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A Novel Treatment of Patients with Chronic Hepatitis C

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A Novel Treatment of Patients with Chronic Hepatitis C A Novel Treatment of Patients with Chronic Hepatitis C Naoky CS. Tsai MD, Neil Shimoda MD, Linda Wong MD, Stanley Shimoda MD, Kimberly Goad RN, Herbert Yee, Miles Chen Abstract: interferon dosage, iron depletion therapy, and prolonged interferon Objectives: Interferon alpha-2b therapy for Chronic Hepatitis C therapy, but the beneficial results have not yet been established. patients has been unsatisfactory. Recombinant Granulocyte Mac Among the different groups of biological response modifiers, rophage Colony-Stimulating Factor has been shown to have anti- GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor) is l23 Recently its viral effects in vivo and in vitro via cytokines a hormone-like glycoprotein cytokine produced by activated T hepatitis B and possibly chronic hepatitis C were effects on chronic lymphocytes, endothelial cells and fibroblasts that stimulates the reported.4’5 We, decided to conduct a pilot study to evaluate the proliferation, maturation and function of hemopoietic cells, aug anti-viral effects of recombinant human GM-CSF mono-therapy in and regulates the secretion patients with chronic hepatitis C and to assess its side effects, ments and modifies the immune system, Methods: A total of 10 patients (male/female: 5/5) (age: 34-60, of other cytokines which are involved in the immune response to mean: 45) seen in our center between 2/95 to 2/96 were randomly viral hepatitis. Recently J. Martin. et al reported HBV-DNA level selected to receive recombThant human Granulocyte Macrophage reduction with GM-CSF alone or in combination with interferon Colony-Stimulating-Factor at 125 ug/m2 subcutaneously daily for alfa-2b.2 Furthermore, in vitro studies of cytokine production by by three times weekly for another 8 weeks. two weeks followed PBMC(peripheral blood mononuclear cells) during GM-CSF treat Biochemical (ALT) and viral (HCV-RNA) responses were measured ment revealed enhanced spontaneous production ofother cytokines.’ prior to treatment and at weeks four and eight. Side effects were recorded. In the treatment of chronic hepatitis C, recombinant GM-CSF has Results: Six out of the ten patients treated had significant viral been used mainly to rescue leukopenic patients during treatment reduction but none became negative. Eight out the ten patients with interferon alpha 2-b. There has been no clinical study in the treated showed biochemical improvement and three out of the eight U.S. to investigate if recombinant GM-CSF by itself has any anti- did had normalized liver enzymes. Age, sex, stage of the disease viral effect against hepatitis C virus. Therefore we decided to influence the response but there seems to be a tendency for not conduct a pilot study treating chronic hepatitis C patients who failed patients with higherpre-treatment viral level to respond virally. Side interferon alfa 2-b therapy with recombinant GM-CSF effects are minimal and well-tolerated. previous assess its side Conclusion: Recombinanthuman Granulocyte Macrophage Colony- alone to observe if there is any anti-HCV effect and to Stimulating-Factor in the dose used has anti-viral effects in the effects. majority of the chronic hepatitis C patients studied. Side effects are minimal and well tolerated. Further study with higher doses and Patients and Methods: treating longer duration is needed to prove its clinical efficacy in Ten patients (five males) with a mean age of 45 yr. (Range 34-60) with chronic hepatitis C. patients who were seen in a tertiary center between 2/95 to 2/96 were selected characteristics can be Introduction: to participate in this trial. The patient’s clinical seen in Table I. All patients had failed previous interferon therapy past few years since interferon alpha 2-b (JFN) was licensed In the and were off interferon or other immunological therapy for at least for treatment of some patients with chronic hepatitis C, it has six months and met the inclusion and exclusion criteria. The proto clear that standard IFN therapy (3 million units subcutane become col was approved by the IRB of the institution. Consent forms were ously three times a week) produces a complete biochemical re signed. After the initial screening visit, all participants received of patients (normalization of ALT at the end of sponse in 50% recombinant GM-CSF (manufactured by Immunex Co. Seattle, however, the majority of responders relapsed after treatment); Washington) at 125 ug/m2 subcutaneously daily for two weeks of therapy. To improve these results, many therapies termination followed by three times a week for another eight weeks. Biochemi have been tried including retreatment with same dose or escalating cal (ALT) and viral response (b-DNA method from Chiron Inc. Summerville, California) were assessed prior to treatment and at week four and eight. Side effects were assessed in each follow-up visit and recorded. Correspondence to: Naoky CS. Tsai MD Naoky C.S. TsaI MD, Associate Professor of Medicine Results: The Liver Center Chief, Section of Hepatobiliary Disease Of the ten patients treated with GM-CSF, six had significant viral St. Francis Medical Center Division of Gastroenterology titer reduction during the first two weeks of daily subcutaneous 2228 Liliha St, #306 Department of Medicine had eradicated the virus. Eight out of the Honolulu, HI 96817 John Burns School of Medicine, University of Hawaii injection. However, none HAWAIi MEDICAL JOURNAL. VOL 58. APRIL 1999 85 _______ ten treated showed ALT improvement and among them three had Table 1.—Patient Charactestics normalized ALT. The clinical data of all ten patients are shown in PreRx Table 1. Three are genotype la, three type ib, one type 2b and three Patient Sex Age Genotype Histology RNA(io’) untypable. Six patients had advanced liver disease and the remain ing four had mild to moderate disease. Age, sex, stage of disease did D.H. M 57 lb CAH >570 not influence the response but there seems to be a tendency for patients with higher viral level to respond. Fig. I, Fig. ha and JIb E.J. F 35 la CPH 326.9 show mean HCV-RNA and ALT level of each patient respectively. FT. M 42 la CPH 68.6 Side effects were minimal and well tolerated. The most common side effect was injection site irritation. Other side effects included FR. M 45 CAH 41.8 flu-like symptoms (which were milder than that of interferon alpha 2-b) and general malaise. Two patients experience urticaria which L.Y. F 59 lb Cirrhosis 167.5 responded to anti-histamine treatment. No cardiopulmonary side K.G. F 34 la CPH 188.1 effects such as CHF or asthma attack were noted. Leukocytosis responses were universal and several patients had eosinophilia (up ML. F 49 4a Cirrhosis Not Done to 40% in one case with urticaria) but dose reduction was not needed. CD. M 35 3a CPH 133.7 Discussion: R.J. M 39 2b Cirrhosis <3.5 Interferon therapy for chronic hepatitis C has been unsatisfactory in attaining sustained response in the majority of patients. Clearly S.L. F 60 lb CPH 46.9 enhancement of the response rate is needed. Of all the anti-viral therapies, interferons were the only agents shown to have anti-viral = CAH Chronic Active Hepatitis effect on hepatitis C virus. Ribavirin and Corticosteroids as CPH = Chronic Persistent Hepatitis monotherapy have been tested but without success in eradication of Figure I.— HCV-RNA Level Changes During Treatment (x!00,000 Copies/mi.) Patients HCV-RNA level pre- and during GM-CSF therapy. No patient has eradicated HCV-RNA but there seems to be a downward trend in the level of HVC-RNA especially in the first four weeks of therapy when daily GM-CSF was administered. (Chiron version 1.0 Quantiplex method). 500 400 DH —, 300 200 100 0 4. PreRx wk4 wk 8 wk 12 HAWAII MEDICAL JOURNAL, VOL 58, APRIL 1999 06 _,f- -J •ø -, L* + + + I Iii +J LL Li week 12 week 12 a) a) E E Ca a) week 8 a) 0) week 8 0 U) week 7 U) a) a) week 7 C, a) a) C, 0 a) a) > > week 6 4: 0 a) week 6 U, a) -j > 0 0 a) > a) 0 0, week 5 . I- -J 0 week 5 . 0 0, I- -j E E 4: week 4 2 Q U) week 4 4: a) > U) 4: a) a) I -J > a) -J week 3 -J -J week 3 Ct a) week 2 c,) a) U- week 2 0) U- week 1 week I C) 0 0 0 0 0 0 0 10 0 10 C) 10 0 10 C) () C’.J C’.J - 0 0 0 0 0 0 0 U, 0 LI) 0 LI) C.., CL — — (ni) .nv the virus. GM-CSF has been used to rescue patients with leukopenia effect on patients with chronic hepatitis C infection. Future studies 4 but its efficacy as monotherapy for with higher dosage and longer duration of therapy or in combination on high dose interferon therapy the treatment of chronic hepatitis C has not been tested. In this study with interferon therapy are needed to prove its clinical efficacy as an we administered rhGM-CSF to ten patients who have failed previ alternative and br adjuvant therapy for patients with chronic hepa ous interferon alpha 2-b treatment to study its anti - HCV effect and titis C. GM-CSF could also play a role in the treatment of those to assess side effects. The dosage given is low at 125 mcg/m2 patients with chronic hepatitis C who have significant leukopenia subcutaneously. The therapy was well tolerated with no significant and were excluded from interferon therapy. side effects. No dose reduction was needed and no patient withdrew from the study.
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