Beniowski, Marek

Berak, Hanna

Bolewska, Beata

Boroń-Kaczmarska, Anna

Cianciara, Janusz

Cieśla, Andrzej

Gietka, Andrzej

Gliwińska, Ewa

Gonciarz, Zbigniew

Gąsiorowski, Jacek

Gładysz, Andrzej

Halota, Waldemar

Horban, Andrzej

Inglot, Małgorzata

Janas-Skulina, Urszula

Janczewska-Kazek, Ewa

Jaskowska, Jolanta

Jurczyk, Krzysztof

Juszczyk, Jacek

Knysz, Brygida

Kryczka, Wiesław

Kuydowicz, Jan

Lakomy, Anna

Logiewa-Bazger, Beata

Mach, Tomasz

Mazur, Włodzimierz

Michalska, Zofia

Modrzewska, Roma

Nazzal, Khalil

Pabjan, Paweł

Piekarska, Anna

Piszko, Paweł

Sikorska, Katarzyna

Szamotulska, Katarzyna

Tomasiewicz, Krzysztof

Topczewska-Staubach, Ewa

Trocha, Hanna

Wasilewski, Marek

Wawrzynowicz-Syczewska, Marta

Wrodycki, Witold

Zarębska-Michaluk, Dorota

Zejc-Bajsarowicz, Małgorzata

Łyczak, Anna

Świętek, Katarzyna

Medical Science Monitor

English

Jagiellonian Univeristy Repository

WWW.MEDSCI MONIT.COMSupplement 1© Med Sci Monit, 2004; 10(Suppl 1): 12-1612Safety and tolerability of the combination therapy with pegylatedinterferon alfa-2a (Pegasys®) and ribavirin (Copegus®) in patientswith chronic hepatitis C in Poland – interim analysis of data fromEAP programAndrzej Horban1, Marek Beniowski2, Hanna Berak1, Beata Bolewska3, Anna Boroń-Kaczmarska4,Janusz Cianciara5, Andrzej Cieśla6, Jacek Gąsiorowski7, Andrzej Gietka8, Ewa Gliwińska8,Andrzej Gładysz7, Zbigniew Gonciarz9, Waldemar Halota10, Małgorzata Inglot7, Urszula Janas-Skulina6,Ewa Janczewska-Kazek2, Jolanta Jaskowska10, Krzysztof Jurczyk4, Jacek Juszczyk3, Brygida Knysz7,Wiesław Kryczka11, Jan Kuydowicz12, Anna Lakomy13, Beata Logiewa-Bazger14, Anna Łyczak15,Tomasz Mach6, Włodzimierz Mazur9, Zofia Michalska13, Roma Modrzewska15, Khalil Nazzal5,Paweł Pabjan11, Anna Piekarska12, Paweł Piszko7, Katarzyna Sikorska13, Katarzyna Szamotulska16,Katarzyna Świętek3, Krzysztof Tomasiewicz15, Ewa Topczewska-Staubach10, Hanna Trocha13,Marek Wasilewski1, Marta Wawrzynowicz-Syczewska4, Witold Wrodycki12, Dorota Zarębska-Michaluk11,Małgorzata Zejc-Bajsarowicz61 Voivodship Hospital of Infectious Diseases, Warsaw, Poland2 Department of Infectious Diseases, Medical University of Silesia, Chorzów, Poland3 Department of Infectious Diseases, University of Medical Sciences in Poznań, Poznań, Poland4 Chair and Department of Infectious Diseases, Pomeranian Medical University, Szczecin, Poland5 Department of Hepatology and Acquired Immune Deficiencies, Institute of Infectious and Parasitic Diseases, Medical University of Warsaw,Warsaw, Poland6 Department of Infectious Diseases and Hepatology, Jagiellonian University, Cracow, Poland7 Department of Infectious Diseases, Medical University of Wrocław, Wrocław, Poland8 Central Clinical Hospital of the Ministry of Internal Affairs and Administration, Department of Hepatology and Internal Diseases, Warsaw,Poland9 Department of Internal Medicine, Medical University of Silesia, Sosnowiec, Poland10 Department of Infectious Diseases, L. Rydygier Medical University, Bydgoszcz, Poland11 Department of Infectious Diseases, Provincional General Hospital, Kielce, Poland12 Clinic of Infectious Diseases and Hepatology, Medical University of Łódź, Poland13 Department of Infectious Diseases, Medical University of Gdańsk, Gdańsk, Poland14 Specialistic Hospital, Department of Infectious Diseases, Chorzów, Poland15 Department and Chair of Infectious Diseases, Medical University, Lublin, Poland16 National Research Institute of Mother and Child, Department of Epidemiology, Warsaw, PolandAuthor’s address: Andrzej Horban, Hospital of Infectious Diseases, ul. Wolska 37, 01-201 Warszawa, Poland, e-mail: ahorban@cdit-aids.med.plSummaryOpen-label, multicenter extended availability program with peginterferon alfa-2a used in combination with ribavirin in patients withCHC in Poland was analysed. Finally, 572 patients were enrolled. The interim analysis of safety and tolerability was performed in190 patients whose data were available after 72 weeks of observation. Mean hemoglobin level was 14.8 g/dl and decreased to week24, then remain stable until the end of therapy and returned to the baseline value. Lekocytes level in week 2 decreased, reach aplateau in week 8 and return to baseline values at end observation. Similar phenomenon was observed with neutrophils. Plateletcount during the treatment fell gradually in week 8 and remained stable. Reported adverse events requiring PEGASYS® or COPE-GUS® dose reduction were also analyzed. The most frequent adverse effect leading to the reduction of peginterferon alfa-2a dose was13Med Sci Monit, 2004; 10(Suppl 1): 12-16 Horban A et al – Safety and tolerability of the combination therapy with pegylated…INTRODUCTIONI Monotherapy with pegylated interferonalfa-2a PEGASYS®The safety and tolerability of pegylated interferon alfa-2a(PEGASYS®) in monotherapy was assessed in phase 2 and3 studies with almost 1580 patients included. The analysisincluded 995 patients who had received at least one doseof pegylated interferon alfa-2a and 584 patients treatedwith standard interferon alfa-2a. The data concerningsafety were based on the treatment period (up to 48weeks) and an observation period of at least 8 weeks aftercompletion of the therapy, whereas adverse effects wereanalyzed to week 72. Approximately 30% of patients havebeen diagnosed as hepatic cirrhosis or advanced fibrosis.The reported adverse effects were typical of interferontherapy, and their incidence was comparable in thegroups treated with pegylated interferon alfa-2a andstandard interferon given 3 × a week therapy. No differ-ences were observed in the frequency of reported seriousadverse events (SAE). The most frequently reportedadverse effects were flu-like symptoms (analogous tothose observed due to enhanced production of endoge-nous interferon in response to viral infections). Otheradverse effects included hair loss, psychical disturbances(irritability, dysphoria, mood disturbances). The adverseeffects were usually mild or moderate in intensity.The necessity of dose modification because of adverseeffects was also similar.In the study by Zeuzem et al. [1] the safety of pegylatedinterferon alfa-2a and standard interferon alfa-2a inmonotherapy was compared. The necessity of treatmentdiscontinuation because of adverse effects was noted in7% of patients treated with pegylated interferon alfa-2aand 10% of those receiving interferon alfa-2a, while thenecessity of dose modification was comparable in bothgroups (19 and 18%).II Safety and tolerability of combined therapy withribavirinThe rate of the treatment discontinuations due toadverse events was lower in the group of patients treat-ed with pegylated interferon alfa-2a (5.8% in monothe-rapy and 7.1% in combination with ribavirin) as com-pared with standard interferon plus ribavirin (9.7%)and higher with respect to treatment discontinuationsbecause of laboratory abnormalities (0.9%, 2.6% and0.9%, respectively) [2].Hadziyannis et al. [3] presented the rates of discontinued24- and 48-week therapies with pegylated interferon alfa-2a – PEGASYS® and ribavirin combination. It was neces-sary to discontinue treatment in 5% and 4% of patientson the 24-week treatment schedule and in 16% and 15%in the group treated for 48 weeks (the patients received800 and 1000/1200 mg daily doses of ribavirin, respec-tively) due to adverse events or laboratory abnormalities.Reduction or omissions of ≥1 doses of pegylated interfer-on alfa-2a was necessary in 30% and 26% in the grouptreated for 24 weeks (on 800 and 1000/1200 mg dailydoses, respectively) and in 33% and 36% for the patientstreated for 48-weeks (on 800 and 1000/1200 mg, respec-tively). The incidence of serious adverse events (SAE)associated with the therapy was 3% and 7% (for 24-weektreatment), and 9% and 10% (for 48-week treatment) [3].Changes of neutrophil counts both during monothera-py and combined therapy were comparable, and theobserved decrease slightly more pronounced than incase of combined therapy with standard interferongiven 3 × a week plus ribavirin. Neutropenia <750,>500 cells/ml (toxicity level 3) was observed in 22%, and< 500 cells/ml (grade 4) in 4.7% of patients.Changes of platelet counts during monotherapy andcombined therapy were comparable, and the observeddecrease slightly more pronounced than in case of com-bined therapy with interferon 3 × a week plus ribavirin.Thrombocytopenia <50.000 cells/ml (toxicity level 3)was noted in 4.9% of patients [4].Lower incidence of fever, myalgia, chills and depressionwas observed in the group treated with pegylated inter-feron alfa-2a in comparison with interferon adminis-tered 3 times a week [2]. Reduced ribavirin dose (800mg/d versus 1000/1200 mg/d) was associated with alower incidence of SAE, less frequent necessity of dosagemodifications and less frequent severe decreases ofhemoglobin level.Manns and al. [5] compared efficacy and safety of pegin-terferon alfa-2b with ribavirin and interferon alfa-2bwith ribavirin at 514 and 505 patients, respectively. Theyfound that overall discontinuation rate was similar (14vs. 13%). Dose decreasing was necessary at 42% and 34%of patients. Higher rate of neutropenia (18% vs. 8%),fever, nausea and injection- site reaction was observed ingroup treated with peginterferon alfa-2b. Injection- sitereaction may be serious (see case report by Gallelli). [6]Lindsay and al. [7] performed randomized, double-blindtrial comparing pegylated interferon alfa-2b to interferonalfa-2b as initial treatment for chronic hepatitis C, con-cluded that no new adverse events were reported, and themajority of adverse events and changes in laboratory val-ues were mild or moderate.neutropenia (81/185), followed by thrombocytopenia (23/185) (12.4%). Anemia was the most frequent reason of ribavirin dosereduction. It was noted in 16 patients out of 18, who had the doses reduced because of adverse effects. Only in 5 patients, the dose wasreduced because of depression or anxiety. Combined therapy was generally well-tolerated, preliminary analysis data confirms similartolerability profile to that observed in phase III clinical trials.Key words: chronic hepatitis C • combination therapy with pegylated interferon alfa-2a and ribavirin • safety and tolerability14Med Sci Monit, 2004; 10(Suppl 1): 12-16 Tolerability of pegylated interferon alfa-2a (PEGASYS®)in patients with liver cirrhosisThe adverse events in patients assigned to pegylated inter-feron alfa-2a at either dose were typical of those seen withstandard IFN. Adverse effects necessitating dose reduc-tion were more frequent in the group receiving 180 µgPEGASYS® than in the group receiving 90 µg dose of thedrug, but the same as for patients receiving standard IFNtherapy. The proportions of patients who had to discon-tinue the therapy were similar in all groups; no patientdiscontinued due to neutropenia, and only two patientsreceiving the higher dose of pegylated interferon alfa-2awere discontinued due to thrombocytopenia [8].Tolerability of pegylated interferon alfa-2a (PEGASYS®)in patients with renal failureIn a small open-label PK study the frequency of report-ed adverse effects increased with the severity of renalinsufficiency. In the group of patients with creatinineclearance >100 ml/min, adverse effects were reportedin 50% of cases, and in the group with creatinine clear-ance <40 ml/min – in 100% [9].III Open-label, multicenter extended availabilityprogram (EAP) with peginterferon-2a (40KD)(PEGASYS®) used in combination with ribavirin(COPEGUS®) in patients with chronic hepatitis Cin PolandSafety and tolerability – study phase summaryTo the study 572 patients in total were enrolled accord-ing to the Roche protocol BV 16209 in 14 centers in thewhole country. Detailed inclusion criteria are given byJuszczyk et al. [10].The following interim analysis was performed in 190patients. The patients were monitored according to the approvedstudy protocol.The study visits were scheduled for weeks 0, 2, 4, 8, 16, 24,32, 40, 48 during treatment and follow-up visits for weeks8 and 24 after the completion of treatment. The moni-tored safety parameters included blood cell count, bio-chemical parameters of liver, kidney and thyroid function.The results of safety parameters assessment after 72weeks of observation and are currently available in 148 of163 patients. This group accounts for 78–85% of patientsenrolled in the study and it seems that analysis at thisstage may be useful for the needs of study monitoring.Table 1 presents the changes of mean hemoglobin levelsduring the therapy.The analysis includes 163 subjects whose complete dataare available. At the baseline, before the treatment,mean hemoglobin level was 14.8 g/dl. In week 2 fromthe start of the therapy, mean hemoglobin value was14.0 g/dl and decreased to week 24 of treatment when itreached the level of 12.5 g/dl. That level remained moreor less stable until the completion of the therapy inweek 48. These values differed from the baseline withstatistical significance (p<0.001).In week 72 of observation, mean hemoglobin levelsreturned to the baseline value of 14.7 g/dl.Table 2 presents the changes of mean leukocyte countsduring the therapy.The analysis includes 162 subjects whose data were avai-lable. The mean baseline leukocyte count at the beginningof treatment was 6.1 (×109/l). In week 2 of the therapy itdecreased to 4.3 (×109/l), reaching in week 8 value of 3.4(×109/l) slowly decreased until to 3.1 (×109/l) in week 48.The difference from the baseline was statistically signifi-cant (p<0.001) Control tests in week 72 of observationconfirmed return of leukocyte count to baseline values atthe level of 5.8 (×109/l).A similar phenomenon (Table 3) was observed withrespect to neutrophils.Mean ±standarddeviation95% confidenceinterval14.8±1.4(14.6–15.0)14.0±1.5(13.8–14.2)13.2±1.5(13.0–13.4)12.9±1.5(12.6–13.1)12.6±1.4(12.4–12.8)12.5±1.4(12.2–12.7)12.6±1.3(12.4–12.8)12.5±1.4(12.3–12.7)12.6±1.4(12.4–12.9)14.7±1.6(14.4–14.9)Table 1. Mean hemoglobin levels (g/dl).Weeks 0 2 4 8 16 24 32 40 48 72Mean ±standarddeviation95% confidenceinterval6.1±1.4(5.9–6.3)4.3±1.5(4.0–4.5)3.7±1.2(3.5–3.8)3.4±1.2(3.2–3.6)3.3±1.0(3.1–3.4)3.3±1.5(3.0–3.5)3.2±1.0(3.1–3.4)3.1±1.1(2.9–3.2)3.1±1.1(3.0–3.3)5.8±1.6(5.6–6.0)Table 2. Mean leukocyte counts (×109/l).Weeks 0 2 4 8 16 24 32 40 48 7215Med Sci Monit, 2004; 10(Suppl 1): 12-16 Horban A et al – Safety and tolerability of the combination therapy with pegylated…To the analysis were included 148 patients. The baselinevalue was 3.2 (×109/l). In week 2, the neutrophil countdecreased to 1.9 (×109/l) reaching a plateau of values rang-ing from 1.5 a 1.7 (×109/l) by week 4. These differenceswere also statistically significant in comparison with thebaseline (p<0.001). After the completion of treatment, inweek 72, the mean neutrophil count was 3.3 (×109/l).Table 4 analyzes mean platelet counts in 158 patients.At the beginning of the treatment, the mean value was198.7×109/l. During the treatment, the platelet countsfell gradually to the level of 137.3×109/l in week 8 andremained at that level until the end of the therapy inweek 48. The difference from the baseline was statisti-cally significant (p<0.001). After the completion oftreatment, mean platelet counts normalized, reachingthe value of 198.1×109/l.The reported adverse events requiring PEGASYS® orCOPEGUS® dose reduction were also analyzed. Fivepatients were excluded from the analysis, because thedates of completion of their treatment were unknown.Thus, the analysis included 185 subjects.It was necessary to reduce (temporarily or permanently)the dose of interferon in 145 cases (what means that adose reduction could take place more than once in a sin-gle patient case), in 18 cases the reduction of ribavirin wasrequired. The most frequent adverse effect leading to thereduction of peginterferon alfa-2a dose was neutropenia(81/185) (43.8%), followed by thrombocytopenia (23/185)(12.4%). Anemia was the most frequent reason of ribavirindose reduction. It was noted in 16 patients out of 18, whohad the doses reduced because of adverse effects. Only in5 patients, the dose was reduced because of depression oranxiety. The data are presented in Table 5.In the analyzed group of 190 patients, the total numberof reported SAE was 15. None of the SAE occurredmore frequently than in one case. The list of suchadverse events is presented in Table 6.CONCLUSIONS• combined therapy with PEGASYS® 180 ug/week/CO-PEGUS® 800 mg/day administered for 48 weeks wasgenerally well-tolerated,Mean ±standarddeviation95% confidenceinterval3.2±1.0(3.0–3.4)1.9±0.9(1.7–2.0)1.6±0.8(1.5–1.7)1.5±0.7(1.4–1.6)1.6±0.6(1.5–1.7)1.7±1.4(1.5–2.0)1.7±0.8(1.6–1.8)1.6±0.8(1.5–1.7)1.7±0.9(1.5–1.8)3.3±1.2(3.1–3.5)Table 3. Mean neutrophil counts (×109/l).Weeks 0 2 4 8 16 24 32 40 48 72Mean ±standarddeviation95% confidenceinterval198.7±53.9(190.2–207.1)160.3±48.5(152.7–168.0)149.5±46.3(142.2–156.7)137.3±45.5(130.2–144.5)138.3±50.3(130.4–146.2)143.3±48.0(135.8–150.9)138.7±46.2(131.5–146.0)134.5±43.2(127.7–141.3)137.1±45.8(129.9–144.3)198.1±54.7(189.5–206.7)Table 4. Mean platelet counts (×109/l).Weeks 0 2 4 8 16 24 32 40 48 72NeutropeniaThrombocytopeniaAnemiaElevated AIAT activityHeadacheAstheniaDepression/anxietyHair lossOthersTotal812313673/2118145101600000118Table 5. Reported adverse events leading to reduction of drug doses.Adverse effect type Dose reductionPEGASYS®Dose reductionCOPEGUS®DiarrhoeaHypertension – aggravationSyncopeFeverSubarachnoid hemorrhageHypothyroidismRenal carcinomaAcute gastroenteritisTonsillitisOpen left tibia fractureThyroiditisThyroid adenomaThumb injuryDepressionPregnancy of patient’s wife (healthy offspring)Total11111111111111115Table 6. Reported serious adverse events (SAE).Adverse effect type Number of cases16Med Sci Monit, 2004; 10(Suppl 1): 12-16 • the therapy requires frequent monitoring of bloodparameters, especially leukocyte and thrombocytecounts. In case of early detection of abnormalities,dose reduction is sufficient,• preliminary analysis of EAP – Pegasys program dataconfirms similar tolerability profile to that observed inphase III clinical trials,• considerably lower depression rates (as comparedwith standard therapy) are interesting,• only 9/190 (4.7%) did not complete the therapy (includ-ing 3.2% withdrawn because of side effects). Accordingto literature data, discontinuation rates reach 10–16.1%.REFERENCES:1. Zeuzem S, Feinman SV, Rasenack J et al: Peginterferon alfa-2ain patients with chronic hepatitis C. N Engl J Med, 2000; 343: 1666-722. Fried MW, Shiffman ML, Reddy R et al: Peginterferon alfa-2a plusribavirin for chronic hepatitis C virus infection. N Engl J Med,2002; 347: 975-823. Hadziyannis S, Sette H Jr, Morgan TR et al: Peginterferon alfa-2aand ribavirin combination therapy in chronic Hepatitis C. A ran-domized study of treatment duration and ribavirin dose. AnnIntern Med, 2004; 140: 346-554. Roche Data on file5. Manns MP et al: Peginterferon alfa-2b plus ribavirin comparedwith interferon alfa-2b plus ribavirin for initial treatment of chronichepatitis C: a randomised trial. Lancet, 2001; 358: 958-656. Gallelli: Bilateral Skin Ulceration after Injection of PegylatedInterferon-alfa-2b in a Patient with Chronic Hepatitis C. Clin DrugInvest, 2003; 23: 615-197. Lindsay KL, Trepo C, Heintges T et al: A Randomized, Double--Blind Trial Comparing Pegylated Interferon Alfa-2b to Interferonalfa-2b as Initial Treatment for Chronic Hepatitis C. Hepatology,2001; 34: 395-4038. Heathcote EJ, Mitchel L, Shiffman ML et al: Peginterferon alfa-2ain patients with chronic hepatitis C and cirrhosis. N Eng J Med,2000; 343: 1673-809. Martin P, Mitra S, Farrington K et al: The pharmacokineticsof pegylated (40 kDa) interferon alfa-2a (PEGASYS®) are unaffect-ed by renal impairment.Abstract AASLD 51st Annual Meeting,Dallas, USA, 200010. Juszczyk J et al: The effectiveness of combined pegylated interferonalfa-2a and ribavirin treatment of chronic hepatitis C – study phasesummary. Med Sci Monit, 2004; 10(Suppl 1): 5-11

Safety and tolerability of the combination therapy with pegylated interferon alfa-2a (Pegasys®) and ribavirin (Copegus®) in patients with chronic hepatitis C in Poland : interim analysis of data from EAP program

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Safety and tolerability of the combination therapy with pegylated interferon alfa-2a (Pegasys®) and ribavirin (Copegus®) in patients with chronic hepatitis C in Poland : interim analysis of data from EAP program

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