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Individualized long-term treatment of chronic hepatitis C with interferon alpha (IFN α) - 2a
}-IEPATOLOGYVol. 34, No. 4, Pt. 2, 2001
AASLD ABSTRACTS
591A
1675
1676
DAILY VERSUS THRICE WEEKLY INTERFERON THERAPY W I T H RIBAVIRIN IN THE TREATMENT OF CHRONIC HEPATITIS C. INTERIM DATA AT 24 WEEKS. Roderick A Remoroza, George Y Wu, University of
I N D M D U A L 1 Z E D LONG-TERM TREATMENT OF CHRONIC HEPATITIS C W I T H INTERFERON ALPHA (IFN ~) - 2A. Patrizia Farci, Giancarlo
Connecticut Health Center, Farmington, CT; Donna Cipolla, Hartford Hospital, Hartford, CT; Renuka Umashanker, Dean Chang, Yale New Haven Hospital, Hamden, CT; Ashan Manohar, Backus Hosp, Norwich, CT; Richard Sheinbaum, Joel Garsten, Waterbury Hospital, Waterbury, CT Background: The standard combination therapy of interferon and ribavirin provides a sustained response rate of about 30% in naive patients with genotype la/lb and about 40% in non-la/lb patients. Viral kinetic studies have shown that the circulating levels of HCV RNA go up 48 hours after the inject:ton of interferon. This suggests that daily interferon may be able to suppress the virus more effectively. Aim: To compare the efficacy of interferon 3 million units daily with ribavirin versus standard combination interferon/ribavirin. Methods: Adult patients with biopsy proven Chronic Hepatitis C, abnormal liver enzymes and positive serum HCV RNA by PCR were enrolled in the study. Patients with other causes of liver disease, decompensated liver disease, significant co-morbid conditions including HIV, severe depression and active use of illicit drugs and alcohol within the past six months were excluded. The patients were randomly assigned to receive either interferon 3 million units daily with 1000 mg of ribavirin per day or interferon 3 million units thrice weekly with 1000 mg of ribavirin per day for 24 to 48 weeks. HCV RNA was measured by PCR at week 24 and if detectable, treatment was discontinued. Patients with undetectable HCV RNA continued to receive treatment for another 24 weeks. Patients who complete 48 weeks of treatment will be followed for another 24 weeks after stopping treatment. Results: There were 50 patients enrolled to date and 19 patients have finished 24 weeks of therapy. Data from these 19 patients are presented in this report as shown in the table. Conclusion: Daily interferon with ribavirin has a significantly higher 24-week response rate when compared to thrice-weekly interferon and ribavirin. Daily interferon was also well tolerated and may be a safe and effective treatment regimen for naive patients. _ Number of Patients Negative Viral Load at 24 Weeks Non lallb Genotype
Daily 11 9 82% 4/tl (36%)
Serra, Luchirlo Chessa, Rita Strazzera, Rosetta Scioscia, Alessandra Coiana, Cinzia Balestrieri, Univ of Cagliari, Cagliari Italy; Pier Luigi Carriero, Massimo Sarracino, Roche Italy, Milan Italy; Friederike Zahm, F Hoffmann-LaRroche ltd, Basel Switzerland; Robert H Purcell, Natl Inst of Health, Bethesda, MD; Angelo Balestrieri, Univ of Cagliari, Cagliari Italy Treatment of chronic hepatitis C with IFN ~ 2a induces a complete response in about 40% of the patients, but more than half relapse soon after stopping therapy. Such high rate of relapse suggests that treatment duration and doses play an important role in maintaining a long-term response. To test this hypothesis, in March 1997 we started in Sardinia a clinical trial based on individualized long-term treatment aimed to identify for each patient the lowest effective dose (LED) of IFN c~2a, which was defined as the dose (between 1 and 6MU) associated with sustained ALT normalization and undetectable serum HCV RNA. Study design: patients (pts) were started at 6MU, TIW, until ALT normalization; this dose was maintained for 2 additional mos and then was reduced by 1MU every 2 mos to reach the lowest dose (1MU, TIW), which was then maintained for 2 yrs. If pts experienced a breakthrough (BT) during the descalating phase, the dose was immediately increased by 1MU per month to reach the individualized LED, which was then maintained for 2 yrs. If ALT normalization did not occur after re-escalating the dose up to 6MU, treatment was interrupted after 3 mos. If a BT occurred during treatment with the LED, IFN was immediately escalated by 1MU every month until a secondary LED was reached which was continued for at least 1yr. In case of non-response or BT at the initial dose of 6MU, treatment was stopped after 6 mos. A total of 79 pts with histologic evidence of chronic hepatitis or cirrhosis, were included: all but 4 were IFN-na.
Thrice Weekiy 8 4 50% t/8 (13%)
1677
1678
VIRAL KINETICS IN CHRONIC HEPATITIS B PATIENTS BEING TREATED BY CONSENSUS INFERFERON (CIF) ALONE OR IN COMBINATION W I T H LAMIVUDINE AND FAMCICLOVtR. Gerhard G Treiber,
COMBINATION THERAPY W I T H BETA AND ALPHA INTERFERON IN PATIENTS W I T H INTERFERON-RESISTANT CHRONIC HEPATITIS C.
Pelmr Malfertheiner, University Hospital, Magdeburg Germany Background: Viral kinetics have been proposed to predict final outcome of HCV infected patients treated by INF. Little information is available about HBV infection. Aim: To investigate the impact of a new highly active INF (CIF) as a monotherapy or in combination with lamivudine and famciclovir (triple therapy) in a pilot study. Methods: 10 out of 40 intended patients have been recruited so far and treated for at least 12 weeks of treatment. They have been randomised to either monotherapy with CIF 9t~g daily (n=5) or CIF 9~g daily plus lamivudine 100 mg daily plus famciclovir 500 mg tid (n=5) for 48 weeks. HBV-DNAwas determined by hybridisation and PCR method (lower detection limit 200 copies/ml) at week 0,2,4,8,12 and every 12 months thereafter. The results of mean log 10 decrease in HBV-DNA were compared to available literature data at week 12 or 16 for interferon-alpha (IFN-alpha), lamivudine (LAM), and famciclovir (FAM). Results: 9 patients could be evaluated at 12 weeks, one of them was a previous non-responder to IFN-alpha and had again no change in HBV-DNA levels (triple arm). Thus results are available from 8 patients (table): All 7/8 patients were negative for HBV-DNAat week 12, one in the CIF-triple arm already converting into anti-HBsAg positve. No serious adverse events have been noticed. Conclusions: CIF-mono seems to induce a more rapid decrease in HBV-DNA than conventional IFN-alpha compared with older literature data (Marinos, Hepatology 1996). CIF-mono is as effective as LAM mono. Combination therapy (LAM-FAM) is better tham LAM alone, CIF-triple therapy produces a very quick and high drop in HBV-DNA, which was consistent in all 4 patients. This combination therapy deserves further investigation by a larger trial. Mean log 10 decreasein HBV-DNAat week12 or 16" of treatment
CIF-mono CIF.,triple IFN.,alpha* IFN-alpha-LAM LAM LAU-FAM
mean Io9 10 decrease Z i4 4.48 0.93 1.61 1,8 2.5
SD 0.5t 0,54 n.a. n,a, 0,2 0,8
Hiroshi Watanabe, Shotaro Sakisaka, Fukuoka University School of Medicine, Fnknoka Japan Background/Aims : The treatment of chronic hepatitis C with a standard regimen of therapy with alpha interferon (1FN) for 6 months results in a sustained response (SR) in a minority of patients with high levels of HCV-RNA. The aim of this study was to assess whether a high dose of interferon and combination therapy with beta and alpha interferon increase efficacy, and to identify the determinants or predictive factors of SR in patients with IFN resistant chronic hepatitis C. Methods: In 95 patients with high levels of HCV-RNA (> 1 Meq/ ml), we compared the efficacy of combination therapy with beta and alpha IFN (n = 51 ) and IFN monotherapy (n = 44). Results: SR was observed in 9 (17.6%) and non-response (NR) in 42(82.4%) with the combination therapy, and in 3 (6.8%) and 41 (93.2%) respectively with monotherapy (p<0.03). There was a significant difference between these two groups. Conclusions: Combination therapy with beta and alpha IFN was superior to IFN monotherapy in patients with high levels of HCV-RNA of chronic hepatitis C, and this combination therapy can be recommended for patients with high levels of HCV-RNA and relapsers of IFN monothrapy
AASLD ABSTRACTS
591A
1675
1676
DAILY VERSUS THRICE WEEKLY INTERFERON THERAPY W I T H RIBAVIRIN IN THE TREATMENT OF CHRONIC HEPATITIS C. INTERIM DATA AT 24 WEEKS. Roderick A Remoroza, George Y Wu, University of
I N D M D U A L 1 Z E D LONG-TERM TREATMENT OF CHRONIC HEPATITIS C W I T H INTERFERON ALPHA (IFN ~) - 2A. Patrizia Farci, Giancarlo
Connecticut Health Center, Farmington, CT; Donna Cipolla, Hartford Hospital, Hartford, CT; Renuka Umashanker, Dean Chang, Yale New Haven Hospital, Hamden, CT; Ashan Manohar, Backus Hosp, Norwich, CT; Richard Sheinbaum, Joel Garsten, Waterbury Hospital, Waterbury, CT Background: The standard combination therapy of interferon and ribavirin provides a sustained response rate of about 30% in naive patients with genotype la/lb and about 40% in non-la/lb patients. Viral kinetic studies have shown that the circulating levels of HCV RNA go up 48 hours after the inject:ton of interferon. This suggests that daily interferon may be able to suppress the virus more effectively. Aim: To compare the efficacy of interferon 3 million units daily with ribavirin versus standard combination interferon/ribavirin. Methods: Adult patients with biopsy proven Chronic Hepatitis C, abnormal liver enzymes and positive serum HCV RNA by PCR were enrolled in the study. Patients with other causes of liver disease, decompensated liver disease, significant co-morbid conditions including HIV, severe depression and active use of illicit drugs and alcohol within the past six months were excluded. The patients were randomly assigned to receive either interferon 3 million units daily with 1000 mg of ribavirin per day or interferon 3 million units thrice weekly with 1000 mg of ribavirin per day for 24 to 48 weeks. HCV RNA was measured by PCR at week 24 and if detectable, treatment was discontinued. Patients with undetectable HCV RNA continued to receive treatment for another 24 weeks. Patients who complete 48 weeks of treatment will be followed for another 24 weeks after stopping treatment. Results: There were 50 patients enrolled to date and 19 patients have finished 24 weeks of therapy. Data from these 19 patients are presented in this report as shown in the table. Conclusion: Daily interferon with ribavirin has a significantly higher 24-week response rate when compared to thrice-weekly interferon and ribavirin. Daily interferon was also well tolerated and may be a safe and effective treatment regimen for naive patients. _ Number of Patients Negative Viral Load at 24 Weeks Non lallb Genotype
Daily 11 9 82% 4/tl (36%)
Serra, Luchirlo Chessa, Rita Strazzera, Rosetta Scioscia, Alessandra Coiana, Cinzia Balestrieri, Univ of Cagliari, Cagliari Italy; Pier Luigi Carriero, Massimo Sarracino, Roche Italy, Milan Italy; Friederike Zahm, F Hoffmann-LaRroche ltd, Basel Switzerland; Robert H Purcell, Natl Inst of Health, Bethesda, MD; Angelo Balestrieri, Univ of Cagliari, Cagliari Italy Treatment of chronic hepatitis C with IFN ~ 2a induces a complete response in about 40% of the patients, but more than half relapse soon after stopping therapy. Such high rate of relapse suggests that treatment duration and doses play an important role in maintaining a long-term response. To test this hypothesis, in March 1997 we started in Sardinia a clinical trial based on individualized long-term treatment aimed to identify for each patient the lowest effective dose (LED) of IFN c~2a, which was defined as the dose (between 1 and 6MU) associated with sustained ALT normalization and undetectable serum HCV RNA. Study design: patients (pts) were started at 6MU, TIW, until ALT normalization; this dose was maintained for 2 additional mos and then was reduced by 1MU every 2 mos to reach the lowest dose (1MU, TIW), which was then maintained for 2 yrs. If pts experienced a breakthrough (BT) during the descalating phase, the dose was immediately increased by 1MU per month to reach the individualized LED, which was then maintained for 2 yrs. If ALT normalization did not occur after re-escalating the dose up to 6MU, treatment was interrupted after 3 mos. If a BT occurred during treatment with the LED, IFN was immediately escalated by 1MU every month until a secondary LED was reached which was continued for at least 1yr. In case of non-response or BT at the initial dose of 6MU, treatment was stopped after 6 mos. A total of 79 pts with histologic evidence of chronic hepatitis or cirrhosis, were included: all but 4 were IFN-na.
Thrice Weekiy 8 4 50% t/8 (13%)
1677
1678
VIRAL KINETICS IN CHRONIC HEPATITIS B PATIENTS BEING TREATED BY CONSENSUS INFERFERON (CIF) ALONE OR IN COMBINATION W I T H LAMIVUDINE AND FAMCICLOVtR. Gerhard G Treiber,
COMBINATION THERAPY W I T H BETA AND ALPHA INTERFERON IN PATIENTS W I T H INTERFERON-RESISTANT CHRONIC HEPATITIS C.
Pelmr Malfertheiner, University Hospital, Magdeburg Germany Background: Viral kinetics have been proposed to predict final outcome of HCV infected patients treated by INF. Little information is available about HBV infection. Aim: To investigate the impact of a new highly active INF (CIF) as a monotherapy or in combination with lamivudine and famciclovir (triple therapy) in a pilot study. Methods: 10 out of 40 intended patients have been recruited so far and treated for at least 12 weeks of treatment. They have been randomised to either monotherapy with CIF 9t~g daily (n=5) or CIF 9~g daily plus lamivudine 100 mg daily plus famciclovir 500 mg tid (n=5) for 48 weeks. HBV-DNAwas determined by hybridisation and PCR method (lower detection limit 200 copies/ml) at week 0,2,4,8,12 and every 12 months thereafter. The results of mean log 10 decrease in HBV-DNA were compared to available literature data at week 12 or 16 for interferon-alpha (IFN-alpha), lamivudine (LAM), and famciclovir (FAM). Results: 9 patients could be evaluated at 12 weeks, one of them was a previous non-responder to IFN-alpha and had again no change in HBV-DNA levels (triple arm). Thus results are available from 8 patients (table): All 7/8 patients were negative for HBV-DNAat week 12, one in the CIF-triple arm already converting into anti-HBsAg positve. No serious adverse events have been noticed. Conclusions: CIF-mono seems to induce a more rapid decrease in HBV-DNA than conventional IFN-alpha compared with older literature data (Marinos, Hepatology 1996). CIF-mono is as effective as LAM mono. Combination therapy (LAM-FAM) is better tham LAM alone, CIF-triple therapy produces a very quick and high drop in HBV-DNA, which was consistent in all 4 patients. This combination therapy deserves further investigation by a larger trial. Mean log 10 decreasein HBV-DNAat week12 or 16" of treatment
CIF-mono CIF.,triple IFN.,alpha* IFN-alpha-LAM LAM LAU-FAM
mean Io9 10 decrease Z i4 4.48 0.93 1.61 1,8 2.5
SD 0.5t 0,54 n.a. n,a, 0,2 0,8
Hiroshi Watanabe, Shotaro Sakisaka, Fukuoka University School of Medicine, Fnknoka Japan Background/Aims : The treatment of chronic hepatitis C with a standard regimen of therapy with alpha interferon (1FN) for 6 months results in a sustained response (SR) in a minority of patients with high levels of HCV-RNA. The aim of this study was to assess whether a high dose of interferon and combination therapy with beta and alpha interferon increase efficacy, and to identify the determinants or predictive factors of SR in patients with IFN resistant chronic hepatitis C. Methods: In 95 patients with high levels of HCV-RNA (> 1 Meq/ ml), we compared the efficacy of combination therapy with beta and alpha IFN (n = 51 ) and IFN monotherapy (n = 44). Results: SR was observed in 9 (17.6%) and non-response (NR) in 42(82.4%) with the combination therapy, and in 3 (6.8%) and 41 (93.2%) respectively with monotherapy (p<0.03). There was a significant difference between these two groups. Conclusions: Combination therapy with beta and alpha IFN was superior to IFN monotherapy in patients with high levels of HCV-RNA of chronic hepatitis C, and this combination therapy can be recommended for patients with high levels of HCV-RNA and relapsers of IFN monothrapy