INTRODUCTION ----------------------------------------------------------------------------2

The purpose of this meeting is: 1) to update the Antivirals Advisory Committee on the data supporting the safety and efficacy of PEGASYS (Pegylated Interferon alfa 2a) in combination with COPEGUS(ribavirin) for the treatment of adult patients with chronic hepatitis C infection and 2) to discuss questions about dosing that may result in request for postmarketing studies.

On -------------------, Hoffman-LaRoche Corporation submitted to FDA a License Application for PEGASYS (peginterferon alfa 2a) and COPEGUS

(ribavirin, USP) combination therapy for the treatment of chronic hepatitis C.

Peginterferon alfa-2a (PEG-IFN) 180 mg administered sc qw

Ribavirin 200 mg/tablet administered po daily in split doses (final dose 1000 or 1200 mg depending on body weight) and taken with food.

Comparator product: Interferon alfa-2b 3 (IFN) 3 MIU administered sc tiw

Ribavirin 200 mg/capsule (Schering/ICN brand) administered po

daily in split doses (final dose 1000 or 1200 mg depending on body

weight) and taken with food.

HCV causes 20% of all cases of acute viral hepatitis and 70-90% of all cases of chronic viral hepatitis. The acute infection is asymptomatic in the majority of cases. Recovery from acute infection occurs in approximately 15% of adults with the remainder developing chronic hepatitis C infection. Patients with chronic HCV infection typically have persistent viremia and in most cases abnormal ALT levels.

In the US, approximately 50% of children and 85% of adults infected with HCV develop chronic hepatitis leading to an overall prevalence of 2.7 million individuals in the US with chronic hepatitis C infection. After decades, liver cirrhosis develops in about 20% of adults with chronic HCV infection within 20 years and 30% within 30years. In children with chronic HCV the incidence of cirrhosis is lower compared to adults possibly due to the shorter duration of infection or a slower progression of disease. The development of cirrhosis is associated with liver failure, with portal hypertension with its related complications and with the development of hepatocellular carcinoma. Chronic HCV infection causes approximately12,000 deaths per year and is the primary reason for liver transplantation in the US. Genotype 1 is the most prevalent HCV genotype in the US (approximately 70% overall) and is less likely to respond to treatment compared with HCV genotypes 2 and 3. In addition to genotype 1, other factors associated with diminished response to treatment are: high circulating HCV viral load (>2x 106 copies/ml serum) and the presence of cirrhosis on histology.

Alpha interferons were the first antiviral agents to be licensed for the treatment of patients with chronic hepatitis C. Alpha interferons can induce loss of detection of circulating HCV RNA, normalization of serum transaminase levels, and a modest reduction in liver inflammation. At 6 months following completion of alpha interferon monotherapy, the proportion of patients with undetectable HCV RNA is low (<20%). The addition of ribavirin to alpha interferon treatment roughly doubles the proportion of responders to approximately 40%. At the time the safety and efficacy trials for this submission were undertaken, alpha interferon and ribavirin represented the most efficacious therapy available for chronic hepatitis C. Peginterferon alfa 2b, both as monotherapy and in combination with ribavirin, was approved for the treatment of chronic hepatitis C in 2001.

Arguably, the risk/benefit of interferon alfa monotherapy for chronic HCV is no longer acceptable especially for patients with poor prognostic factors such as genotype 1 or high viral titers. Fewer than 10% of patients with chronic hepatitis C with cirrhosis or genotype 1 achieve sustained viral response with interferon alfa monotherapy.

There is no definitive evidence that the loss of detection of circulating HCV RNA six months after the end of treatment (sustained viral response), which is the primary outcome measure of most studies, will decrease the incidence of serious long-term outcomes including progression of liver disease to cirrhosis and the development of hepatocellular carcinoma.

Alpha interferons adversely affect a number of organ systems and may induce a number of serious toxicities including neuropsychiatric disorders, autoimmune disorders, ischemic disorders and disorders of host defenses. The majority of patients on alpha interferons experience fatigue and flu-like symptoms; alpha interferons also commonly induce nausea, vomiting, anorexia and weight loss. They may induce liver decompensation in patients with chronic liver failure. Interferons are abortifacients.

Toxic effects of ribavirin include hemolytic anemia, teratogenicity, embryocidal activity and mutagenesis. The main dose-limiting toxicity of ribavirin is hemolytic anemia which if severe may induce ischemic cardiac or neurologic events. The anemia is usually reversible following discontinuation of treatment.

Study Hypothesis: The pegylation of interferon alfa 2a will increase the treatment response and tolerability of that agent against chronic hepatitis C due to the improved pharmacokinetic properties that result from pegylation with increased exposure to more consistent serum concentration for 7 days and the possibility of once a week dosing.

The clinical development program comprised 19 phase 1 clinical pharmacology studies (14 to support PEG-IFN alfa-2a and 5 to support Ribavirin). The 14 clinical pharmacology studies of PEG-IFN alfa-2a were part of the monotherapy development program. Table 1 lists the principal clinical safety and efficacy studies.

Including patients participating in the two pivotal studies to be discussed, a total of 1377 patients have received PEG-IFN alfa 2a alone in a range of doses but predominantly 180mg sc as part of the phase 1 clinical pharmacology studies; 357 patients have been exposed to Roche’s ribavirin alone and 1843 have been exposed to the combination of PEG-IFN-alfa 2a plus Roche’s ribavirin

The phase 2 study, NV15800 was a randomized, open label study in patients with chronic hepatitis C without cirrhosis in which all patients received PEG-IFN alfa-2a and ribavirin combination therapy. The major focus of this study was to ascertain the impact of food upon ribavirin absorption as well as the safety of the combination of peginterferon alfa 2a and ribavirin. Given the very few patients studied, the conclusions that can be drawn from this study are very limited. The study will not be considered further here. No dose-ranging studies of PEG-IFN in combination with ribavirin were carried out.

The dose of peginterferon was selected on the basis of analyses of data of peginterferon monotherapy. The efficacy of peginterferon alfa-2a monotherapy in adult patients not previously treated was evaluated in four clinical studies. These trials were comparative, open-label, randomized, with 48-week of therapy followed by 24 weeks of follow-up. A total of 1600 patients were enrolled, 996 patients were treated with PEGASYS.

The number of responders to peginterferon alfa-2a monotherapy was higher than the number of responders to unpegylated interferon alfa-2a monotherapy. The addition of ribavirin to unpegylated interferon alfa increases the number of responders. The sponsor hypothesized that the addition of ribavirin to peginterferon alfa-2a would further increase the number of responders.

The rationale for dose of peginterferon alfa-2a selected for the phase 3 studies was in part based on the analysis of treatment response and safety in peginterferon monotherapy study NV15496. In that study the sustained viral response achieved by both 135mg and 180mg doses of peginterferon once weekly SC were indistinguishable. The sponsor observed that the histologic responses in the peginterferon 135mg group and the interferon alfa-2a group were not different. However the histologic response of the peginterferon 180mg group appeared to be higher than that of the interferon alfa-2a group. The incidence of adverse events appeared to be similar in the 135mg and 180mg peginterferon dose groups. The sponsor concluded that the 180 mg peginterferon dose should be tested in the pivotal studies.

The dose of ribavirin chosen for study was 1000 or 1200 mg po daily based on body weight < or > 75 kg. This is the recommended dose for interferon alfa-2b and ribavirin combination therapy. Patients were instructed to take ribavirin with food because of evidence that food increases the bioavailability of ribavirin.

"A Phase III, Randomized, Multicenter Efficacy and Safety Study

Comparing the Combination of Pegylated-Interferon alfa 2a and Ribavirin

to REBETRON in the Treatment of Patients with Chronic HCV Infection"

Randomized, multicenter, international, partially blinded, active controlled (REBETRON) phase 3 study of two Peginterferon alfa 2a regimens in 1149 treatment naïve patients with histologically, serologically and virologically documented chronic hepatitis C. Subjects were randomly assigned to one of three treatment arms: Peginterferon alfa 2a monotherapy, peginterferon alfa 2a combined with ribavirin, or Intron A‚/Rebetol‚ on a 1:2:2 basis. Subjects were treated for 48 weeks and were followed for 24 weeks.

Ribavirin

The dose adjustment guidelines for ribavirin were the same across study groups. Ribavirin was to be reduced to 600 mg per day if (1) a patient without significant cardiovascular disease experienced a fall in hemoglobin to <10 g/dL and >8.5 g/dL or (2) a patient with stable cardiovascular disease experienced a fall in hemoglobin by >2 g/dL during any 4 weeks of treatment. Once a patient’s ribavirin dose was held due to either a lab abnormality or adverse event, the investigator could attempt to increase the dose of ribavirin to 600 mg daily, and further to 800 mg daily. However, it was not recommended that ribavirin be increased to its original assigned dose (1000-1200 mg).

Peginterferon and interferon

If a patient experienced a clinically significant adverse event or a laboratory abnormality, the dose of peginterferon or interferon was lowered to pre-specified levels

based on the degree of severity of the event as shown below.

The table below shows the guidelines for lowering the dose of peginterferon when patients experienced neutropenia or thrombocytopenia.

The dose of interferon was to be reduced to 1.5 MIU tiw if a patient experienced a fall in white blood count to <1.5 X 109/l ( but >1.0x109/l) or a fall in neutrophil count to <.75x109/l (but >.5x109/l) or a platelet count to <50x109/l (but >25x109/l)

If four or more consecutive doses of test drug were held or otherwise not administered (i.e. the patient had not received test medication for more than 28 days), the patient was considered intolerant of the test medication or non-compliant.

Men and women outpatients ≥ 18 years of age with serologically and histologically proven CHC, elevated ALT, and detectable HCV RNA. Excluded were patients with HIV, other forms of hepatitis, a history of severe psychiatric or cardiac disease, severe seizure disorders, severe retinopathy, or previous interferon or ribavirin therapy.

The primary outcome was a combined endpoint of non-detectable serum HCV-RNA (<100 copies/ml by a commercial PCR assay) and normal serum ALT activity after the 24-week treatment-free follow-up period (nominally 72 weeks).

The following were the principal secondary outcomes:

-End-of-treatment virologic and biochemical responses

-Sustained virological and biochemical responses

-End-of-follow-up histological changes from pretreatment.

In both studies, study subjects who did not demonstrate either a virologic response (HCV negative or ≥2 log10 decrease ) or a biochemical response(normal ALT) could be withdrawn from the study by 12 weeks of therapy and were to be withdrawn from study if unresponsiveness persisted by 24 weeks.

One certified laboratory performed all HCV RNA PCR determinations. Local laboratories could be used for repeat testing required for safety assessments.

Patients were assessed for safety at weeks 1, 2, 4, 6 and 8 and then every 4 weeks during treatment and follow-up. Patients who were prematurely withdrawn from treatment were followed for 12 weeks after treatment. Following the initiation of treatment, quantitative viral titers were also obtained at weeks 4, 12 and 24 only if the qualitative titer was positive. Qualitative titers (AMPLICOR) were obtained at weeks 4, 12, 24, 48, 60 and 72. Serum ALT activities were obtained by the same schedule for safety assessments. The liver biopsy at baseline and week 72 was reviewed by one pathologist.

Primary efficacy analysis

Amendment D: Three hundred additional patients were added to protocol to ensure that the study could detect a statistically significant treatment difference of at least 10% improvement of PEG-IFN plus ribavirin over REBETRON. This decision was based on a blinded interim analysis of week 4 virological data. The total study population was raised to 1125 and the 1:2:2 randomization was retained. A liver biopsy at 48 weeks in a portion of patients was added (50 in each arm) to evaluate safety issues. The week 12 discontinuation policy for non-responders was made optional in light of literature reports of success with 24 weeks.

Amendment E, G: Previously, 150 patients (13% of total) were scheduled to have an end of treatment biopsy. To increase concordance with other studies, the numbers and timing of liver biopsies were changed to 225 patients or 20% at end of follow-up. Twenty patients treated with Rebetron‚ would have end-of-treatment liver biopsies.

Amendment H: The definition of sustained virologic response was two consecutive HCV RNA measurements ≥ 21 days apart measured ≥ 408 days with the lower limit of week 60. To be considered a responder, a patient had to have normal serum ALT activity and no detectable virus at the end of untreated-follow-up period

There were 81 participating study centers in US, Europe, Australia, Taiwan, Mexico, and Brazil. Differences in treatment response between geographic regions have been observed in studies of interferon therapies. These differences are attributable at least in part to differences in the distribution of baseline demographic and disease factors that predict response to treatment. For this reason the distribution of baseline variables, the treatment responses, and the safety data were analyzed by subdividing the study population into U.S., non-US, Europe, and "Other". The centers in the US contributed 41% of the patients participating in the study.

1149 patients were randomized; 28 patients were randomized but did not receive any treatment. The two comparison arms had equivalent numbers of individuals randomized but untreated. Table 3 shows that somewhat fewer subjects in the PEG-IFN monotherapy and IFN-alfa 2b+ ribavirin arms completed 48 weeks of treatment compared to the PEG-IFN +ribavirin arm (67% versus 76%). This difference was due to higher numbers of subjects withdrawn from the protocol for futility at 24 weeks in those two arms. The remainder of the withdrawals from the protocol were mostly for adverse events or laboratory abnormalities (See review of safety).

The mean age of study participants was approximately 43 years and this mean is within the age group (30-49 years of age) with the highest HCV prevalence in the US. The study protocol excluded pediatric patients. There was no upper age limit but very few elderly patients were enrolled. The mean weight of participants was approximately 79 kg in all three arms with the recorded range from 42 to 156 kg. The subjects enrolled in US centers were on average heavier than subjects enrolled in non-US centers (See Table 4). Peginterferon alfa-2a and interferon alfa-2b were administered as fixed doses and the ribavirin was crudely weight-adjusted based on body weight above or below 75 kg. Given the wide range in body weights of study subjects, the differences in body weight between subjects in US and Non-US centers, and the fixed or crude weight-adjusted dosing, the analysis of safety and efficacy by body weight would be an important review objective.

Approximately 2/3 of the participants were men. This gender distribution is consistent with the higher prevalence of HCV in men. Approximately 84% of participants were Caucasian. Overall 5% of participants were black, (11% of US participants). Approximately 5% of participants both in the total population and in the US sites were Hispanic. Since the prevalence of HCV in the US is higher in African Americans and in Hispanics compared to Caucasians, these two ethnic minorities were under-represented in the study. Response to interferon therapy is lower in African Americans and in Hispanics for reasons not fully understood. It should be noted that the sponsor has already undertaken studies to assess the safety and efficacy of peginterferon alfa-2a and ribavirin combination therapy in patients from these ethnic groups.

Table 4 summarizes the patient demographics in the treated population. US patients weigh more, have somewhat higher body mass index and are also older compared to Non-Us patients.

a Analysis group: Treated patients

The demographic characteristics were reasonably well distributed across the treatment groups (not shown).

The means of acquisition of HCV infection was similar across treatment groups (Table 5). The predominant mode of transmission was injection drug use. The second highest source of HCV in participants was sporadic or unknown and the third most common was transfused blood products.

Table 5. Infection Source and HCV Genotype PEG-IFN alfa-2a N = 227 N % PEG-IFN alfa-2a Ribavirin 1000-1200mg N = 465 N % IFN alfa-2b Ribavirin 1000-1200mg N = 457 N % Infection Source             Injection drug use 82 (36) 197 (42) 182 (40) Transfusion 47 (21) 87 (19) 101 (22) Unknown 72 (32) 134 (29) 127 (28)

Approximately two thirds of participants in the study were infected with genotype 1 (Table 6); the number was somewhat higher in US study patients compared to non-US patients (see Table 7). The distribution of genotype 1 observed in the study patients is consistent with the incidence of this genotype in HCV infected patients in the US population. Among the non-genotype 1, only types 2 and 3 were significantly represented in the study. The proportion of patients with high viral load was evenly distributed across the three study arms for the entire population and in geographic subgroups. No relationship has been established between the rate of disease progression or severity of liver disease and the HCV genotype or the number of circulating HCV-RNA copies. Both viral genotype and viral load predict response to interferon treatment, however, with high viral load genotype 1 having the least likelihood of response to interferon treatment.

It is also established that patients with cirrhosis have a lower likelihood of responding to interferon therapy. The proportion of patients who had cirrhosis at baseline was numerically similar across the study arms with 25 (17%) of PEG-IFN monotherapy, 40 (13%) of PEG-IFN/ribavirin and 32 or (11%) of the Interferon alfa-2b/ribavirin having histologic evidence of cirrhosis at baseline. The incidence of cirrhosis was numerically lower in Non-US centers (Europe in particular) compared to the US centers (Table7).

a Analysis group: Treated patients

The primary comparison in this study was between PEG-IFN alfa 2a plus ribavirin and IFN alfa 2b plus ribavirin. The purpose of the PEG-IFN monotherapy arm was to provide information on the impact of ribavirin on both efficacy and safety when used in combination with PEG-IFN. The intent to treat population was used for the efficacy analysis and was defined as all subjects randomized whether or not they received treatment.

The primary endpoint in this study was the combined sustained (24-weeks post-treatment) virologic and biochemical response. Table 8 shows a numerical difference (6%) that favors peginterferon alfa-2a and ribavirin over interferon alfa-2b and ribavirin. The p value for the difference was 0.057. Peginterferon alfa-2a and ribavirin combination therapy was superior to peginterferon alfa-2a monotherapy.

1Intent- to-treat population

2Global test of treatment difference: P<0.001

Table 9 shows a secondary efficacy analysis using sustained virologic response at 24 weeks post treatment. In this analysis, the treatment difference between PEG-IFN alfa 2a plus ribavirin and IFN-alfa-2b plus ribavirin is 8% and this difference does achieve statistical significance. Both regimens performed better than the PEG-IFN monotherapy which was consistent with expectations. There is a good concordance between biochemical and virologic response. However in a few patients who achieved a sustained virologic response, transaminase levels had not returned to normal by endpoint. The possibility exists that in some of these cases the ALT elevation might be unrelated to CHC.

1Intent- to-treat population

2Global test of treatment difference: P<0.001

Other secondary endpoint consider virologic and biochemical response at either the end of follow-up (72 wks) or at the end of therapy (48 wks) and are shown in Table 10. These endpoints provided evidence in support of the superiority of peginterferon alfa-2a and ribavirin, over interferon alfa-2b and ribavirin.

1Intent-to-treat population

Efficacy endpoints for pivotal trials of interferon-based therapies for CHC have evolved with the advent of validated assays for HCV RNA. The first interferon therapies were licensed based on demonstration of normalization of serum transaminase levels (biochemical response) supported by improvement in liver histology. Subsequently biochemical response combined with loss of detection of HCV RNA (virologic response) became a standard primary efficacy outcome. The agency’s current thinking is that virologic response alone is appropriate as a primary efficacy endpoint. The Anti-Viral Drugs Advisory Committee on December 12, 2001, endorsed the use of a sustained virologic response 24 weeks after the completion of treatment. While the p value for the pre-specified primary endpoint comparing PEGASYS and COPEGUS with REBETRON was 0.057 , a number of secondary endpoints including virologic response alone or biochemical response alone provided strong support for the superiority of peginterferon alfa-2a and ribavirin over interferon alfa-2b and ribavirin.

Finally, changes in liver histopathology in response to treatment were evaluated in a subset of patients. A liver biopsy with histology consistent with chronic hepatitis C within 12 months of enrollment was required for enrollment in the study. Paired liver biopsies were obtained after treatment in approximately 20% of patients. Response to treatment based on Histologic Activity Score was defined as >2 point decrease in score from baseline. Over 70% of patients in all treatment groups were observed to have a modest reduction in inflammation compared to baseline (Table 11). Approximately 20% of patients had no change in inflammation score and 3-5% had an increase in inflammation score.

When histologic response is compared to sustained viral response it would appear that those patients who had a sustained virologic response are more likely to have a histologic response. Overall, the number of subjects with paired biopsies is small, the improvement in histology from baseline is modest and there are no statistically significant differences between the treatment groups.

Patients with HCV RNA negative at the end of treatment but positive at the end of follow-up (24 weeks post-treatment) were considered to have relapsed. The proportion of patients who relapsed (positive or missing HCV-RNA) was highest in the PEG-IFN monotherapy group. As for the two combination therapy groups, the relapse rate in the PEG-IFN alfa 2a/ribavirin group was higher than in the IFN alfa 2b/ribavirin group (see Table 12). It should also be noted that the end of treatment response rate of the PEG-IFN alfa 2a/ ribavirin group was higher than that of the IFN-alfa 2b/ribavirin group.

The majority of individuals who ultimately achieve a sustained virologic response have negative HCV-RNA at 12 weeks of therapy. Those proportions were 75% in the PEG-IFN monotherapy group, 84% in the PEG-IFN/ribavirin group and 78% in the IFN/ribavirin group. By 24 weeks, those numbers had increased to 91% in the PEG-IFN monotherapy group, and 95% in the two combination therapy groups.

The attainment of a negative HCV-RNA at 12 weeks also has predictive value for the success of a subject in achieving a sustained viral response (see Table 13). In the PEG-IFN alfa 2a plus ribavirin group, 205 of the 279 patients who were HCV RNA negative at 12 weeks achieved sustained virologic response for a positive predictive value of 73%. On the other side, 134 of 174 patients who ultimately did not achieve sustained virologic response had a positive HCV-RNA at 12 weeks, a 77% negative predictive value. Those same positive and negative predictive values for the IFN-alfa 2b/ ribavirin were similar with a 74% positive predictive value and 82% negative predictive value. In contrast, the positive predictive value for the monotherapy arm was 54% with a negative predictive value of 88% presumably reflecting the lower efficacy of the monotherapy.

This study allowed for continuation of participation beyond 24 weeks for patients who had either evidence of virologic response (negative HCV RNA or ≥2 log 10 drop in viral titer) or evidence of a biochemical response (normalization of ALT). Expanding the definition of viral response to include subjects who have a positive HCV RNA but whose viral titer has decreased ≥2 log 10 permits even greater negative predictive value. As shown in Table 14, of the subjects receiving PEG-IFN alfa 2a/ribavirin only two not meeting this definition ultimately had a sustained viral response for a negative predictive value of 97%.

a2 consecutive HCV RNA negative at >12 wks post-treatment

Patients with viral genotype 1, regardless of viral load, had a lower response rate compared to patients with other genotypes (Table 15). Patients with high viral load (>2x106 copies of HCV RNA/ml serum) also had lower responses compared to patients with low viral load.

Patients with both genotype 1 and high viral load were least likely to respond both in the PEG-IFN alfa 2a/ribavirin group (39%) and in the IFN/ribavirin group (32%). The influence of viral load appeared to be less in non-genotype 1 patients in the PEG-IFN/ ribavirin group.

1Intent-to-treat population

The effect of age, gender, ethnicity, cirrhosis on treatment response was examined in the three study groups. The effects were consistent across groups and were also consistent with previous observations (see Table 16). The effect of these factors on treatment response was also examined by geographic region and did not yield notable new hypotheses (not shown).

In general, younger patients had higher treatment responses with all three regimens compared to older patients (Table 16). The efficacy in US patients was lower than in non-US at most age categories.

atreated population

Overall there was little difference between the SVR rate of men and women in this study.

Response rates were lower in Black and Hispanic patients compared with the response rate in Caucasians. African Americans made up the vast majority of Black patients enrolled (48/53). The response rate in Asian patients on the other hand was higher than Caucasians. The validity of these observations is somewhat questionable due to the very low numbers of minority patients that were enrolled in this study.

The unfavorable effect of cirrhosis on treatment response was observed in all three treatment arms. In each arm, individuals with cirrhosis had a 9-14 point lower percentage of viral response. PEG-IFN alfa-2a and ribavirin combination therapy induced higher responses than IFN alfa 2b and ribavirin combination therapy (41% versus 35%). The US versus non-US trends favoring the latter are seen again in these subgroups.

Roughly 40% of study patients were enrolled in the US; 40% of the other patients were enrolled in Europe, and roughly 20% were enrolled in Australia, Taiwan, Mexico, Brazil. Table 16 shows that overall the proportion of virologic responders in each of the treatment arms was higher in patients enrolled at non-US centers compared to patients enrolled at US centers. Various prognostic factors were explored to examine this treatment difference. The difference in response was attributable to a higher proportion in US compared to non-US in poor prognostic baseline variables including older age, higher body weight, higher proportion of HCV1 or cirrhosis.

Exploratory analyses were conducted to analyze treatment effect in US and non-US populations in subgroups defined by body weight, genotype, and baseline viral titer. These analyses are provided in Appendix 1 (see Tables 17 and 18). A logistic regression analysis including genotype, viral titer, geographic region, and weight found that the geographic region was not a significant factor contributing to treatment response. Thus, the differences in sustained virological response for the overall population observed between US and non-US patients appear to be largely due to imbalance in other important prognostic factors for response.

Nearly all patients experienced one or more adverse events (Table 19). The incidence of severe adverse events was similar across groups. Serious adverse events were numerically higher in the peginterferon groups (12%) compared to the interferon/ribavirin group (9%). The incidence of treatment discontinuation for adverse events or laboratory abnormalities was 10-11% in the combination therapy groups and 7% in the peginterferon monotherapy group overall. The incidence of dose modification of the interferon therapy for adverse event or laboratory abnormality was higher for peginterferon (27-32%) compared to interferon (18%). The most common reason for dose modification was neutropenia and/or thrombocytopenia. The incidence of withdrawal from treatment was not different between the interferon combination arms. Also, the incidence of treatment discontinuation or modification was not different in the US centers compared to non-US centers. The higher rates of SAEs and dose modification suggest the potential for greater toxicity of PEG-IFN and ribavirin compared to IFN and ribavirin.

The incidence of new adverse events was summarized for the treatment period, the post-treatment period and the treatment and post-treatment periods combined

Table 20 shows that the incidence of the most common adverse events for the treatment plus post-treatment period was not higher in the peginterferon/ribavirin group compared to the interferon/ribavirin group.

The most common adverse event was a systemic reaction consisting of fatigue/weakness/asthenia with or without headache, fever, chills/rigors. The second most common group of adverse events was neuropsychiatric with irritability, insomnia, impaired concentration/memory impairment, depression, anxiety/nervousness. The musculoskeletal system was commonly affected with myalgias and arthralgia. GI manifestations were also prominent (nausea, vomiting, anorexia, weight loss, abdominal pain, diarrhea). Finally skin manifestations included alopecia, dermatitis, pruritus, and injection site reactions.