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Thrombocytopenia (T) in patients with chronic hepatitis C: Management with interleukin 11
are greater than 90%, in chronically infected patients and these are the vast majority- and testing is not teasible, cure rates with the current best treatmem-peginterfemn alfa-2a (plNF) plus ribavirm (RBV-is only 56% and tot the most common viral genntype type 1A only 46%.Given the potential severe neuropsychiatrie symptoms from INF, including hfe threatening depression, psychiatric disease can be a relative, or even absolute, contraindieation to HCV treatment.We have tound that adding high dose pamxetine (Paxil) (40mr BID) and quetiapme (300rag QHS) to INF and RBV has resulted in an excellent HCV cure rate, seven of nine treated patients (eight with type 1A genotype virus), with no suicide attempts or other major psychiatric decompensation. All of the patients had long standing mood disorders and six of the nine had cnncomitant psychotic illness. None of the patients were HIV+ or HepBsAg + Eight of the nine patients had genntype 1A virus, the other patient had genotype 3A.Eight of the patients had chronic HCV infection and one had more acute disease Six of the eight patients with genotype 1A cleared the virus, as did the one patient with genotype 3A.Two patients were also taking olanzapine (Zyprexa).Might these medicines also augment or boost the effica W of INF + RB~?Indeed, while paroxetine is traditionally considered to be an antidepressant, and quetiapine an antlpsychotic medicine these medicines have other pharlnacologlc properties that could be crucial in lighting HCV: pamxetine is a potent nitric oxide synthase (NOSY inhibitor, and quetiapine is a po+ent histamine receptor antagonist (Olanzapine is also a potent histamine receptor antagonist.) As both nitric oxide and histamine are positive tmphie tactors lot HCV, we believe that tha paroxetine and quetiapine may augment INF and RBV by antagonizing these factors by lowering systemic or local levels of NOS and inhibiting histamine activity.Larger trials of high dose paroxetine and quetiapine to supplement INF and RBV in psychiatric and general patients with chronic HCV infection are warranted
failed treatment with interferon alfa had no demonstrable effect on serum aminotransferase levels or HCV viral citer. Whether higher doses, longer duration or combination therapy are effective against HCV remains to be determined. T1226 Thrombocytopenia (T) in Patients with Chronic Hepatitis C: Management with Interleukin 11 Charles L. Mendenhall, Abdur R. Shakir, Elizabeth A. Zoiss, Catrina Reese, Hal Bui, Stephen Goldberg, Gary" A. Roselle Of the 4 million people infected with HCV in the US it is estimated that treatment is interrupted or prewemed in 1 million due to thrombocytopenia. In many instances this is the result of portal hypertensinn with secondary" platelet pooling and destruction in the spleen. Peripheral platelet antibody destruction may also contribute even in the absence of severe liver injury. Once therapy is initiated the process is further exacerbated by bone marrow suppression associated with interferon therapy (1FN). These combination of events may result in life threatening T. Purpose: Describe T in the veteran population and indicate one con-ective therapeutic action. Results: T (<120,000) was observed prior to treatment in 25% of 56 patients undergoing therapy for HCV+ Therapy consisted of INF alfa 2b + ribavirin (R) (n= 20), Pegintefleron afl'a PEG IFN 2b (PEG IFN) (n= 12), and PEG IFN 2a (n= i0). Platelet changes from baseline(% decrease)at time 2,12,26,48 weeks were + 5.2%,-0.7%,-7.2%,-4.1% on R; q8.9%, +27%, -33.5%, -27.7% on PEG IFN 2b and were + 27.4%, -38.1%, -23.4%,(week 48 in progress) on PEG IFN 2a. Of these, 25% needed interleukin 11 (ILll) to prevent IFN dose reduction or discontinuation and 5% required ILl1 prior to IFN to raise platelets to recomnrended sate IFN treatment levels. All patients responded to ILl 1. Only side effect Observed was fluid accumulation in 5% of subjects, which was easily managed with diuretics. Conclusion: T is a common problem before and during HCV therapy' with IFN. Management with ILl1 petTnits continuation of 1FN therapy without dose reduction.
T1224
Clearance of hepatitis C virus with the optimal Cyclic and Periodic Interferon Treatment regimen consisting of induction treatment with natural interferon beta followed by maintenance treatment with interferon alpha in interferonresistant patients Yutaka Kishida, Masatumi Naitoh, Kazuhiro lCatayama, Tuhru Kashixvagi, Norio Hayashi
T1227
Background/Aim: Because natural mterferon(1FN) beta gis,es more rapid and higher peaks of IFN in the blood and liver compared with 1FN alpha and can achieve early and rapid viral clearance, induction treatment(IT) with natural IFN beta was considered to be optimal based on the HCV dynamics theory. To ovetvome IFN-resistance, a pilot study of Cyclic and Periodic Interferon Treatment (CP1T) with natural IFN beta plus IFN alpha was peribrmed in two, patients with lFN-resistant chronic hepatitis C(CHC) with high viral load and the ett~ct of CP1T on the kinetics of HCV were investigated. Methods: The patients was a 65years+old male with lFN-resistant la CH.C+ CPIT consisted of 14 cycles of IT with uIFN beta 6 MU/day daily' tbr 2 weeks Mlwed by maintenance treatment (MT) with nlFN alpha 6 MU/day three tinles/week for 2-6 weeks. The serum ALT, HCV.RNA, clone bands and base diversity in HVR1, IFN sensitt;4ty detemlinmg region (ISDR), 2'+5'OAS and beta 2 microglobuhn (MG) were serially investigated. Results: During CPIT, enhanced increased 2'-5'OAS, inhfbition of the emergence of IFN+resistance quasispecies populations, decrease in number of clone and base in HVR1, and change from mtermitten+type to mutant-type in NSSA amino acid (ISDR) were observed. MT of IFN alpha at 6-2 week cycles showed that decrease of HCV.PdNAwas largest with a 2 week cycle. 14 cycles of CP1T were completed without prevention of breakthrough and HOe" viremia relapsed afier completion of the whole course of CPIT. The optimal CPIT regnnen consisting of 6 cycles of 1T with nlFN beta Ibr 2 weeks folbved by MT with rlFN alpha 2b for 2 weeks was carried out in an another patient with IFN-resistant lb CH.C, and induced early rapid HCV clearance and sustained virological and biochemical response at~er beta 2 MG and ALT elevation. Conclttsion: Because 2'+5' OAS, beta 2 MG and ALT were increased by, nlFN beta, the antiviral effect and immunoregulatory- effect of nlFN beta n~ay be higher than those of IFN alpha. The optimal CP1T regimen in patients with IFN+resistant CHC improved IFN-resistance, viremia and ALT, suggesting that the optimal CPIT regimen is more effective than current IFN therapy. Furthermore, in addition to the basis of the optimal CPIT reginten suitable for antis,iral activity, an imnmnomodulator is suggested to be needed for the development of a ttrerapentic strategy" for lFN-resistant hepatitis C.
Imatinib (STI571; GleevecR) - a New Approach in the Treatment of Biliary Tract Cancer? Marcus W Wiedmann, Joachim Mossner, Karel Caca Background: Biliary tract cancer is associated with a poor prognosis due to wide resistance to chemotherapeutic agents and radiotherapy. Imatinib is an inhibitor of specific tyrosine kinases It was found to inhibit the BCR-ABL tyrosine kinase resulting from the translocation t(9;22) in chronic myelnid leukemia (CML) as well as c-kit and platelet-derived growth factor (PDGF) receptor tyrosine kinases+ The aim of this study was to determine the expression of c-kit and PDGF receptor and the eflects of imatinib on proliferation and apoptosis in biliary tract cancer cell lines. Methods: The expression of c+kit and PDGF receptor mRNA was examined in 12 biliary tract cancer cell lines (8 bile duct cancer cell lines and 4 gallbladder cancer cell lines) using semiquantitative RT+PCR. Cells were treated with imatinib (1, 10, 20 and 50 uM/L) for 6 days and cell proliferation was determined by BrdU..staimng. Cytotoxicity was assessed by try'pan blue staining and rate ofapoptosis examined by annexm V/propidium iodide flow cytometric assay. Results: c-kit and PDGF mRNA expression was detected m 50% and 75% of the cell lines, respectively-, lmatinib (10 and 20 uM/L) was cytotoxic in all cell lines examined The cytotoxicity was significantly higher in c-kit positne cell lines (p<0,02) and was independent from PDGF receptor expression status. Incubation of c-kit and PDGF receptor negative cell lines with imatinib resulted in a moderate cytotox~e+ ity, only. Additionally, treatment of cells with imatinib was associated with a strong induction of apoptosis, but no inhibition of proliferation Conclusions: lmatinib exerts marked eflects on biliary+tract cancer cell lines by induction of apoptosis. These eftects seem to be dependent on c-kit expression The results indicate a potential role of imatinib for treatment of biliary tract cancers. T1228
Striking Elevation in Plasma Nociceptin Level in Patients with Hepatocellnlar Carcinoma Ferenc Szalay, Monika B. Hantos, Andrea Horvath, Lasz/o P. Lakatos, Aniko Folhoffer, Kinga Dunkel, Dabna Hegedus, Komeha Tekes
T1225
Pilot Study of Interferon Gamma for Chronic Hepatitis C Alejandm Soza, Theo Heller, Edward Doo, Kittiehai Promrat, Glen Lutchman, Ltjun Mi, Yoon Park, Harvey Alter, Henry H Hsu, Marc Ghaw, Jake Liang, jay H, Hoofnagle
Background: Nociceptin (NC) is the endogenous agonist of OP4 receptor. NC/OP4 systera is a new peptide-based signalling pathway, involved in the modulation of pain and cognition High blood level was reported in patients with acute and chronic pain, and in Wilson disease An accidental observation led us to investigate NC in hepatocellular carcinoma (HCC) and other chronic liver diseases (CLD). Methods: Plasma NC was measured by RD, (125I-Nociceptin kit, Phoenix Pham'tacenticals, Phoenix, USA) with minimum sensitivity of 1 pg/mk in patients with CLD. Patients/Results: Although NC levels were elevated ni patients with Wilson disease (14+0 _+2.7 pg/mL, n = 26), primary biliary cirrhosis (12.1 -+ 3.2pg/rak, n = 2 1 ) and liver cirrhosis (12.8_+4+0pg/mL, n = 15) compared to the health), comrols (9.2 _+1.8pg/mL, n = 29, p<0.001 for each), in patients with HCC a ten-fold increase was found (105+9_+ 14.4pg/mL, n = 29,p<0+0001). High plasma NC levels were found in HCC patients both with pain (n = 12) and without pain (n = 6)+ Conclusion: Very high NC level may be a marker of malignant liver tumour and/or may be an indicator of the altered NU OP4 system Since high NC level was found in patmnts with advanced HCC without any pain, it could represent a compensatory mechanism to modulate pare perception.
There are currently no therapies of proven benefit for patients with chronic hepatitis C who fail to respond to interieron alia-based therapies, lnterteron gamma, a cytokine w{th no homology to mtederon alfa, has marked antiviral effects in vitro in the hepatitis C virus (HOe') replicon system. The aims of this pilot study were to determine the antiviral eftects and safety of recombinant interferon gamma- lb in patients with chronic hepatitis C. Methods: Eleven patients were randomly assigned to receive intedemn gamma m a dose of either 100 or 200 ~tg sc thrice weekly for 4 weeks. All patients were infected with HCV genotype 1 and had not achieved a sustained response to a previous course of therapy' with interferon alia with or withont ribavirin (6 vrere non-responders and 5 were relapsers). HCV RNA levels were measured 3 times before treatment, then at 6, 12, 18, 24, 48 hours and at 1, 2, 3 4 6 and 8 weeks after starting treatment. Results: There was no change in HCV RNA citer during therapy (mean level pre = 0.82 ++ 0.12; mean level at 4 weeks = 0.78 + + 0.11 million 1U/mL; no patient had more than a one log change during the 14 time points). Therapy was associated with sigmi~cant reductions in neutrophil counts (mean reduction 33%), lymphocyxe counts (14%) and hematocrit (3%)+ Platelet counts remained unaffected. Similarly, ALT levels were unchanged (mean pre = 80 + - 45 IU/ml, mean at 4 weeks = 72 + - 25 IUknL, p=NS). There were no differences in response between the high and low dose groups or between previous non-responders and relapsers+ Treatment was well tolerated in all patients, with minimal fluqike symptoms and no slgmficant xvorsening in quality of fite scores. No severe adverse events were noted. Conclusions: A 4-week course of conventional doses of interferon gamma as monotherapy in patients who had previously'
AASLD Abstracts
A-770
failed treatment with interferon alfa had no demonstrable effect on serum aminotransferase levels or HCV viral citer. Whether higher doses, longer duration or combination therapy are effective against HCV remains to be determined. T1226 Thrombocytopenia (T) in Patients with Chronic Hepatitis C: Management with Interleukin 11 Charles L. Mendenhall, Abdur R. Shakir, Elizabeth A. Zoiss, Catrina Reese, Hal Bui, Stephen Goldberg, Gary" A. Roselle Of the 4 million people infected with HCV in the US it is estimated that treatment is interrupted or prewemed in 1 million due to thrombocytopenia. In many instances this is the result of portal hypertensinn with secondary" platelet pooling and destruction in the spleen. Peripheral platelet antibody destruction may also contribute even in the absence of severe liver injury. Once therapy is initiated the process is further exacerbated by bone marrow suppression associated with interferon therapy (1FN). These combination of events may result in life threatening T. Purpose: Describe T in the veteran population and indicate one con-ective therapeutic action. Results: T (<120,000) was observed prior to treatment in 25% of 56 patients undergoing therapy for HCV+ Therapy consisted of INF alfa 2b + ribavirin (R) (n= 20), Pegintefleron afl'a PEG IFN 2b (PEG IFN) (n= 12), and PEG IFN 2a (n= i0). Platelet changes from baseline(% decrease)at time 2,12,26,48 weeks were + 5.2%,-0.7%,-7.2%,-4.1% on R; q8.9%, +27%, -33.5%, -27.7% on PEG IFN 2b and were + 27.4%, -38.1%, -23.4%,(week 48 in progress) on PEG IFN 2a. Of these, 25% needed interleukin 11 (ILll) to prevent IFN dose reduction or discontinuation and 5% required ILl1 prior to IFN to raise platelets to recomnrended sate IFN treatment levels. All patients responded to ILl 1. Only side effect Observed was fluid accumulation in 5% of subjects, which was easily managed with diuretics. Conclusion: T is a common problem before and during HCV therapy' with IFN. Management with ILl1 petTnits continuation of 1FN therapy without dose reduction.
T1224
Clearance of hepatitis C virus with the optimal Cyclic and Periodic Interferon Treatment regimen consisting of induction treatment with natural interferon beta followed by maintenance treatment with interferon alpha in interferonresistant patients Yutaka Kishida, Masatumi Naitoh, Kazuhiro lCatayama, Tuhru Kashixvagi, Norio Hayashi
T1227
Background/Aim: Because natural mterferon(1FN) beta gis,es more rapid and higher peaks of IFN in the blood and liver compared with 1FN alpha and can achieve early and rapid viral clearance, induction treatment(IT) with natural IFN beta was considered to be optimal based on the HCV dynamics theory. To ovetvome IFN-resistance, a pilot study of Cyclic and Periodic Interferon Treatment (CP1T) with natural IFN beta plus IFN alpha was peribrmed in two, patients with lFN-resistant chronic hepatitis C(CHC) with high viral load and the ett~ct of CP1T on the kinetics of HCV were investigated. Methods: The patients was a 65years+old male with lFN-resistant la CH.C+ CPIT consisted of 14 cycles of IT with uIFN beta 6 MU/day daily' tbr 2 weeks Mlwed by maintenance treatment (MT) with nlFN alpha 6 MU/day three tinles/week for 2-6 weeks. The serum ALT, HCV.RNA, clone bands and base diversity in HVR1, IFN sensitt;4ty detemlinmg region (ISDR), 2'+5'OAS and beta 2 microglobuhn (MG) were serially investigated. Results: During CPIT, enhanced increased 2'-5'OAS, inhfbition of the emergence of IFN+resistance quasispecies populations, decrease in number of clone and base in HVR1, and change from mtermitten+type to mutant-type in NSSA amino acid (ISDR) were observed. MT of IFN alpha at 6-2 week cycles showed that decrease of HCV.PdNAwas largest with a 2 week cycle. 14 cycles of CP1T were completed without prevention of breakthrough and HOe" viremia relapsed afier completion of the whole course of CPIT. The optimal CPIT regnnen consisting of 6 cycles of 1T with nlFN beta Ibr 2 weeks folbved by MT with rlFN alpha 2b for 2 weeks was carried out in an another patient with IFN-resistant lb CH.C, and induced early rapid HCV clearance and sustained virological and biochemical response at~er beta 2 MG and ALT elevation. Conclttsion: Because 2'+5' OAS, beta 2 MG and ALT were increased by, nlFN beta, the antiviral effect and immunoregulatory- effect of nlFN beta n~ay be higher than those of IFN alpha. The optimal CP1T regimen in patients with IFN+resistant CHC improved IFN-resistance, viremia and ALT, suggesting that the optimal CPIT regimen is more effective than current IFN therapy. Furthermore, in addition to the basis of the optimal CPIT reginten suitable for antis,iral activity, an imnmnomodulator is suggested to be needed for the development of a ttrerapentic strategy" for lFN-resistant hepatitis C.
Imatinib (STI571; GleevecR) - a New Approach in the Treatment of Biliary Tract Cancer? Marcus W Wiedmann, Joachim Mossner, Karel Caca Background: Biliary tract cancer is associated with a poor prognosis due to wide resistance to chemotherapeutic agents and radiotherapy. Imatinib is an inhibitor of specific tyrosine kinases It was found to inhibit the BCR-ABL tyrosine kinase resulting from the translocation t(9;22) in chronic myelnid leukemia (CML) as well as c-kit and platelet-derived growth factor (PDGF) receptor tyrosine kinases+ The aim of this study was to determine the expression of c-kit and PDGF receptor and the eflects of imatinib on proliferation and apoptosis in biliary tract cancer cell lines. Methods: The expression of c+kit and PDGF receptor mRNA was examined in 12 biliary tract cancer cell lines (8 bile duct cancer cell lines and 4 gallbladder cancer cell lines) using semiquantitative RT+PCR. Cells were treated with imatinib (1, 10, 20 and 50 uM/L) for 6 days and cell proliferation was determined by BrdU..staimng. Cytotoxicity was assessed by try'pan blue staining and rate ofapoptosis examined by annexm V/propidium iodide flow cytometric assay. Results: c-kit and PDGF mRNA expression was detected m 50% and 75% of the cell lines, respectively-, lmatinib (10 and 20 uM/L) was cytotoxic in all cell lines examined The cytotoxicity was significantly higher in c-kit positne cell lines (p<0,02) and was independent from PDGF receptor expression status. Incubation of c-kit and PDGF receptor negative cell lines with imatinib resulted in a moderate cytotox~e+ ity, only. Additionally, treatment of cells with imatinib was associated with a strong induction of apoptosis, but no inhibition of proliferation Conclusions: lmatinib exerts marked eflects on biliary+tract cancer cell lines by induction of apoptosis. These eftects seem to be dependent on c-kit expression The results indicate a potential role of imatinib for treatment of biliary tract cancers. T1228
Striking Elevation in Plasma Nociceptin Level in Patients with Hepatocellnlar Carcinoma Ferenc Szalay, Monika B. Hantos, Andrea Horvath, Lasz/o P. Lakatos, Aniko Folhoffer, Kinga Dunkel, Dabna Hegedus, Komeha Tekes
T1225
Pilot Study of Interferon Gamma for Chronic Hepatitis C Alejandm Soza, Theo Heller, Edward Doo, Kittiehai Promrat, Glen Lutchman, Ltjun Mi, Yoon Park, Harvey Alter, Henry H Hsu, Marc Ghaw, Jake Liang, jay H, Hoofnagle
Background: Nociceptin (NC) is the endogenous agonist of OP4 receptor. NC/OP4 systera is a new peptide-based signalling pathway, involved in the modulation of pain and cognition High blood level was reported in patients with acute and chronic pain, and in Wilson disease An accidental observation led us to investigate NC in hepatocellular carcinoma (HCC) and other chronic liver diseases (CLD). Methods: Plasma NC was measured by RD, (125I-Nociceptin kit, Phoenix Pham'tacenticals, Phoenix, USA) with minimum sensitivity of 1 pg/mk in patients with CLD. Patients/Results: Although NC levels were elevated ni patients with Wilson disease (14+0 _+2.7 pg/mL, n = 26), primary biliary cirrhosis (12.1 -+ 3.2pg/rak, n = 2 1 ) and liver cirrhosis (12.8_+4+0pg/mL, n = 15) compared to the health), comrols (9.2 _+1.8pg/mL, n = 29, p<0.001 for each), in patients with HCC a ten-fold increase was found (105+9_+ 14.4pg/mL, n = 29,p<0+0001). High plasma NC levels were found in HCC patients both with pain (n = 12) and without pain (n = 6)+ Conclusion: Very high NC level may be a marker of malignant liver tumour and/or may be an indicator of the altered NU OP4 system Since high NC level was found in patmnts with advanced HCC without any pain, it could represent a compensatory mechanism to modulate pare perception.
There are currently no therapies of proven benefit for patients with chronic hepatitis C who fail to respond to interieron alia-based therapies, lnterteron gamma, a cytokine w{th no homology to mtederon alfa, has marked antiviral effects in vitro in the hepatitis C virus (HOe') replicon system. The aims of this pilot study were to determine the antiviral eftects and safety of recombinant interferon gamma- lb in patients with chronic hepatitis C. Methods: Eleven patients were randomly assigned to receive intedemn gamma m a dose of either 100 or 200 ~tg sc thrice weekly for 4 weeks. All patients were infected with HCV genotype 1 and had not achieved a sustained response to a previous course of therapy' with interferon alia with or withont ribavirin (6 vrere non-responders and 5 were relapsers). HCV RNA levels were measured 3 times before treatment, then at 6, 12, 18, 24, 48 hours and at 1, 2, 3 4 6 and 8 weeks after starting treatment. Results: There was no change in HCV RNA citer during therapy (mean level pre = 0.82 ++ 0.12; mean level at 4 weeks = 0.78 + + 0.11 million 1U/mL; no patient had more than a one log change during the 14 time points). Therapy was associated with sigmi~cant reductions in neutrophil counts (mean reduction 33%), lymphocyxe counts (14%) and hematocrit (3%)+ Platelet counts remained unaffected. Similarly, ALT levels were unchanged (mean pre = 80 + - 45 IU/ml, mean at 4 weeks = 72 + - 25 IUknL, p=NS). There were no differences in response between the high and low dose groups or between previous non-responders and relapsers+ Treatment was well tolerated in all patients, with minimal fluqike symptoms and no slgmficant xvorsening in quality of fite scores. No severe adverse events were noted. Conclusions: A 4-week course of conventional doses of interferon gamma as monotherapy in patients who had previously'
AASLD Abstracts
A-770