Peginterferon alfa-2a: A review of approved and investigational uses

CLINICAL THERAPEUTICs®/VoL.2 6 , N o . 7, 2 0 0 4

New Drugs

Peginterferon Alfa-2a: A Review of Approved and Investigational Uses S. James Matthews, PharmD, 1 Christopher McCoy, PharmD, BCPS 2 ~Department of Pharmacy Practice, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, and 2Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts

ABSTRACT

Background: In October 2002, the US Food and Drug Administration approved peginterferon alfa-2a for the management of chronic hepatitis C virus (HCV) infection. The addition of polyethylene glycol (PEG) moiety to the interferon (IFN) molecule results in a product with altered pharmacokinetic properties. Objective: The aim of this article is to review the pharmacology, medication interactions, adverse events (AEs), and approved or investigational uses of PEG-IFN alfa-2a for viral hepatitis and oncologic conditions. Methods: Relevant articles were identified through searches of MEDLINE (1980-July 2003) and EMBASE (1980-July 2003). Search terms included, but were not limited to, peginterferon alfa-2a, pharmacohinetics, pharmacology, pharmacodynamics, and therapeutic use, as well as terms for specific disease states and AEs. Further publications were identified from citations of resulting papers. Results: Pegylation of IFN alfa-2a results in major changes in the pharmacokinetics of the product. Absorption is prolonged and serum concentrations are sustained over the dosing regimen. PEG-IFN alfa-2a has been shown to be more effective with or without ribavirin (RBV), in the management of treatment-naive patients with chronic HCV infection, than unmodified IFN alfa-2a with or without RBV. Results in other disease states are still preliminary. AEs are similar, in incidence and severity, to those occurring with unmodified IFN. They include earlier hematologic symptoms and fewer influenza-like symptoms. Drug-drug interactions are the same as those occurring with the unmodified IFN product. Conclusions: The pharmacokinetic profile of IFN alfa-2a is improved by pegylation, which enables less frequent administration and results in improved efficacy with a similar side-effect profile. Combination of PEG-IFN alfa-2a with RBV is associated with a greater chance of achieving a sustained virologic response in treatmentnaive patients with chronic HCV, compared with unmodified IFN alfa-2a/RBV combinations. Documentation of efficacy in other conditions awaits results of controlled clinical trials. (Clin 7her. 2004;26:991-1025). Copyright @ 2004 Excerpta Medica, Inc. Key words: peginterferon alfa-2a, pharmacokinetics, therapeutic use, adverse events. AcceptedJor publication April 29, 2004. Printed in the USA. Reproduction in whole or part is not pernfitted.

Copyright @ 2004 Excerpta Nedica, Inc.

0149 2918/04/$19.00

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INTRODUCTION

Interferon (IFN) alfa-2a is part of the family of related type I IFNs (or-multiple subtypes, ~-single form). 1 A major use, alone or with ribavirin (RBV), a synthetic guanosine analogue, is in the management of patients with chronic hepatitis C virus (HCV) infection, 2-* which affects up to 170 million people worldwide. 2,3 Approximately 60% to 85% and 10% to 15% of patients develop chronic infection and cirrhosis of the liver, respectively.5,6 These patients are at risk for hepatic failure and hepatocellular carcinoma (0%3% per year once cirrhosis is present). 5,6 Standard or unmodified IFN alfa is administered by the SC route, in a 3-times-weekly dosing regimen. Sustained virologic response (SVR), defined as an undetectable level of HCV RNA 6 months after the completion of therapy, is limited when unmodified IFN alfa is used alone; efficacy improves dramatically with the administration of RBV.2-<6 It is believed that the lack of efficacy may be due to the inability of the unmodified IFN alfa product to provide sustained inhibition of HCV.2 Patients who have an SVR usually do not suffer a relapse; they experience reduced liver pathology and have a decreased risk of developing hepatocellular carcinoma. 7-11 Peginterferon alfa-2a* joins a growing number of therapeutic agents that are pegylated by incorporation of a polyethylene glycol (PEG) moiety into the active product, n,13 Extensive reviews of the pegylation process have been published. 2,n,13 PEG-IFN alfa-2a is 1 of 2 available pegylated forms of IFN alfa (in addition to PEG-IFN alfa-2a, there is PEG-IFN alfa-2bt). Pegylation of the IFN alfa molecule is undertaken primarily to enhance the pharmacokinetic properties of unmodified IFN alfa, which enables once-weekly dosing. PEG-IFN alfa-2a was approved in October 2002 for the management of adults with chronic HCV who have compensated liver disease and have not been treated with IFN alfa previously. 1. In December 2002 it was approved for use with RBV~ for the same indication. Currently, the National Institutes of Health recommends the use of PEG-IFN alfa plus RBV in the treatment of chronic HCV infection. 6 Investigational use of *Trademark: Pegasus ® (Roche Pharmaceuticals, Nutley, New Jersey). *Trademark: PEG-Intron® (Schering Corporation, Kenilworth, NewJersey). *Trademark: Copegus ® (Roche hboratories, Nutley, New Jersey).

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PEG-IFN alfa-2a includes therapy for hepatitis B, chronic myelogenous leukemia, advanced renal cell carcinoma, and metastatic malignant melanoma. 1>19 This article reviews the pharmacokinetics of PEG-IFN alfa-2a, its approved and investigational uses, adverse events (AEs), and drug interactions associated with its use. HETHODS

Relevant articles were identified through searches of MEDLINE (1980-July 2003) and EMBASE (1980-July 2003). Search terms included, but were not limited to,

pegnterferon alfa-2a, pharmacokinetics, pharmacology, pharmacodynamics, and therapeutic use, as well as terms for specific disease states and AEs. Additional publications were identified from the reference lists of the resulting articles. Abstracts from national meetings included those presented at the 54th Annual Meeting of the American Association for the Study of Liver Disease, October 24-28, 2003, Boston, Massachusetts. CHEHISTRY

IFN alfa-2a is derived using recombinant DNA technology that involves inserting a cloned human leukocyte IFN gene into Escherichia coli. 1. To form the pegylated product, the IFN alfa-2a molecule is linked covalently to a single-branched bismonomethoxy PEG chain (40,000 daltons). This provides a combined molecule with a molecular weight of -60,000 daltons. Linkage of this chain to a single site on the IFN alfa molecule provides a stable amide bond to lysine, of which 4 major positional isomers have been noted. 2° PHARHACOKINETICS

This pharmacokinetic review includes comparisons between unmodified IFN alfa and PEG-IFN alfa-2a. Direct comparisons between PEG-IFN alfa-2a and PEG-IFN alfa-2b will be made where available. The pharmacokinetic parameters of PEG-IFN alfa-2a are depicted in Table I. Pharmacokinetic parameters are similar in male and female subjects receiving PEG-IFN alfa-2a. 1, PEG-IFN alfa-2a enables sustained absorption, limited volume of distribution, and a prolonged half-life, compared with unmodified IFN alfa-2a. 2,n,13 These properties make possible onceweekly dosing, stable blood concentrations throughout the dosing interval, and improved efficacy in the management of patients with chronic HCV, compared with unmodified IFN alfa-2a. 2,12,13

S.J.Matthews and C. McCoy

Table I. Pharmacokinetics of pegylated interferon alfa-2a.

Condition

Reference

No. of Subjects

Dose, (pg) SC

Cmax (ng/mL), mean (_+ SD)

Tm~× (h), mean (_+ SD)

Single dose

21 21 22 22

10~ 10~ 12~ 12b

90 (IV) 180 180
NR 14.2 (2.5) 10.3 (4.0) 9.1 (3.7)

NR 78 (27) 81 (23) 116 (36)

23 23

14c 16c

180f 180 h

15.4 (4.4) 25.6 (8.8) i

80 (28) 45 (36)

24

6a

90

5.6 (2.0)

24 25

6d 6

90 f 180f

4.7 (I.5) 18.1 (30)

Young Elderly Hultiple dose Renal function CLcr (>100 mUmin) 40 mUmin g CLcr> 20 mUmin Hemodialysis

TI/2 (h), mean (_+ SD)

CI/F (mdh), mean (_+ SD)

AUC (ng'h/mL)

60 (25) 82 (38) NR NR

NR NR 1295 (872)J 1663 (962)J

NR NR

83 (50) 60 (25)

1820 (586) k 3334 (994) k

81 (36)

76 (23)

118 (68)

653 (316) k

104 (14) 78 (24)

117 (68) 90 (25)

80 (22) 50 (34)

582 (177) k 2215 (29) k

68 77 61 II0

(3 I) (45) (37) (73)

CI/F = apparent body clearance;AUC = area under the concentration4ime curve; Clcr= creatinine clearance. ~Healthy adults. gPatients age >60 years. hMultiple dose. bHealthy elderly males. iCmax ~eady state. cPatients with chronic hepatitis C. dpatients with ~able chronic renal failure. JAUClast. ePatients age 18 25 years.

kAUC~I68'

fSingle dose.

Absorption

Unmodified IFN alfa is well absorbed, with a reported bioavailability of >80% when administered by the IM or SC routes. 21 Bioavailability of PEG-IFN alfa-2a after SC administration is 61%. 21 The absorption halflife of unmodified IFN alfa-2a and PEG-IFN alfa-2a is 2.3 hours and 50 hours, respectively, m The absorption half-life of unmodified IFN alfa-2b is 2.3 hours. 26 The time to achievement of maximum serum concentrations (Tmax) is markedly increased by pegylation compared with unmodified IFN. The Tmax for unmodified IFN alfa-2a varies from 7.3 to 12 hours. 21,2r-29 The mean Tmax of PEG-IFN alfa-2a is - 8 0 hours (Table I). These results were found in healthy adults and patients with compensated chronic HCV Near dose-proportional maximum serum concentrations (Cmax) of PEG-IFN alfa-2a were obtained at - 8 0 hours after the first dose (4.9 [2.5] ng/mL [90 pg dose] and 7.8 [0.7] ng/mL [180 pg dose]). 3° The manufacturer of PEG-IFN alfa-2a states that the Cmax and area under the concentration-time curve (AUC) are dose proportional. 1. In a multiple dose study of PEG-IFN alfa-2a (180 pg/wk), the mean initial Cmax, Tmax, and AUC were 15.4 ng/mL, 80 hours, and 1820 ng.h/mL, respectively. 2s After multiple dosing,

the mean Cmax, Tmax, and AUC were 25.6 ng/mL, 45 hours, and 3334 ng.h/mL, respectively (Table I). The increased Cmax likely reflects accumulation over time. No increase in serum concentrations occurred when steady state was achieved. 2s Absorption is delayed in healthy males >60 years of age (mean Tmax 116 hours for PEG-IFN alfa-2a), compared with a mean of 61 hours in healthy males 18-25 years old (Table I). The delayed absorption of IFN alfa-2a, in addition to the increased elimination half-life (see Elimination section), results in more constant plasma concentrations compared with unmodified IFN alfa. Limited data exist on the pharmacokinetics of PEG-IFN alfa-2a in children with chronic HCV. Schwarz et al sl presented data on the absorption of PEG-IFN alfa-2a after SC administration in 14 treatment-naive HCV-infected children. The children received PEG-IFN alfa-2a ([180 pg/1.73 m 2] X patient body surface area [BSA]) for 48 weeks with a 24-week follow-up period. Rapid and sustained absorption was noted after the first dose, with mean concentrations 24 and 96 hours after the dose of 22.3 + 8.2 ng/mL and 19.0 + 8.4 ng/mL, respectively. Steady-state concentrations were reached by week 993

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12 of therapy, and mean steady-state trough concentrations were 24.3 + 13.7 ng/mL. Distribution

The mean apparent volume of distribution of unmodified IFN alfa-2a and PEG-IFN alfa-2a are 31 to 73 L and - 6 to 14 L, respectively. 12,32 It is clear from the available data that PEG-IFN alfa-2a shows decreased distribution compared with unmodified IFN alfa-2a. Animal studies have shown that the highest concentrations of IFN alfa-2a occur in the blood and liver. 33 The limited distribution explains why PEG-IFN alfa-2a can be administered as a standard dose, rather than on a dose-per-weight basis. 32 Metabolism

Animal studies have found that unmodified IFN alfa is filtered by the glomeruli and reabsorbed in the proximal tubules. IFN alfa is broken down during reabsorption, and small amounts of unchanged IFN are found in the urine. 27 The liver plays a small part in the elimination of unmodified IFN alfa. 27 Additional catabolism may occur via interactions with cellular IFN receptors. 26 In contrast, animal studies showed that PEG-IFN alfa-2a is metabolized primarily by the liver) 3 Metabolic byproducts are eliminated in the urine and consist of fragments of IFN attached to segments of the PEG moiety.

alfa-2b is 6, whereas it is >40 for unmodified IFN alfa. 13 A recent study comparing the pharmacokinetics of PEG-IFN alfa-2a and -2b has been published in abstract form. 34 Following a 180-1~g/wk dose of PEGIFN alfa-2a, serum concentrations increased, reaching Cmax 48 tO 168 hours after dosing, and remained stable over time. In contrast, PEG-IFN alfa-2b (1.0-bt/kg dose concentrations) was undetectable in 30% and 78% of subjects after 120 and 168 hours, respectively. The effect of renal function on the pharmacokinetics of PEG-IFN alfa-2a has been studied. 2<25 The Cmax distribution and CI/F in subjects with stable chronic renal impairment are comparable to those in patients with normal renal function (Table 1). 21-25 Mean values for half-life, Cm~x, and Tma x a r e similar to those in healthy adults compared with patients on hemodialysis (Table I). The CI/F of PEG-IFN alfa-2a was 25% to 45% lower in patients on hemodialysis compared with subjects who had normal kidney function (Table 1). 14'24'25 Dose adjustment is necessary in patients with end-stage renal disease who are receiving hemodialysis. 14 Unmodified IFN alfa and PEG-IFN alfa-2a are not appreciably cleared by hemodialysis. 25,35,36 The prolonged half-life, reduced C1/E, and tight peak-totrough ratio translate into sustained serum concentrations throughout the dosing interval for PEG-IFN alfa-2a.

Elimination

With a half-life ranging between 4 and 16 hours, 27 unmodified IFN alfa is rapidly eliminated from the body. Mean apparent clearance (C1/F) varies from 4.86 to 21 L/h. 27 The half-life of PEG-IFN alfa-2a varies from a mean of 61 to 110 hours and the C1/F varies from 60 to 118 mL/h in subjects with stable renal function (Table I). The half-life of IFN alfa-2a was found to be increased in elderly subjects; however, an accurate half-life determination may not have been possible because of the prolonged absorption t i m e . 22 Steady-state concentrations of PEG-IFN alfa-2a occur after 5 to 8 weeks of weekly administration. 23 The peak-to-trough concentration (before the next dose) of PEG-IFN alfa-2a at 48 weeks of therapy ranges from 1.5 to 2.0.14,23 Trough concentrations after 48 weeks of therapy are approximately twice as high as after 1 week of PEGIFN alfa-2a.14 The peak-to-trough ratio for PEG-IFN 994

MECHANISM

OF ACTION

The precise mechanism of action has not been determined for IFN alfa products. IFN alfa has been shown to induce antiviral and immunomodulatory actions in stimulated cells. 1,3r Much of the investigation into the mechanism of action has revolved around the use of IFN alfa in the management of patients with chronic HCV. One hypothesis is that IFN alfa binds to a common receptor site on the surface of target cells. This interaction sets off a series of steps that results in the formation of IFN-stimulated gene (ISG) factor 3. 37 This factor then binds to the IFN-stimulated response element of cellular genes called ISGs, ultimately resulting in synthesis of ISG products. Animal studies have shown that HCV and reproduction cause the expression of ISGs. 38'39 IFN alfa stimulates the release of more than 20 effector proteins, including protein kinase, Mx proteins, RNA-specific adenosine deami-

s.j. Matthews and C. McCoy

nase, and others. *°-.2 The biologic effect of these ISG products is responsible for the therapeutic impact of IFN alfa on HCV..3,** Kamal et a1.5 studied the immunomodulatory effect of IFN alfa-2a in 42 patients with HCV The mean patient age was 42.0 (9.5) years and included 25 male (M) and 17 female (F) subjects. Twelve of 14 patients in each group were infected with HCV genotype 1. Researchers investigated the effect of unmodified IFN alfa-2a* (n = 14, group A) and PEG-IFN alfa-2a with (n = 14, group B) or without RBV (n = 14, group C) on HCV-specific CD4 + T-helper cell and cytokine responses. HCV-specific IFN gamma (IFN- 7) production, a marker of Thl activity, and interleukin 4 (IL-4) production, a marker of Th2 activity, were the primary cytokines measured in the study. The main therapeutic end point was the achievement at the end of the study of an SVR in 14%, 42%, and 57% of patients in groups A, B, and C, respectively (P = 0.001, group A vs B; and P < 0.001, group A vs C). The initial strong CD4 + T-cell response to HCV proteins, decline in HCV titers, and increase in IFN- T production at the higher dose (3 X 6 MIU/wk) of unmodified IFN alfa-2a were not sustained when the dose was lowered to 3 MIU 3 times/wk. Patients responding to PEG-IFN alfa-2a (with or without RBV), however, maintained a strong HCV-specific CD4 + T-cell response and consistently reacted to core and nonstructural antigens compared with patients receiving unmodified IFN alfa-2a (P < 0.001). After the initiation of therapy, an increase in the number of IFN-y-producing cells and a decrease in the number of IL-4-producing cells were noted in 6 of 14 patients in group A (P value not provided). A Thl cytokine pattern (increase in number of IFN- Tproducing cells in response to HCV antigens) was noted in patients receiving PEG-IFN alfa-2a (with or without RBV). This response was sustained in patients achieving an SVR. A significant production of IL-4 was not detected at any time after treatment in groups B or C (P value not provided). The authors concluded that the higher rate of SVR in patients receiving PEG-IFN alfa-2a (with or without RBV) was a result of the drug's ability to induce a strong sustained HCVspecific CD4 + Thl response. .5 They propose that the observed improvement in HCV-specific CD4 + *Trademark: Roferon ® (Roche Laboratories, Nutley, New Jersey).

Thl response, with combined PEG-IFN alfa-2a and RBV administration, results from a restored antigenpresenting function of dendritic cells. .6 RBV combined with PEG-IFN alfa-2a significantly improves the possibility of achieving an SVR in patients with chronic HCV infection compared with unmodified IFN alfa with RBV or PEG-IFN alfa-2a alone. *<.7 Although RBV has no direct antiviral effect against HCV, studies have shown an improvement in serum alanine aminotransferase (ALl) concentrations when used as monotherapy in patients with chronic HeM. "+8''+9 Significant histologic improvement in liver biopsy results has been noted by some, but not all, investigators. .8,.9 The exact mechanism of action of RBV, when combined with IFN alfa therapy, is unknown; however, several hypotheses have been proposed. Meier et aP ° postulated that RBV inhibits DNA, RNA, and protein synthesis, which leads to a decrease in synthesis of proinflammatory cytokines, such as IFN, and induces apoptosis of cells in the inflammatory infiltrate in the infected liver. The proposed modulation of the Thl/Th2 cytokine-mediated immune response, with an emphasis on the type 1 cytokine profile, is consistent with results presented above with combined therapy with PEG-IFN alfa2a. .5,51,52 The mutagenic activity of RBV on HCV has also been proposed as a possible mechanism. 53 PHARMACODYNAMICS

Neopterin and 2',5'-oligoadenylate synthetase (OAS) concentrations are noted to rise in patients receiving PEG-IFN alfa-2a. 1. Neopterin concentrations reflect activation of cellular immunity. 5. OAS has been used as a marker of IFN alfa antiviral activity in patients with chronic HCV.2<55 OAS fell quickly after reaching maximal concentration (24 hours after a dose) for unmodified IFN alfa-2a, but remained near peak concentrations throughout the 1-week dosing interval for PEG-IFN alfa-2a. 56 Patients with the lowest creatinine clearance (<40 and >20 mL/min) or who were elderly (>60 years) receiving PEG-IFN alfa-2a experienced reduced Cmax and area between the effect curve of OAS compared with those with better renal function (creatinine clearance >40 mL/min) and patients between 18 and 25 years. 22,2. This finding indicates that these subjects may be less sensitive to PEG-IFN alfa-2a stimulation of OAS production. The clinical significance of these findings is unknown. 995

CLINICALTHERAPEUTICS®

Zeuzem et al 5r compared the viral kinetics of unmodified IFN alfa-2a and PEG-IFN alfa-2a in 33 patients with chronic HCV. Patients (n = 16, group A) received 6 million units (MU) of unmodified IFN alfa2a, 3 times/wk by the SC route for 12 weeks. The dose was subsequently decreased to 3 MU, 3 times/wk for another 36 weeks. PEG-IFN alfa-2a was administered by SC injection at a dosage of 180 t~g/wk for 48 weeks (n = 17, group B). Patients were well matched for age (group A, 41 [11]; group B, 42 [11]); and M/F ratio (group A, 11/5; group B, 13/4). An SVR was defined as undetectable serum HCV RNA levels 24 weeks after therapy completion. A first-phase decline in HCV RNA was noted in 79% and 76% of patients receiving unmodified IFN and PEG-IFN alfa-2a, respectively. This response was noted within 48 hours of initiation of IFN therapy. Fluctuations of viral load occurred in most patients treated with unmodified IFN alfa-2a. Increases in viral load occurred after 24 hours in most patients receiving unmodified IFN alfa-2a, but in only 2 of those in the PEG-IFN alfa-2a group. The reduction of viral load was similar between the 6 MU of unmodified IFN-2a and PEG-IFN alfa-2a during the first 48 hours. The first phase of viral decline was rapid and thought to reflect the degradation rate of free virus. 58,59 After 24 to 48 hours, the viral decline slowed and a second phase of HCV RNA decay was noted. Patients were divided into 3 groups, depending on the pattern of second-phase HCV RNA decline: flat, slow, or rapid. No patient in either group with an initial flat second-phase HCV RNA decline achieved an SVR. The likelihood of achieving an SVR was higher in slow and rapid responders treated with PEG-IFN alfa-2a (56%) than in those receiving unmodified IFN alfa-2a (36%) (no P value available). The secondphase decline was thought to reflect the degradation rate of infected cells. 58,59 Others have proposed that the second phase may reflect the elimination of virus from infected hepatocytes. 6° The first and second phase of HCV RNA decline was significantly steeper if the patient had been infected with a non-HCV 1 genotype, rather than an HCV 1 strain of virus (P = 0.045 and P < 0.001, respectively.) The response likely reflects the greater susceptibility of the non-HCV 1 genotypes (HCV 2, HCV 3) to the actions of IFN alfa2a.
The effect of the addition of RBV to therapy on HCV viral kinetics with unmodified IFN alfa-2a and PEG-IFN alfa-2a has been explored. Herrmann et a161 studied the effect on the viral kinetics of adding RBV in 34 patients receiving PEG-IFN alfa-2a treatment for chronic HCV infection (genotype 1). Patients were randomly assigned to receive unmodified IFN alfa-2b* 3 times/wk, plus RBV (n = 7, group A, 49 [9] years of age, 43% M), or 180 l~g of PEG-IFN alfa-2a administered once/wk with (n = 10, group B, 47 [13] years of age, 70% M) or without RBV (n = 17, group C, 43 [9] years of age, 82% M). The length of therapy was 48 weeks in all groups and RBV was given at a dose of between 1000 (<75 kg) and 1200 mg (>75 kg) daily, depending on body weight. Attainment of an end-of-treatment response (ETR) of undetectable serum HCV RNA level and an SVR were the primary therapeutic end points. In addition to the 2 phases discussed above (similar for all treatment groups), the authors noted a third phase of viral decay in 4 of 7 in group A; 8 of 9 in group B; and 9 of 16 in group C. Viremia increased in 6 patients during the second phase and an SVR was noted in 14%, 50%, and 12% in group A, group B, and group C, respectively. The difference among the 3 groups was not significant (P = 0.63). In this study, the first phase was attributed to the clearance of free virus and the second phase represented the loss of pretreatment infected cells. The third phase of viral decline began about 7 to 28 days after therapy was initiated and was observed in 61% of patients. The third phase, kinetic parameters, derived from all 3 treatment groups, showed the best predictive value for an ETR (P = 0.001) but did not achieve significance for SVR (P = 0.11). The authors attributed the third phase to a treatment-enhanced loss of HCVinfected cells and observed that this phase was more pronounced in patients receiving PEG-IFN alfa-2a with RBV compared with PEG-IFN alfa-2a alone (P = 0.02). The authors propose that the increased SVR in patients receiving combined PEG-IFN alfa-2a and RBV was due to the ability of the latter to enhance the immune clearance of infected cells. Neumann et a162 noted a variety of HCV viral decay patterns in treatment-naive patients taking PEG-IFN *Trademark: Rebetron® (Schering-Plough Corporation, Kenilworth, New

Jersey).

S.J.Matthews and C. McCoy

alfa-2a and RBV. Patients were categorized by response to therapy, with a rapid viral response (RVR) defined as a second slope faster than 0.3 log IU/mL per wk. Ninety-two percent of patients (n = 60) infected with HCV genotype 2 or 3 had a biphasic viral decline pattern compared with 44% of patients with genotype 1 (n = 104). A delayed response (<0.5 log IU/mL) after the first week without a viral decline occurred in 5% and 18% of genotype 2 or 3 and genotype 1 patients, respectively. A triphasic pattern was noted in 3% of patients with genotype 2 or 3 and 38% of patients infected with genotype 1. Patients with genotype 2 or 3 had an RVR (100%) regardless of initial viral decline pattern. Patients with genotype 1 had an RVR of 100% with biphasic decline, 62% with triphasic decline, and 16% with delayed decline. Pawlotsky et al 6s compared the viral kinetics in patients (n = 270) infected with HCV genotypes 1, 3, and 4 (n = 14). The HCV RNA serum levels were monitored during the first 4 weeks of therapy with PEG-IFN alfa-2a 180 pg/wk plus RBV (10001200 mg/d). Patient groups were well matched for baseline characteristics. Early viral kinetics were similar between HCV genotypes 1 and 4 but were significantly different for HCV genotype 3 compared with HCV genotypes 1 and 4 (P < 0.05). A triphasic decay pattern was more frequent in HCV 1 and 4 compared with genotype 3. The authors concluded that the early viral kinetics of HCV 4 are similar to that of genotype 1 in patients treated with PEG-IFN alfa-2a plus RBV. Zeuzem et al 6. performed a study to determine whether individualizing therapy for chronic HCVinfected patients, based on early viral responses to treatment, increased the likelihood of achieving an SVR, defined as undetectable serum HCV RNA (<50 IU/mL) 24 weeks after the end of therapy. The study included 273 patients who received PEG-IFN alfa-2a (180 pg/wk) and RBV (1000-1200 mg/d based on body weight) for 6 weeks. Patients (n = 270) were then randomized into 1 of 6 groups, based on the observed viral kinetics for an additional 42 weeks. Group A was divided into 2 subgroups (A1 and A2), both of which included rapid viral responders with an HCV RNA decline of at least 99% during the first month of treatment. For group A1, RBV was discontinued, and for group A2, treatment was shortened to 24 weeks. Group B was divided into 2 subgroups (B1 and B2), both of which included slow partial respond-

ers, undefined by criteria. For group B1, histamine was added to therapy, and for group B2, treatment was prolonged to 72 weeks. Group C included fiat partial responders, undefined by criteria, and histamine was added to therapy. Nonresponders were assigned to group D and were re-treated with PEGIFN alfa-2a 360 pg/wk plus RBV. The standard treatment group continued PEG-IFN alfa-2a (180 pg/wk) and RBV (1000-1200 mg/d based on body weight) for the remaining 42 weeks. The authors stated that the groups were similar in characteristics and baseline serum viral concentrations. Overall comparison of those infected with HCV genotype 1 showed that 49% and 56% of patients had an SVR in the individualized and standard therapy groups, respectively (P = NS). Similarly, in patients with HCV genotype 2 or 3, 90% (individualized) and 87% (standard treatment) experienced an SVR (P = NS). Interestingly, in the rapid responder groups (A1, A2, and standard), 79%, 65%, and 79% of patients, respectively, with HCV genotype 1 showed an SVR. Patients with HCV genotype 2 or 3 (A1, A2, and standard) had an SVR of 89%, 95%, and 89%, respectively. It appears from this study that individualized therapy was no better than standard therapy in the management of patients. More studies with larger numbers of patients will be necessary to determine whether the observed efficacy of early discontinuation of RBV in patients who are rapid responders is reproducible. Direct comparisons of the 2 pegylated products as they relate to viral HCV RNA kinetics are limited. Bruno et al 6s compared the effect of PEG-IFN alfa-2a and PEG-IFN alfa-2b on the viral HCV RNA kinetics in 22 patients with chronic HCV Ten patients received 180 pg/wk of PEG-IFN alfa-2a and 12 received 1.0 pg/kg of PEG-IFN alfa-2b once/wk. All patients received RBV at a dosage between 1000 and 1200 mg/d. Viral HCV RNA load did not differ between the 2 groups for weeks 1 and 4. However, by week 12, the viral load was significantly lower for the PEG-IFN alfa-2a group compared with the PEG-IFN alfa-2b group (P < 0.01). T H E R A P E U T I C USE Hepatitis C Infection

The major therapeutic use of PEG-IFN has been in the treatment of patients with chronic HCV infection.

997

CLINICALTHERAPEUTICS®

HCV is an RNA virus and a member of the flavivirus group. Six HCV genotypes and more than 50 subtypes may cause human disease. 3,6 The prevalence of HCV genotypes varies worldwide with the following associations: genotypes la and lb are most common in western Europe (85%-90%) and the United States (80%), followed by genotypes 2 and 3; genotype 4 prevails in Egypt; genotype 5 in South Africa; and genotype 6 in Southeast Asia) It is important to determine which genotype is infecting a patient because the response to therapy is genotype dependent. Patients infected with genotype 2 or 3 respond better to therapy than those infected with genotype 1. 3,66 Definitions of therapy efficacy are as follows, with any deviations noted in the individual studies. An SVR is defined as an undetectable HCV RNA level at week 72 (24 weeks off therapy). A biochemical ETR is defined as a normalization of serum ALT concentrations to a level at or below the upper limit of normal (ULN) after 48 weeks of therapy; a sustained biochemical response is a normalization of serum ALT concentrations to a level at or below ULN at 72 weeks. A histologic response is defined as a >2-point decrease in the total histologic activity index (HAI) between liver biopsies obtained at baseline and at week 72.

Monotherapy with Pegylated Interferon Alfa-2a Reddy et a167 compared the efficacy and safety of PEG-IFN alfa-2a with unmodified IFN alfa-2a in patients with chronic HCV infection without cirrhosis. Patients had not received prior therapy for HCV infection. The trial was an open-label, randomized study performed in the United States and multiple centers. Patients were assigned to receive PEG-IFN alfa-2a once-weekly doses of 45 l~g (n = 20, 41.9 [4.8] y, 65% M, 90% white [W], 10% black [B]); 90 big (n = 20, 43.1 [6.7] y, 70% M, 95% W, 5% Asian [A]); 180 l~g (n = 45, 42.0 [6.4] y, 82% M, 89% W, 9% B, 2% other); or 270 big (n = 41, 41.6 [5.7] y, 85% M, 88% W, 10% B, 2% other) or 3 MU 3 times/wk of unmodified IFN alfa-2a (N = 33, 41.8 [5.9] y, 79% M, 79% W, 12% B, 3% A, 6% other), all administered SC for 48 weeks. Therapeutic end points included SVR, sustained biochemical response, histologic response, and virologic and biochemical responses at the end of 48 weeks of treatment. Efficacy was determined on an intent-to-treat basis. Genotype analysis of HCV was 998

performed on all patients and revealed a predominance of HCV genotype 1. Patient groups were fairly well matched; however, the unmodified IFN alfa-2a group had a higher baseline HCV RNA concentration, a greater proportion of genotype 1, and more patients with bridging fibrosis than the PEG-IFN alfa-2a treated groups. These differences may explain the lower response to therapy in the group. Partial results of the study are listed in Table TT. Of the 159 randomized patients, 122 completed 48 weeks of therapy. Reasons for study discontinuation were not discussed, except for dropouts resulting from AEs. The likelihood of achieving an SVR was significantly higher in patients receiving PEG-IFN alfa-2a above the 45 txg dose compared with unmodified IFN alfa-2a (90 l~g, P = 0.009; 180 l~g, P = 0.001; 270 l~g, P = 0.004). The chance of achieving an SVR increased maximally in patients receiving the 180 l~g dose (36% of patients) (Table TT). As expected, patients infected with genotype 1 did not achieve an SVR as frequently as those infected with non-HCV 1 genotypes. More specifically, 31% of subjects infected with genotype 1 virus had an SVR compared with 50% of those infected with non-HCV 1 genotypes when treated with the PEG-IFN alfa-2a 180 l~g dose. The chance of achieving a sustained biochemical response increased in a dose-related manner from the 45 txg to the 180 txg dose (Table TT). Thirty-eight percent of patients receiving the 180 l~g dose achieved a sustained biologic response compared with 9% with unmodified IFN alfa-2a (P = 0.004). Virologic response at the end of 48 weeks was statistically different for PEG-IFN alfa-2a doses above 45 big (90 big, P = 0.01; 180 big, P = 0.001; 270 big, P = 0.001) compared with unmodified IFN alfa-2a. Sixty percent and 56% of subjects had undetectable HCV RNA concentrations at 48 weeks in the PEGIFN alfa-2a doses of 180 l~g and 270 l~g, respectively (Table TT). The biochemical response at week 48 was significantly different only for the PEG-IFN alfa-2a dose of 180 l~g compared with unmodified IFN alfa-2a (P = 0.04). Histologic response was noted in all but 2 subjects (270 big PEG-IFN alfa-2a group) who also achieved an SVR. This occurred despite persistent elevation of serum ALT. A histologic response (88 patients with paired biopsy samples) occurred in 55% of patients receiving unmodified IFN alfa-2a and 42% to 60% receiving PEG-IFN alfa-2a, even though they did

s.j. Matthews and C. McCoy

Table II. Management of chronic hepatitis C virus (HCV) infection peginterferon (PEG-IFN) alfa-2a monotherapy.

Reference

Therapy*

Dose

No. of Patients

Biochemical Response IIIT

Reddy et a167

IFN PEG-IFN PEGqFN PEG-IFN PEG-IFN IFN

3 NUt 45 iJg$ 90 iJg$ 180 iJg$ 270 IJg$ 3 NUt

33 20 20 45 41 88

10 25 38 27 15

90 yg$

Heathcote et al6s

PEG-IFN Zeuzem et a169

9

BVRII

Virologic ETR (%)#

SVR (%)**

NA NA NA NA NA 8

12 30 45 60 56 14

3 10 30 36 29 8

96

20

15

42

15

PEGqFN IFN

180 IJg$ 6 NU, 3 NU§

87 264

34 25

30 17

44 28

30 19

PEGqFN

180 yg$

267

45

38

69

39

BVR = biochemical and virologic response; ETR = end-of-treatment response; SVR = sustained virologic response; NA = not available. *Interferon alfa-2a. %C administration 3 times weekly for 48 weeks. $SC administration once weekly for 48 weeks. §SC administration of 6 NU 3 times weekly for 12 weeks followed by 3 NU 3 times weekly for 36 weeks. IIAt 72 weeks. ITAn alanine aminotransferase value below the upper limit of normal at the end of the follow-up period.

#Undetectable levels of HCV RNA at the end of 48 weeks oftherap~z ~Undetectable levels of HCV RNA at the end of the follow-up period (72 weeks).

not experience an SVR. In general, AEs were similar in the treatment groups, with some exceptions. Irritability (20%-35% vs 13%), depression (27%38% vs 10%), and pruritus (10%-15% vs 3%) occurred more commonly in the PEG-IFN alfa-2a groups, and myalgia (63% vs 3%-65%) and dizziness (23% vs 10%-20%) were reported more often in the unmodified IFN alfa-2a group. Median platelet and neutrophil count decreased in a dose-dependent manner in the PEG-IFN alfa-2a groups. The likelihood of having therapy discontinued due to AEs and laboratory changes was higher in the PEG-IFN alfa-2a groups (9% unmodified IFN alfa-2a compared with 10%, 0%, 22%, and 20% for PEG-IFN alfa-2a 40 pg, 90 pg, 180 pg, and 270 pg, respectively). Heathcote et a168 investigated the utility of PEGIFN alfa-2a in patients with chronic HCV infection and cirrhosis, or bridging fibrosis, using an openlabel, randomized, parallel-dose design. Patients who were treatment-naive were assigned to receive either PEG-IFN alfa-2a 90 pg (n = 96, 47.2 [8.4] )7, 74% M, 91% W, 1% B, 2% A, 6% other) or 180 pg (n = 87, 47.1 [8.7] y, 72% M, 86% W, 6% B, 2% A, 6% other) administered once weekly or 3 MU of unmodified IFN alfa-2a 3 times/wk (n = 88, 46.9 [7.6], 70% M,

88% W, 6% B, 3% A, 3% other) (Table II). All medications were administered via the SC route. Efficacy criteria were identical to those utilized in the study by Red@ et al. 67 Efficacy was determined on an intentto-treat basis except for histologic response. All 3 groups had similar baseline characteristics. Of the 271 randomized patients, 209 and 221 completed 48 and 72 weeks of the study, respectively. Reasons for not completing the study included AEs, refusal of therapy or failure to return, lack of benefit, and adverse laboratory effects. An SVR was noted in 8% (unmodified IFN alfa-2a) and 15% and 30% (PEGIFN alfa-2a 90 pg and 180 pg, respectively) of treated patients (Table II). The difference in SVR was statistically significant between the 180 pg dose of PEG-IFN alfa-2a compared with unmodified IFN alfa-2a (P = 0.001). The chance of achieving an SVR was lower in patients infected with HCV genotype 1 than in those infected with non-HCV-1 or unknown genotype. An SVR occurred in 2% (unmodified IFN alfa-2a), 5%, and 13% (PEG-IFN alfa-2a 90 pg and 180 pg, respectively) of those subjects infected with genotype 1. The SVR was 15% (unmodified IFN alfa-2a), 29%, and 51% (PEG-IFN alfa-2a 90 pg and 180 pg, respectively) in patients infected with 999

CLINICALTHERAPEUTICS®

non-HCV-1 or unknown genotype. The virologic response at 48 weeks was significantly different for the 2 PEG-IFN alfa-2a doses compared with unmodified IFN alfa-2a (P = 0.001) (Table TT). Biochemical response at 72 weeks was significantly different for the 180 l~g PEG-IFN alfa-2a dose (34%) compared with unmodified IFN alfa-2a (15%) (P = 0.004). The percentage of patients experiencing a combined virologic and biochemical response at 72 weeks was the same as that for the virologic response (Table TT). Of those patients who had paired liver biopsies (N = 184), the histologic response was significantly different for those subjects receiving the PEG-IFN alfa-2a 180 l~g dose compared with unmodified IFN alfa-2a (P = 0.02). Patients who achieved an SVR also had a histologic response (80% unmodified IFN alfa-2a; 100% and 88% PEG-IFN alfa-2a 90 l~g and 180 l~g, respectively). Patients who did not achieve an SVR experienced a histologic response at a rate of 26% (unmodified IFN alfa-2a), 33%, and 36% (PEG-IFN alfa-2a 90 l~g and 180 l~g). A randomized study performed by Pockros et alr° compared the efficacy of 2 doses of PEG-IFN alfa-2a with unmodified IFN alfa-2a in patients with chronic HCV infection. No patients had received prior therapy for HCV infection. Patients were assigned to receive PEG-IFN alfa-2a doses of either 180 l~g (n = 210, group A) or 135 txg (n = 215, group B) administered once weekly, or 3 MU 3 times/wk of unmodified IFN alfa-2a (n = 214, group C). All patients were treated for 48 weeks with treatment end points including SVR and histologic response, as defined above. Data were analyzed on an intent-to-treat basis. A majority of patients in each group were infected with HCV genotype 1 and proportions were similar in each group (group A, 71%; group B, 65%; and group C, 65%). An SVP, was achieved in 28%, 28%, and 11% of patients treated with PEG-IFN alfa-2a 180 l~g, 135 l~g, and unmodified IFN alfa-2a, respectively (P = 0.001). Subgroup analysis of subjects infected with HCV genotype 1 revealed an SVR in 22%, 19%, and 7% of patients in the PEGIFN alfa-2a groups and unmodified IFN group, respectively (P = 0.001 for the PEG-IFN 180 l~g group compared with the unmodified IFN group; and P = 0.002 for the PEG-IFN 135 txg group compared with the unmodified IFN group). Histologic response was identified in 58%, 48%, and 45% of patients treated with PEG-IFN alfa-2a 180 l~g, 135 l~g, and unmodified IFN 1000

alfa-2a, respectively (P = 0.017 for the PEG-IFN 180 l~g group compared with unmodified IFN group). Zeuzem et a169 performed a Phase III, randomized, open-label study comparing PEG-IFN alfa-2a with unmodified IFN alfa-2a in treatment-naive patients with chronic HCV infection. Patients in the unmodified IFN alfa-2a group received 6 MU 3 times/wk for 12 weeks, followed by 3 MU 3 times/wk for an additional 36 weeks. Patients in the PEG-IFN alfa-2a group received a 180 l~g dose each week for 48 weeks. The definitions of efficacy were the same as those cited in the studies mentioned above. 67,68 Except for histologic response, the analysis of efficacy was based on an intention to treat. A majority of patients in each group were infected with HCV genotype 1, and other baseline characteristics between the 2 groups were similar. Mean (SD) baseline patient ages were 41.0 (9.2) and 40.6 (10.3) years in the unmodified IFN alfa-2a and PEG-IFN alfa-2a groups, respectively. Sixty-seven percent of subjects were male in both groups. In the unmodified IFN alfa-2a and PEG-IFN alfa-2a groups, the study population comprised 85% and 86% W, 2% B (both groups), 10% and 9% A, and 3% other ethnicities (both groups), respectively. Five hundred thirty-one patients were randomized and 360 completed the study; 161 completed 48 weeks on unmodified IFN alfa-2a, and 154 completed the follow-up period, while 223 subjects completed 48 weeks and 206 the follow-up period in the PEG-IFN alfa-2a group. Major reasons for dropout were failure to comply with therapy, poor therapeutic response, refusal of therapy, AEs, and adverse laboratory events. An SVR was achieved in 39% of patients in the PEG-IFN alfa-2a group, compared with 19% in the unmodified IFN alfa-2a group (P = 0.001) (Table TT). Twenty-eight percent of subjects infected with HCV genotype 1 had an SVR on PEG-IFN alfa-2a therapy. The percentage of patients experiencing a sustained biochemical response was 45 and 25 for the PEG and unmodified IFN alfa-2a groups, respectively (P = 0.001). The ETR virologic and combined biochemical and virologic responses were significantly different in the PEG group than in the unmodified IFN group (P = 0.001) (Table TT). Of subjects who did not have a virologic or biochemical response, 44% to 47% had a histologic response at week 72.

S.J. Matthews and C. McCoy

These 4 randomized trials demonstrate that PEGIFN alfa-2a regimens (135 pg and 180 pg dose/wk) are statistically more likely than unmodified IFN alfa2a to induce an SVR in patients with chronic HCV infection with or without cirrhosis of the liver. 6r-r° SVRs varied from 28% to 39% for those patients receiving the PEG-IFN alfa-2a 180 pg/wk dosage compared with 3% to 19% in the unmodified IFN group (Table 11)70 These studies demonstrate that the 180 pg/wk dosing regimen is associated with the best outcome compared with the other doses studied. 67-7° Although the 135 pg dose achieved the same SVR as the 180 pg dosing regimen, the histologic response was no different from that of unmodified IFN alfa-2a. 7° Based on these results, the manufacturer recommends the 180 pg/wk dosage initially for patients receiving PEG-IFN alfa-2a. 1~ Interestingly, even patients who have had a relapse after an ETR, or no response, may experience a histologic response. This result indicates that treatment may be beneficial, regardless of whether or not an SVR is achieved. Patients on IFN therapy who experience an ETR usually relapse at 4 and 8 weeks after medication discontinuation. 71 Relapse rarely occurs if a patient remains HCV negative for 12 weeks or more. 7~ The chance of achieving an SVR in patients infected with HCV genotype 1 varied from 13% to 31% for 180 pg PEG-IFN alfa-2a compared with 0%-15% for unmodified IFN alfa-2a. 67-69 In patients infected with non-HCV 1 or unknown genotype, the response was approximately 41% to 50% in the 180 pg PEG-IFN alfa-2a groups. 67,68 No direct comparison between PEG-IFN alfa-2a or -2b has been performed. Direct comparisons between these 2 products will be necessary to determine comparative efficacy and safety. HEALTH-RELATED Q U A L I T Y O F LIFE AND COST-EFFECTIVENESS ANALYSIS: I

Rasenack et a172 have compared the effect of PEG-IFN alfa-2a with unmodified IFN alfa-2a on the healthrelated quality of life (QOL) of treated patients. To measure fatigue, the 10-item Fatigue Severity Scale (FSS), including the visual analog scale (VAS) for fatigue severity, was used. rs The Short-Form Health Survey (SF-36) was employed to measure health-related QOL. 7~ Both assessment tools were administered before each physician visit at weeks 2, 12, 24, 48, and

72. Mean scores (FSS and SF-36) were analyzed over the 48 weeks of treatment, using repeated-measures, mixed-model analyses of covariance (ANCOVAs). Two hundred sixty-seven patients received 180 pg/wk of PEG-IFN alfa-2a and 264 received unmodified IFN alfa-2a 6 MIU 3 times/wk for 12 weeks, followed by 3 MIU 3 times/wk. Both treatments were continued for a total of 48 weeks. The PEG-IFN alfa-2a group had better (P < 0.01) mean FSS total scores at weeks 2, 12, and 24 and FSS VAS scores (P < 0.01) at weeks 2, 12, and 48 versus the unmodified IFN alfa-2a group. At week 2, the mean SF-36 domain scores were (P < 0.01 to P < 0.05) better in all 8 domains for the PEG-IFN alfa-2a group, compared with the subjects taking unmodified IFN alfa-2a. At week 12, the mean SF-36 domain scores were (P < 0.01 to P < 0.05) better in 7 of 8 domains for the PEG-IFN group compared with the subjects taking unmodified IFN. The SF-36 scores for weeks 24 and 48 were not statistically different for the 2 groups. The mean FSS and SF-36 scores were (P < 0.001 to P = 0.021) improved in patients who achieved an SVR compared with those who did not experience an SVR. Differences in the SF-36 scores of 5 or more points (PEG-IFN alfa-2a over unmodified IFN alfa-2a) were noted in the domains of vitality, bodily pain, and mental health, making them clinically and socially relevant. 7~ Differences in the SF-36 scores of 10 points (PEG over unmodified IFN) were noted in the domains of role limitations (physical and emotional), making these clinically meaningful. 7~ Patients treated with PEG-IFN alfa-2a demonstrated improved health-related QOL compared with those receiving unmodified IFN alfa-2a, experiencing less fatigue and body pain as well as being better able to perform on a daily basis. Kim and Poterucha 7s recently performed a costbenefit analysis using data from a previously published study of PEG-IFN alfa-2a monotherapy for patients with chronic HCV infection. Three thousand subjects with compensated chronic HCV infection were included in the computer model. Patients were divided into 2 groups--the first receiving PEG-IFN alfa-2a therapy for 48 weeks, and the second receiving no therapy. Projections for disease progression, complications, and premature discontinuation of therapy were programmed into the simulation. Ten years after therapy discontinuation, patients in the PEG-IFN group had a reduced risk of hepatic decom1001

CLINICALTHERAPEUTICS@

pensation (2%-7%) and hepatocellular carcinoma (3%). A reduction of mortality due to disease was noted in 2% and 10% of patients treated with PEGIFN alfa-2a for genotype 1 and other genotypes, respectively. Cost savings of $2600 (genotype 1) and $10,900 (other genotypes) were noted for avoidance of future hepatic decompensation or hepatocellular carcinoma. The authors concluded that the use of PEG-IFN alfa-2a for patients with compensated chronic HCV infection was cost-effective, especially in subjects infected with non-HCV-1 genotypes. C O M B I N A T I O N T H E R A P Y W I T H PEGYLATED I N T E R F E R O N A L F A - 2 A A N D RIBAVIRIN

Fried et al~7 conducted a randomized controlled study to compare the efficacy and safety of PEG-IFN alfa-2a with unmodified IFN alfa-2b, both combined with RBV, in the management of patients with chronic HCV infection. All patients were treatment-naive to IFN. Patients were assigned to receive PEG-IFN alfa-2a 180 l~g/wk plus RBV (n = 453, 42.8 [10.1] y, 72% M, 82% W, 6% B, 6% A, 6% other); 3 MU of unmodified IFN alfa-2b, 3 times/wk plus RBV (n = 444, 42.3 [9.6] y, 73% M, 87% W, 3% B, 5% A, 5% other); or PEG-IFN alfa-2a 180 txg/wk plus placebo (n = 224, 67% M, 83% W, 6% B, 5% A, 6% other) for 48 weeks. RBV was adjusted according to the patient's body weight and administered twice daily for 48 weeks (1000 mg if <75 kg, or 1200 mg if >75 kg). Patients were randomized according to HCV genotype and country of origin. The primary end point was achievement of an SVR. An ETR, as defined above, was also reported. Subjects who received at least 1 dose of medication were included in the analysis of efficacy. Patients who were available for at least 1 safety evaluation after baseline were eligible for the safety assessment. Of the 1149 patients who were randomized, 1121 received at least 1 dose of medication. Failure to meet the inclusion criteria or refusal to comply with the protocol or administrative issues resulted in exclusion from the study. Patient characteristics were similar at baseline. Sixty-nine percent of patients receiving PEG-IFN alfa-2a plus RBV experienced an ETR compared with 52% taking unmodified IFN alfa-2b plus RBV (P < 0.001). The ETR was also significantly different for the PEG-IFN alfa-2a/RBV group compared with the placebo group (69% vs 59%, P = 0.01). 1002

Comparison of overall SVR showed a response of 56% and 44% for the PEG-IFN alfa-2a/RBV group compared with the unmodified IFN alfa-2b/RBV group, respectively (P < 0.001). The likelihood of achieving an SVR was also statistically different for PEG/RBV compared with placebo (29%, P < 0.001). The SVR in patients (HCV genotype 1) receiving PEG/RBV compared with placebo and unmodified IFN alfa-2b/RBV was 46%, 21% (P < 0.001), and 36% (P = 0.01), respectively. In patients infected with HCV genotype 2 or 3, the likelihood of achieving an SVR was statistically different in the PEG/RBV group compared with those receiving unmodified IFN alfa2b/RBV (76% vs 61%, P = 0.005). Subjects infected with genotype 4 experienced SVRs of 77% (PEG/RBV), 44% (PEG/placebo), and 36% (unmodified IFN alfa2b/RBV). A P value was not generated due to the small number of patients in each group. Patients with a high baseline serum HCV RNA concentration (>2 million copies) were more likely to experience an SVR while receiving PEG/RBV than unmodified IFN alfa-2b/RBV (53% vs 41%, P = 0.003). The authors performed an analysis of the predictability of an early virologic response (EVR; a 2-log decrease in baseline HCV RNA levels or no detectable serum HCV RNA) at 12 weeks of therapy and the achievement of an SVR. Sixty-five percent of subjects with an EVR at 12 weeks had an SVR, whereas patients without an early response (97%) did not achieve an SVR. Laboratory events and AEs were similar among the 3 groups. Fever, myalgia, rigors, and depression occurred more commonly in the unmodified IFN alfa-2b/RBV group compared with the PEG/RBV group (P < 0.001, P = 0.02, P < 0.001, P = 0.01, respectively). Withdrawal from the study due to adverse laboratory events or AEs was similar among the treatment groups. A randomized, double-blind study determined the relative efficacy of 24 weeks of therapy, compared with 48, of PEG-IFN alfa-2a with 2 different dosing regimens of RBV.76 A total of 1284 treatment-naive patients (85% W) were divided into 4 treatment groups, based on HCV genotype 1 versus n o n HCV-1, and low (<2 million copies/mL) versus high (>2 million copies/mL) baseline viral load. 77 Fifty-eight percent of patients were infected with HCV genotype 1 and 14% had stable cirrhosis. 76 Patients received 1 of the following regimens: (A) PEG-IFN alfa-2a plus

S.J.Matthews and C. McCoy

RBV 800 mg/d for 24 weeks (41 y, 68% M); (B) PEGIFN alfa-2a plus RBV 800 mg/d for 48 weeks (43 y, 63% M); (C) PEG-IFN alfa-2a plus RBV based on weight between 1000 to 1200 mg/d for 24 weeks (42 y, 66% M); or (D) PEG-IFN alfa-2a plus RBV 1000 to 1200 mg/d for 48 weeks (43 y, 66% M). r8 All patients received the same dosage of PEG-IFN (180 pg/wk). Efficacy assessment was based on the SVR as defined above. The SVRs for patients infected with HCV genotype 1 were A, 29% (n = 101); B, 40% (n = 250); C, 41% (n = 118); and D, 51% (n = 271) (no P value available), rr,r8 The SVR for patients infected with HCV genotype 1 with high viremia was A, 16%; B, 35%; C, 26%; D, 46%; with low viremia: A, 41%; B, 53%; C, 51%; D, 61% (no P value available). Patients infected with HCV 2 or 3 had SVRs of A, 78% (n = 106); B, 73% (n = 111); C, 78% (n = 162); and D, 77% (n = 165). rr,rs Subjects with bridging fibrosis or cirrhosis with HCV 1 responded best to regimen D (SVR, 41%)78 Marcellin et al r9 noted a similar SVR rate in subjects (N = 171) with HCV and compensated cirrhosis with regimen D (49%). This study indicated that patients infected with HCV 1 should receive PEG-IFN alfa-2a 180 pg/wk with RBV (1000-1200 mg/d in 2 divided doses) for 48 weeks, whereas patients with HCV 2 or 3 can be treated for 24 weeks with PEG-IFN alfa-2a 180 pg/wk plus RBV 800 mg/d in divided doses, rr Ferenci et al8° performed a retrospective analysis of the study performed by Fried et al"+r to determine the effect of HCV genotype and adherence on the positive and negative predictive value of achieving an SVR using an EVR to combination therapy with PEG-IFN alfa-2a and RBV. EVR was defined as a >2 loglo decline in HCV RNA from baseline, or an HCV RNA level below detectable concentrations by 12 weeks of therapy. Eighty-six percent of all patients studied had an EVR and 56% achieved an SVR. The EVR positive and negative predictive values were calculated at 65% and 97%, respectively. Seventy-five percent of the treatment-adherent patients (having received >80% of prescribed regimen) who had an EVR achieved an SVR compared with only 48% of subjects with an EVR and poor adherence (<80% of prescribed regimen). The corresponding SVR in adherent patients achieving an EVR for HCV 1 or HCV 2 or 3 was 67% and 88%, respectively. Patients who achieve an EVR at 12 weeks of therapy and are adherent have a higher likelihood

of achieving an SVR compared with nonadherent patients. Others have noted the importance of adherence in achieving an SVR in this patient population. 81 A direct comparison of the 2 available PEG-IFN alfa products has not been performed. A literature review has determined that there are no major differences in the 2 products as they relate to the ability to induce an SVR.82 The manufacturer of PEG-IFN alfa-2b has announced plans to conduct a large-scale (2880 patients) comparison study of the 2 PEG-IFN products combined with RBV 83 H E A L T H = R E L A T E D Q U A L I T Y O F LIFE A N D C O S T - E F F E C T I V E N E S S A N A L Y S I S : II

Hassanein et al8~ have performed a health-related QOL analysis of a large multinational study of patients treated with PEG-IFN alfa-2a plus RBV or unmodified IFN alfa-2b plus RBV in the management of chronic HCV."+r The FSS and SF-36 were used to assess the effect of therapy on health-related QOL. rs,r'+ The surveys were administered at weeks 2, 12, 24, 48, and 72. A repeated-measures, mixed-model ANCOVA was used to analyze the survey results. Patients receiving PEG-IFN alfa-2a plus RBV reported better healthrelated QOL measures on both SF-36 and FSS surveys over the 48 weeks of therapy than those receiving unmodified IFN alfa-2b/RBV. Statistically significant differences were noted in vitality (P = 0.02), social functioning (P = 0.04), body pain (P = 0.002), and fatigue (P = 0.02). Patients receiving PEG-IFN alfa-2a plus placebo also fared better on health-related QOL measures (SF-36 and FSS) compared with patients in the unmodified IFN alfa-2b/RBV group (P < 0.05 to P < 0.001). Patients who achieved an SVR had improved QOL, with the greatest improvement over baseline in role--emotional, vitality, general health, and role-physical domains in the SF-36 survey. Additional analysis of the study results noted improvements in health-related QOL scores in favor of the PEG/RBV group as early as week 2 of therapy, ss Jensen et a186 used a Markov model to compare life expectancy and cost of medical therapy of PEG-IFN alfa-2a plus RBV with unmodified IFN alfa-2b plus RBV for patients with chronic HCV infection. The authors analyzed outcomes in all patients treated for 48 weeks and in patients receiving genotype-specific therapy. Outcome measures included quality-adjusted life-years (QALYs) and lifetime medical care costs. 1003

CLINICALTHERAPEUTICS@

Patients receiving PEG/RBV therapy showed a 0.9 year (0.7 QALY) increase in life expectancy and a cost savings of $3761 in lifetime medical costs compared with unmodified IFN alfa-2b/RBV Using a genotypespecific analysis, a similar increase in life expectancy was noted and medical cost savings were $6079. If an SVR was achieved, an additional 7.8 years (6.7 QALYs) were gained and a medical cost savings of $50,588 projected. The authors concluded that the combination of PEG-IFN alfa-2a plus RBV positively affects life expectancy and saves medical costs compared with unmodified IFN alfa-2b with RBV.

in a higher rate of SVR in this group remains to be determined. Data on the responses of groups C and D were not presented in the abstract. Study enrollment and analysis continues. In another recent abstract, 89 patients with chronic HCV infection with genotype 1 were randomized to receive PEG-IFN alfa-2a 180 l~g/wk and RBV 400 mg BID for either 48 or 72 weeks. Enrolled patients were followed for a 24-week period after the end of therapy. Of the 459 patients enrolled, 305 have completed follow-up. Preliminary data did not show an advantage of prolonged therapy in patients with HCV 1 receiving combination therapy.

Longer Treatment Duration

Efforts to improve SVR have included prolonging therapy in select patients. A recent study was designed to investigate the effect on SVR rate of 48 versus 72 weeks of therapy and 24 weeks of follow-up. 87,88 Additional information concerning study results has been published in abstract form. 88 Patients who were treatment-naive with chronic HCV, receiving PEG-IFN alfa-2a (180 l~g/wk) with RBV (400 mg BID) and who had not achieved an EVR were randomly assigned to either an additional 44 weeks (group A) or 68 weeks (group B) of combination therapy Patients with an EVP, were assigned to 2 groups (C or D) based on their HCV genotype and baseline viral load. Group C included patients with HCV genotype 2 or 3 or HCV genotype 1 or 4 with a viral load of <800,000 UI/mL and received combination therapy for an additional 20 weeks. Group D included patients with HCV genotype 1 or 4 and a viral load of >800,000 UI/mL and were to be treated for an additional 44 weeks. An EVR occurred in 36% of patients (N = 511). Patient characteristics were similar in the 44- and 68-week groups (mean age 42 y, 37% F). Undetectable HCV RNA levels at the end of therapy were noted in 74% and 81% of patients in the 44- and 68-week groups, respectively (P values not provided). The longer therapy from 48 to 72 total weeks did not result in an increased incidence of thrombocytopenia or neutropenia. However, the dropout rate was 17% in the 48-week group compared with 36% in the 72-week group. The authors did not delineate a reason for this higher rate of dropout in the 72-week group. ETR was greater for patients in the 68-week group compared with the 44-week group (no P values provided). Whether this difference will result 1004

NONRESPONDERS A study to determine the efficacy of PEG-IFN alfa-2a plus RBV in treatment-experienced patients who were nonresponders versus unmodified IFN alfa-2a with or without RBV has recently been launched. 9° Patients were considered nonresponders if they had a positive HCV RNA level after treatment for at least 12 weeks and within 4 weeks of completing therapy with unmodified IFN alfa-2a with or without RBV. If testing for HCV RNA was not performed, patients were considered to be nonresponders if they had a persistently elevated serum ALT before, during, and after the treatment period. Six hundred four patients completed the lead-in component of the study. The mean age of patients was 49.9 years, 73% M, 77% W, 14% B, and 89% were infected with HCV genotype 1. All patients had severe fibrosis and 39% had cirrhosis on liver biopsy. All subjects meeting the criteria listed above were placed on PEG-IFN alfa-2a 180 l~g/wk with either 1000 mg/d of RBV (<75 kg) or 1200 mg/d (>75 kg). Patients who had undetectable HCV RNA concentrations after 20 weeks of combination therapy continued therapy for a total of 48 weeks with a 24-week follow-up period. Nonresponders (PEG-IFN alfa-2a/RBV) were defined as being HCV RNA positive after 20 weeks of combination therapy. These patients were entered into the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study In this trial, nonresponding patients were randomly assigned to PEG-IFN alfa-2a alone (dose reduced to 90 txg/wk) or no therapy for 3.5 years. Three hundred sixty patients (60%) had detectable HCV RNA in serum at 20 weeks and were considered for randomization.

S.J. Matthews and C. McCoy

Two hundred ten subjects responded to treatment and completed a total of 48 weeks of therapy. Thirtysix percent and 39% required a dose adjustment of their PEG-IFN alfa-2a or RBV, respectively, due to AEs. HCV RNA in the blood reoccurred between 24 and 48 weeks in 3% of patients. An ETR response was achieved in 32% of patients and 18% achieved an SVR. An SVR was achieved at a significantly higher rate in patients who had previously failed monotherapy with unmodified IFN alfa-2a (28%) compared with those who had taken a combination of unmodified IFN plus RBV (12%) (P < 0.001). Other factors that contributed to an SVR were patient age <60 years (19% vs 6%, P = 0.011), nonblack ethnicity (20% vs 6%, P < 0.002), and HCV genotype 2 or 3 (59% vs 14%, P < 0.001). These preliminary data show a lower response to PEG-IFN alfa-2a plus RBV therapy in those who previously failed to respond to unmodified IFN alfa-2a with or without RBV The authors of the study continue to analyze this patient cohort to determine the effect of prolonged therapy on progression of cirrhosis, need for transplantation, and incidence of hepatocellular carcinoma. Diago et a191 have presented preliminary data investigating varying doses of PEG-IFN alfa-2a plus RBV (1000-1200 mg/d based on body weight) in patients who have failed therapy with unmodified IFN alfa-2a plus RBV Patients had remained HCV RNA positive after >22 weeks of unmodified IFN alfa-2a/RBV therapy This is an open-label study in which patients (HCV genotype 1) were randomized to either 180 (n = 28, 41.1 [9.3] y, 75% M), 270 (n = 20, 44.1 [9.8] y, 75% M), or 360 pg/wk (n = 24, 41.0 [9.3] y, 83% M) of PEGIFN alfa-2a plus RBV and treated for 12 weeks, and then 180 pg/wk plus RBV for an additional 36 weeks. Patients who failed to achieve an undetectable HCV RNA level after 12 weeks of therapy were dropped from the study Seventy-two patients were included in this analysis. The rates of virologic response after 12 weeks of therapy increased with the dose of PEG-IFN alfa-2a (21.4%, 180 pg/wk; 35%, 270 pg/wk; and 45.8%, 360 pg/wk). AEs and abnormal laboratory findings were similar among the 3 groups. SVR status has yet to be determined because the study is still in progress. Efforts to improve outcomes in nonresponders have included the addition of immunomodulators or amantadine to therapy with PEG-IFN with or without RBV Preliminary investigations into the value of corn-

bining the immunomodulator thymalfasin with PEGIFN alfa-2a, with or without RBV, have been published in abstract form. 92,93 The goal of these studies is to determine the efficacy of combination therapy in HCV-infected patients who were nonresponders to unmodified IFN with or without RBV EVR was assessed at 12 weeks of therapy and was defined as >2 log reduction or an undetectable level of HCV RNA at week 12. Although preliminary response was encouraging, more research will be necessary to determine whether the EVR translates into an SVR. A randomized, multicenter, open-label study has been initiated to measure the effectiveness of the combination of PEG-IFN alfa-2a plus RBV with amantadine compared with unmodified IFN plus RBV and amantadine in subjects with HCV infection.9~ Patients had failed to respond to therapy with unmodified IFN/RBV after at least 12 weeks of therapy. The patient population included 185 individuals randomly assigned to 1 of 2 treatment groups: Group A (mean age, 48.9 y) received PEG-IFN alfa-2a 180 pg/wk plus RBV 800 to 1000 mg/d plus amantadine 200 mg/d; and group B (49.1 y) received unmodified IFN 6 MU/D for 4 weeks followed by 20 weeks of 3 MU/D, and then 3 MU 3 times a week for an additional 24 weeks plus RBV and amantadine at the same dosages noted above. All patients were to be treated for 48 weeks with a 24week follow-up period. At the time of presentation, 152 patients had completed 48 weeks of therapy, while 136 patients had completed 24 weeks of follow-up. Baseline patient characteristics were similar for both groups; however, dose reductions were necessary in 22% of patients in group A compared with 1% in group B (P = 0.006). Virologic response after 48 weeks of therapy was 42% (group A) compared with 22% (group B) (P = 0.008). An SVR was achieved in 21% of group A and in 12% of group B patients. Although the study is still in progress, preliminary responses of 21% are similar to the initial findings of the HALT-C study (18°/o). 90 Controlled studies comparing PEG-IFN alfa2a plus RBV compared with the same combination plus amantadine will be necessary to determine the value of the addition of amantadine to therapy in nonresponders with unmodified IFN/RBV regimens. RELAPSE

Goncales et al9s presented preliminary data on the value of re-treating patients who had achieved an

1005

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undetectable HCV RNA level at the end of therapy with PEG-IFN alfa-2a plus RBV but who had suffered a relapse during the follow-up period. The study consisted of 64 patients (69% HCV 1 and 31% n o n HCV-1) who received a maximum dose of 180 t~g/wk of PEG-IFN alfa-2a and between 1000 and 1200 mg/d of RBV, based on body weight. Patients were treated for a total of 48 weeks. Initial dosage adjustment of both medications was allowed if the patient had a previous AE that required a dose adjustment. The patient was allowed to take the dose that was tolerated previously. No further information concerning dosage adjustment was available. ETR virologic response was available for 59 patients. Ninety percent of subjects had an undetectable HCV RNA level after 48 weeks of combination therapy. Eighty-eight percent and 93% of patients infected with genotype 1 or genotype 2 or 3, respectively, had undetectable HCV RNA levels. The study, still in progress, has yet to determine whether the good response to retreatment at 48 weeks will translate into an SVR. Parise et a196 presented recent initial findings in patients treated with PEG-IFN alfa-2a plus RBV who failed, or experienced a relapse to, therapy with unmodified IFN-based therapies after at least 24 weeks of therapy. Patients were assigned to therapy with PEG-IFN alfa-2a 180 l~g/wk and RBV 800 mg/d for 48 weeks. Patient characteristics included a mean age of 48 years, 83% M, 85% W, and 37% with cirrhosis of the liver. A virologic response was defined as an undetectable HCV RNA test during treatment or at the end of therapy. Patients who were nonresponders to previous unmodified IFN therapies experienced a virologic response of 69% (n = 96) and 60% (n = 72) at 24 and 48 weeks of therapy, respectively. Preliminary data indicate that 89% (n = 35) and 80% (n = 35) of relapse patients had achieved a virologic response by the end of 24 and 48 weeks of treatment, respectively. The frequency of achievement of an SVR remains to be determined. Herrine et al9r investigated the utility of combining PEG-IFN alfa-2a with other antiviral and immunomodulatory agents in HCV-infected patients who had relapsed on unmodified IFN/RBV therapy Patients who had relapsed or had an increase in HCV RNA levels during therapy were assigned to 1 of 4 treatment groups. Group A (n = 32) received PEG-IFN alfa-2a plus RBV 800 mg/d to 1000 mg/d in split doses; 1006

group B (n = 29) received PEG-IFN alfa-2a plus 1000 mg of mycophenolate mofetil orally BID; group C (n = 31) received PEG-IFN alfa-2a and amantadine 100 mg orally BID; and group D (n = 31) received PEG-IFN alfa-2a plus amantadine 100 mg orally BID plus RBV 800 mg to 1000 mg daily in split doses. All groups received 180 l~g/wk of PEG-IFN alfa-2a. Treatment duration was 48 weeks with a 24-week follow-up. An SVR was achieved in 37.5% of group A, 17.2% of group B, 9.7% of group C, and 45.2% of group D subjects (no statistical analysis was provided). C o m b i n a t i o n with A m a n t a d i n e in T r e a t m e n t Naive Patients

Ideo et a198 presented preliminary results of a large, randomized multicenter study comparing the efficacy of therapy consisting of PEG-IFN alfa-2a plus RBV or amantadine in treatment-naive subjects with chronic HCV infection. Seven hundred thirty-four patients were randomly assigned to 2 groups. Group A received PEG-IFN alfa-2a 180 l~g/wk with RBV 1000 to 1200 mg/d, while group B received the same PEGIFN alfa-2a dose plus amantadine 200 mg/d for a total of 48 weeks and a 24-week follow-up. Patient characteristics included a 2:1 M/F ratio, a mean age of 45.3 years, cirrhosis in 31.4%, and HCV genotype 1 or 4 in 59.6% of patients. Of the 734 patients enrolled, 296 had reached 48 weeks of therapy. At 48 weeks, 81.3% (HCV 1 or 4) and 98.4% (HCV 2 or 3) of patients in group A had achieved an undetectable HCV RNA level. In contrast, in group B, 55.8% (HCV 1 or 4) and 91.7% (HCV 2 or 3) had achieved an undetectable HCV RNA level. The study showed that amantadine was not an equivalent substitute for RBV as combination/adjunctive therapy. No statistical analysis was presented in the abstract. In another randomized controlled study, 360 treatment-naive patients with chronic HCV infection were assigned to 3 study g r o u p s . 99 Group A received PEG-IFN alfa-2a 180 l~g/wk plus RBV with amantadine 200 mg/d, group B received unmodified IFN alfa-2a 3 MU 3 times/wk plus RBV with amantadine 200 mg/d, and group 3 received unmodified IFN alfa2a 3 MU 3 times/wk plus RBV. RBV dosage was 1000 to 1200 mg/d, based on body weight in all study groups. Treatment was continued for 48 weeks with a 24-week follow-up. Patients were a mean age of 53 years, 55% M, 23% with severe fibrosis or cirrhosis,

S.J.Matthews and C. McCoy

and 57% infected with HCV 1. Two hundred ten patients had completed 48 weeks of therapy at the time of publication. The virologic response by group at 48 weeks was 59.5%, group A; 29.1%, group B; and 27.4%, group C. Neither statistical analysis nor frequency of SVR were provided. SELECT PATIENT POPULATIONS Hepatitis C Virus Genotype 4

HCV 4 is not a common pathogen in the United States but has prevalences of 60% in Saudi Arabia and 90% in Egypt. As with HCV 1, therapy with unmodified IFN/RBV has resulted in a poor likelihood of achieving an SVR.loo,~o~ Shobokshi et al ~°2 conducted an open-label study in which 180 HCV 4-infected patients were assigned to 3 treatment groups. Group A (n = 60) received PEG-IFN alfa-2a 180 pg/wk plus RBV 400 mg BID, group B (n = 60) received PEG-IFN alfa-2a 180 pg/wk, and group C (n = 60) received unmodified IFN alfa-2a 4.5 MU 3 times/wk plus RBV 400 mg BID. Treatment was for 48 weeks with a 24-week follow-up. EVR was assessed and defined as a 2 log decline or an undetectable HCV RNA level at 12 weeks of therapy. An SVR was achieved in 50% of group A, 28% of group B, and 30% of group C patients. An SVR was achieved in 65.2% (group A) and 47.2% (group B) of subjects who had an EVR. The SVR rate for group C was not given. No statistical analysis was reported in the abstract. Diago et al ~°1 reviewed the results of therapy in patients (n = 49) infected with HCV 4 in 2 Phase III studies. Sixty-nine percent of patients were male and 24% had cirrhosis. Combining the results of both studies, 79% of patients treated with PEG-IFN alfa-2a 180 pg/wk plus RBV (1000 to 1200 mg/d based on body weight) for 48 weeks achieved an SVR. In contrast, 63% and 67% of subjects treated with PEG-IFN alfa-2a and RBV 800 mg/d for 48 weeks or 1000 mg to 1200 mg for 24 weeks, respectively, achieved an SVR. No patient treated with PEG-IFN alfa-2a and RBV 800 mg for 24 weeks achieved an SVR. No statistical analysis was provided in the abstract. Thakeb et al ~°3 randomly assigned 100 patients with chronic HCV 4 infection to two treatment groups. Group A (n = 51) received PEG-IFN alfa-2a 180 pg/wk plus RBV 1000 to 1200 mg/d based on body weight, and group B (n = 49) received 3 MU of unmodified IFN 3 times weekly plus RBV, for a total of 48 weeks of

therapy. Follow-up was performed at 24 weeks after therapy. An SVR was achieved in 68.6% of group A compared with 16.4% of group B (P < 0.001). Patients infected with HCV 4 appear to respond well to PEG-IFN alfa-2a plus RBV therapy. The highest likelihood of achieving an SVR occurred with treatment consisting of PEG-IFN alfa-2a 180 pg/wk plus RBV 1000 to 1200 mg/d based on body weight administered for 48 weeks. Black Patients

The prevalence (3.2%) of HCV infection in blacks is higher than in whites (1.5%). 1°~ Compared with whites, blacks with chronic HCV infection appear to have a decreased response to IFN therapy with or without RBV.10~-106 In a post hoc analysis of randomized Phase II and Phase III studies (N = 1205), Shiffman et al ~°6 compared the efficacy of PEG-IFN alfa-2a (180 pg/wk) with unmodified IFN alfa-2a (3 MU or 6 MU followed by 3 MU, 3 times/wk) in both black and white patients. Virologic and biochemical responses of 2 points decrease in HAI score were used as study end points. Fifty-five black patients were included in the study (28 patients received unmodified IFN alfa-2a and 27 received PEG-IFN alfa-2a). Fifty percent were male, 80% were infected with HCV genotype 1, and 25% had, or developed, cirrhosis during the study. Baseline characteristics were similar in the 2 study groups. An SVR was observed in 0% and 15% of black patients receiving unmodified IFN alfa-2a or PEG-IFN alfa-2a, respectively. In white patients, an SVR was observed in 13% receiving unmodified IFN alfa-2a compared with 35% of those treated with PEG-IFN alfa-2a. All black patients who had an SVR also experienced a sustained biochemical response. Jeffers et al 1°7 published an open-label study comparing the efficacy of PEG-IFN alfa-2a plus RBV therapy in black patients (n = 78) versus white patients (n = 28) with chronic HCV infection. Patients were treatment-naive and received PEG-IFN alfa-2a 180 pg/ wk plus RBV (1000-1200 mg/d based on body weight) for 48 weeks with a 24-week follow-up period. Patients with HCV RNA levels of >1 × 106 IU/mL were considered to have a high viral load (HVL). EVR was defined as an HCV RNA <50 IU/mL, or >2 log~o drop in HCV RNA from baseline at 12 weeks of therapy. An undetectable HCV RNA level at week 72 was defined as an 1007

CLINICALTHERAPEUTICS®

SVR, and a normal serum ALT at 72 weeks was defined as a sustained biochemical response. Histologic response was recorded by comparison of baseline and follow-up liver biopsies. Of the 106 original patients, 62 (80%) blacks and 22 (79%) whites completed the study Baseline characteristics for the black group were a mean age of 46 years, 72% M. The mean age of the white patients was 45 years, with 61% M. The black patients had a higher baseline viral load (45/78; 58%) compared with white patients (12/28; 43%). An SVR was achieved in 26% of black and 39% of white patients. Among patients with a baseline HVL, an SVR was achieved in 20% of blacks and 25% of whites. An EVR was observed for 47 black patients with 20 achieving an SVR. The negative predictive value (NPV) of EVR was 100% for both treatment groups. Histologic evaluation showed improvement in fibrosis in 25% (13/53 B) and 6% (1/16 W) of subjects with repeat liver biopsies. No statistical analysis was provided in the abstract. PEG-IFN alfa-2a plus RBV has an improved outcome compared with unmodified IFN alfa-2a or PEG-IFN alfa-2a alone in black patients with chronic HCV infection. However, the response is still less than that of white patients. Black patients may experience improved histology even without achieving an SVR. lo8 Many theories have been proposed to explain the disparate response to therapy between blacks and whites, lo5 A large multicenter trial, Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (VIRAHEP-C), is currently enrolling patients to further investigate the antiviral response of black patients compared with white patients to PEG-IFN alfa-2a plus RBV.lo9 Normal Alanine Aminotransferase

Normal ALT levels may be noted in about 30% of patients with chronic HCV infection. 6 Liver inflammation (P < 0.02) and fibrosis progression rate (P = 0.002) are significantly lower in patients with normal ALT levels, compared with patients with persistently elevated ALT levels. M° QOL, however, is similarly impaired as in HCV-infected patients with elevated ALT levels. 1lo Results of an international, multicenter, randomized trial of the efficacy of PEG-IFN alfa-2a plus RBV in chronic HCV-infected patients with normal ALT levels have been published in abstract form. 111 Four hundred ninety-one patients were randomized into 3 treatment groups. Group A (n = 212, median age 44 years, 42% M) received PEG-IFN alfa-2a

1008

180 l~g/wk plus RBV 800 mg/d for 24 weeks; group B (n = 210, 44 y, 39% M) received the same therapy as group A for 48 weeks; and group C (n = 69, 41 y, 38% M) received no therapy and were followed for 72 weeks. Patients with cirrhosis, other liver diseases, or coinfection with HIV were excluded from the study Baseline and demographic features were comparable among the 3 groups. An SVR was achieved in 30% of group A, 52% of group B, and 0% of group C patients (P < 0.001). For HCV 1-infected patients, an SVR was noted in 13% of group A and 40% of group B (P < 0.001). Patients infected with genotypes 2 or 3 achieved an SVR in 72% (group A) and 78% (group B) of patients (P = NS). Treatment results are similar to those reported previously for patients with chronic HCV infection and elevated ALT levels, r
Hepatitis C is a major cause of cirrhosis of the liver and liver failure requiring a liver transplant. 112 Hepatitis C frequently recurs after liver transplantation and may result in allograft failure.3,6 RBV is not well tolerated after orthotopic liver transplantation. Vogel et al M2 published initial results of a randomized, multicenter study investigating the efficacy of PEG-IFN alfa-2a in patients with recurrent HCV infection following liver transplantation. Patients had received their transplant from 6 to 60 months before the study, were treatment-naive, and were assigned to 1 of 2 treatment groups. Group A (n = 33, mean [SD] age 52.7 [7.9] y, 76% M, 79% HCV 1, 82% HVL) received PEG-IFN alfa-2a 180 l~g/wk, and group B (n = 32, 50.7 [6.5] y, 81% M, 75% HCV genotype 1, 84% HVL) received no therapy. Treatment was continued for 48 weeks with a 24-week follow-up. Patients with viral loads of <1 million IU/mL and >1 million IU/mL were designated as low and high viral loads, respectively An undetectable HCV RNA level was considered a positive response to therapy Two patients with biopsy-proven rejection in group A withdrew from the study. Ten patients in group A (2 during the follow-up period) and 6 patients in group B have been dropped from the study. At least 1 serious AE was experienced by 45% of group A patients (n = 15) and 25% of group B patients (n = 8). As of publication, 46 patients had completed 48 weeks of therapy At 48 weeks of therapy, 35% of group A (8/32) and 0% of group B (0/32) patients had an undetectable

S.J.Matthews and C. McCoy

HCV RNA level. Although these results are encouraging, it is not known how many patients will achieve an SVR. Further study will be necessary to determine the value of PEG-IFN alfa-2a in this patient population. H u m a n ImmunodeficiencyVirus Coinfection

In the United States and Europe, between 15% and 30% of people infected with HIV are also infected w i t h HCV. M3-M5 Conflicting data exist concerning the effect of HCV infection on the progression of HIV disease. Greub et al M6 noted an increase in progression to an AIDS-defining event or to death in patients coinfected with HCV. Others could not corroborate these findings, however. ~~r Reports of the use of PEGIFN alfa-2a in the management of HCV,q-IIV-coinfected patients are limited to abstracts. Several large studies have been completed that have assessed the use of PEG-IFN alfa-2a with or without RBV in co-infected subjects. The goal of the AIDS Pegasys RBV International Co-infection Trial (APRICOT) study was to investigate the efficacy and safety of unmodified IFN alfa-2a (3 MIU 3 times/wk) plus RBV (800 rag/d) in HCV/HIV-coinfected patients. Patients were divided into 3 groups: unmodified IFN alfa-2a, group A (n = 285); PEG-IFN alfa-2a 180 pg/wk plus placebo, group B (n = 286); PEG-IFN alfa-2a 180 pg/wk plus RBV, group C (n = 289). M8 The mean (SD) age of study patients was 40 (7.6) years, 81% M, 80% W, and 60% were infected with HCV 1. Patients had compensated liver disease, a CD4 + count _>100 cells/mE, and stable HIV disease (with or without HIV therapy). Patients were randomized to the 3 treatment groups. Overall, the SVR rates were 12%, 20%, and 40% for groups A, B, and C, respectively (P = 00.78, B vs A; and P < 0.001, C vs A and B). SVRs for patients infected with HCV genotype 1 were 7% in group A, 14% in group B, and 29% in group C. Therapy was discontinued due to AEs or laboratory abnormalities in 15%, 16%, and 15% of patients in groups A, B, and C, respectively. Another study, by Chung et al, n9 included 133 coinfected subjects. Patients received treatment with unmodified IFN alfa-2a plus escalating doses of RBV or PEG-IFN alfa-2a with the same escalating regimen of RBV (600-1000 rag/d). Patient characteristics were well matched and included a mean age of 40 years, 81% M, 77%-78% had HCV 1, and the median CD4 + cell count was 444 to 492 cells/mm 3. An SVR was

achieved in 12% and 27% of subjects treated with unmodified IFN/RBV and PEG-IFN/RBV, respectively (P < 0.03). An SVR was achieved in 6% (unmodified IFN) and 14% (PEG-IFN) of patients infected with genotype 1, however. Twelve percent of patients stopped therapy in each treatment group due to AEs. These results are encouraging and favor the use of PEG-IFN alfa-2a plus RBV over regimens with unmodified IFN alfa-2a in the management of HCV/ HIV-coinfected patients. Researchers have yet to determine the best dosing regimen and patient characteristics most likely to result in an SVR. Children

Sparse data exist about the management of children and adolescents with chronic HCV. An SVR after treatment with unmodified IFN therapy has been documented in between 33% and 45% of patients. 6 A study investigating the safety, efficacy, and pharmacokinetics of PEG-IFN alfa-2a in children with chronic HCV infection has been published in abstract form. 31 Patients were treatment-naive and received monotherapy with PEG-IFN alfa-2a at a dose normalized to the patient's BSA ([180 pg/1.73 m 2] X patient BSA). Therapy duration was 48 weeks with a 24-week follow-up period. The primary study outcome measure was an undetectable HCV RNA level at weeks 12, 24, 48, and 72. The study enrolled 14 patients, aged 2 to 8 years, and 12/13 were infected with HCV genotype 1. Tests found HCV RNA undetectable in 57% and 43% of patients at weeks 12 and 24, respectively. An SVR was achieved in 38% of subjects. Four patients were dropped from the study: 1 lacked a viral response at 24 weeks, 2 developed elevated transaminases, and 1 had an exacerbation of an existing hypertriglyceridemia. AEs were consistent with those common to therapy with PEGIFN alfa-2a and were considered mild in most cases. Five subjects had a dose reduction due to neutropenia. The response in this small study was consistent with SVR rates noted in monotherapy with unmodified IFN. Additional studies will be necessary to determine the place in therapy of PEG-IFN alfa-2a for chronic HCV infection in children. A D V E R S E E V E N T PROFILE

The AEs reported with use of PEG-IFN alfa-2a are similar to standard (ie, unmodified) IFN alfa-2a prod1009

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ucts and greatly similar to PEG-IFN alfa-2b, since these are structurally similar products. 12° However, with changes in the pharmacokinetics of the PEG products, there are some differences in associated AEs. Influenza-like symptoms, such as myalgias, fever, and malaise, have been noted in up to 51% of patients but were found to be less frequent than unmodified IFN in 1 trial. 1`+,`+7,68,69Similar to AEs of unmodified IFN products, neuropsychiatric disorders (eg, anxiety and depression) occur in up to 26% of patients, although depression was also noted to be less frequent with unmodified IFN in 1 trial. 1`+,`+7,68,69 Nonetheless, a warning exists for all IFN products for fatal or lifethreatening neuropsychiatric disorders, including suicide and depression. This warning is emphasized in patients with underlying depression. Hematologic dyscrasias, such as anemia and neutropenia, the result of direct inhibition on progenitor cell proliferation in the bone marrow, 121 appear to occur at a rate similar to, or higher than, that with unmodified IFNs. l`+,`+r,6r-69,12°The manufacturer recommends that patients with a neutrophil count <1500 cells/mm3, a baseline hemoglobin <10 g/dL, or a baseline platelet count <90,000 cells/mm3 be treated cautiously with PEG-IFN with careful monitoring of cell lines during therapy. 1`+ A review of the safety measurements collected from the 3 largest Phase III trials, and a summary of data from the US Food and Drug Administration briefing document follow. `+r,68,69,122 Table III summarizes the relative rates from each trial in a comparative manner. In the comparative efficacy and safety trial by Fried et al, `+r patients were randomized to PEG-IFN alfa-2a 180 l~g/wk, with or without RBV, or unmodified IFN alfa-2b plus RBV. Withdrawal rates, often a reflection of AEs, were similar between the unmodified IFN alfa-2b and PEG-IFN alfa-2a treatment arms (11% vs 10%, P = NS). Protocol-defined dose reductions were required in 32% of the PEG-IFN alfa-2a-treated patients compared with 27% in the placebo group (P = NS). Hematologic abnormalities were the most common reason, although the authors reported that dose modification could have been secondary to multiple AEs. In this trial, neutropenia occurred more commonly among the PEG-IFN alfa-2a-treated patients, with or without RBV, compared with the unmodified IFN alfa-2b-treated patients. However, 1010

this difference was not tested for statistical significance (20% vs 17% vs 5%). `+7 Neutropenia was classified as grade 4 (absolute neutrophil count [ANC] <500) in 4 of these cases. Thrombocytopenia was observed, particularly during the first 14 days of treatment, across all 3 groups: PEGIFN alfa-2a plus RBV, PEG-IFN alfa-2a plus placebo, and unmodified IFN alfa-2b plus RBV; there was no analysis for statistical significance (4% vs 6% vs <1%). Drug-related anemia was more pronounced in the patients being treated adjunctively with RBV compared with those being treated with only an IFN. Hemoglobin values decreased by a maximal value of 3.7 g/dL in the PEG-IFN alfa-2a plus RBV group, and by 3.6 g/dL in the IFN alfa-2b plus RBV group compared with the decrease among patients receiving PEG-IFN plus placebo by 2.2 g/dL in the first 8 weeks of therapy. Influenza-like symptoms occurred more frequently in the unmodified IFN plus RBV group than the PEGIFN alfa-2b plus RBV group: 50% compared with 42% (P = 0.02), and 56% compared with 43% (P < 0.001), respectively. Depression was also observed less frequently in the PEG-IFN alfa-2a-treated group compared with the unmodified IFN alfa-2b group (22% vs 30%, P = 0.01). A recent study by Schwaiger et al noted that depression, induced by IFN therapy, appears to result from serotonin depletion. 123 IFN antibodies were discovered in 14 patients (4.8%). However, of these patients, 9 were able to complete the study and achieved an SVR. Other notable and common AEs described among the patients in the PEG-IFN alfa-2a plus RBV cohort were fatigue (54%), insomnia (37%), nausea (29%), and irritability (24%). In the open-label trial by Zeuzem et al, 69 safety results were similar. Five hundred thirty-one patients were randomized to either PEG-IFN alfa-2a or unmodified IFN alfa-2a 3 times/wk with dose reductions due to AEs required at similar rates (19% and 18%, respectively; P = NS). Discontinuation for any reason was noted in 7% of the patients treated with the PEG-IFN product and 10% of patients treated with the unmodified product. Neutropenia, requiring dose reduction, was noted in 11% of the patients treated with PEG-IFN and in 7% of the patients receiving unmodified IFN (P = NS). Neutropenia was classified as grade 4 in 12 patients treated with PEG-IFN and in 4 patients treated with unmodified IFN (P = NS).

S.J.Matthews and C. McCoy

Table III. Relative safety measurements from 3 large Phase III trials of pegylated interferon (PEG-IFN) alfa-2a.* No. (%) off Patients Zeuzem et a169

Adverse Events Dropouts/ discontinuations Dose modifications ADRs Laboratory abnormalities Alopecia Cough Decreased appetffe Depression Diarrhea Dizziness Fatigue Fever Headache Impaired concentration Myalgia Nausea

Prurffis Rigors Upper abdominal pain Vomiting

PEG-IFN alfa-2a (n = 265)

Fried et a147

IFN alfa-2a (n = 261)

Heathcote et al6s

PEG-IFN PEG-IFN IFN alfa-2a + RBV alfa 2a + P alfa-2b + RBV IFN alfa-2a (n = 453) (n = 224) (n = 444) (n = 88)

PEG-IFN PEG-IFN alfa-2a 90 tJg alfa-2a 180 tJg (n = 96) (n = 87)

27 (I0) 47 (18) 30 (I I)

119 (26)

78 (35)

154 (35)

9 (I0)

I I (I I)

12 (I4)

51 (19) 21 (8)

143 (32)

53 (23)

144 (33)

29 (34)

28 (29)

37 (42)

NR

NR

NR

NR

NR

NR

37 (14) 72 (27) 25 (9)

24 (9) 96 (37) 25 (10)

219 (49) 128 (28) NR

63 (28) 48 (21) NR

120 (27) 151 (34) NR

NR 19 (22) 4 (5)

NR 14 (I 5) 10 (10)

53 (20) 43 (16) 51 (19) 60 (23) 160 (60) 99 (37) 160 (60)

55 (21) 59 (23)

96 (21) 100 (22)

24 (I I) 45 (20)

98 (22) 134 (30)

6 (7) 18 (21)

14 (I5) 20 (21)

22 (26)

53 42 70 35 73

(20) (16) (65) (52) (66)

NR NR 242 (54) 195 (43) 211 (47)

NR NR 98 (44) 85 (38) II 5 (51)

NR NR 244 (55) 247 (56) 230 (52)

16 (19) 14 (16) 52 (60) 31 (36) 46 (53)

20 (21) 19 (20) 51 (53) 28 (29) 51 (53)

21 (24) 13 (15) 53 (62) 33 (38) 53 (62)

14 (5) 10 (42) 55 (21) 29 (18) 72 (27)

29 (I I) I I (43) 91 (35) 32(12) 12 (43)

NR 189 (42) 130 (29) 101 (22) 106 (24)

NR 94 (42) 58 (26) 41 (18) 52 (23)

NR 220 (50) 145 (33) 88(20) 157 (35)

10 (12) 33 (38) 29 (34) 7(8) 39 (45)

6 (6) 35 (36) 29 (30) 15(16) 36 (38)

6 (7) 44 (5 I) 29 (34) 14(16) 37 (43)

35 (13) 16(6)

37 (14)

NR NR

NR NR

NR NR

21 (24) 13 (15)

18 (19) 12 (12)

22 (26) II (13)

19 (7)

32 (12)

NR

5 (17) 5 (17)

2 (14)

RBV = ribavirin; P = placebo;ADRs = adverse drug reactions;NR = not collected or reported by authors. ~Description of raw score and percentage of patients is depicted for dropouts and discontinuations, dose modifications,ADR rate overall, laboratory abnormalities overall, and specificADRs (eg, fatigue,fever, myalgia).

Thrombocytopenia, defined as a platelet count <50,000/mL, was described equally among 4 patients in each group. Anemia was reported in 3 cases in the PEG-IFN-treated group, but in none of those in the unmodified IFN treatment group (P = NS). Although no statistical analysis was reported for these rates, influenza-like symptoms of rigors and fever were more common in the unmodified IFN-treated group than were headache, fatigue, or myalgia. Alopecia was also more common in the unmodified IFN-treated group. Generalized depression and insomnia were more commonly observed in the unmodified IFN-treated group,

although the authors reported 4 cases of severe depression and 1 case of psychosis in the PEG-IFN-treated group. AEs reported more frequently in the PEG-IFN cohort (Table III) were dizziness (23%), pruritis (18%), and localized inflammation at the injection site (10%); however, no statistical analysis was performed to confirm this. Researchers in the Heathcote et aP 8 trial studied the relative safety of PEG-IFN alfa-2a at 2 dosing strategies compared with unmodified IFN alfa-2a therapy in patients with HCV and cirrhosis. Two hundred seventyone patients were randomized to either PEG-IFN alfa-2a 1011

CLINICALTHERAPEUTICS@

at a dose of 180 txg/wk or 90 txg/wk, or to unmodified IFN alfa-2a, 3 MU 3 times/wk. Dose modifications were allowed when AEs, including changes in cell counts, occurred. Discontinuation was attributable to AEs in 8% of the standard IFN group and 7% and 13% of the PEG-IFN alfa-2a-treated groups (P = NS) at 90 and 180 txg/wk, respectively. Laboratory abnormalities were specifically identified as the rationale for drug discontinuation in 2% compared with 4% and 1% among these same groups (P = NS). In the unmodified IFN alfa2a group, dose reductions were enlisted primarily due to neutropenia (14%) compared with the PEG-IFN alfa-2a groups (9% and 10%, P = NS). Severe thrombocytopenia rates, defined as a platelet count <50,000/mL, were higher in patients treated with PEG-IFN alfa-2a: 26% in the 90 txg group and 19% in the 180 txg group, compared with 7% of all patients treated with unmodified IFN (P < 0.001 and P = 0.04, respectively). The authors reported stabilization in all cases when drugs were discontinued. Grade 4 neutropenia (ANC <500/mL) was noted at similar rates among the 3 groups (3% with unmodified IFN, 3% and 1% with the PEG-IFN products at 90 and 180 l~g/wk, P = NS). No patients suffered an infection or serious hemorrhage as a result of any of these changes in blood cell counts. Three smaller safety trials/series documented the relative effects of PEG-IFN alfa-2a on cell lines. A summary of the findings can be found in Table IV. In an observational crossover study by Homoncik et al, 12. the effects on platelet count and activity of 1 dose of unmodified IFN alfa-2a followed by weekly PEG-IFN alfa-2a for 36 weeks were summarized. While decreases in platelet counts were noted, platelet activity was relatively unchanged. Howell et al ~2s recorded the relative safety and efficacy of PEGIFN alfa-2a plus RBV in black patients compared with white patients. Neutropenia and anemia were noted in both groups with some differences in the time-toeffect and relative rates. Peck-Radosavljevic et al ~26 described the relative effects of PEG-IFN alfa-2a and PEG-IFN alfa-2b compared with unmodified IFN alfa-2b on neutrophils, platelets, and hemoglobin. Hypersensitivity, manifested as a skin rash, has been noted in multiple trials. A severe skin rash has been described in a case series by Jessner et al, ~27 wherein 3 patients developed a delayed rash requiring drug discontinuation. Two of these patients were receiving PEG-IFN alfa-2b and 1 was receiving PEG-IFN alfa1012

2a. Two of the 3 patients were switched to unmodified IFN therapy with resolution and without recurrence of the rash. The third patient was not rechallenged. A single report of potential interstitial pneumonitis with adult respiratory distress syndrome was recently described by Abi-Nassif et a1128 in a 49-year-old man who had received 2 weekly doses of RBV and PEGIFN alfa-2b. The patient had no history of pulmonary disease, but upon presentation required admission to the intensive care unit, intravenous steroids, chest tube placement, and intubation. The patient died 26 days after admission, of bacteremia and fungemia. The mechanism of this potentially related AE is unknown but may be secondary to a localized autoimmune response to the medication. AEs of unmodified IFN regimens, which have yet to be elucidated with PEG-IFNs, include retinopathies, homicidal ideation, hearing loss, pneumonitis, asthma exacerbations, and sarcoidosis. 129-~33Many of the AEs associated with PEG-IFN may be somewhat allayed by dose reduction. However, there is the risk of reduction to a dose ineffective for eradication of the virus. ~2° Some side effects can be preempted or treated with other medications, including granulocyte cell-stimulating factor or granulocytemacrophage colony-stimulating factor for neutropenia, oprelvekin for thrombocytopenia, erythropoietin for anemia, and selective serotonin reuptake inhibitors for depression.13"+-139 S A F E T Y IN P R E G N A N C Y

PEG-IFN alfa-2a has been classified as pregnancy category C when used without RBV The addition of RBV increases the danger of this classification to category X. ~* Little to no collaborative data are available on the safety of PEG-IFN alfa-2a in humans or animals during pregnancy. In Rhesus monkeys, unmodified IFN administered at 20 to 500 times the human weekly dose was associated with no teratogenic events. No information is currently available on the distribution of PEGIFN into breast milk and thus there are no published data on the safety of the drug in the breastfed child. DRUG INTERACTIONS

The number of recorded drug-drug interactions for PEG-IFN alfa-2a is small, resting primarily on drugs with similar AEs (eg, magnification of neutropenia with RBV) or drugs intended for treatment of comorbid dis-

S.J.Matthews and C. McCoy

Table IV. Summary of small safety trials/series with peginterferon (PEG-IFN) alfa 2a: Specific effects on cell counts.

Study Homoncik et a1124

Howell et all2S

No. of Subjects 21

106

Dosing Regimen

Hematologic Effects

One dose of 9 MU IFN, then PEGqFN alfa-2a 180 tag/wk x 36 wk

MPC 15% lower than baseline after dose I (P < 0.009). Platelet activity as measured by vWF-Ag increased by 23% after dose I (P < 0.008). ivlPC 36% lower than baseline at 36 wk after the initiation of PEGqFN alfa-2a (P < 0.005). Platelet activity as measured by vWF-Ag unchanged at 36 weeks (P > 0.33)

PEGqFN alfa-2a 180 tag/wk plus RBV* for 48 wk, with 24 wk of treatment-free follow-up

Population W (n=28) AA (n=78)

ANC Hgb Decrease to Reduction (%) <8.5 g/dL (%) 5 I1 45*

Platelet Decrease to <50,000/mm s (%)

7 5

4 5

Dose modifications off PEGqFN alfa-2a, withheld or reduced, among 46% of AA patients and 29% of W patients due primarily to neutropenia (37% and 18% f o r A A and W, respectively)

Pecb Radosavljevic et a1126

46

One dose of 10 HU IFN alfa-2b (Intron A ® (n = 36) OR 9 MU of IFN alfa-2a (Roferon® (n = 10) THEN 5 ivlU/d of IFN (Intron A®: n = 30) x 21 days OR 180 tJg of PEGqFN alfa-2a weekly (n = 10) x 21 days OR 1.5 tag/kg body weight of PEGqFN alfa-2b weekly x 21 days (n = 6)

Median % Change in Cell Counts from Baseline at Day 21 Hematology Measure Hgb§ Platelets Leukocytes

IFN (n = 30)

PEGq FN (n = 16)

P

5 ~8 ~i0

8 ~5 39

0.05 0.05 0.05

Decrease by a median of 22% of neutrophils within 24 hours for platelets and 5% for Hgb after single dose. Recovery of platelets and neutrophils within 7 days (P < 0.001) but not Hgb (P = 0.28) vWF-Ag =von Willebrand factor antigen;MPC = mean platelet count;AA = African American;W = white; RBV = ribavirin;ANC = absolute neutrophil count; Hgb = hemoglobin. ~1000 or 1200 mg orally based on body weight (<75 kg or >75 kg). ~Decline occurred later,by week 6;ANC nadir 1.7 + 0.10 x 109/L SDecreasesu~ained during treatment and returned to pretreatment levels at follow-up;ANC nadir 1.6 + 0.09 x 109/L §Hgb reduction between the two groups, P = 0.01 I.

ease states (eg, HCV/HIV coinfection). However, the hepatic dysfunction associated with the underlying disease, chronic HCV, may augment these effects. Directly hepatotoxic agents used in combination with PEG-IFN alfa-2a can elicit additive drug toxicities. ~ For instance, when didanosine was coadministered with PEG-IFN alfa-2a, the manufacturer reported cases of fatal hepatic failure, peripheral neuropathy, pancreatitis, and lactic acidosis. 1<~22 Use of ritonavir or ritonavir plus saquinavir in HIV patients infected with hepatitis C or B virus has been associated with increased rates of

severe hepatotoxicity. 1~° The nonnucleoside reverse transcriptase inhibitor nevirapine also has been associated with a higher incidence of advanced liver fibrosis. M PEG-IFN alfa-2a, in combination with RBV, may additionally antagonize stavudine and zidovudine antiretroviral activity, secondary to inhibition of phosphorylation. >U22 Use of alternate antiretroviral agents is recommended in addition to heightened patient observation for signs of hepatotoxicity. Because PEG-IFN alfa-2a is not dependent on extensive oxidative metabolism, it is not subject to the

lO13

CLINICALTHERAPEUTICS®

inductive or inhibitory activity of other agents. PEGIFN alfa-2a is, however, a mild inhibitor of cytochrome (CYP) 450 1A2, the enzyme responsible for metabolism of drugs such as theophylline, risperidone, clozapine, tricyclic antidepressants, and caffeine.122 The described effects of inhibition on CYP450 1A2 have been documented with theophylline. 122 Treatment with PEG-IFN alfa-2a once weekly for 4 weeks in healthy subjects taking theophylline was associated with a 25% increase in the total theophylline concentration-time AUC. The resultant effects were nausea, vomiting, palpitations, and seizures. The effect was tempered by a reduction in the dose of theophylline by 25%. Attempts to define inhibitory or inductive effects on the other major CY enzymes, 2D6, 2C9, 2C19, and 3A4, have resulted in minimally observed effects.122 The substrate drugs studied were tolbutamide (2C9), mephenytoin (2C19), debrisoquine (2D6), and dapsone (3A4), with no demonstrable change in concentration-time AUC. PEG-IFN alfa-2a and methadone do not appreciably affect each otherg actions. 1~2 RBV does not affect the disposition of PEG-IFN alfa but may add to its hematologic AEs.lq,29 P R E D I C T O R S OF R E S P O N S E TO HONOTHERAPY AND EARLY S T O P P I N G RULES

Although the current standard of therapy for HCV consists of combination therapy with PEG-IFN plus RBV, there may be cases in which the patient cannot tolerate RBV and must be treated with PEG-IFN alone. 6 A review of the predictors of response for subjects receiving monotherapy with PEG-IFN alfa2a has been published.l~3 Data were compiled from the studies discussed above. 68-7° Multiple logistic regression analysis of baseline parameters was used to ascertain their predictive value for attaining an SVR. The change in viral load at weeks 4, 8, 12, and 24 and SVR were analyzed using receiver operating characteristic (ROC) curves (180-t~g/wk group). Viral response was defined as undetectable HCV RNA via polymerase chain reaction (PCR) (<100 copies/mL qualitative assay or <1000 copies/mL by quantitative assay) or >2 loglo decrease from baseline by week 4, 8, or 12 in patients in the PEG-IFN alfa-2a 180-1~g/wk group. The following baseline parameters were found to be independently predictive of an SVR: genotype 1014

non-1 (P < 0.001), serum HCV RNA levels <2 million copies/mL (P < 0.001), no cirrhosis present (P < 0.001), ALT quotient >3 (P < 0.001), body weight <85 kg (P < 0.011), age <40 years (P < 0.02), and HA1 >10 (P < 0.042). The ALT quotient is defined as the patientb average ALT values before therapy, divided by the ULN. Race and gender had no effect on the chance of achieving an SVR using the combined data of the 3 studies. Comparable predictors of response have been noted for patients receiving unmodified IFN alfa. 1~,1~5 Therapy was not withheld in subjects who did not have favorable baseline factors. The ROC analysis for patients with an HCV RNA of <100 copies/mL or a 2 loglo drop in viral load from baseline at weeks 4, 8, and 12 showed a positive predictive value (PPV) and an NPV at week 4 (PPV, 0.54; NPV, 0.91), week 8 (PPV, 0.49; NPV, 0.95), and week 12 (PPV, 0.46; NPV, 0.98). Therefore, if a patient has achieved an HCV RNA of <100 copies/mL or a >2 loglo drop in viral load from baseline at 12 weeks of PEG-IFN alfa-2a 180 l~g/wk, he or she would have a 46% (PPV) chance of achieving an SVR. However, if this fall in viral load has not been achieved by week 12, only 2% of these patients would achieve an SVR. The authors advise that for a patient receiving PEGIFN alfa-2a 180 l~g/wk as monotherapy for chronic HCV infection, consideration of whether to continue or stop therapy should be based on the HCV RNA concentration at week 12 of therapy. Twelve weeks was suggested based on the high NPV noted. The National Institutes of Health consensus development conference has adopted this recommendation. 6 P R E D I C T O R S OF R E S P O N S E T O COHBINATION THERAPY WITH RIBAVIRIN A N D EARLY S T O P P I N G RULES

Using a multiple logistic regression model, Fried et al~7 noted 3 baseline factors associated with a significant likelihood of achieving an SVR in patients receiving PEG-IFN alfa-2a with RBV. Patients infected with a non-1 HCV genotype (P < 0.001) who were <40 years of age (P < 0.001) and weighed <75 kg (P = 0.002) were more likely to have an SVR. Davis has reviewed two studies using PEG-IFN alfa-2a or -2b plus RBV to determine whether an early viral response to therapy could predict the likelihood of achieving an SVR and be used to develop early

S.J.Matthews and C. McCoy

stopping rules for therapy. ~7,~6 Data were derived from 965 patients who received PEG-IFN alfa-2a (180 pg/wk plus RBV, 1000-1200 mg/d) or PEG-IFN alfa-2b (1.5 pg/kg per week plus RBV 800 mg/d). Sixty-seven percent and 29% of patients were infected with HCV 1 or genotype 2 or 3, respectively. 1~6 The EVR which had the best NPV for SVR (98.4%) was determined to be a fall in HCV RNA from baseline by >2 log~o units or an undetectable level, as measured by a quantitative PCR method at 12 weeks of therapy27 Therefore, if therapy had been discontinued in those patients who had not demonstrated an EVR, 1.6% of subjects would have achieved an SVR had therapy been continued. Subgroup analysis by HCV genotype also showed that the above definition of EVR was applicable regardless of infection with genotype 1 or genotype 2 or 3. The NPV for patients infected with genotype 1 or genotypes 2 or 3 was 99% and 91%, respectively. Based on the findings of this analysis, the author recommended that patients infected with genotype 1 who achieve an EVR at 12 weeks should complete a full 48 weeks of combination therapy. Subjects who do not achieve an EVR should have therapy discontinued. If an EVR is achieved but HCV RNA is still detectable, patients should be retested at 24 weeks, and if still positive for HCV RNA using a sensitive qualitative PCR method, therapy should be discontinued. This recommendation is based on an analysis of patients in the PEG-IFN alfa-2b trial in which 23 patients who achieved an EVR at 12 weeks but were still HCV positive were retested at 24 weeks of therapy. None of the 10 patients who were still HCV positive at 24 weeks achieved an SVR, while 6 of 13 who were HCV negative at 24 weeks achieved an SVR. The author also concluded that patients infected with HCV 2 or 3 need not undergo viral load testing at 12 weeks and should automatically be treated for a total of 24 weeks. Using these guidelines, the decision to stop therapy at 12 weeks if there was no response for patients with HCV 1 would have cut treatment costs by 16%. The author warns about extrapolating these findings to other HCV-infected patient populations. Studies to develop even earlier therapy discontinuation rules (1 or 4 weeks) have been performed, but with only relatively few patients. ~7,~8 Larger controlled studies will be necessary to ascertain the applicability of these methods.

D O S I N G G U I D E L I N E S FOR PATIENTS W I T H C H R O N I C HEPATITIS C V I R U S

If the patient fails to demonstrate an EVR after 12 to 24 weeks of therapy, consideration of discontinuation of therapy should be entertained. <~ Pegylated Interferon Alfa-2a Monotherapy in Treatment-Naive Patients

The recommended dosage is PEG-IFN alfa-2a 180 pg/wk for 48 weeks, 1~ administered by the SC route in the thigh or abdomen. Monotherapy should be reserved for those subjects who cannot tolerate RBV or who have a contraindication to RBV therapy, such as pregnancy or creatinine clearance <50 mL/min.6,~4 If a patient fails to demonstrate an EVR after 12 to 24 weeks, therapy discontinuation should be considered (see discussion above on stopping rules for monotherapy). ~ The authors recommend that readers review the manufacturer's package insert for additional contraindications of combination therapy. ~ Pegylated Interferon Alfa-2a Plus Ribavirin in Treatment-Naive Patients

Patients infected with HCV genotypes 1 or 4 should be treated with PEG-IFN alfa-2a 180 pg/wk with RBV (1000 mg/d in 2 divided doses [<75 kg], or 1200 mg/d in 2 divided doses [>75 kg]) for 48 weeks. ~ Patients infected with HCV genotype 2 or 3 should be treated with 180 pg/wk plus 800 mg for RBV in 2 divided doses daily for 24 weeks. ~ Data are insufficient to make recommendations for patients infected with HCV genotype 5 or 6. If a patient fails to demonstrate an EVR after 12 to 24 weeks, therapy discontinuation should be considered (see discussion above on stopping rules for combination therapy). ~ Readers should refer to the manufacturerg package insert for complete dosing recommendations and precautions. ~ I N V E S T I G A T I O N A L USES

The therapeutic benefit of PEG-IFN alfa-2a is being investigated in a variety of conditions, including hepatitis B, chronic myelogenous leukemia, renal cell carcinoma, and metastatic malignant melanoma (Table V).ls-19 The results of the study by Cooksley et al is in patients with chronic hepatitis B are encouraging; however, more studies will be necessary with larger numbers of patients (with or without other therapy leg, lamivudine]) to determine the advantage

1015

r-

Table V. Summary of investigational uses of peginterferon (PEG-IFN) alfa-2a. Condition and ReFer-ence

Study Design and Patient Population

_z r-1-

Dosing Regimen

End Points of Ther-apy

Summary of Results C

Hepatitis B infection Cooksley et a115

R, OL Phase II trial of patients with HBeAg+ chronic hepatitis. 74 % M, 97% A, and 9% had or developed cirrhosis

PEG-IFN alfa-2a 90 tJg (n -- 49), 180 tJg (n = 46), or 270 ~g (n = 48) per week or 4.5 HIU IFN alfa-2a (n = 5 I) for 24 wk with a 24 wk follow-up

Loss of HBeAg, hepatitis B virus DNA levels to 500,000,ALT normalization, seroconversion to anti-HBe, and combined response (loss of HBeAC, undetectable HBV D N A levels) ITT analysis

At week 24 of follow-up, no significant change in individual parameter was noted between the PI groups and IFN group. However, when the PI groups were combined, 24% vs 12% IFN group experienced a combined response (P -- 0.036) 2% and 4% of subjects discontinued therapy due to AEs in the PI and IFN groups, respectively. Dose modifications due to laboratory abnormalities (neutropenia and increase in ALT) were more common in the PI groups (22% 30%) vs IFN (I 0%)

Chronic myelogenous leukemia Lipton et a116

PEG-IFN alfa-2a 450 tJg/week (n -- 71) median duration of therapy 358 days or IFN alfa-2a 9 MIU once daily (n -- 73) median duration of therapy 318 days

CR and HR were evaluated

During 12 months of therapy a major CR was noted in 35.2% (PI) vs 18% (IFN) (P = 0.016). A complete CR was achieved in 15.5% (PI) and 6.8% (IFN).A complete HR was recorded in 69% (PI) vs 41. I% (IFN) (P < 0.00 I).Withdrawal due to AEs occurred in 8.5% (PI) and 21.9% (IFN).AEs were those expected with IFN therapy.

Phase 1/11trial and Philadelphia chromosome positive patients with chronic phase CML

2 week run-in period with imatinib mesylate monotherapy followed by PEG-IFN alfa-2a (n = 32) for 8 weeks

Safety and tolerability of combination therapy, CR, HR, and molecular response rate were evaluated

Grade 1/2 nonhematologic toxicity common (flu-like symptoms/fatigue, skin rash, and diarrhea), Grade 3/4 cytopenias (40.6%), fewer in groups 3 and 5

69% M with median age of 41 years

Group I (n = 7) 400 mg/day imatinib + 90 lag/wk (P), group 2 (n = 6) 400 mg/d imatinib + 180 tJg/wk (P), group 3 (n = 4) 300 mg/d imatinib + 90 tJg/wk (P), group 4 (n = 8) 300 mg/d of imatinib + 180 tJg/wk (P), group 5 (n -- 7) 400 mg/d ofimatinib alone for 6 weeks, then 300 mg/d from day 43 + 180 tJg/wk (P) for 8 weeks (I 4 weeks total therapy)

R, OL trial in patients with early chronic-phase Philadelphia chromosome positive, CM L Hedian age 42 years (PI) and 48 years (IFN). DP and HPS were similar in both groups

Hochhaus et a117

Combining all treatment responses, a complete HR was achieved in 94% of subjects, 29% had a complete CR and 68% had a major CR, the ratios of BCR-ABL/ABL reached a median level of 4.6% (no statistical analysis was presented)

(continued)

®

Table V. (Continued) Condition and Re[er-ence

Study Design and Patient Population

Renal cell carcinoma iViotzer et a118 Phase II OL trial with advanced renal cell carcinoma 78% H, median age 60 years, 62% prior nephrectomy, and 27% had a favorable risk clinical features (ivISKCC criteria)

Metastatic malignant melanoma Dummer et a119 R, OL, Phase II trial Patients were stage IV AJCC metastatic malignant melanoma

Dosing Regimen

PEG-IFN alfa-2a 450 tJg/week (n = 40) for 24 weeks, each cycle lasted 28 days and no rest period between cycles, patients with stable disease or a major response (complete or partial) after 2 cycles continued on therapy until unacceptable toxicity or disease progression

End Points of Ther-apy

Based on W H O criteria, toxicity according to common toxicity criteria

Summary of Results

12.5% or patients achieved a major response (5/40), I patient had a complete response (disease-free at 15+ months on therapy), 4 had a partial response (progressionfree 5.9, 13. I, 15.4,and 19+ months), 50% had stable disease and 32.5% disease progression, 63% were alive at 12 months During the study 23% of subjects required dosage adjustment to 360 (n : 8) or 270 tJ/wk (n -- I) due to toxicity. Grade 3/4 hematologic toxicity included neutropenia (n -- 6), lymphopenia (n -- 7), and thrombocytopenia (n -- I).The most frequent AEs were fatigue, fever, nausea, headache, and rigors.

PEG-IFN alfa-2a 180 tJg (n = 48), or 360 ~Jg (n = 53), or 450 ~Jg (n = 49) given weekly for 24 weeks

Major tumor response (complete response + partial response), tolerability and safety

A major tumor response was noted in 6.3% 7.6% and 12% of subjects receiving the 180, 360, and 450 doses, respectively. Neither the time to major response, disease progression, nor duration of major response differed between dosing groups. Dosage adjustments due to AEs or laboratory abnormalities occurred in 23% 5 I%, and 4 I% of the 180, 360, and 450 dosing groups, respectively The most Frequently reported AEs included fatigue, pyrexia, rigors, nausea, myalgia, headache, and dizziness 4% 17%,and 12% of subjects withdrew due to AEs in the 180, 360, and 450 groups, respectively

"-4

M = male;A = Asian; HBeAg = hepatitis B e antigen;ALT = alanine aminotransferase;HBV = hepatitis B virus; ITT = intent to treat;AE = adverse event; CNL = chronic myelogenousleukemia;R = randomized; OL = open-label; PI = pegylated interferon alfa-2a;CR = cytogenic response;HR = hematologic response;DP = demographic parameters; HPS = Hasford prognostic scores;WHO = World Health Organization;P1SKCC= Memorial Sloan Kel:[eringCancer Center; AJCC = American Joint Commission on Cancer Statistics.

:Z

Q_

Z O

CLINICALTHERAPEUTICS®

of this therapy over existing modalities. 1~9 In the studies by Lipton et a116 and Hochhaus et al, ~7 in patients with chronic myelogenous leukemia, it is unknown whether progression-free or overall survival will be influenced in these patients. From the data available thus far, the efficacy of PEG-IFN alfa-2a in patients with renal cell carcinoma and metastatic malignant melanoma is similar to that of unmodified IFN alfa-2a. ~8 Further research will be necessary to determine the benefit of PEG-IFN alfa-2a, if any, over unmodified IFN in patients with renal cell carcinoma and metastatic malignant melanoma. CONCLUSION

PEG-IFN alfa-2a is approved in the management of treatment-naive patients with stable chronic HCV infection. The pegylation of IFN alfa-2a markedly alters the pharmacokinetic profile of the IFN product. Absorption is delayed and sustained, distribution is decreased, and elimination time is prolonged. These changes result in more constant and sustained serum concentrations and make once-weekly dosing regimens possible. Unmodified IFN alfa-2a is usually administered 3 times/wk and serum concentrations of IFN fluctuate greatly. Controlled randomized trials have shown that therapy with PEG-IFN alfa-2a, with or without RBV, is more effective in achieving an SVR than is unmodified IFN alfa-2a with or without RBV. Patients infected with HCV 1 or 4 are less likely to achieve an SVR than those infected with genotype 2 or 3. More research is necessary to address this disparity, particularly in determining how best to treat nonresponders, patients who relapse during or after therapy, children, blacks, and patients undergoing liver transplantation. Therapy with PEG-IFN alfa-2a is cost effective and increases a patientg QOL. Influenza-like side effects, such as pyrexia, myalgia, and depression, were found to appear less often than with unmodified IFN alfa-2a in 1 trial, ~7 but rates of hematologic abnormalities were not statistically different from the unmodified drug. ~7,68,69 A trial to determine the comparability of the 2 PEG-IFN products on the market (PEG-IFN alfa-2a and -2b) is in progress. Studies of the investigational use of PEG-IFN alfa2a are in early stages. Many have not reached study end points and the number of patients are generally small. More work is necessary to determine the role of PEG-IFN alfa-2a in the management of patients

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A d d r e s s for c o r r e s p o n d e n c e : S. James Matthews, R.Ph., PharmD, Associate Professor of Clinical Pharmacy, 237 Mugar Hall, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115. E-mail: [email protected]

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