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Use of interferon α-2b and ribavirin for the treatment of patients with chronic hepatitis C with normal ALT levels
596A
AASLD ABSTRACTS
HEPATOLOGYO c t o b e r 2 0 0 1
1695
1696
USE OF INTERFERON o~-2B AND RIBAVIRIN FOR TREATMENT OF PATIENTS W I T H CHRONIC HEPATITIS C W I T H NORMAL ALT LEVELS. Craig A Sponseller, Kathleen M Koehler, Bruce R Bacon, Saint Louis University, St. Louis, MO
SERUM RIBAVIRIN REMAINING AFTER END OF IFNoL-2B + RIBAVIRIN COMBINATION THERAPY MAY IMPACT SERUM HCV RNA PATTERN IN CHRONIC HEPATITIS C. Takeshi Okanoue, Kyoto Prefectural University of Medicine, Kyoto Japan; Kyuichi Tanikawa, International Institute for Liver Research, K u r n m e Japan; Hiroshi Suzuki, Yamanashi University School of Medicine, Yokohama Japan; S h i r t Iino, St-Marianna University School of Medicine, Kawasaki Japan; Koichi Kanai, Toshiba Hospital, Tokyo Japan; J a p a n Ribavirin Study Group, Japan, Osaka J a p a n
BACKGROUND: Recommendations from the 1997 NIH Consensus Conference for treatment of patients with chronic hepatitis C (HCV) is to only treat those with elevated ALT levels. Approximately 30% of patients with chronic HCV have normal ALT levels. Treatment in this patient g r o u p is controversial. O u r large experience of treating patients with n o r m a l ALT levels suggests that the sustained virologic response rate is similar to the rates reported for patients with elevated ALT levels. AIM: To determine the sustained virologic response rate in naive patients with chronic HCV a n d n o r m a l ALT levels treated with standard dosages of interferon o~-2h a n d ribavirin (I & R). METHODS: Naive patients with chronic HCV a n d persistently n o r m a l ALT levels were asked to participate in this multi-center investigator initiated study. All patients enrolled were treated with interferon c~-2b 3 million units SQ TIW a n d ribavirin at 1000rag to 1200rag per day. Loss of detectable HCV RNA serves as the major parameter guiding treatment decisions a n d final evaluation of response. For each patient, the genotype a n d stage of fibrosis was designated prior to therapy a n d ALT values were recorded periodically according to a schedule a n d reported as a percent of the u p p e r limit of n o r m a l (ULN) for the laboratory in w h i c h the assay was performed. Treatment decisions followed the current standard of care guidelines for each genotype. All patients are followed for 6 m o n t h s post-treatment or discontinuation. RESULTS: As of J u n e 1, 2001, a total of 108 patients have been enrolled from 30 sites. Eighty-three patients (77%) are Caucasian, 13 (12%) are African American, 6 (5%) are Hispanic a n d the r e m a i n i n g 6% are other races. Sixty-three patients (58%) are female a n d the m e a n age of the enrolled patients is 45 years. None of the patients has cirrhosis. The majority of patients have stage 0 or stage 1 fibrosis (68.5%). Sixty-eight (63%) are genotype 1, 25 are genotype 2 (23%), 4 are genotype 3 (3.7%), a n d 1 is genotype 4. The m e a n ALT prior to treatment was 65% of the ULN. Sixteen of 23 patients (70%) are HCV RNA negative at 24 weeks of therapy. Twelve (75%) are genotype 1. The m e a n ALT levels at week 24 were 46.7% of the ULN, There are no patients b e y o n d treatment week 24. CONCLUSION: Preliminary data of naive patients with chronic HCV a n d n o r m a l ALT levels treated with s t a n d a r d doses of I & R appears to follow the reported in-treatment response rates of chronic HCV patients with elevated ALT levels.
Objective: Almost all recurrence of hepatitis C virus occurs within 4 weeks after the end of treatment with IFN monotherapy. A characteristic of combination therapy with ribavirin is reported to be the dearly reduced rate of recurrence after the end of treatment. The viral recurrence pattern following combination therapy with ribavirin was examined compared with IFN~-2b monotherapy. The relationship to serum ribavirin concentrations after the end of treatment was also examined. Methods: Subjects for study were chronic hepatitis C (CHC) patients with genotype lb and high viral titers. By double-blind method, patients received 6 or 10 MIU of IFNa-2b six times a week for 2 weeks followed by 6 MIU three times a week for 22 weeks. The combination therapy groups also received 600 or 800 rag of ribavirin daily. Follow-up examination was conducted at 6 months after the end of treatment. HCV RNA was measured pre-dose, 4, 12, and 24 weeks after the start of treatment, and 4, 12, and 24 weeks after the end of treatment. Ribavirin concentrations were examined in CHC patients separate from this study at pre-dose, 4, 8, 12, 16, and 24 weeks after the start of treatment, and 4, 8 and 12 weeks after the end of treatment. Blood sampling was conducted during the treatment period during clinic visits before the administration of ribavirin. Results: Virological evaluation was conducted with 184 patients who received combination therapy and 88 patients who received monotherapy. Eighty percent of patients were male and mean age was 48 years. Almost all patients had extremely high viral load, with HCV RNA of 500 kcopies/mL or less, 500 to 850 kcopies/mL, and 850 kcopies/mL or more as measured by RT-PCR accounting for 25%, 27%, and 48%, respectively, in the combination therapy groups and 22%, 29%, and 49%, respectively, in the monotherapy group. HCV RNA negativity was observed during the treatment period at Week 4, 12, and 24 in 21%, 59%, and 70% with combination therapy in contrast to 7%, 33%, and 39% with monotherapy. Superior sustained negativity was also observed with combination therapy, with negativity rates at 4,12, and 24 weeks after the end of treatment of 31%, 22%, and 19% in contrast to 3%, 3%, and 2% with monotherapy. Viral recurrence occurred within the first 4 weeks after the end of treatment with monotherapy as observed in past clinical studies whereas recurrence is observed to occur sporadically even after 4 weeks after the end of treatment with combination therapy. The change in serum ribavirin concentrations was evaluated in 28 CHC patients. A difference in HCV RNA negativity rates is already observed at 4 weeks after the start of treatment. This is thought to be attributed to the additive effect of ribavirin, the serum levels of which have increased close to steady state by this time point. Serum concentrations of ribavirin at 4, 8 and 12 weeks after the end of treatment are observed to be about one-seventh, 1/33 and 1/300 of Cmin at the end of treatment, suggesting that ribavirin remaining in serum may account for the difference between monotherapy and combination therapy in HCV RNA negativitypattern after the end of treatment.
1697
1698
EFFECT OF RIBAVIRIN DOSE REDUCTION ON SERUM RIBAVIRIN LEVELS AND HEMOGLOBIN LEVELS, Yoshiyasu Karino, Sappro Kosei Hospital, Sapporo Japan; Kyuichi Tanikawa, International Institute Liver Research, K u r u m e Japan; Hiroshi Suzuki, Yamanashi University School of Medicine, Yokohama Japan; Shiro Iino, St-Marianna University School of Medicine, KawasakiJapan; Koichi Kanai, Toshiba Hospital, Tokyo J a p a n ; J a p a n Ribavirin Study Group, Japan, Osaka J a p a n
PROSPECTIVE, RANDOMIZED AND CONTROLLED STUDY OF THE EFFICACY AND TOLERANCE OF INTERFERON ALPHA 2B PLUS RIBAVIRIN IN CHRONIC HEPATITIS C NON RESPONDERS TO PRIOR INTERFERON COURSES. Ricardo M Otero, H de la Princesa, Madrid Spain; For
Objective: The dose of ribavirin is reduced if hemoglobin levels fall below 10 g/dL during IFNc~-2b + ribavirin combination therapy. The relationship between change in serum ribavirin concentrations as a result of dose reduction and recovery of hemoglobin levels was examined. Methods: Patients were divided into those who had their ribavirin dose reduced by 200 mg/day and those who completed treatment according to protocol, and serum ribavirin levels and hemoglobin levels were compared. IFNec-2b was administered at a dose of 6 MIU 6 times a week for the first 2 weeks, followed by 3 times a week for 22 weeks. Ribavirin was administered at a dose of 600 rag/day to patients weighing 60 kg or less and 800 rag/day to those weighing over 60 kg for 24 weeks. Blood samples for the measurement of ribavirin concentrations were collected before the administration of ribavirin at 4, 8, 12, 16, and 24 weeks after the start of treatment. Patients must have had a baseline hemoglobin level of at least 12 g/dL for inclusion in the study. The dose of ribavirin was reduced by 200 mg/day if hemoglobin levels fell below 10 g/dL and was discontinued if hemoglobin fell to below 8.5 g/dL Results: 62 patients received lFNa-2b + ribavirin combination therapy. Age ranged from 27 to 64 years. Forty-two were male, and 20 were female. Distribution of genotypes was as follows: 43 patients with lb, 8 with 2a, and 8 with 2b. Reduction of the ribavirin dose was required in 15 patients, and 45 atients completed treatment according to protocol. Treatment was discontinued or other reasons in two patients. Serum ribavirin levels were measured in 28 patients. No difference in patient background was observed between patients measured for serum ribavirin levels and those who were not. Nine out of the 28 patients measured for ribavirin levels had their dose reduced. Dose reduction occurred in almost all cases during Week 4 to 8 after the start of treatment. Cmin of serum ribavirin concentrations at Week 4 in patients who required dose reduction was 2182/zg/mL. This was not significantly different from 1651/~g/mL observed with the 19 patients who maintained their original dose levels, but patients with high levels were included. Serum ribavirin concentrations at Week 8 were similar between both groups but thereafter, a decrease of 106 to 616/~g/mL was observed as a result of the 200 mg/day dose reduction. At 4 weeks after the end of treatment, a mean decrease of 115p,g/mL was also observed. Hemoglobin levels were maintained above 8.5 g/dL in 1 ] patients and completion of treatment at the reduced dose was possible. This was thought to be the effect of the reduction of the ribavirin dose. Ribavirin had to be discontinued, however, in 4 patients clue to further reduction of hemoglobin levels. Conclusion: As a result of the 200 rag/day dose reduction, serum ribavirin levels were decreased between 106 to 616/zg/mL with recovering of hemoglobin levels. Because ribavirin dose levels Is very Important to get the better efficacy, It should accelerate to establish the way not to be reduced ribavirin original dose levels.
p
BACKGROUND The combination therapy with Interferon c~-2B (IFNct-2B) plus Ribavirin (RIB) at s t a n d a r d doses for the treatment of patients with chronic hepatitis C (CHC) w h o were non-responders to prior I F N a treatment, induces a sustained response of about 16%. For the time being, it has not been s h o w n increasing IFNR dose m a y elicit a greater response rate. OBJECTIVES To compare the efficacy a n d safety of a regimen (A) comprising 5 MU IFN~-2B TIW plus RIB against the standard dosage (B) of 3 MU IFNa-2B TIW plus RIB for the treatment of CHC non-responders patients to a prior course of lFNaalone. MATERIAL AND METHODS Prospective study, randomized per blocks. Interim analysis of the biochemical a n d virological response at the 6 - m o n t h observation period in 312 patients ( A = 161, B = 151) out of an overall sample of 860 patients. For the p u r p o s e of the study, 85 centers t h r o u g h o u t Spain have been p r o p o s e d to participate, a n d currently, more t h a n 78% (67) of them are active. F r o m April 99 to December 00, 549 patients (63,8% of the p l a n n e d sample population) have been enrolled. The study remains ongoing a n d it is scheduled to conclude in J u n e 2002. ANALYSIS OF DATA The interim analysis presented here evaluates the intention to treat response after 6 m o n t h therapy, measured in terms of s e r u m n o r m a l transaminases values plus negative HCV RNA levels detection. RESULTS Analysis of available data at the 6 - m o n t h period from 312 patients s h o w that overall response has been achieved in 46.8% of this sample population. 81 patients (50.3%) respond to regimen A against 65 patients with regimen B (43.1%). Within regimen A 49.7% ( n = 8 0 ) of patients has not achieved a response, whereas this p r o p o r t i o n with regimen B is 56.9% ( n = 8 6 ) . So far, 42 patients have been w i t h d r a w n (28 patients in the g r o u p A a n d 14 patients in the g r o u p B), a n d 11 serious adverse events have been reported (7 in the g r o u p A a n d 4 in the g r o u p B). CONCLUSIONS These preliminary results are likely to s h o w a trend towards the achievement of a greater therapeutic response rate in the g r o u p A treated with 5 MU IFNa-2B plus RIB. This initial trend should be finally confirmed b y further analysis at the end of the treatment period after 6 m o n t h s follow u p (sustained response). The tolerance safety of combination therapy was similar in b o t h treatment groups.
AASLD ABSTRACTS
HEPATOLOGYO c t o b e r 2 0 0 1
1695
1696
USE OF INTERFERON o~-2B AND RIBAVIRIN FOR TREATMENT OF PATIENTS W I T H CHRONIC HEPATITIS C W I T H NORMAL ALT LEVELS. Craig A Sponseller, Kathleen M Koehler, Bruce R Bacon, Saint Louis University, St. Louis, MO
SERUM RIBAVIRIN REMAINING AFTER END OF IFNoL-2B + RIBAVIRIN COMBINATION THERAPY MAY IMPACT SERUM HCV RNA PATTERN IN CHRONIC HEPATITIS C. Takeshi Okanoue, Kyoto Prefectural University of Medicine, Kyoto Japan; Kyuichi Tanikawa, International Institute for Liver Research, K u r n m e Japan; Hiroshi Suzuki, Yamanashi University School of Medicine, Yokohama Japan; S h i r t Iino, St-Marianna University School of Medicine, Kawasaki Japan; Koichi Kanai, Toshiba Hospital, Tokyo Japan; J a p a n Ribavirin Study Group, Japan, Osaka J a p a n
BACKGROUND: Recommendations from the 1997 NIH Consensus Conference for treatment of patients with chronic hepatitis C (HCV) is to only treat those with elevated ALT levels. Approximately 30% of patients with chronic HCV have normal ALT levels. Treatment in this patient g r o u p is controversial. O u r large experience of treating patients with n o r m a l ALT levels suggests that the sustained virologic response rate is similar to the rates reported for patients with elevated ALT levels. AIM: To determine the sustained virologic response rate in naive patients with chronic HCV a n d n o r m a l ALT levels treated with standard dosages of interferon o~-2h a n d ribavirin (I & R). METHODS: Naive patients with chronic HCV a n d persistently n o r m a l ALT levels were asked to participate in this multi-center investigator initiated study. All patients enrolled were treated with interferon c~-2b 3 million units SQ TIW a n d ribavirin at 1000rag to 1200rag per day. Loss of detectable HCV RNA serves as the major parameter guiding treatment decisions a n d final evaluation of response. For each patient, the genotype a n d stage of fibrosis was designated prior to therapy a n d ALT values were recorded periodically according to a schedule a n d reported as a percent of the u p p e r limit of n o r m a l (ULN) for the laboratory in w h i c h the assay was performed. Treatment decisions followed the current standard of care guidelines for each genotype. All patients are followed for 6 m o n t h s post-treatment or discontinuation. RESULTS: As of J u n e 1, 2001, a total of 108 patients have been enrolled from 30 sites. Eighty-three patients (77%) are Caucasian, 13 (12%) are African American, 6 (5%) are Hispanic a n d the r e m a i n i n g 6% are other races. Sixty-three patients (58%) are female a n d the m e a n age of the enrolled patients is 45 years. None of the patients has cirrhosis. The majority of patients have stage 0 or stage 1 fibrosis (68.5%). Sixty-eight (63%) are genotype 1, 25 are genotype 2 (23%), 4 are genotype 3 (3.7%), a n d 1 is genotype 4. The m e a n ALT prior to treatment was 65% of the ULN. Sixteen of 23 patients (70%) are HCV RNA negative at 24 weeks of therapy. Twelve (75%) are genotype 1. The m e a n ALT levels at week 24 were 46.7% of the ULN, There are no patients b e y o n d treatment week 24. CONCLUSION: Preliminary data of naive patients with chronic HCV a n d n o r m a l ALT levels treated with s t a n d a r d doses of I & R appears to follow the reported in-treatment response rates of chronic HCV patients with elevated ALT levels.
Objective: Almost all recurrence of hepatitis C virus occurs within 4 weeks after the end of treatment with IFN monotherapy. A characteristic of combination therapy with ribavirin is reported to be the dearly reduced rate of recurrence after the end of treatment. The viral recurrence pattern following combination therapy with ribavirin was examined compared with IFN~-2b monotherapy. The relationship to serum ribavirin concentrations after the end of treatment was also examined. Methods: Subjects for study were chronic hepatitis C (CHC) patients with genotype lb and high viral titers. By double-blind method, patients received 6 or 10 MIU of IFNa-2b six times a week for 2 weeks followed by 6 MIU three times a week for 22 weeks. The combination therapy groups also received 600 or 800 rag of ribavirin daily. Follow-up examination was conducted at 6 months after the end of treatment. HCV RNA was measured pre-dose, 4, 12, and 24 weeks after the start of treatment, and 4, 12, and 24 weeks after the end of treatment. Ribavirin concentrations were examined in CHC patients separate from this study at pre-dose, 4, 8, 12, 16, and 24 weeks after the start of treatment, and 4, 8 and 12 weeks after the end of treatment. Blood sampling was conducted during the treatment period during clinic visits before the administration of ribavirin. Results: Virological evaluation was conducted with 184 patients who received combination therapy and 88 patients who received monotherapy. Eighty percent of patients were male and mean age was 48 years. Almost all patients had extremely high viral load, with HCV RNA of 500 kcopies/mL or less, 500 to 850 kcopies/mL, and 850 kcopies/mL or more as measured by RT-PCR accounting for 25%, 27%, and 48%, respectively, in the combination therapy groups and 22%, 29%, and 49%, respectively, in the monotherapy group. HCV RNA negativity was observed during the treatment period at Week 4, 12, and 24 in 21%, 59%, and 70% with combination therapy in contrast to 7%, 33%, and 39% with monotherapy. Superior sustained negativity was also observed with combination therapy, with negativity rates at 4,12, and 24 weeks after the end of treatment of 31%, 22%, and 19% in contrast to 3%, 3%, and 2% with monotherapy. Viral recurrence occurred within the first 4 weeks after the end of treatment with monotherapy as observed in past clinical studies whereas recurrence is observed to occur sporadically even after 4 weeks after the end of treatment with combination therapy. The change in serum ribavirin concentrations was evaluated in 28 CHC patients. A difference in HCV RNA negativity rates is already observed at 4 weeks after the start of treatment. This is thought to be attributed to the additive effect of ribavirin, the serum levels of which have increased close to steady state by this time point. Serum concentrations of ribavirin at 4, 8 and 12 weeks after the end of treatment are observed to be about one-seventh, 1/33 and 1/300 of Cmin at the end of treatment, suggesting that ribavirin remaining in serum may account for the difference between monotherapy and combination therapy in HCV RNA negativitypattern after the end of treatment.
1697
1698
EFFECT OF RIBAVIRIN DOSE REDUCTION ON SERUM RIBAVIRIN LEVELS AND HEMOGLOBIN LEVELS, Yoshiyasu Karino, Sappro Kosei Hospital, Sapporo Japan; Kyuichi Tanikawa, International Institute Liver Research, K u r u m e Japan; Hiroshi Suzuki, Yamanashi University School of Medicine, Yokohama Japan; Shiro Iino, St-Marianna University School of Medicine, KawasakiJapan; Koichi Kanai, Toshiba Hospital, Tokyo J a p a n ; J a p a n Ribavirin Study Group, Japan, Osaka J a p a n
PROSPECTIVE, RANDOMIZED AND CONTROLLED STUDY OF THE EFFICACY AND TOLERANCE OF INTERFERON ALPHA 2B PLUS RIBAVIRIN IN CHRONIC HEPATITIS C NON RESPONDERS TO PRIOR INTERFERON COURSES. Ricardo M Otero, H de la Princesa, Madrid Spain; For
Objective: The dose of ribavirin is reduced if hemoglobin levels fall below 10 g/dL during IFNc~-2b + ribavirin combination therapy. The relationship between change in serum ribavirin concentrations as a result of dose reduction and recovery of hemoglobin levels was examined. Methods: Patients were divided into those who had their ribavirin dose reduced by 200 mg/day and those who completed treatment according to protocol, and serum ribavirin levels and hemoglobin levels were compared. IFNec-2b was administered at a dose of 6 MIU 6 times a week for the first 2 weeks, followed by 3 times a week for 22 weeks. Ribavirin was administered at a dose of 600 rag/day to patients weighing 60 kg or less and 800 rag/day to those weighing over 60 kg for 24 weeks. Blood samples for the measurement of ribavirin concentrations were collected before the administration of ribavirin at 4, 8, 12, 16, and 24 weeks after the start of treatment. Patients must have had a baseline hemoglobin level of at least 12 g/dL for inclusion in the study. The dose of ribavirin was reduced by 200 mg/day if hemoglobin levels fell below 10 g/dL and was discontinued if hemoglobin fell to below 8.5 g/dL Results: 62 patients received lFNa-2b + ribavirin combination therapy. Age ranged from 27 to 64 years. Forty-two were male, and 20 were female. Distribution of genotypes was as follows: 43 patients with lb, 8 with 2a, and 8 with 2b. Reduction of the ribavirin dose was required in 15 patients, and 45 atients completed treatment according to protocol. Treatment was discontinued or other reasons in two patients. Serum ribavirin levels were measured in 28 patients. No difference in patient background was observed between patients measured for serum ribavirin levels and those who were not. Nine out of the 28 patients measured for ribavirin levels had their dose reduced. Dose reduction occurred in almost all cases during Week 4 to 8 after the start of treatment. Cmin of serum ribavirin concentrations at Week 4 in patients who required dose reduction was 2182/zg/mL. This was not significantly different from 1651/~g/mL observed with the 19 patients who maintained their original dose levels, but patients with high levels were included. Serum ribavirin concentrations at Week 8 were similar between both groups but thereafter, a decrease of 106 to 616/~g/mL was observed as a result of the 200 mg/day dose reduction. At 4 weeks after the end of treatment, a mean decrease of 115p,g/mL was also observed. Hemoglobin levels were maintained above 8.5 g/dL in 1 ] patients and completion of treatment at the reduced dose was possible. This was thought to be the effect of the reduction of the ribavirin dose. Ribavirin had to be discontinued, however, in 4 patients clue to further reduction of hemoglobin levels. Conclusion: As a result of the 200 rag/day dose reduction, serum ribavirin levels were decreased between 106 to 616/zg/mL with recovering of hemoglobin levels. Because ribavirin dose levels Is very Important to get the better efficacy, It should accelerate to establish the way not to be reduced ribavirin original dose levels.
p
BACKGROUND The combination therapy with Interferon c~-2B (IFNct-2B) plus Ribavirin (RIB) at s t a n d a r d doses for the treatment of patients with chronic hepatitis C (CHC) w h o were non-responders to prior I F N a treatment, induces a sustained response of about 16%. For the time being, it has not been s h o w n increasing IFNR dose m a y elicit a greater response rate. OBJECTIVES To compare the efficacy a n d safety of a regimen (A) comprising 5 MU IFN~-2B TIW plus RIB against the standard dosage (B) of 3 MU IFNa-2B TIW plus RIB for the treatment of CHC non-responders patients to a prior course of lFNaalone. MATERIAL AND METHODS Prospective study, randomized per blocks. Interim analysis of the biochemical a n d virological response at the 6 - m o n t h observation period in 312 patients ( A = 161, B = 151) out of an overall sample of 860 patients. For the p u r p o s e of the study, 85 centers t h r o u g h o u t Spain have been p r o p o s e d to participate, a n d currently, more t h a n 78% (67) of them are active. F r o m April 99 to December 00, 549 patients (63,8% of the p l a n n e d sample population) have been enrolled. The study remains ongoing a n d it is scheduled to conclude in J u n e 2002. ANALYSIS OF DATA The interim analysis presented here evaluates the intention to treat response after 6 m o n t h therapy, measured in terms of s e r u m n o r m a l transaminases values plus negative HCV RNA levels detection. RESULTS Analysis of available data at the 6 - m o n t h period from 312 patients s h o w that overall response has been achieved in 46.8% of this sample population. 81 patients (50.3%) respond to regimen A against 65 patients with regimen B (43.1%). Within regimen A 49.7% ( n = 8 0 ) of patients has not achieved a response, whereas this p r o p o r t i o n with regimen B is 56.9% ( n = 8 6 ) . So far, 42 patients have been w i t h d r a w n (28 patients in the g r o u p A a n d 14 patients in the g r o u p B), a n d 11 serious adverse events have been reported (7 in the g r o u p A a n d 4 in the g r o u p B). CONCLUSIONS These preliminary results are likely to s h o w a trend towards the achievement of a greater therapeutic response rate in the g r o u p A treated with 5 MU IFNa-2B plus RIB. This initial trend should be finally confirmed b y further analysis at the end of the treatment period after 6 m o n t h s follow u p (sustained response). The tolerance safety of combination therapy was similar in b o t h treatment groups.