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P.238 High sustained virological response (SVR) rates with peginterferon alpha-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in haemodialysed CHC patients awaiting renal transplant
Posters: 02d. Hepatitis C - treatment study is based in 3 teaching hospitals in Sydney and Newcastle, Australia. Patients receive treatment for 6 months and will be followed up for an additional 6 months. Markers of liver injury (F2-isoprostanes) and fibrosis (hyaluronic acid) will be monitored. Liver biopsy was not included in the protocol as ethics approval was unlikely to be provided to a trial of a formally untested therapy. 98 participants have been recruited (67% male, 33% female), of whom 63% are genotype 1, 31% are genotype 3 and other 6%. The age range is 22-75 years, mean age is 47 years. 57% were naive to, and 43% were nonresponders to antiviral therapy. Hepatitis C genotype and viral load are measured at baseline; viral load was re-measured at 6 months and 6 months post treatment. Results: Since the study is ongoing, unblinded results are unavailable. However, alanine aminotransferase (ALT) normalisation has occurred in 20% of the study cohort, 77% of whom were genotype 1. Of these, 31% were refractory to interferon and ribavirin therapy. HCV RNA viral load data were completed for 17 participants (2/17 had 1 log reduction, 2/17 had 1 log increase, 1/17 had a 2 log increase). Conclusion: Patients are tolerating the trial preparations well and there have been no significant side effects. Final results are expected in December 2007.
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Blood distribution of non-phosphorylated and phosphorylated forms of ribavirin in patients treated for chronic hepatitis C
M. Gagnieu 1, C. Souvignet 2 *, R Rojat 1, M. Maynard 2, R Pradat 2, J. Dumortier 3, C. Tr~po 2. 1Pharmacology, H6pital Edouard Herriot,
2Hepatology, HStel Dieu, 3Digestive diseases, HSpital Edouard Herriot, Lyon, France Background and Objectives: Pharmacokinetics population studies have previously shown that during combination therapy of hepatitis C, higher ribavirin concentrations at week 4 of treatment were associated with a higher sustained virological response rate. However ribavirin has a large volume of distribution and its concentrations display a great inter-individual variability. So measurements of ribavirin plasma levels could allow monitoring of ribavirin administration according to individual metabolism of the drug, and possibly improve response rates. After absorption, ribavirin is phosphorylated by adenosine kinase and converted to ribavirin triphosphate, which is considered as the active metabolite of the drug. The objective of this study was to investigate the disposition of non-phosphorylated and phosphorylated forms of ribavirin among the different blood compartments: plasma, erythrocytes, and whole blood, in order to define the most convenient assay for therapeutic drug monitoring of ribavirin. Methods: Non-phosphorylated and total (non-phosphorylated + phosphorylated) ribavirin levels were assayed in plasma, erythrocyte, and whole blood samples from patients undergoing ribavirin treatment for chronic hepatitis C. Plasma samples were prepared immediately after blood sampling to prevent in vitro ribavirin redistribution between compartments. Relationship between ribavirin concentrations according to molecular forms of the drug was investigated in the different compartments using logistic regression model. Results: Non-phosphorylated ribavirin levels were similar in plasma (2.17±0.67mg/L) and whole blood (1.89±0.75mg/L). In whole blood, total ribavirin was nearly 50-fold higher than nonphosphorylated ribavirin. In addition, high relationships were noted between whole blood and plasma for non-phosphorylated ribavirin (r = 0.841; p ~<0.0001), and between whole blood and erythrocytes for total ribavirin (r = 0.780; p < 0.0001). Conclusion: In conclusion, data suggest that whole blood samples would be a convenient material for assaying both nonphosphorylated and phosphorylated forms of ribavirin. Extemporaneous frozen blood samples could be an alternative to plasma specimens when conditions for rapid separation of plasma are not useable in routine clinical practice. This assay will avoid the risk of underestimating ribavirin levels due to transport and phosphorylation of ribavirin into erythrocytes during sample storage. In addition it would offer the advantage to investigate the presumed pharmacologically active form of ribavirin (phosphorylated) in addition to the usual one (non-phosphorylated).
$135
~High
sustained virological response (SVR) rates with peginterferon alpha-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in haemodialysed CHC patients awaiting renal transplant
M. Rendina 1 *, A. Schena 2, N.M. Castellaneta 1, E Losito 1, A.C. Amoruso 1, G. Stallone 2, ER Schena 2, A. Di Leo 1, A. Francavilla 1. 1Department of Emergency and Organ
Transplantation, Section of Gastroenterology, 2Section of Nephrology, University of Bari, Bari, Italy Background and Objectives: There is much debate as to whether haemodialysed CHC pts awaiting renal transplant should receive interferon-based combination therapy. In this pilot study we prospectively investigated the efficacy and safety of Peg-IFN,Y,-2a (40KD) plus ribavirin in haemodialysed CHC pts awaiting renal transplant. Methods: Treatment-naive adult haemodialysis pts with CHC and detectable HCV RNA awaiting renal transplant received Peg-IFN,Y,-2a (40KD) (PEGASYS ®) 135pg/wk plus ribavirin (COPEGUS ®) 200mg/d for either 24 (genotype 2/3) or 48 (genotype 1) wks. All pts also received concomitant epoetin-,Y, at a dose of 12,00018,000 IU/wk, which was increased to ~40,000 IU/wk in pts whose haemoglobin (Hb) fell to ~8.5g/dL during treatment. If Hb levels remained uncorrected despite increasing the dose of epoetin-,q the dose of ribavirin was reduced to 200 mg every other day. The primary endpoint was SVR (undetectable HCV RNA after 24 wks untreated follow-up). Outcomes in treated pts were compared with those of a group of matched untreated control haemodialysis pts. Results: After 4 wks of Peg-IFN,Y,-2a (40KD) plus ribavirin, 24/25 pts had undetectable HCV RNA. 20/25 treated pts completed treatment; reasons for early withdrawal were renal transplant at wk 20 [n=2], ribavirin-related severe anaemia (Hb 5.4g/dL) at wk 12 [n = 1], Peg-IFN,Y,-2a (40KD)-related dermatitis at wk 16 [n = 1] and non-response after 24 wks in a genotype 1 patient [n = 1]. 24/25 pts achieved an end-of-treatment response and an SVR, including the 4 pts (who were genotype 2/3) who withdrew early for reasons other than non-response (Table). Eighteen of 25 pts had an Hb level 48.5 g/dL during treatment and had their epoetin-,Y, dose increased. Of these, only 6 required that the dose of ribavirin be reduced to 200 mg every other day.
End-of-treatment response, N (%) SVR, N (%)
Peg-IFNct-2a (40KD) plus ribavirin (n = 25)
No treatment (n = 25)
24 (96)* 24 (96)*
0 (0) 0 (0)
*p<0.001 vs no treatment (Chi-square test).
Conclusion: Peg-IFN,Y,-2a (40KD) plus ribavirin is highly effective and well tolerated in HCV-infected haemodialysed pts awaiting renal transplant, indicating that it is possible to successfully treat pts in this setting. The high response rates associated with Peg-IFN,Y,-2a (40KD) plus ribavirin in this study may be due, in part, to absorption of HCV particles onto the dialyser membrane. These results should be confirmed in larger studies. ~
Hepatitis C antiviral therapy in cirrhotic patients
RR.D. Oliveira, A.C. Freitas, EM. Tengan, T. Bacchella, M.C.C. Machado, E. Abdala*. Infectious Disease and Liver
Transplantation Division, University of Sbo Paulo Medical School, Sbo Paulo, Brazil Background and Objectives: Hepatitis C virus (HCV) infection is the main cause of hepatic insufficiency leading to liver transplantation (LT). After LT, recurrence of infection is virtually universal and aggressive. The viral load pre-LT is associated with recurrence severity. Antiviral treatment of cirrhotic patients could reduce this severity, but the safety and efficacy are controversial, mainly in those with decompensated cirrhosis. The objective of the study is to describe the virological response and the safety of antiviral therapy in 37 cirrhotic patients, and to compare them between compensated and decompensated ones. Methods: Retrospective analysis of 37 patients with HCV cirrhosis who received antiviral therapy with conventional or pegylated interferon (IFN), associated or not to ribavirin (RBV); 17 patients had decompensated cirrhosis and were on LT waiting list, and 20
r
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•
Blood distribution of non-phosphorylated and phosphorylated forms of ribavirin in patients treated for chronic hepatitis C
M. Gagnieu 1, C. Souvignet 2 *, R Rojat 1, M. Maynard 2, R Pradat 2, J. Dumortier 3, C. Tr~po 2. 1Pharmacology, H6pital Edouard Herriot,
2Hepatology, HStel Dieu, 3Digestive diseases, HSpital Edouard Herriot, Lyon, France Background and Objectives: Pharmacokinetics population studies have previously shown that during combination therapy of hepatitis C, higher ribavirin concentrations at week 4 of treatment were associated with a higher sustained virological response rate. However ribavirin has a large volume of distribution and its concentrations display a great inter-individual variability. So measurements of ribavirin plasma levels could allow monitoring of ribavirin administration according to individual metabolism of the drug, and possibly improve response rates. After absorption, ribavirin is phosphorylated by adenosine kinase and converted to ribavirin triphosphate, which is considered as the active metabolite of the drug. The objective of this study was to investigate the disposition of non-phosphorylated and phosphorylated forms of ribavirin among the different blood compartments: plasma, erythrocytes, and whole blood, in order to define the most convenient assay for therapeutic drug monitoring of ribavirin. Methods: Non-phosphorylated and total (non-phosphorylated + phosphorylated) ribavirin levels were assayed in plasma, erythrocyte, and whole blood samples from patients undergoing ribavirin treatment for chronic hepatitis C. Plasma samples were prepared immediately after blood sampling to prevent in vitro ribavirin redistribution between compartments. Relationship between ribavirin concentrations according to molecular forms of the drug was investigated in the different compartments using logistic regression model. Results: Non-phosphorylated ribavirin levels were similar in plasma (2.17±0.67mg/L) and whole blood (1.89±0.75mg/L). In whole blood, total ribavirin was nearly 50-fold higher than nonphosphorylated ribavirin. In addition, high relationships were noted between whole blood and plasma for non-phosphorylated ribavirin (r = 0.841; p ~<0.0001), and between whole blood and erythrocytes for total ribavirin (r = 0.780; p < 0.0001). Conclusion: In conclusion, data suggest that whole blood samples would be a convenient material for assaying both nonphosphorylated and phosphorylated forms of ribavirin. Extemporaneous frozen blood samples could be an alternative to plasma specimens when conditions for rapid separation of plasma are not useable in routine clinical practice. This assay will avoid the risk of underestimating ribavirin levels due to transport and phosphorylation of ribavirin into erythrocytes during sample storage. In addition it would offer the advantage to investigate the presumed pharmacologically active form of ribavirin (phosphorylated) in addition to the usual one (non-phosphorylated).
$135
~High
sustained virological response (SVR) rates with peginterferon alpha-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in haemodialysed CHC patients awaiting renal transplant
M. Rendina 1 *, A. Schena 2, N.M. Castellaneta 1, E Losito 1, A.C. Amoruso 1, G. Stallone 2, ER Schena 2, A. Di Leo 1, A. Francavilla 1. 1Department of Emergency and Organ
Transplantation, Section of Gastroenterology, 2Section of Nephrology, University of Bari, Bari, Italy Background and Objectives: There is much debate as to whether haemodialysed CHC pts awaiting renal transplant should receive interferon-based combination therapy. In this pilot study we prospectively investigated the efficacy and safety of Peg-IFN,Y,-2a (40KD) plus ribavirin in haemodialysed CHC pts awaiting renal transplant. Methods: Treatment-naive adult haemodialysis pts with CHC and detectable HCV RNA awaiting renal transplant received Peg-IFN,Y,-2a (40KD) (PEGASYS ®) 135pg/wk plus ribavirin (COPEGUS ®) 200mg/d for either 24 (genotype 2/3) or 48 (genotype 1) wks. All pts also received concomitant epoetin-,Y, at a dose of 12,00018,000 IU/wk, which was increased to ~40,000 IU/wk in pts whose haemoglobin (Hb) fell to ~8.5g/dL during treatment. If Hb levels remained uncorrected despite increasing the dose of epoetin-,q the dose of ribavirin was reduced to 200 mg every other day. The primary endpoint was SVR (undetectable HCV RNA after 24 wks untreated follow-up). Outcomes in treated pts were compared with those of a group of matched untreated control haemodialysis pts. Results: After 4 wks of Peg-IFN,Y,-2a (40KD) plus ribavirin, 24/25 pts had undetectable HCV RNA. 20/25 treated pts completed treatment; reasons for early withdrawal were renal transplant at wk 20 [n=2], ribavirin-related severe anaemia (Hb 5.4g/dL) at wk 12 [n = 1], Peg-IFN,Y,-2a (40KD)-related dermatitis at wk 16 [n = 1] and non-response after 24 wks in a genotype 1 patient [n = 1]. 24/25 pts achieved an end-of-treatment response and an SVR, including the 4 pts (who were genotype 2/3) who withdrew early for reasons other than non-response (Table). Eighteen of 25 pts had an Hb level 48.5 g/dL during treatment and had their epoetin-,Y, dose increased. Of these, only 6 required that the dose of ribavirin be reduced to 200 mg every other day.
End-of-treatment response, N (%) SVR, N (%)
Peg-IFNct-2a (40KD) plus ribavirin (n = 25)
No treatment (n = 25)
24 (96)* 24 (96)*
0 (0) 0 (0)
*p<0.001 vs no treatment (Chi-square test).
Conclusion: Peg-IFN,Y,-2a (40KD) plus ribavirin is highly effective and well tolerated in HCV-infected haemodialysed pts awaiting renal transplant, indicating that it is possible to successfully treat pts in this setting. The high response rates associated with Peg-IFN,Y,-2a (40KD) plus ribavirin in this study may be due, in part, to absorption of HCV particles onto the dialyser membrane. These results should be confirmed in larger studies. ~
Hepatitis C antiviral therapy in cirrhotic patients
RR.D. Oliveira, A.C. Freitas, EM. Tengan, T. Bacchella, M.C.C. Machado, E. Abdala*. Infectious Disease and Liver
Transplantation Division, University of Sbo Paulo Medical School, Sbo Paulo, Brazil Background and Objectives: Hepatitis C virus (HCV) infection is the main cause of hepatic insufficiency leading to liver transplantation (LT). After LT, recurrence of infection is virtually universal and aggressive. The viral load pre-LT is associated with recurrence severity. Antiviral treatment of cirrhotic patients could reduce this severity, but the safety and efficacy are controversial, mainly in those with decompensated cirrhosis. The objective of the study is to describe the virological response and the safety of antiviral therapy in 37 cirrhotic patients, and to compare them between compensated and decompensated ones. Methods: Retrospective analysis of 37 patients with HCV cirrhosis who received antiviral therapy with conventional or pegylated interferon (IFN), associated or not to ribavirin (RBV); 17 patients had decompensated cirrhosis and were on LT waiting list, and 20