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Cytokine kinetic and response to interferon α (IFN) alone or in association with amantadine or ribavirin in HCV positive patients
Papers read by title
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C06/005
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I
CYTOKINE KINETIC AND RESPONSE TO INTERFERON a (IFN) ALONE OR IN ASSOCIATION WITH AMANTADINE OR RIBAVIRIN IN HCV POSITIVE PATIENTS E Torre, S. RossoP, R. Giusto, R. Brizzolara, N. Sinelli, N. Campo, A. Picciotto Gastroenterology Unit, University of Genoa, Italy. 1Department of Gastroenterology, Mannheim, Germany. The ncdmnisms of action of IFN incinde direct ~ v h - a ] effeas as well as k ~ n c c ~ d u b t c ~ effects with enhmcenent of the effector arm of the
m n u m syuem. Ahn of this stay was to evalmte seda~y l x o ~ mmkers (soluble TNF a p 5 5 and p75 receptt~s) and T-help~- type 1 (IFN y, ILl2), type 2 (ILl0) ~ in ~ e first month oflrealment with IFN alone or h association with other ~ a ~ ; ~ Amantadine or lh~aviri~ Twentytwo patients with chronic ~ C received IFN 3MU daily (7 p(s); IFN 3MU daily plus Amantadi~ 200 mg(7 pts~, IFN 3MU daily plus ~ a v i r m 112 gr (8 pts), for six months. Blood samples were drawn at baseline, at 6, 12, 24, 30 and 48 houm from the beginningofthe trealment; and at the yd, 7t, 15~ and 30~ day. All cytokines and ~ w e ~ evaluated by ELISA and HCVRNA by Cobas Amplicor HCV (cut-off 1.00E+02 copies/ml; Roche). Independently to type of or outcome to the treatment, sTNF-55 and 75 presented a increment within the first 24 hrs, to then slabilised at a higher level then beseline, (iae~at~. Lower levels of sTNF-75 were present a t ~ day 3 in pafie~ who then became HCV-RNA negative at day 30 (p=0.01; MannWhitney U test). No significar~ ~ have bee~ ~ for IFI~ or ILl2 wilhin the first 30 days among ~ or ~ . Instead, whereas no diffw=~es w~e observed for ILIO among treatments, a significant r~hction from baseline levels, unrelated to the type of Imatment, was observed among responders and non responde~ to the Irealnm'a, after the 3'd day of t r e a t m ~
(p=O.02)."[hesedats show that IFN increasesi x o ~
matk~ with a
the~dk¢ reduction in IXs who b¢c(m~eHCV-RNA negative, but indicate how respome to treaWaent is related to a redu_.aionin the T-helper 2 activity.
C06/006
I
EFFICACY AND SAFETY OF INTERFERON AND RIBAVIRIN THERAPY IN HIV-HCV COINFECTED PATIENTS H. Zvlberbere. Y. Benhamou. M.L. Chaix. H. Fontaine, C. Rouzioux, C. Katlama. T. Povnard. C. Br6chot. S. Pol Liver unit and virology laboratory, Inserm U370, C H U Necker, C H U Piti6 Salp6tri6re, Paris, France. Background/Aim: Increased severity of liver disease and poor response rate to a-interferon in HIV-HCV coinfected patients stress the need of more potent anti-HCV therapies. Efficacy and safety of intefferon-n'bavirin combination therapy in HIV infected subjects including potent interference with anti-HiV drug i. e. zidovudine, stavudine, is however unknown. Patients: 35 patients (9 never treated by interferon or rihavirine) treated with combined antiretroviral therapy including zidovudine (n--9) or stavudine (n=19) received ribavirin and c,-intefferon. Sixteen had cirrhosis. Genotype was 1:21 (60%); 2:2 (6%) 3: 8~23%); others: 4 (11%). Methods: The HIV viral load (Monitor test) and the CD4 cells count were measured at the beginning and at 3-month intervals of rihavirin plus ct-interferon therapy during a mean period of 9 + 3months. Efficacy of bitherapy was assessed according to virological response at M6 in all patients. Results: In 28 patients receiving AZT or D4T there was no significant variation of the HIV viral load nor oftha CD4 cell count at 3, 6 or 9 months of ribavirin therapy compared to baseline values; 3/28 (11%) had increased HIV viral load (more than 0.5 log) leading to discontinuation of rihavirin in one. Ten of 35 (28.6%) experienced a primary response at M6. Median hemoglobin concentration decreased significantly at month 3 and 6 of ribavirin therapy (p < 0.0002) leading to withdrawal therapy and decrease doses in one and 2 patients respectively. Conclusions: l- despite in vitro interactions between ribavirin, zidovudine and stavudine, significant variation in H1V replication does not usually occur in HCV-HIV coinfected patients receiving ribavirin; 2- a-interferon and ribavirin combination therapy induces a primary virological response in 28.5% of treated subjects; 3- anemia is a frequent adverse event.
178
c0s/0o7 I
MANAGEMENT AND REFERRAL PATTERNS OF PATIENTS WITH HEPATITIS C BY PRIMARY CARE PHYSICIANS: IMPACT OF AN EDUCATIONAL PROGRAMME P. Del Po~,io. C. Jamoletti, M. Iazzetti l, A. Filippi ~, M. Mattiello, M. Mazzoleni]~ R. Vailati Hepatology Unit, Osp. Treviglio (Bg), Italy. lSociet/t Ital. Med. Gen. (Sez. Lombardia), Italy.
Desion of the study: 47 (31%) out of 150 Pdmary Care Physicians (PCP) of a local Health District with a high prevalence of hepatotropic viruses joined an educational programme on hepatitis C organized by our Unit and by the italian Society of Primary Care Physicians (SIMG). We initially determined the knowledge, current behaviour and referral patterns of PCP by means of a questionnaire, clinical vignettes and educational meetings. In the second phase the official guidelines on hepatitis C were mailed to PCP and subsequently discussed to finally develop a joined protocol for cost-effective management and referral, We then evaluatedall the new patients referred to our Unit by trained (T) and untrained (U) PCP in the following 9 months in order to assess the number and appropdateness of referrals. Results: The majority (83%) of T-PCP can identify patients at dsk for hepatitis C and begin a correct initial management or referral. They however order excessive diagnostic tests (HCV-RNA and Ultrasound) and cannot reliably identify well compensated cirrhotics. ARer completion of the programme T-PCP referred less patients than before. (28% vs 46% of the total number of referrals, p<0.01 Chi sq)and were more accurate than U-PCP ( 61% vs36% of appropriate referrals, p<0.02) The most frequent causes of inappropriate referrals were: lack of important laboratory tests (T:43% U:40%), unnecessary consultation (T:35% U:38%) and "too eady" referrals (T:14% U:17%).'too late" referrals were observed only in the U-PCP. Years in practice, specialty and number of cared patients did not influence the appropdateness of referrals. Conclusions: An educational programme with active involvement of PCP and a joined protocol can improve the utilization of specialty care in the management of hepatitis C.
I
cos/oo8 I
EFFECT OF 12 M O N T H alFN AND RIBAVIRIN COMBINATION THERAPY IN CHRONIC HEPATITIS C UNRESPONSIVE TO alFN A. Bellobuono. S. Temvini. D. Grimoldi, G.M. Id6o, L. Mondazzi, E Brasca, G. Iddo Center for Liver Diseases, S. Giuseppe Hospital, Milan, Italy. edFN and Ribevirin (RBV) combination therapy, usually administered for 6 months, was found to have a low efficacy in chronic hepatitis C (CHC) uraeslxmsive to IFN. Aim : to evaluate the efficacy of 12 months RBV and ~ combination therapy in mneslxmsive patients, ccmpering three differont schedules. Patients and treatment : one hundred and twenty patients um'esponsive to ¢zlFH f¢~CHC (75.8% with genotype 1) have been Ueated for 12 months with IFHct2b (5 MU/tiw) eandRBV (1-1.2 g/day) combination therapy ((2) (44 pts), or RBV for 3 months followed by C (38 pts), or edFN for 3 months followed by C (38 pts). Serum ALT levels were evaluated monthly dmmg treatment and for at least 6 months follow-up. Sexton HCV RHA was evaluated using RT-PCR (detection limit = 100 copies/ml) evory 3 months during treatment and follow-up. The nmmalization of ALT and the cleorance of HCVRNA at the 3mmonthand at the end of therapy were respectively considered Early Response (ER) and EndTherapy Response (ETR). The maintenance of normal ALT and negative HCV for 6 month follow-up was defined Sustained Response (SR). HCV 8enotype was identified according to the method of Okamoto. Chi square test was used for statistical evaluation. Results : overall ETR and SR in relation to treatment rates were 28.3% (34/120) and 17.5% (21/120) respective ,. The response rates are reported in the table : IFN & RBV RBV IFN followed by Ii~ followedby RBV P ER 11/44 (25%)* 0138 (0%) 3/38 (8%) 0.01 ErR 13/44 (29.5%) 10/38 (26.3%) 11/38 (28.9%) NS SR 10144(22.7%) 5/38 (13.2%) 6/38 (15.8%) NS SR was significantly more flequent in genotype n¢~-I (37.9%) than in genotype 1 (11%, p < 0.01). Ceadmiom : No significant difference in ETR and 8R between the three schedules was found. Combination treatment semned to be useful mainly in umespoasive patientsinfectedwith gonotypenou-l.
[
C06/005
I
I
CYTOKINE KINETIC AND RESPONSE TO INTERFERON a (IFN) ALONE OR IN ASSOCIATION WITH AMANTADINE OR RIBAVIRIN IN HCV POSITIVE PATIENTS E Torre, S. RossoP, R. Giusto, R. Brizzolara, N. Sinelli, N. Campo, A. Picciotto Gastroenterology Unit, University of Genoa, Italy. 1Department of Gastroenterology, Mannheim, Germany. The ncdmnisms of action of IFN incinde direct ~ v h - a ] effeas as well as k ~ n c c ~ d u b t c ~ effects with enhmcenent of the effector arm of the
m n u m syuem. Ahn of this stay was to evalmte seda~y l x o ~ mmkers (soluble TNF a p 5 5 and p75 receptt~s) and T-help~- type 1 (IFN y, ILl2), type 2 (ILl0) ~ in ~ e first month oflrealment with IFN alone or h association with other ~ a ~ ; ~ Amantadine or lh~aviri~ Twentytwo patients with chronic ~ C received IFN 3MU daily (7 p(s); IFN 3MU daily plus Amantadi~ 200 mg(7 pts~, IFN 3MU daily plus ~ a v i r m 112 gr (8 pts), for six months. Blood samples were drawn at baseline, at 6, 12, 24, 30 and 48 houm from the beginningofthe trealment; and at the yd, 7t, 15~ and 30~ day. All cytokines and ~ w e ~ evaluated by ELISA and HCVRNA by Cobas Amplicor HCV (cut-off 1.00E+02 copies/ml; Roche). Independently to type of or outcome to the treatment, sTNF-55 and 75 presented a increment within the first 24 hrs, to then slabilised at a higher level then beseline, (iae~at~. Lower levels of sTNF-75 were present a t ~ day 3 in pafie~ who then became HCV-RNA negative at day 30 (p=0.01; MannWhitney U test). No significar~ ~ have bee~ ~ for IFI~ or ILl2 wilhin the first 30 days among ~ or ~ . Instead, whereas no diffw=~es w~e observed for ILIO among treatments, a significant r~hction from baseline levels, unrelated to the type of Imatment, was observed among responders and non responde~ to the Irealnm'a, after the 3'd day of t r e a t m ~
(p=O.02)."[hesedats show that IFN increasesi x o ~
matk~ with a
the~dk¢ reduction in IXs who b¢c(m~eHCV-RNA negative, but indicate how respome to treaWaent is related to a redu_.aionin the T-helper 2 activity.
C06/006
I
EFFICACY AND SAFETY OF INTERFERON AND RIBAVIRIN THERAPY IN HIV-HCV COINFECTED PATIENTS H. Zvlberbere. Y. Benhamou. M.L. Chaix. H. Fontaine, C. Rouzioux, C. Katlama. T. Povnard. C. Br6chot. S. Pol Liver unit and virology laboratory, Inserm U370, C H U Necker, C H U Piti6 Salp6tri6re, Paris, France. Background/Aim: Increased severity of liver disease and poor response rate to a-interferon in HIV-HCV coinfected patients stress the need of more potent anti-HCV therapies. Efficacy and safety of intefferon-n'bavirin combination therapy in HIV infected subjects including potent interference with anti-HiV drug i. e. zidovudine, stavudine, is however unknown. Patients: 35 patients (9 never treated by interferon or rihavirine) treated with combined antiretroviral therapy including zidovudine (n--9) or stavudine (n=19) received ribavirin and c,-intefferon. Sixteen had cirrhosis. Genotype was 1:21 (60%); 2:2 (6%) 3: 8~23%); others: 4 (11%). Methods: The HIV viral load (Monitor test) and the CD4 cells count were measured at the beginning and at 3-month intervals of rihavirin plus ct-interferon therapy during a mean period of 9 + 3months. Efficacy of bitherapy was assessed according to virological response at M6 in all patients. Results: In 28 patients receiving AZT or D4T there was no significant variation of the HIV viral load nor oftha CD4 cell count at 3, 6 or 9 months of ribavirin therapy compared to baseline values; 3/28 (11%) had increased HIV viral load (more than 0.5 log) leading to discontinuation of rihavirin in one. Ten of 35 (28.6%) experienced a primary response at M6. Median hemoglobin concentration decreased significantly at month 3 and 6 of ribavirin therapy (p < 0.0002) leading to withdrawal therapy and decrease doses in one and 2 patients respectively. Conclusions: l- despite in vitro interactions between ribavirin, zidovudine and stavudine, significant variation in H1V replication does not usually occur in HCV-HIV coinfected patients receiving ribavirin; 2- a-interferon and ribavirin combination therapy induces a primary virological response in 28.5% of treated subjects; 3- anemia is a frequent adverse event.
178
c0s/0o7 I
MANAGEMENT AND REFERRAL PATTERNS OF PATIENTS WITH HEPATITIS C BY PRIMARY CARE PHYSICIANS: IMPACT OF AN EDUCATIONAL PROGRAMME P. Del Po~,io. C. Jamoletti, M. Iazzetti l, A. Filippi ~, M. Mattiello, M. Mazzoleni]~ R. Vailati Hepatology Unit, Osp. Treviglio (Bg), Italy. lSociet/t Ital. Med. Gen. (Sez. Lombardia), Italy.
Desion of the study: 47 (31%) out of 150 Pdmary Care Physicians (PCP) of a local Health District with a high prevalence of hepatotropic viruses joined an educational programme on hepatitis C organized by our Unit and by the italian Society of Primary Care Physicians (SIMG). We initially determined the knowledge, current behaviour and referral patterns of PCP by means of a questionnaire, clinical vignettes and educational meetings. In the second phase the official guidelines on hepatitis C were mailed to PCP and subsequently discussed to finally develop a joined protocol for cost-effective management and referral, We then evaluatedall the new patients referred to our Unit by trained (T) and untrained (U) PCP in the following 9 months in order to assess the number and appropdateness of referrals. Results: The majority (83%) of T-PCP can identify patients at dsk for hepatitis C and begin a correct initial management or referral. They however order excessive diagnostic tests (HCV-RNA and Ultrasound) and cannot reliably identify well compensated cirrhotics. ARer completion of the programme T-PCP referred less patients than before. (28% vs 46% of the total number of referrals, p<0.01 Chi sq)and were more accurate than U-PCP ( 61% vs36% of appropriate referrals, p<0.02) The most frequent causes of inappropriate referrals were: lack of important laboratory tests (T:43% U:40%), unnecessary consultation (T:35% U:38%) and "too eady" referrals (T:14% U:17%).'too late" referrals were observed only in the U-PCP. Years in practice, specialty and number of cared patients did not influence the appropdateness of referrals. Conclusions: An educational programme with active involvement of PCP and a joined protocol can improve the utilization of specialty care in the management of hepatitis C.
I
cos/oo8 I
EFFECT OF 12 M O N T H alFN AND RIBAVIRIN COMBINATION THERAPY IN CHRONIC HEPATITIS C UNRESPONSIVE TO alFN A. Bellobuono. S. Temvini. D. Grimoldi, G.M. Id6o, L. Mondazzi, E Brasca, G. Iddo Center for Liver Diseases, S. Giuseppe Hospital, Milan, Italy. edFN and Ribevirin (RBV) combination therapy, usually administered for 6 months, was found to have a low efficacy in chronic hepatitis C (CHC) uraeslxmsive to IFN. Aim : to evaluate the efficacy of 12 months RBV and ~ combination therapy in mneslxmsive patients, ccmpering three differont schedules. Patients and treatment : one hundred and twenty patients um'esponsive to ¢zlFH f¢~CHC (75.8% with genotype 1) have been Ueated for 12 months with IFHct2b (5 MU/tiw) eandRBV (1-1.2 g/day) combination therapy ((2) (44 pts), or RBV for 3 months followed by C (38 pts), or edFN for 3 months followed by C (38 pts). Serum ALT levels were evaluated monthly dmmg treatment and for at least 6 months follow-up. Sexton HCV RHA was evaluated using RT-PCR (detection limit = 100 copies/ml) evory 3 months during treatment and follow-up. The nmmalization of ALT and the cleorance of HCVRNA at the 3mmonthand at the end of therapy were respectively considered Early Response (ER) and EndTherapy Response (ETR). The maintenance of normal ALT and negative HCV for 6 month follow-up was defined Sustained Response (SR). HCV 8enotype was identified according to the method of Okamoto. Chi square test was used for statistical evaluation. Results : overall ETR and SR in relation to treatment rates were 28.3% (34/120) and 17.5% (21/120) respective ,. The response rates are reported in the table : IFN & RBV RBV IFN followed by Ii~ followedby RBV P ER 11/44 (25%)* 0138 (0%) 3/38 (8%) 0.01 ErR 13/44 (29.5%) 10/38 (26.3%) 11/38 (28.9%) NS SR 10144(22.7%) 5/38 (13.2%) 6/38 (15.8%) NS SR was significantly more flequent in genotype n¢~-I (37.9%) than in genotype 1 (11%, p < 0.01). Ceadmiom : No significant difference in ETR and 8R between the three schedules was found. Combination treatment semned to be useful mainly in umespoasive patientsinfectedwith gonotypenou-l.