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Comparison of outcomes, treatment selection and completion in hepatitis C patients in academic and community based ambulatory treatment centers
422A
AASLD ABSTRACTS
HEPATOLOGY O c t o b e r 2 0 0 1
999
1000
COMPARISON O F O U T C O M E S , T R E A T M E N T S E L E C T I O N A N D C O M PLETION IN HEPATITIS C PATIENTS IN ACADEMIC AND COMMUN I T Y BASED A M B U L A T O R Y T R E A T M E N T C E N T E R S . D o n a l d J e n s e n , Scott Coder, D e p a r t m e n t of Hepatology, Rush Presbyterian Saint Luke's Medical Center, Chicago, IL; G o e r g e Harb, Nick S Poulios, Roche Pharmaceuticals, Nutley, NJ; Alicia Shillington, E h a b Hasan, EPI-Q, Ine, O a k h r o o k Terrace, IL; M a r y Vance, D e p a r t m e n t of Hepatology, Rush Presbyterian Saint Luke's Medical Center, Chicago, IL
A F R I C A N A M E R I C A N S H A V E A L O W E R VIRAL CLEARANCE R A T E W I T H C O M B I N A T I O N I N T E R F E R O N A N D R I B A V I R I N T H E R A P Y FOR HEPATITIS C: RESULTS O F T W O M U L T I - C E N T E R T R I A L S . Eric J Lawitz, Matt H e p b u r n , N o r m a S Cantu, Lisa M H e p b u r n , Shailesh C Kadakia, The A l a m o Study G r o u p , Brooke A r m y Medical Ctr, SanAntonio, TX
Most published data on antiviral therapy for hepatitis C virus (HCV) infection is derived from controlled trials conducted at academicmedical centers. In a large clinical study, 48 weeks of combinationtherapy with interferonand ribavirinwas associatedwith a 40% sustainedresponserate and a 20%discontinuation rate for adverse effects (McHutchison et al., N Engl J Med 1998; 339:1485-92). Linle information is available about patient management and treatment outcomes in clinical practice settings. We studied outcomes in interferon (IFN) naive patients with documentedHCV infection treated at academicinstitutions and community-basedclinics. Charts from 176 patients treatedfor HCV (74 from 2 academiccenters and 102 from 5 communitycare centers) were retrospectivelyevaluatedto document outcomes,diagnostic utilization, treatmentselection,and duration. Included patients were age ->18 years,were anti-HCVseropositive or had detectable HCV RNA in serum before treatment, initiated treatment 48 weeks prior to inclusion (regardlessof treatmentcompletion),and were prescribedeither IFN alone, injectedsubcutaneously three timesweekly,or in combinationwith daily oral rihavirin.Excludedwere those with previous psychiatric disorders, previous organ transplant, prior IFN failure, clinicaltrial enrollees,decompensatad cirrhosis, or Human lmmunodeficiencyVirus (HIV)co-infection.Patients at academiccenters (AC) and community-basedtreatment clinics (CC) were similar with respect to age (43.9 years vs. 45.8), gender (43.2%malesvs. 57.8%),and racial/ethnicbackground(69%Caucasianvs. 71%, 1I% AfricanAmericanvs. 9%, and 7%Hispanicvs. 4%),respectively.A greaterpercentageof AC patientsunderwent genotypetesting and liver biopsy (Table I). In addition, biopsies from AC patients had a higher mean grade (2.12 vs. 1.69, p = 0.005) and diseasestage (2.0 vs. 1.49, p = 0.01) than CC patients. Of those genotyped,AC patients showed higher incidence of genotype 1 (Table 1), although not statisticallysignificant.Mean 1FN dose at onset of therapy was approximately3 million units three times weekly, and ribavirin dose was slightly greater than 1000 mg qd regardlessof setting. Only 39.8% of all patients completedeither 24 or 48 weeks of therapy based upon genotype. Most frequent reasons for treatment dropout included non-response (29.7% AC vs. 30.4%CC), patient non-adherence(6.8%AC vs. 9.9% CC), and adverseevents (17.6%AC vs. 23.5% CC), with no significantdifferences.AC patients receivedIFN/ribavirincombinationtherapy, had greatervirologicend of treatment(ETVR),and sustainedresponses(SVR)than CC counterparts(Table 1). Follow-up viral load measurement ranged from 3 - 12 months after treatment cessation but was performedon only 50%of the entire population (n= 88) regardlessof setting. Patientswith detectablevirus at ETVRwere considerednon-SVRat followup.Amongall patients, there is a high rate of dropout prior to completing 24/48 weeks of therapy. Dropout rates are greater and SVRare much lower than reported in clinical trials. Despiteapparent increasedseverityof AC patients, outcomesappear improvedcomparedto CC. AC patients were more likely to achievenon-detectableviral levelsthan CC counterparts.There are also significantdifferencesbetweensettings concerningdiagnosticutilization. Theseresults suggesta role for continuing medicaleducationregardingthe treatmentof HCVto achievea consistentstandard of care.
Table 1. Setting
Liver Bx performed
Academic Community P value
89.2% 71.6% 0.005
Genotyping %genotype %IFNIRBV ETVR SVRHCV performed 1 treatment HCV RNA RNA 78.4% 31.4% < 0.001
65.6% 50,0% NS
87,0% 67,6% 0.02
83,0% 37.5% 0,002
29.1% 14.6% 0.05
Background: Prior studies h a v e suggested that African A m e r i c a n s have a l o w e r response to interferon-based Hepatitis C therapy, b u t race has n o t b e e n described as an i n d e p e n d e n t predictor of t r e a t m e n t o u t c o m e using multivariate analysis. Aim: To evaluate the viral clearance in African Anericans treated w i t h interferon based therapy. Methods: Data w e r e analyzed f r o m two o n g o i n g m u l t i - c e n t e r trials. T h e first s t u d y w a s a n o n r a n d o m i z e d trial w i t h a t r e a t m e n t r e g i m e n of 5 million units of Interferon alfa 2b daily + 1 0 0 0 - 1 2 0 0 m g ribavirin daily for 4 w e e k s followed by 3 million units of I n t e r f e r o n alfa 2b daily + 1 0 0 0 - 1 2 0 0 m g ribavirin for 44 weeks. In the s e c o n d study, participants w e r e r a n d o m i z e d to receive either s t a n d a r d c o m b i n a t i o n t h e r a p y for 48 w e e k s (interferon alfa 2b three times a w e e k a n d ribavirin) or the daily c o m b i n a t i o n t h e r a p y as outlined in the first study. A n e g a t i v e H C V RNA by PCR at twelve w e e k s w a s considered viral clearance. S u b g r o u p analysis of subjects treated at Brooke A r m y Medical Center was p e r f o r m e d to a t t e m p t to control for access to care a n d i n c o m e level. These subjects consisted of military p e r s o n n e l a n d beneficiaries, each of w h o m h a d consistent access to care a n d a stable baseline income. Multiple logistic regression analysis was p e r f o r m e d w i t h the following variables to d e t e r m i n e i n d e p e n d e n t predictors of viral clearance: age, alanine a m i n o t r a n s f e r a s e (ALT), baseline HCV-RNA, b o d y m a s s index, gender, genotype, liver biopsy grade a n d stage, prior interferon therapy, a n d race. T h e s a m e analysis for 70 African A m e r i c a n s w h o c o m p l e t e d 24 w e e k s of P E G - I n t e r f e r o n alfa2b a n d ribavirin will be available for the a n n u a l meeting. Results: A total of 659 subjects (49 or 7.5% w e r e African A m e r i c a n ) received daily interferon w i t h ribavirin a n d 156 subjects (30 or 19.2% w e r e African A m e r i c a n ) received s t a n d a r d c o m b i n a t i o n therapy. Being African A m e r i c a n was a n i n d e p e n d e n t p r e d i c t o r of failure to achieve viral clearance, w i t h a n odds ratio of 0.18 (0.070.46 w i t h 95% CI). T h e lack of therapeutic r e s p o n s e did n o t i m p r o v e w h e t h e r s t a n d a r d (OR 0.09, 0.01-0.96 w i t h 95% CI) or daily (OR 0.18, 0.06-0.51 w i t h 95% CI) t h e r a p y w a s given. In s u b g r o u p analysis of subjects treated at Brooke A r m y Medical Center, b e i n g African A m e r i c a n was a n i n d e p e n d e n t predictor of failure to achieve viral clearance (OR 0.09, 0.02-0.49 w i t h 95% CI). Conclusion: African A m e r i c a n s h a v e a decreased viral clearance rate w i t h interferon a n d ribavirin c o m b i n a t i o n t h e r a p y i n d e p e n d e n t of a m u l t i t u d e of factors that could influence t r e a t m e n t o u t c o m e .
1001
1002
DOSAGE OF R I B A V I R I N I N PATIENTS W I T H HEPATITIS C SHOULD BE BASED O N R E N A L F U N C T I O N : A P O P U L A T I O N P I t A R M A C O K I N E T I C ANALYSIS. A n n e t t e Bruchfeld, Division of Renal Medicine, Karolinska Institute a n d H u d d i n g e U n i v Hospital, S t o c k h o l m Sweden; Karin Lindahl, Robert Schvarcz, Division of Infectious Diseases, H u d d i n g e U n i v Hospital, S t o c k h o l m Sweden; Lars StC*hle, Division of Clinical P h a r m a c o l o g y , H u d d i n g e U n i v Hospital, S t o c k h o l m S w e d e n
O R A L A D M I N I S T R A T I O N O F L A C T O F E R R I N L O W E R S SERUM HCVRNA LEVELS IN PATIENTS W I T H GENOTYPE-1B-RELATED CHRONIC HEPATITIS C. N a o k i K u m a g a i , Satoshi Y s u n e m a t s u , Kanji T s u c h i m o t o , Kitasato Institute Hospital, M i n a t o - k u Japan; Koji Yamauchi, S u s u m u Teraguchi, Hirotoshi Hayasawa, Nutritional Science Laboratory, Morinaga Milk I n d u s t r y CO , LTD, T o k y o Japan; H i d e t s u g u Saito, H i r o m a s a Ishii, Sch of Medicine, Keio Univ, T o k y o J a p a n
Background: A c o m b i n a t i o n of interferon-alfa a n d ribavirin is s t a n d a r d t h e r a p y for c h r o n i c hepatitis C (HCV). Ribavirin dosage is c u r r e n t l y based on bodyweight. T h e a i m of this s t u d y was to critically evaluate c u r r e n t dosage r e c o m m e n d a t i o n s on the basis of a p o p u l a t i o n p h a r m a c o k i n e t i c analysis. Methods: 398 ribavirin p l a s m a c o n c e n t r a t i o n samples w e r e collected f r o m 63 patients u n d e r g o i n g t r e a t m e n t for HCV. 44 patients h a d n o r m a l r a n g e s e r u m creatinine w i t h a n e s t i m a t e d g l o m e r u l a r filtration rate ( G F R = e s t i m a t e d creatinine clearance) of 57-144 m L / m i n . A n o t h e r 19 patients h a d renal i m p a i r m e n t w i t h a G F R of 5-57 m L / m i n . P o p u l a t i o n factors w e r e age, gender, b o d y - w e i g h t , s e r u m creatinine a n d GFR. A p o p u l a t i o n p h a r m a c o k i n e t i c analysis w a s p e r f o r m e d by n o n - l i n e a r m i x e d effect modelling. Results: Ribavirin clearance was f o u n d to be linearily d e p e n d a n t o n renal f u n c t i o n w i t h a smaller n o n - r e n a l clearance c o m p o n e n t . Renal function w a s a significantly better predictor of ribavirin clearance t h a n b o d y - w e i g h t . T h e v o l u m e of distribution, w h i c h w a s p r o p o r tional to b o d y w e i g h t ( V = 3 5 . 5 x b o d y - w e i g h t ) , was large, w h i c h resulted in a long half-life (100-600 h o u r s d e p e n d i n g on renal function) a n d a long time to steady state (2-14 w e e k s ) . T h e r e w a s a n inter-individual variability in ribavirin total clearance. Conclusion: Ribavirin initial dosage s h o u l d be based o n renal f u n c t i o n a n d n o t o n b o d y weight. A ribavirin dosing s c h e d u l e to r e a c h a n i n t e n d e d target c o n c e n t r a t i o n is p r o p o s e d w h i c h takes GFR into account. Ribavirin m o n i t o r i n g is useful for optimising H C V t r e a t m e n t n o t only in renal insufficiency, b u t also in o t h e r patients c o n s i d e r i n g the time to steady state as well as the inter-individual variability in ribavirin clearance.
Background and Aims: In Japan the majority of patients with chronic hepatitis C (CH-C) are infected with HCV genotype lb, which is associated with a significantly lower response rate to interferon o~(IFN) treatment (around 20%). Even in infection with HCV genotype lb, patients with low viremia ( < 100K1U/ml) at baseline show a high long-term complete response rate (over 50%) to IFN treatment. Lactoferrin (LF), which is a milk protein belonging to the iron transport family is known as a primary defense protein against pathogenic microorganisms including viruses. A pilot study has been reported in which LF decreased serum HCV-RNA concentrations in patients with CH-C. In this study, we examined the use of LF in CH-C patients with genotype lb and high viremia to lower serum HCV-RNA levels to < 100 KIU/ml and improve the response rate to IFN treatment. Methods: Fourteen CH-C patients with genotype lb and high viremia (>100 KIU/ml) were given LF at a dose of 600 mg/day. HCV-RNA was assessed by quantitative PCR and biochemical parameters were measured at baseline, 12 and 24 weeks. Thirteen corresponding CH-C patients were also followed for 24 weeks without LF treatment. Written informed consent was obtained from all patients. Results: Serum HCV-RNA levels (mean +SD) in the LF group at baseline, 12 and 24 weeks were 505 ---244, 347 ---294 and 366 -+297 KIU/ml, respectively ( baseline vs. 12 weeks p<0.05). Three patients (21%) showed a decrease in serum HCV-RNA to <100KIU/ml at 12 weeks (650 KIU/ml at baseline to 69 KIU/ml at 12 weeks, 240 to 82 KIU/ml, 110 to 30 K1U/ml, respectively) and 4 did so at 24 weeks (750 KIU/ml at baseline to 73 KIU/ml at 24 weeks, 740 to 53 KIU/ml, 650 to 60 KIU/ml, 560 to 78 KIU/ml, respectively; the third case overlapped with the first case at 12 weeks). Six patients (43%) showed low viremia (<100 KlU/ml) at either 12 or 24 weeks during LF administration. In the control group, there was no significant change of serum HCV-RNA levels between baseline and 12 weeks (638 -+232 and 588 -+251, respectively). Also, no patient in the control group showed low viremia of <100 KtU/ml at any time. Although there was no significant change of serum ALT levels during LF administration ( 79 +51 IU/ml at base line, 74 +44 at 12 weeks and 63 +31 at 24 weeks), 6 patients with relatively high ALT levels ( >70 IU/ml, which was twice the upper limit of normal) showed a significant decline of ALT levels at 12 weeks compared with baseline (the mean -+ SD of ALT at base line,12 and 24 weeks were 124 + 4 7 , 9 9 -+51 IU/ml and 65 -+30, respectively; baseline vs. 12 weeks p<0.02). There was no significant change of serum ALT levels in the control group. No adverse effect associated with LF administration was observed during the study. Conclusion and Discussion: Oral administration of LF significantly lowered serum HCV-RNA levels in CH-C patients with genotype lb and high viremia. Six out of 14 patients (43%) showed low viremia ( < 100 KIU/ml) during the administration. Therefore pretreatment with LF to CH-C patients might improve the response rate to IFN treatment by lowering serum HCV-RNA levels at baseline.
AASLD ABSTRACTS
HEPATOLOGY O c t o b e r 2 0 0 1
999
1000
COMPARISON O F O U T C O M E S , T R E A T M E N T S E L E C T I O N A N D C O M PLETION IN HEPATITIS C PATIENTS IN ACADEMIC AND COMMUN I T Y BASED A M B U L A T O R Y T R E A T M E N T C E N T E R S . D o n a l d J e n s e n , Scott Coder, D e p a r t m e n t of Hepatology, Rush Presbyterian Saint Luke's Medical Center, Chicago, IL; G o e r g e Harb, Nick S Poulios, Roche Pharmaceuticals, Nutley, NJ; Alicia Shillington, E h a b Hasan, EPI-Q, Ine, O a k h r o o k Terrace, IL; M a r y Vance, D e p a r t m e n t of Hepatology, Rush Presbyterian Saint Luke's Medical Center, Chicago, IL
A F R I C A N A M E R I C A N S H A V E A L O W E R VIRAL CLEARANCE R A T E W I T H C O M B I N A T I O N I N T E R F E R O N A N D R I B A V I R I N T H E R A P Y FOR HEPATITIS C: RESULTS O F T W O M U L T I - C E N T E R T R I A L S . Eric J Lawitz, Matt H e p b u r n , N o r m a S Cantu, Lisa M H e p b u r n , Shailesh C Kadakia, The A l a m o Study G r o u p , Brooke A r m y Medical Ctr, SanAntonio, TX
Most published data on antiviral therapy for hepatitis C virus (HCV) infection is derived from controlled trials conducted at academicmedical centers. In a large clinical study, 48 weeks of combinationtherapy with interferonand ribavirinwas associatedwith a 40% sustainedresponserate and a 20%discontinuation rate for adverse effects (McHutchison et al., N Engl J Med 1998; 339:1485-92). Linle information is available about patient management and treatment outcomes in clinical practice settings. We studied outcomes in interferon (IFN) naive patients with documentedHCV infection treated at academicinstitutions and community-basedclinics. Charts from 176 patients treatedfor HCV (74 from 2 academiccenters and 102 from 5 communitycare centers) were retrospectivelyevaluatedto document outcomes,diagnostic utilization, treatmentselection,and duration. Included patients were age ->18 years,were anti-HCVseropositive or had detectable HCV RNA in serum before treatment, initiated treatment 48 weeks prior to inclusion (regardlessof treatmentcompletion),and were prescribedeither IFN alone, injectedsubcutaneously three timesweekly,or in combinationwith daily oral rihavirin.Excludedwere those with previous psychiatric disorders, previous organ transplant, prior IFN failure, clinicaltrial enrollees,decompensatad cirrhosis, or Human lmmunodeficiencyVirus (HIV)co-infection.Patients at academiccenters (AC) and community-basedtreatment clinics (CC) were similar with respect to age (43.9 years vs. 45.8), gender (43.2%malesvs. 57.8%),and racial/ethnicbackground(69%Caucasianvs. 71%, 1I% AfricanAmericanvs. 9%, and 7%Hispanicvs. 4%),respectively.A greaterpercentageof AC patientsunderwent genotypetesting and liver biopsy (Table I). In addition, biopsies from AC patients had a higher mean grade (2.12 vs. 1.69, p = 0.005) and diseasestage (2.0 vs. 1.49, p = 0.01) than CC patients. Of those genotyped,AC patients showed higher incidence of genotype 1 (Table 1), although not statisticallysignificant.Mean 1FN dose at onset of therapy was approximately3 million units three times weekly, and ribavirin dose was slightly greater than 1000 mg qd regardlessof setting. Only 39.8% of all patients completedeither 24 or 48 weeks of therapy based upon genotype. Most frequent reasons for treatment dropout included non-response (29.7% AC vs. 30.4%CC), patient non-adherence(6.8%AC vs. 9.9% CC), and adverseevents (17.6%AC vs. 23.5% CC), with no significantdifferences.AC patients receivedIFN/ribavirincombinationtherapy, had greatervirologicend of treatment(ETVR),and sustainedresponses(SVR)than CC counterparts(Table 1). Follow-up viral load measurement ranged from 3 - 12 months after treatment cessation but was performedon only 50%of the entire population (n= 88) regardlessof setting. Patientswith detectablevirus at ETVRwere considerednon-SVRat followup.Amongall patients, there is a high rate of dropout prior to completing 24/48 weeks of therapy. Dropout rates are greater and SVRare much lower than reported in clinical trials. Despiteapparent increasedseverityof AC patients, outcomesappear improvedcomparedto CC. AC patients were more likely to achievenon-detectableviral levelsthan CC counterparts.There are also significantdifferencesbetweensettings concerningdiagnosticutilization. Theseresults suggesta role for continuing medicaleducationregardingthe treatmentof HCVto achievea consistentstandard of care.
Table 1. Setting
Liver Bx performed
Academic Community P value
89.2% 71.6% 0.005
Genotyping %genotype %IFNIRBV ETVR SVRHCV performed 1 treatment HCV RNA RNA 78.4% 31.4% < 0.001
65.6% 50,0% NS
87,0% 67,6% 0.02
83,0% 37.5% 0,002
29.1% 14.6% 0.05
Background: Prior studies h a v e suggested that African A m e r i c a n s have a l o w e r response to interferon-based Hepatitis C therapy, b u t race has n o t b e e n described as an i n d e p e n d e n t predictor of t r e a t m e n t o u t c o m e using multivariate analysis. Aim: To evaluate the viral clearance in African Anericans treated w i t h interferon based therapy. Methods: Data w e r e analyzed f r o m two o n g o i n g m u l t i - c e n t e r trials. T h e first s t u d y w a s a n o n r a n d o m i z e d trial w i t h a t r e a t m e n t r e g i m e n of 5 million units of Interferon alfa 2b daily + 1 0 0 0 - 1 2 0 0 m g ribavirin daily for 4 w e e k s followed by 3 million units of I n t e r f e r o n alfa 2b daily + 1 0 0 0 - 1 2 0 0 m g ribavirin for 44 weeks. In the s e c o n d study, participants w e r e r a n d o m i z e d to receive either s t a n d a r d c o m b i n a t i o n t h e r a p y for 48 w e e k s (interferon alfa 2b three times a w e e k a n d ribavirin) or the daily c o m b i n a t i o n t h e r a p y as outlined in the first study. A n e g a t i v e H C V RNA by PCR at twelve w e e k s w a s considered viral clearance. S u b g r o u p analysis of subjects treated at Brooke A r m y Medical Center was p e r f o r m e d to a t t e m p t to control for access to care a n d i n c o m e level. These subjects consisted of military p e r s o n n e l a n d beneficiaries, each of w h o m h a d consistent access to care a n d a stable baseline income. Multiple logistic regression analysis was p e r f o r m e d w i t h the following variables to d e t e r m i n e i n d e p e n d e n t predictors of viral clearance: age, alanine a m i n o t r a n s f e r a s e (ALT), baseline HCV-RNA, b o d y m a s s index, gender, genotype, liver biopsy grade a n d stage, prior interferon therapy, a n d race. T h e s a m e analysis for 70 African A m e r i c a n s w h o c o m p l e t e d 24 w e e k s of P E G - I n t e r f e r o n alfa2b a n d ribavirin will be available for the a n n u a l meeting. Results: A total of 659 subjects (49 or 7.5% w e r e African A m e r i c a n ) received daily interferon w i t h ribavirin a n d 156 subjects (30 or 19.2% w e r e African A m e r i c a n ) received s t a n d a r d c o m b i n a t i o n therapy. Being African A m e r i c a n was a n i n d e p e n d e n t p r e d i c t o r of failure to achieve viral clearance, w i t h a n odds ratio of 0.18 (0.070.46 w i t h 95% CI). T h e lack of therapeutic r e s p o n s e did n o t i m p r o v e w h e t h e r s t a n d a r d (OR 0.09, 0.01-0.96 w i t h 95% CI) or daily (OR 0.18, 0.06-0.51 w i t h 95% CI) t h e r a p y w a s given. In s u b g r o u p analysis of subjects treated at Brooke A r m y Medical Center, b e i n g African A m e r i c a n was a n i n d e p e n d e n t predictor of failure to achieve viral clearance (OR 0.09, 0.02-0.49 w i t h 95% CI). Conclusion: African A m e r i c a n s h a v e a decreased viral clearance rate w i t h interferon a n d ribavirin c o m b i n a t i o n t h e r a p y i n d e p e n d e n t of a m u l t i t u d e of factors that could influence t r e a t m e n t o u t c o m e .
1001
1002
DOSAGE OF R I B A V I R I N I N PATIENTS W I T H HEPATITIS C SHOULD BE BASED O N R E N A L F U N C T I O N : A P O P U L A T I O N P I t A R M A C O K I N E T I C ANALYSIS. A n n e t t e Bruchfeld, Division of Renal Medicine, Karolinska Institute a n d H u d d i n g e U n i v Hospital, S t o c k h o l m Sweden; Karin Lindahl, Robert Schvarcz, Division of Infectious Diseases, H u d d i n g e U n i v Hospital, S t o c k h o l m Sweden; Lars StC*hle, Division of Clinical P h a r m a c o l o g y , H u d d i n g e U n i v Hospital, S t o c k h o l m S w e d e n
O R A L A D M I N I S T R A T I O N O F L A C T O F E R R I N L O W E R S SERUM HCVRNA LEVELS IN PATIENTS W I T H GENOTYPE-1B-RELATED CHRONIC HEPATITIS C. N a o k i K u m a g a i , Satoshi Y s u n e m a t s u , Kanji T s u c h i m o t o , Kitasato Institute Hospital, M i n a t o - k u Japan; Koji Yamauchi, S u s u m u Teraguchi, Hirotoshi Hayasawa, Nutritional Science Laboratory, Morinaga Milk I n d u s t r y CO , LTD, T o k y o Japan; H i d e t s u g u Saito, H i r o m a s a Ishii, Sch of Medicine, Keio Univ, T o k y o J a p a n
Background: A c o m b i n a t i o n of interferon-alfa a n d ribavirin is s t a n d a r d t h e r a p y for c h r o n i c hepatitis C (HCV). Ribavirin dosage is c u r r e n t l y based on bodyweight. T h e a i m of this s t u d y was to critically evaluate c u r r e n t dosage r e c o m m e n d a t i o n s on the basis of a p o p u l a t i o n p h a r m a c o k i n e t i c analysis. Methods: 398 ribavirin p l a s m a c o n c e n t r a t i o n samples w e r e collected f r o m 63 patients u n d e r g o i n g t r e a t m e n t for HCV. 44 patients h a d n o r m a l r a n g e s e r u m creatinine w i t h a n e s t i m a t e d g l o m e r u l a r filtration rate ( G F R = e s t i m a t e d creatinine clearance) of 57-144 m L / m i n . A n o t h e r 19 patients h a d renal i m p a i r m e n t w i t h a G F R of 5-57 m L / m i n . P o p u l a t i o n factors w e r e age, gender, b o d y - w e i g h t , s e r u m creatinine a n d GFR. A p o p u l a t i o n p h a r m a c o k i n e t i c analysis w a s p e r f o r m e d by n o n - l i n e a r m i x e d effect modelling. Results: Ribavirin clearance was f o u n d to be linearily d e p e n d a n t o n renal f u n c t i o n w i t h a smaller n o n - r e n a l clearance c o m p o n e n t . Renal function w a s a significantly better predictor of ribavirin clearance t h a n b o d y - w e i g h t . T h e v o l u m e of distribution, w h i c h w a s p r o p o r tional to b o d y w e i g h t ( V = 3 5 . 5 x b o d y - w e i g h t ) , was large, w h i c h resulted in a long half-life (100-600 h o u r s d e p e n d i n g on renal function) a n d a long time to steady state (2-14 w e e k s ) . T h e r e w a s a n inter-individual variability in ribavirin total clearance. Conclusion: Ribavirin initial dosage s h o u l d be based o n renal f u n c t i o n a n d n o t o n b o d y weight. A ribavirin dosing s c h e d u l e to r e a c h a n i n t e n d e d target c o n c e n t r a t i o n is p r o p o s e d w h i c h takes GFR into account. Ribavirin m o n i t o r i n g is useful for optimising H C V t r e a t m e n t n o t only in renal insufficiency, b u t also in o t h e r patients c o n s i d e r i n g the time to steady state as well as the inter-individual variability in ribavirin clearance.
Background and Aims: In Japan the majority of patients with chronic hepatitis C (CH-C) are infected with HCV genotype lb, which is associated with a significantly lower response rate to interferon o~(IFN) treatment (around 20%). Even in infection with HCV genotype lb, patients with low viremia ( < 100K1U/ml) at baseline show a high long-term complete response rate (over 50%) to IFN treatment. Lactoferrin (LF), which is a milk protein belonging to the iron transport family is known as a primary defense protein against pathogenic microorganisms including viruses. A pilot study has been reported in which LF decreased serum HCV-RNA concentrations in patients with CH-C. In this study, we examined the use of LF in CH-C patients with genotype lb and high viremia to lower serum HCV-RNA levels to < 100 KIU/ml and improve the response rate to IFN treatment. Methods: Fourteen CH-C patients with genotype lb and high viremia (>100 KIU/ml) were given LF at a dose of 600 mg/day. HCV-RNA was assessed by quantitative PCR and biochemical parameters were measured at baseline, 12 and 24 weeks. Thirteen corresponding CH-C patients were also followed for 24 weeks without LF treatment. Written informed consent was obtained from all patients. Results: Serum HCV-RNA levels (mean +SD) in the LF group at baseline, 12 and 24 weeks were 505 ---244, 347 ---294 and 366 -+297 KIU/ml, respectively ( baseline vs. 12 weeks p<0.05). Three patients (21%) showed a decrease in serum HCV-RNA to <100KIU/ml at 12 weeks (650 KIU/ml at baseline to 69 KIU/ml at 12 weeks, 240 to 82 KIU/ml, 110 to 30 K1U/ml, respectively) and 4 did so at 24 weeks (750 KIU/ml at baseline to 73 KIU/ml at 24 weeks, 740 to 53 KIU/ml, 650 to 60 KIU/ml, 560 to 78 KIU/ml, respectively; the third case overlapped with the first case at 12 weeks). Six patients (43%) showed low viremia (<100 KlU/ml) at either 12 or 24 weeks during LF administration. In the control group, there was no significant change of serum HCV-RNA levels between baseline and 12 weeks (638 -+232 and 588 -+251, respectively). Also, no patient in the control group showed low viremia of <100 KtU/ml at any time. Although there was no significant change of serum ALT levels during LF administration ( 79 +51 IU/ml at base line, 74 +44 at 12 weeks and 63 +31 at 24 weeks), 6 patients with relatively high ALT levels ( >70 IU/ml, which was twice the upper limit of normal) showed a significant decline of ALT levels at 12 weeks compared with baseline (the mean -+ SD of ALT at base line,12 and 24 weeks were 124 + 4 7 , 9 9 -+51 IU/ml and 65 -+30, respectively; baseline vs. 12 weeks p<0.02). There was no significant change of serum ALT levels in the control group. No adverse effect associated with LF administration was observed during the study. Conclusion and Discussion: Oral administration of LF significantly lowered serum HCV-RNA levels in CH-C patients with genotype lb and high viremia. Six out of 14 patients (43%) showed low viremia ( < 100 KIU/ml) during the administration. Therefore pretreatment with LF to CH-C patients might improve the response rate to IFN treatment by lowering serum HCV-RNA levels at baseline.