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Effect of initial treatment of chronic hepatitis C with interferon-alpha2b and ribavirin on health-related quality of life
AASLDA1427
April 2000
parameters were eva luated through catheteri zatio n (liver blood flow LBF, transhepatic pressure gradient WHVP and HVPG). Additional liver function tests (MEGX-test, ICG-test) were perfo rmed . Histology includ ed a standardized coding (4 levels) regardi ng degree of fat, inflammation, necrosis, ce ll volume, cholestasis and fibrosis. Results: The PD- calculated portal flow volume correlated we ll with the LBF (r= 0.82, p=0.023). With increa sed liver cell size (smaller than ce ll hydrops) the PD- calcul ated portal flow volume increased (r = 0.6, p = 0.039) and the RI of hep atic artery decre ased (r= -0.57 , p=0.032). Enlarged cell size was assoc iated with an incre ment of ICG- clearan ce (normal vs. enlarge d: 3.43:':0.97 vs. 4.72 :': 1.09 mll min/kgKG, p = O.OI, Wilcoxon) and redu ced cholestasis (normal vs. enlarge d: 139 :':4 9 vs. 49:':32 UIl, p = 0.OO6). The increment of ICG-clearance correlated inverse with the WHVP (r=-O.77, p=0.000 7) and the RI (r = -0.56, p=0.06). Elevation of the WHVP as a sign of portal hyperten sion produced increased RI values (r= 0.5 1) and decreased pulsatility of the portal vein (r = -0.45). The histological degree of inflammation was the most important factor for the increment of HVPG (r= 0.60, p= O.OI ). Concl usion: I. Th e non invasive PD- calc ulated portal flow measurem ents correlated significant with the liver blood flow measured by invasive hemody namics . 2. In animal studies a improv ement of liver function with increase d hepat ocyte volume was found. Th is is the first clinical investigation, in which a positive correlation of liver cell size (smaller than cell hydrops), liver function and liver perfusion could be demonstrated . 6478 ALT ELEVATION WITH INTERFERON INDUCTION THERAPY: A COMPARISON OF INTRON A® VS. INFERGEN®. Terry D. Box , Mark E. Boschert, John H. Bowers, Steven G. De sautel s, W illiam R. Hut son , 1. Ray Thom ason, Jane E. Christiansen, Kate Rose, Paul J. Gaglio, Mount We st Gastroenterology, Salt Lake City, UT ; Tu lane Med Sch , New Orleans, LA. Treatment nai ve patients with HCV RNA confirme d (RT-PCR) chro nic hepatitis C (HCV ) infection were treated in two different treatment protoco ls using daily doses of interferon alpha-2b and ribavirin (Rebetron®) or interfero n alfaco n- I (Infergen®). Th e impact of the treatment regimens on ALT levels is compared. Ten (10) patients were treated with 5 million units (MU ) Intron A® and 1000 mgm ribavirin daily for 4 weeks, followed by 44 week s of Intron A® 5 MU TrW and daily ribav irin 1000 mgm . Eight (8) patients were treated with Infergen ® 15 meg daily for 4 week s, follow ed by Infergen® 15 meg or 9 meg TrW for 44 weeks . Laboratory data including ALT level was analyzed at baseline, treatment week s I, 2, 4, 8, 12 and every four weeks there afte r while on treatment in both study groups. One of ten (1/ 10) Rebetron® treated patients experienced ALT elevation from baseline levels in the first four weeks of treatment. Five of eight (5/8) Infergen® treated patients ex perienced ALT elevation from baselin e le vels in the first four weeks of treatm ent. After cessatio n of daily Intron A® dosing, ALT elevation resolved within four weeks in the sole patient on Rebetron® who had experien ced an early rise in ALT. Afte r cessa tion of daily Inferg en® dosing, ALT elevation returned to baseline in three of five (3/5) patien ts, within four week s, but persisted at treatment week 12 in one of five (1/5 ). Conclusions: eALT eleva tion from baseline occurs much more commonly with daily Infergen® induction treatment than with daily Intron A® induction treatment. ePossible exp lanations include: ea greater up-regulation of the immune system with 15 mcg Infergen® elnfergen® dosed at 15 meg daily has more direct hep atotoxicity than Intron A® dosed at 5 MU daily. eAnalysis of adverse eve nts, end of treatment data and sustai ned response data in these two gro ups will perhaps shed light on the mechan ism of the ALT elevation and its relationship to treatment outc ome . Increased ALT IromBaseline
Rebetron ®
Inlergen®
Week 4 WeekS Week 12
Hl 0 = 10% 0/9 = 0%
5/8 = 63%
0/8 = 0''''
1/5= 20%
Studies supportedby grantsfromScherinq-Plouqh and Amgen.
2J7 = 29%
6479 EFFECT OF INITIAL TREATMENT OF CHRONIC HEPATITIS C WITH INTERFERON-ALPHA2R AND RIRAVIRIN ON HEALTHRELATED QUALITY OF LIFE. Jam es R. Burton, Jr., Th omas A. Shaw-St iffel , Univ of Rochester Med Ctr, Roch ester, NY. Introduction: Nearly 4 million Americans have hepatitis C. Patients with chronic hepat itis C (CHC) have been shown to have reduced health-r elated quality of life (HRQOL). HRQ OL has been shown to declin e duri ng initial treatment with inte rferon or retreatment with interferon or combination therapy. Improved HRQOL is seen in these same patien ts if a sustained virologic and/or biological response is achieve d. So far , no studies have looked at HRQOL in patients with CHC receiving combination therapy as initial therapy. Meth ods: Nineteen naive patient s with CHC were enrolled to received interferon and ribaviro n for a total of 48 weeks. HRQ OL was assessed using the Hepatitis Quality of Life Que stionaire (HQLQ ) (co ntaining the generic SF-36 Health Survey, three additional ge neric sca les, and two hepa titis speci fic sca les). Patients completed the HQLQ at entry, during treatment, and at follow-up po st treatment. Virolo gic response was defined as HCV PCR < 100 copies. Results: Six patients (32 %) had to withdraw from the stud y due to side effect s of treatment. One was lost to follow-up after 24 weeks of treatment. Of those completing at least 24 weeks of treatment, 4/17 (24%) had a virological response. Baseline HRQOL scores in our 19 patients were higher than in CHC patients in other studies, but generally less than those seen in previously desc ribed control populations. Ten pat ients completed at least 24 weeks of treatment and completed a HQLQ at 12 and/o r 24 weeks after the treatment period ended. In those completing 48 weeks of treatment (n = 12), mean HRQOL scores were highter at ent ry com pared to at the end of ther apy. Mean HRQOL scores at entry and durin g post-trea tment follow- up were higher in the responders co mpared to the non-r esponders. Conclu sion : Patients with chronic hepatitis C undergoing initia l treatm ent with co mbination therapy showe d declines in HRQOL duri ng trea tment. Averag e HRQ OL scores were higher in viro logical responders both at entry and after treatm ent. Although these differences were not statistically significant given the small numb er of patient s co mpleti ng treat ment in this study, these data are cons istent with publi shed findings of patients treated with interferon alone and those retreated with interferon or combinatio n therap y. Furth er study is needed to confirm these findings. 6480 WILSON'S DISEASE IN EASTERN GERMANY: HIGH FRE· QUENCY OF THE HI069Q MUTATION AND CORRELATION WITH THE NEUROLOGICAL MANIFESTATION. Karel Caca, Peter Ferenci, Hans Juergen Kuehn, Helmut Willgerodt , Joachim Moe ssner , Frieder Berr , Medicine Clin II, Univ Leipzig, Leipzig, Germ any; Innere Medi cine IV, Univ Wien , Wien, Austria; Neurologische Clin, Univ Leipzig, Leipzig, Germ any; Kinderklinik, Uni v Leipzig, Leipzig, Germany. Wilson's Disease (WD) is an autoso mal recessive disorder of biliary copper excretion, manifesting as chro nic liver disease (HM) and/or neurological impairment (NM) due to progressive accumulation of copper in vario us organs. More than 100 mutations in the WD gene , a copper trans porting P-type ATP ase (ATP7B), have been described so far. Although most mutations occur in only a few families or patient s, a higher freque ncy of the H1069Q mutation has been reported for patients with Eastern or Northern Eu ropean origin. Th erefore we determ ined the frequen cy of th is mutation and other mutations in Eastern Germ any and looked for genotype-phenotype correlatio ns. Me thods: DNA was isolated from periph eral blood co llected from 82 patients (4 1 male. 4 1 female) from 74 indepe ndent fam ilies (50 NM; 32 HM ). Mutational analysis of ATP7 B HI 069Q was perform ed by direct sequencing exon 14 PCR -products. Additionallyexons 1-21 of AT P7B were amplified and sequence d from 18 patients hetero zygou s for H1069Q and 5 patient s lackin g the HI 069Q mutation. Results: 27(33 %) were H 1069Q Homozygotes, 40 (49%) H l 069Q Heterozygotes and 15 (18 %) had other mutations . In 24/28 alleles with additional mutatio ns a putative seco nd disease causi ng mutation could be identified. The seco nd most frequent mutation was C3400del found in 7 alleles (I homozygous). We found 2 novel mutat ions (P760L and IVS IO+ 2:T-C) and a varie ty of polymorphisms (most co mmon K832R). HI069Q Homozygotes were older (22± 6 years) , showed preferentially a neurological manifestation (96 % NM ) and a Kayser-Fl eischer (KF) ring (88% KF) compared to HI069Q Heterozygotes (17 :':7 y.l58% NMl 60% KF) and pa tients with other mutations (16:': 10 y.l l% NMlI6% KF). We found no gender preference of the H I069Q mutation. 5/6 patient s with the C3400del mutation showed a hepatic manife station of their WD . Conclusions: The H1069Q mutati on shows a very high frequency (82%)in WD patients from Eastern Germany. There is a clear correlation with the neurological manifestation of WD in our patient group. The C340 0del mutation may be associated with the hepatic manifestation of WD . Genetic diagnosis seems to be a reach able task in this region, especially for patient s with neurological manife station .
April 2000
parameters were eva luated through catheteri zatio n (liver blood flow LBF, transhepatic pressure gradient WHVP and HVPG). Additional liver function tests (MEGX-test, ICG-test) were perfo rmed . Histology includ ed a standardized coding (4 levels) regardi ng degree of fat, inflammation, necrosis, ce ll volume, cholestasis and fibrosis. Results: The PD- calculated portal flow volume correlated we ll with the LBF (r= 0.82, p=0.023). With increa sed liver cell size (smaller than ce ll hydrops) the PD- calcul ated portal flow volume increased (r = 0.6, p = 0.039) and the RI of hep atic artery decre ased (r= -0.57 , p=0.032). Enlarged cell size was assoc iated with an incre ment of ICG- clearan ce (normal vs. enlarge d: 3.43:':0.97 vs. 4.72 :': 1.09 mll min/kgKG, p = O.OI, Wilcoxon) and redu ced cholestasis (normal vs. enlarge d: 139 :':4 9 vs. 49:':32 UIl, p = 0.OO6). The increment of ICG-clearance correlated inverse with the WHVP (r=-O.77, p=0.000 7) and the RI (r = -0.56, p=0.06). Elevation of the WHVP as a sign of portal hyperten sion produced increased RI values (r= 0.5 1) and decreased pulsatility of the portal vein (r = -0.45). The histological degree of inflammation was the most important factor for the increment of HVPG (r= 0.60, p= O.OI ). Concl usion: I. Th e non invasive PD- calc ulated portal flow measurem ents correlated significant with the liver blood flow measured by invasive hemody namics . 2. In animal studies a improv ement of liver function with increase d hepat ocyte volume was found. Th is is the first clinical investigation, in which a positive correlation of liver cell size (smaller than cell hydrops), liver function and liver perfusion could be demonstrated . 6478 ALT ELEVATION WITH INTERFERON INDUCTION THERAPY: A COMPARISON OF INTRON A® VS. INFERGEN®. Terry D. Box , Mark E. Boschert, John H. Bowers, Steven G. De sautel s, W illiam R. Hut son , 1. Ray Thom ason, Jane E. Christiansen, Kate Rose, Paul J. Gaglio, Mount We st Gastroenterology, Salt Lake City, UT ; Tu lane Med Sch , New Orleans, LA. Treatment nai ve patients with HCV RNA confirme d (RT-PCR) chro nic hepatitis C (HCV ) infection were treated in two different treatment protoco ls using daily doses of interferon alpha-2b and ribavirin (Rebetron®) or interfero n alfaco n- I (Infergen®). Th e impact of the treatment regimens on ALT levels is compared. Ten (10) patients were treated with 5 million units (MU ) Intron A® and 1000 mgm ribavirin daily for 4 weeks, followed by 44 week s of Intron A® 5 MU TrW and daily ribav irin 1000 mgm . Eight (8) patients were treated with Infergen ® 15 meg daily for 4 week s, follow ed by Infergen® 15 meg or 9 meg TrW for 44 weeks . Laboratory data including ALT level was analyzed at baseline, treatment week s I, 2, 4, 8, 12 and every four weeks there afte r while on treatment in both study groups. One of ten (1/ 10) Rebetron® treated patients experienced ALT elevation from baseline levels in the first four weeks of treatment. Five of eight (5/8) Infergen® treated patients ex perienced ALT elevation from baselin e le vels in the first four weeks of treatm ent. After cessatio n of daily Intron A® dosing, ALT elevation resolved within four weeks in the sole patient on Rebetron® who had experien ced an early rise in ALT. Afte r cessa tion of daily Inferg en® dosing, ALT elevation returned to baseline in three of five (3/5) patien ts, within four week s, but persisted at treatment week 12 in one of five (1/5 ). Conclusions: eALT eleva tion from baseline occurs much more commonly with daily Infergen® induction treatment than with daily Intron A® induction treatment. ePossible exp lanations include: ea greater up-regulation of the immune system with 15 mcg Infergen® elnfergen® dosed at 15 meg daily has more direct hep atotoxicity than Intron A® dosed at 5 MU daily. eAnalysis of adverse eve nts, end of treatment data and sustai ned response data in these two gro ups will perhaps shed light on the mechan ism of the ALT elevation and its relationship to treatment outc ome . Increased ALT IromBaseline
Rebetron ®
Inlergen®
Week 4 WeekS Week 12
Hl 0 = 10% 0/9 = 0%
5/8 = 63%
0/8 = 0''''
1/5= 20%
Studies supportedby grantsfromScherinq-Plouqh and Amgen.
2J7 = 29%
6479 EFFECT OF INITIAL TREATMENT OF CHRONIC HEPATITIS C WITH INTERFERON-ALPHA2R AND RIRAVIRIN ON HEALTHRELATED QUALITY OF LIFE. Jam es R. Burton, Jr., Th omas A. Shaw-St iffel , Univ of Rochester Med Ctr, Roch ester, NY. Introduction: Nearly 4 million Americans have hepatitis C. Patients with chronic hepat itis C (CHC) have been shown to have reduced health-r elated quality of life (HRQOL). HRQ OL has been shown to declin e duri ng initial treatment with inte rferon or retreatment with interferon or combination therapy. Improved HRQOL is seen in these same patien ts if a sustained virologic and/or biological response is achieve d. So far , no studies have looked at HRQOL in patients with CHC receiving combination therapy as initial therapy. Meth ods: Nineteen naive patient s with CHC were enrolled to received interferon and ribaviro n for a total of 48 weeks. HRQ OL was assessed using the Hepatitis Quality of Life Que stionaire (HQLQ ) (co ntaining the generic SF-36 Health Survey, three additional ge neric sca les, and two hepa titis speci fic sca les). Patients completed the HQLQ at entry, during treatment, and at follow-up po st treatment. Virolo gic response was defined as HCV PCR < 100 copies. Results: Six patients (32 %) had to withdraw from the stud y due to side effect s of treatment. One was lost to follow-up after 24 weeks of treatment. Of those completing at least 24 weeks of treatment, 4/17 (24%) had a virological response. Baseline HRQOL scores in our 19 patients were higher than in CHC patients in other studies, but generally less than those seen in previously desc ribed control populations. Ten pat ients completed at least 24 weeks of treatment and completed a HQLQ at 12 and/o r 24 weeks after the treatment period ended. In those completing 48 weeks of treatment (n = 12), mean HRQOL scores were highter at ent ry com pared to at the end of ther apy. Mean HRQOL scores at entry and durin g post-trea tment follow- up were higher in the responders co mpared to the non-r esponders. Conclu sion : Patients with chronic hepatitis C undergoing initia l treatm ent with co mbination therapy showe d declines in HRQOL duri ng trea tment. Averag e HRQ OL scores were higher in viro logical responders both at entry and after treatm ent. Although these differences were not statistically significant given the small numb er of patient s co mpleti ng treat ment in this study, these data are cons istent with publi shed findings of patients treated with interferon alone and those retreated with interferon or combinatio n therap y. Furth er study is needed to confirm these findings. 6480 WILSON'S DISEASE IN EASTERN GERMANY: HIGH FRE· QUENCY OF THE HI069Q MUTATION AND CORRELATION WITH THE NEUROLOGICAL MANIFESTATION. Karel Caca, Peter Ferenci, Hans Juergen Kuehn, Helmut Willgerodt , Joachim Moe ssner , Frieder Berr , Medicine Clin II, Univ Leipzig, Leipzig, Germ any; Innere Medi cine IV, Univ Wien , Wien, Austria; Neurologische Clin, Univ Leipzig, Leipzig, Germ any; Kinderklinik, Uni v Leipzig, Leipzig, Germany. Wilson's Disease (WD) is an autoso mal recessive disorder of biliary copper excretion, manifesting as chro nic liver disease (HM) and/or neurological impairment (NM) due to progressive accumulation of copper in vario us organs. More than 100 mutations in the WD gene , a copper trans porting P-type ATP ase (ATP7B), have been described so far. Although most mutations occur in only a few families or patient s, a higher freque ncy of the H1069Q mutation has been reported for patients with Eastern or Northern Eu ropean origin. Th erefore we determ ined the frequen cy of th is mutation and other mutations in Eastern Germ any and looked for genotype-phenotype correlatio ns. Me thods: DNA was isolated from periph eral blood co llected from 82 patients (4 1 male. 4 1 female) from 74 indepe ndent fam ilies (50 NM; 32 HM ). Mutational analysis of ATP7 B HI 069Q was perform ed by direct sequencing exon 14 PCR -products. Additionallyexons 1-21 of AT P7B were amplified and sequence d from 18 patients hetero zygou s for H1069Q and 5 patient s lackin g the HI 069Q mutation. Results: 27(33 %) were H 1069Q Homozygotes, 40 (49%) H l 069Q Heterozygotes and 15 (18 %) had other mutations . In 24/28 alleles with additional mutatio ns a putative seco nd disease causi ng mutation could be identified. The seco nd most frequent mutation was C3400del found in 7 alleles (I homozygous). We found 2 novel mutat ions (P760L and IVS IO+ 2:T-C) and a varie ty of polymorphisms (most co mmon K832R). HI069Q Homozygotes were older (22± 6 years) , showed preferentially a neurological manifestation (96 % NM ) and a Kayser-Fl eischer (KF) ring (88% KF) compared to HI069Q Heterozygotes (17 :':7 y.l58% NMl 60% KF) and pa tients with other mutations (16:': 10 y.l l% NMlI6% KF). We found no gender preference of the H I069Q mutation. 5/6 patient s with the C3400del mutation showed a hepatic manife station of their WD . Conclusions: The H1069Q mutati on shows a very high frequency (82%)in WD patients from Eastern Germany. There is a clear correlation with the neurological manifestation of WD in our patient group. The C340 0del mutation may be associated with the hepatic manifestation of WD . Genetic diagnosis seems to be a reach able task in this region, especially for patient s with neurological manife station .