 3 mlU QD Vs. TIW + RBV (800 g/d) for 48 wks in 180 IFN- and RBV-na'ive, HIV-infected pts with compensated HCV-relatedliver disease on stable HIV treatment regimens. Exclusion criteria: active 01, active substance abuse, severe psychiatric disease, and CD4 count < lO0/mm 3, Liver biopsy is recommended. Efficacy assessments (HCV RNA) are performed at treatment

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