HCV infection is a major health problem; the global prevalence

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6: Safety and Antiviral Activity of Albinterferon Alfa-2b Dosed Every Four Weeks in Genotype 2/3 Chronic Hepatitis C Patients VINCENT G. BAIN,* KELLY D. KAITA, PAUL MAROTTA, ERIC M. YOSHIDA, MARK G. SWAIN,* ROBERT J. BAILEY, # KEYUR PATEL, PATRICK W. CRONIN,** ERIK PULKSTENIS,** JOHN G. MCHUTCHISON, and G. MANI SUBRAMANIAN** *University of Alberta, Edmonton, Canada; University of Manitoba, Winnipeg, Canada; London Health Sciences Center, London, Ontario, Canada; University of British Columbia, Vancouver, Canada; # University of Calgary, Alberta, Canada; Duke Clinical Research Institute, Durham, North Carolina; and **Human Genome Sciences, Inc, Rockville, Maryland See Bortolotti F et al on page 1900 for the companion article in the June 2008 issue of Gastroenterology. Background & Aims: A phase 2, randomized, multicenter, open-label study evaluated the safety and efficacy of albinterferon alfa-2b in interferon- treatment-naïve patients with genotype 2/3, chronic hepatitis C virus infection. Methods: Forty-three patients were randomly assigned in a 1:1 ratio to receive subcutaneous albinterferon alfa-2b every 4 weeks (q4wk) or every 2 weeks (q2wk) with oral ribavirin 800 mg/day for 24 weeks. Primary efficacy end point was sustained virologic response (undetectable hepatitis C virus RNA 24 weeks after completion of treatment). Insulin resistance was also assessed. Results: The safety of albinterferon alfa-2b was acceptable, with a similar adverse event profile in both treatment arms. Discontinuation as a result of adverse events occurred in 4.5% and 14.3% of patients in the q4wk and q2wk arms, respectively. No dose reductions caused by adverse events were reported in the q4wk arm versus 9.5% in the q2wk arm. Rapid viral response rates at week 4 were 68.2% and 76.2% for the q4wk and q2wk arms, respectively; the corresponding sustained virologic response rates were 77.3% and 61.9%. Insulin resistance at baseline was significantly associated with lower sustained virologic response rates independent of body mass index. Conclusions: Albinterferon alfa-2b administered at 4-week intervals was safe and well-tolerated and demonstrated significant antiviral activity in patients with genotype 2/3, chronic hepatitis C virus. Insulin resistance appeared to have an independent effect on treatment response. HCV infection is a major health problem; the global prevalence of patients with chronic hepatitis C (CHC) is estimated to average 3% (range, 0.1% 5% in different countries) or up to 170 million people. 1,2 Although infection with genotype 1 HCV is predominant in North America and Europe, infection with genotype 2 or 3 generally represents 20% 30% of all patients with CHC. Significant progress has been made during the past decade in the treatment of CHC patients, with sustained virologic response (SVR) being achieved in 70% 80% of patients infected with genotype 2 or 3 after 24 weeks of treatment with pegylated interferon- (PEG-IFN- ) and ribavirin (RBV). 3 5 Given the enhanced sensitivity of genotypes 2 and 3 HCV to IFN therapy, recent studies have explored the possibility of reducing the dose or shortening treatment duration to weeks. 6 8 However, recent data from a large multicenter study demonstrated that 24 weeks of treatment resulted in superior SVR rates compared with shorter treatment durations. 8 Albinterferon alfa-2b (alb-ifn) is an 85.7-kd protein consisting of recombinant human IFN- -2b genetically fused to recombinant human albumin. In vitro assays have shown that alb-ifn retains the antiviral properties of IFN-, whereas in vivo studies in macaques demonstrated a prolonged elimination half-life compared with unmodified IFN-. 9,10 Dose-ranging phase 1/2 studies of alb-ifn in patients with CHC demonstrated an acceptable safety profile at doses up to 1200 g, an extended half-life of 150 hours, and evidence of dose-dependent antiviral activity. 11,12 Recent phase 2 studies have explored the feasibility of dosing alb-ifn every 4 weeks (q4wk) or every 2 weeks (q2wk) in IFN- treatmentnaïve patients with genotype 1 CHC 13 and in nonresponders to IFN- based regimens. 14 Recent studies have highlighted the association between host metabolic responses (ie, insulin resistance) and clinical outcomes in the treatment of CHC. 8,15,16 Insulin resistance is a major feature of the metabolic syndrome, 17 is associated with steatosis and fibrosis progression, and is an important predictor of poor response to antiviral therapy in patients with genotype 1 CHC. 18,19 Furthermore, HCV might directly induce insulin resistance through genotype-specific effects on intrahepatic insulin-signaling pathways that might also impair IFN- signaling. 15 Prior studies have evaluated insulin resistance primarily in relation to the genotype 1 HCV infection and have not examined its impact on virologic responses to IFN-based therapy in genotype 2 or 3. The present phase 2, open-label study assessed the safety and efficacy of alb-ifn administered subcutaneously q4wk or q2wk in combination with daily oral RBV in IFN- treatment-naïve patients with genotype 2 or 3 CHC. A higher alb-ifn dose of q4wk was chosen to improve on the early antiviral response observed previously with a g q4wk dose in an IFN treatmentnaïve, genotype 1, CHC population. 13 The g q2wk dose arm was previously shown to be safe in an IFN-treatment nonresponder population with CHC. 14 This regimen provides alb-ifn exposure with peak drug levels similar to those seen with the q4wk Abbreviations used in this paper: AE, adverse event; alb-ifn, albinterferon alfa-2b; ANC, absolute neutrophil count; BMI, body mass index; CHC, chronic hepatitis C; ETR, end-of-treatment response; Hb, hemoglobin; HOMA-IR, homeostasis model assessment of insulin resistance; IFN, interferon; ITT, intention-to-treat; LOD, limit of detection; LOQ, limit of quantitation; PEG-IFN-, peginterferon alfa; q2wk, every 2 weeks; q4wk, every 4 weeks; RBV, ribavirin; RVR4, rapid virologic response at week 4; SVR, sustained virologic response by the AGA Institute /08/$34.00 doi: /j.cgh

2 702 BAIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 6 regimen, but with twice the overall exposure. In addition, the present study explored the association of insulin resistance with antiviral response in this genotype 2 or 3 CHC population. Patients and Methods Patient Selection Adults with genotype 2 or 3 CHC who had not previously received IFN- therapy were enrolled in this study. Patients were excluded if they had decompensated liver disease, other potential etiologies of chronic liver disease, thrombocytopenia ( 100,000 platelets/mm 3 ), neutropenia ( 1800 neutrophils/mm 3 ), history of moderate severe psychiatric disease, immunologically mediated disease, uncontrolled thyroid disease, coinfection with hepatitis B or human immunodeficiency virus, a thrombotic disorder, alcohol or drug dependence, or a substantial coexisting medical condition. The study was performed at 7 centers in Canada between October 2005 and March Study Agents Albinterferon alfa-2b is secreted in fermentation from a host vector system by using Saccharomyces cerevisiae. The yeast cells are separated, and the product is purified by using multiple conventional chromatographic and ultrafiltration steps. Protein concentration was assessed by spectrophotometry at an absorbance of 280 nm. The compound is prepared as a sterile, single-use, lyophilized product. The Food and Drug Administration approved generic RBV RIBASPHERE (Three Rivers Pharmaceuticals, Cranberry Township, PA), in capsule form, was used. Study Design Patients were enrolled in this open-label study in 2 dose cohorts to receive subcutaneous alb-ifn q4wk or q2wk. A sample size of at least 20 patients per arm was chosen to provide initial data for alb-ifn in patients with genotype 2 or 3 CHC, rather than provide statistical power for formal hypothesis testing. All patients also received oral RBV 800 mg/day. Treatment duration was 24 weeks, with 24-week follow-up. The randomization was a 1:1 equal allocation to treatment groups, stratified by baseline viral load ( vs 800,000 IU/mL) and genotype (2 vs 3). The study protocol recommended stepwise ( 1 level) alb-ifn dose reductions from 1500 to 1200, 900, and 700 g to manage adverse events (AEs). Criteria for dose reductions for hematology included reducing the alb-ifn dose for an absolute neutrophil count (ANC) of /mm 3 or platelet count of 30,000 50,000/mm 3 and holding or delaying the dose for an ANC 500/mm 3 or platelet count 30,000/mm 3. The dose of RBV was reduced to 600 mg/day for a hemoglobin (Hb) level g/dl and was held for a level 8.5 g/dl. Likewise, dose reductions (1 3 levels or holding the dose) were recommended for managing moderate severe AEs on the basis of the discretion of the clinical investigator. The use of growth factors was prohibited in this study. The research ethics boards of participating centers approved the protocol. All patients provided written informed consent. Human Genome Sciences, Inc, Rockville, MD, sponsored the study and was responsible for data collection and statistical analyses. The study was conducted according to the International Conference on Harmonisation Good Clinical Practice standards. Hepatitis C Virus RNA and Genotype HCV RNA levels were assessed by real-time polymerase chain reaction (CE-marked COBAS Ampliprep/COBAS Taqman HCV test; Roche Diagnostics, Basel, Switzerland). The dynamic range of this assay was 43 IU/mL 69 million IU/mL. The limit of quantitation (LOQ) was 43 IU/mL, and the lower limit of detection (LOD) was 10 IU/mL. HCV genotyping was based on hybridization of the amplified segment of the 5= nontranslated region of the HCV genome, with oligonucleotide probes representing genotype 2 or 3 (Abbott Diagnostics assay; Abbott Laboratories, Abbott Park, IL). Safety Assessments Evaluation of safety included AE monitoring, physical examination, and clinical laboratory assessments (ie, hematology, serum chemistry, and urinalysis). Safety was assessed from baseline through completion of treatment and the follow-up period. The severity of AEs was graded by using the toxicity tables of the Division of Microbiology and Infectious Diseases (National Institute of Allergy and Infectious Diseases, Bethesda, MD). Efficacy Assessments The primary efficacy end point was SVR, defined as HCV RNA LOD 24 weeks after completion of treatment. Secondary efficacy end points included rapid virologic response at week 4 (RVR4) and week 12, defined as HCV RNA LOQ. End-of-treatment response (ETR) refers to patients with HCV RNA LOD at completion of treatment. Adherence to alb-ifn and RBV was calculated as the ratio of total dose received to total dose planned (on the basis of 24 weeks of planned fulldose treatment) expressed as a percent. Insulin Resistance The protocol included an exploratory analysis of insulin resistance estimated at baseline by homeostasis model assessment of insulin resistance (HOMA-IR), according to the method described by Matthews et al. 20 However, not all patients had both baseline fasting samples and protocol-specified postbaseline samples, resulting in 31 evaluable patients for analysis. The HOMA-IR score was computed with the following formula: fasting plasma glucose (mmol/l) fasting serum insulin ( IU/L) A cutoff of HOMA-IR 2 was prespecified to indicate insulin resistance, as has been reported previously. 19 Statistical Methods The modified intent-to-treat (ITT) analysis included all patients who received 1 dose of alb-ifn. For continuous outcomes, mean, median, standard deviation, minimum, maximum, and number of patients per arm were presented. For categorical outcomes such as presence of AEs or SVR, counts and percentages were reported, and testing was performed with the likelihood ratio test or Fisher exact test when expected contingency table cell counts were small (ie, 5). The presence of insulin resistance and its association with viral response were tested with Fisher exact test. All statistical tests were 2-sided and performed at a significance level of 0.05, unless otherwise specified. Because of the exploratory nature of the study, no -adjustment for multiple end points/analyses was used. All statistical analyses were performed with SAS V9.1 (SAS Institute, Inc, Cary, NC), R statistical package (R Foundation for

3 June 2008 alb-ifn IN GENOTYPE 2/3 CHRONIC HEPATITIS C 703 Table 1. Patient Characteristics Demographics q4wk (n 22) q2wk (n 21) Total (N 43) P value Mean age SD, y Gender: male 15 (68.2%) 15 (71.4%) 30 (69.8%).82 Ethnicity: white 17 (77.3%) 19 (90.5%) 36 (83.7%).41 Genotype 2 10 (45.5%) 10 (47.6%) 20 (46.5%).89 Genotype 3 12 (54.5%) 11 (52.4%) 23 (53.5%) Mean HCV RNA SD, log 10 IU/mL ,000 IU/mL 13 (59.1%) 15 (71.4%) 28 (65.1%).39 Mean BMI SD, kg/m Mean weight SD, kg Mean HOMA-IR SD Insulin resistance, HOMA-IR 2 8/16 (50.0%) 6/15 (40.0%) 14/31 (45.2%).58 SD, standard deviation. Statistical Computing), Prism (GraphPad Software, Inc, San Diego, CA), or WinNonlin (Pharsight Corporation, Mountain View, CA). Results Patient Demographics Of 52 patients who were screened, 46 were randomized, 5 failed to meet study criteria, and 1 withdrew. Three patients withdrew consent after randomization, resulting in 43 patients randomized and treated. Demographics were consistent with the overall genotype 2 or 3 CHC population in Canada and are summarized in Table 1. There were no statistically significant differences between treatment arms in demographic variables or baseline disease characteristics. Mean age was 44.4 years, and mean body mass index (BMI) was 28.2 kg/m 2. The majority of patients (65.1%, n 28) had a high baseline HCV RNA ( 800,000 IU/mL), with a mean value of 6.1 log 10 IU/mL. The study had slightly more patients with genotype 3 (53.5%, n 23) than genotype 2 (46.5%, n 20) CHC. Of 31 evaluable patients, mean HOMA-IR at baseline was 2.3; the overall proportion of insulin-resistant patients was 45.2% and was similar between genotypes. Baseline hyperglycemia (serum glucose 140 mg/dl) was noted in 1 patient, and none had history of Table 2. Summary of Safety and Tolerability Safety parameters q4wk (n 22) q2wk (n 21) P value Severe AE 6 (27.3%) 5 (23.8%).79 Discontinued 3 (13.6%) 8 a (38.1%).06 Discontinued because 1 (4.5%) 3 (14.3%).34 of AE alb-ifn dose reduction 0 2 (9.5%).23 because of AE alb-ifn dose reduction because of laboratory abnormalities 0 3 (14.3%).11 a Five patients discontinued for reasons not related to alb-inf (left the country on business; difficulty swallowing ribavirin capsules; financial pressure and inability to take time off work; stopped before the last dose to prepare for a bodybuilding competition; and lack of motivation). diabetes mellitus. Because liver biopsy was not required for inclusion in the study, data on liver fibrosis were available for only 9 patients (2 of 9 had fibrosis stage F3 and 7 of 9 had F0 2 scored by METAVIR). Table 3. Most Frequent Moderate Severe Adverse Events Reported in 10% of Patients in Either Treatment Arm MedDRA preferred term q4wk (n 22) q2wk (n 21) P value Headache 12 (54.5%) 10 (47.6%).65 Fatigue 8 (36.4%) 7 (33.3%).83 Chills 6 (27.3%) 6 (28.6%).92 Myalgia 4 (18.2%) 6 (28.6%).49 Nausea 4 (18.2%) 6 (28.6%).49 Pyrexia 4 (18.2%) 5 (23.8%).72 Weight decreased 2 (9.1%) 6 (28.6%).13 Back pain 2 (9.1%) 5 (23.8%).24 Mood altered 2 (9.1%) 5 (23.8%).24 Arthralgia 2 (9.1%) 4 (19.0%).41 Dry skin 3 (13.6%) 3 (14.3%) 1.0 Alopecia 2 (9.1%) 3 (14.3%).66 Cough 3 (13.6%) 2 (9.5%) 1.0 Insomnia 3 (13.6%) 2 (9.5%) 1.0 Tremor 1 (4.5%) 4 (19.0%).19 Vomiting 1 (4.5%) 4 (19.0%).19 Depression 1 (4.5%) 3 (14.3%).34 Dry mouth 3 (13.6%) 1 (4.8%).61 Pruritus generalized 3 (13.6%) 1 (4.8%).61 Dysgeusia 3 (14.3%).11 Productive cough 3 (14.3%).11 MedDRA, Medical Dictionary for Regulatory Activities. Table 4. Hematologic Reductions Hematology q4wk (n 22) q2wk (n 21) P value ANC 750/mm 3 2 (9.1%) 5 (23.8%) /mm (4.8%).49 Hemoglobin 10 g/dl 0 2 (9.5%).23 Platelet 50,000/mm (4.8%).49

4 704 BAIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 6 Figure 1. Change in median ANCs and platelet counts (PLT ) during the 24-week treatment duration and at weeks 4 and 12 of follow-up (FU) after completion of treatment. a P.05. Safety and Tolerability The overall safety profile of alb-ifn is shown in Table 2. The incidence of severe AEs and discontinuations caused by AEs were comparable between the 2 treatment arms. One patient in the g q4wk treatment arm discontinued as a result of moderate fatigue, 1 self-discontinued as a result of moving away, and 1 became lost to follow-up after 16 weeks of treatment. The reasons for discontinuation caused by AEs in the q2wk arm were mild fatigue, suicidal ideation, and 1 death caused by accidental morphine overdose (prescribed for injuries after a car accident). In addition, 5 patients discontinued as a result of reasons unrelated to alb-ifn (Table 2). There was a trend toward more moderate severe AEs in the q2wk arm in some cases (Table 3). The types of AEs observed were consistent with those expected with IFN therapy. The most common laboratory abnormality was a reduction in hematologic parameters (Table 4). Fewer patients in the q4wk arm experienced reductions in ANC 750/mm 3 (2 of 22 [9.1%] vs 5 of 21 [23.8%]; P.24), and no patient experienced reductions in Hb 10 g/dl or platelet counts 50,000/mm 3. In the q2wk arm, stepwise dose reductions were implemented successfully, and there were no discontinuations as a result of hematologic toxicity. The dynamics of absolute change in ANC and platelet counts during the study period are shown in Figure 1. The magnitude of reductions in ANC and platelet counts was less in the q4wk arm, reaching statistical significance with respect to mean percent reduction from baseline at weeks 8, 12, and 24 for ANC and at weeks 6, 8, 12, 16, 20, and 24 for platelet counts (P.05). In both treatment arms, the maximal reductions were observed after the first dose, the levels stabilized by week 8, and there was rapid recovery within 12 weeks of treatment completion in both treatment arms. Antiviral Activity Comparable antiviral activity was observed in both the g q4wk and q2wk treatment arms, with a high proportion of patients achieving RVR4 (68.2% for q4wk vs 76.2% for q2wk; P.56) and HCV RNA LOQ at week 12 (95.5% for q4wk vs 85.7% for q2wk; P.34) (Figure 2). Of the 39 patients who achieved HCV RNA LOQ at week 12, an ETR was achieved in 38 patients (97%). Of the remaining 4 patients, 1 achieved ETR. The SVR rates by ITT analysis were 77.3% for the q4wk arm and 61.9% for the q2wk arm (P.27; Figure 3). The lower observed SVR rate in the q2wk arm is reflective of the 5 patients who self-discontinued as a result of reasons unrelated to alb-ifn. Although this study is too small to draw definitive conclusions about baseline predictors of SVR, exploratory univariate analysis was performed. Age was significantly associated with SVR (P.04), in that patients achieving SVR were 6 years younger on average. Higher baseline alanine transaminase was observed in patients achieving SVR, although the association was not statistically significant (P.26). There was no consistent association between SVR and genotype, which was most likely due to the small subgroup sizes (Figure 3). No association was observed between SVR and sex, baseline -glutamyl transpeptidase, high baseline HCV RNA, or high BMI/ body weight. Adherence to treatment (defined as patients who received 80% of the planned, full-dose, 24-week alb-ifn treatment) showed a high SVR rate for the g q2wk treatment arm, which was comparable for the q4wk arm (85.7% vs 78.9%; P 1.0). RVR4 was highly predictive of SVR for both treatment arms; 96% of adherent patients who demonstrated an RVR4 achieved SVR. Relapse rates (detectable HCV RNA during follow-up in patients who achieved ETR) were 19.0% (4 of 21) and 27.8% (5 Figure 2. On-treatment antiviral response rates.

5 June 2008 alb-ifn IN GENOTYPE 2/3 CHRONIC HEPATITIS C 705 Figure 3. SVR rates: overall and in genotypes (Gt) 2 and 3. Figure 4. Relation between SVR and baseline insulin resistance. Boxplot representation of HOMA-IR in patients with CHC who achieved SVR and those who failed to achieve SVR. a P.002. of 18) for the g q4wk and q2wk treatment arms, respectively (P.71). Of the 4 patients who relapsed in the q4wk arm, 1 discontinued at week 16, and 3 patients completed 24 weeks of treatment and were 80% adherent to therapy; of the latter 3 patients, 2 did not achieve RVR4 (achieving RNA clearance at weeks 6 and 20, respectively), and 1 did achieve RVR4. Of the 5 patients who relapsed in the q2wk arm, 1 was counted as a relapse because of missing data (ITT analysis); 2 discontinued early at weeks 4 and 12, respectively; 1 patient had a BMI of 38 kg/m 2 and became HCV RNA negative at week 12; and 1 patient with genotype 3 CHC achieved RVR4 but had a baseline HOMA-IR of 1.9, suggesting some degree of insulin resistance. Insulin Resistance Values for HOMA-IR were available for 31 patients at baseline and during treatment. Of these patients, 14 (45.2%) had a baseline HOMA-IR 2; a lower HOMA-IR was associated with SVR (Table 5 and Figure 4). No genotype-specific differences in baseline HOMA-IR were observed. The associations between baseline HOMA-IR and RVR4, antiviral response at week 12, and SVR are shown in Table 5. Strong negative and statistically significant associations were observed between pretreatment insulin resistance and both SVR (P.02) and RVR4 (P.02), which are consistent with the high predictive value of SVR in patients who achieved RVR4. These associations maintained this level of statistical significance when controlling for patient BMI and weight in a logistic regression model. A subanalysis of patients who were 80% adherent to treatment yielded similar results. In addition, patients with insulin resistance had a slightly higher mean HCV Table 5. Association Between Insulin Resistance and Antiviral Response HOMA-IR 2 (n 14) HOMA-IR 2 (n 17) P value Mean BMI SD, kg/m Week 4 HCV RNA LOQ 6 (42.9%) 15 (88.2%).02 Week 12 HCV RNA LOQ 11 (78.6%) 17 (100%).08 SVR 6 (42.9%) 15 (88.2%).02 SD, standard deviation. RNA level at baseline (6.4 vs 6.0 log 10 IU/mL; P.17). Changes in HOMA-IR levels during the study did not reveal significant differences, although overall these levels tended to be lower in the majority of patients after completion of treatment. Median decline in HOMA-IR at 12 weeks after treatment was 0.33 (P.22). Of note, 4 of the 6 patients with a pretreatment HOMA-IR 2 who achieved SVR had significant decreases in HOMA-IR at 12 weeks after treatment. Discussion Although PEG-IFN- in combination with RBV has improved SVR rates to approximately 70% 80% in patients with genotype 2 or 3 CHC, 5 8 agents that improve convenience and tolerability while maintaining therapeutic effectiveness would be highly valued. The novel recombinant protein alb-ifn has an extended half-life that supports q2wk or q4wk dosing. In this study, alb-ifn q4wk was shown to be efficacious (SVR rate of 77.3%), with an excellent safety and tolerability profile. Furthermore, no patient in the q4wk treatment arm required dose reductions as a result of hematologic toxicity or AEs, enabling high adherence to treatment (86.4%). Although the overall safety of alb-ifn q2wk was comparable, the higher discontinuation rate in this treatment arm (largely unrelated to alb-ifn treatment) contributed to the lower observed SVR rate by ITT analysis. Incremental improvement in the SVR rate to 85.7% was observed in adherent patients in the q2wk treatment arm. Rapid viral clearance, as assessed by RVR4, has been shown to be highly predictive of SVR during PEG-IFN- therapy in patients with genotype 2 or 3 CHC. 6 8 In this study, a positive predictive value for SVR of 96% was seen in adherent patients who achieved RVR4. No genotype-specific differences were observed; previously, these have been shown to be an important determinant of response. 6 8 In addition to the small sample size, the lack of liver biopsy information to assess liver histology (fibrosis, steatosis, or steatohepatitis) in the majority of patients represents a limitation of this analysis. The impact of liver histology and genotype-specific differences in efficacy is being explored in an ongoing phase 3 study of alb-ifn. In the present study, insulin resistance was shown to be independently (of BMI and weight) associated with reduced

6 706 BAIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 6 response to alb-ifn plus RBV in patients with genotype 2 or 3 CHC. The associations between insulin resistance (HOMA-IR), liver steatosis, and response to IFN-based therapy are currently being explored extensively. In a recent study of PEG-IFN- and RBV in patients with genotype 1 CHC, the SVR rate was found to be significantly higher in patients with HOMA-IR 2 than in those with HOMA-IR The molecular basis for the genotype-specific differences seen in genotypes 1 and 3 HCV has been partly explained by interactions of the HCV core protein of genotypes 3a and 1b with insulin-receptor substrates 1 and 2 and other factors involved in the insulin-signaling pathway. 21 Furthermore, viral clearance and SVR are thought to improve insulin resistance, -cell function, and hepatic insulin-receptor substrate-1 and -2 expression. 22 Other mechanisms of insulin resistance include altered fatty-acid metabolism leading to increased circulating free fatty acids and accumulation of fatty acyl-coenzyme A esters. HCV gene expression has been shown to alter host-cell cholesterol/lipid metabolism, in particular, by inducing the expression and post-translational activation of sterol regulatory element binding proteins. 23 To further explore the associations of insulin resistance and lipogenesis with antiviral response in the present study, urine and serum samples were collected, with future efforts planned to explore lipid metabolite profiles before and during treatment with alb-ifn in this genotype 2 or 3 CHC population. In conclusion, alb-ifn in combination with RBV showed promising antiviral activity in patients with genotype 2 or 3 CHC. Phase 3 clinical trials of alb-ifn in patients with genotypes 1, 2, and 3 CHC are ongoing. References 1. World Health Organization. Hepatitis C (fact sheet no. 164). Updated October Available at: factsheets/fs164/en/. Accessed on September 14, Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005;5: Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferonalpha2a and ribavirin combination therapy in chronic hepatitis 11. Balan V, Nelson DR, Sulkowski MS, et al. A Phase I/II study evaluating escalating doses of recombinant human albumininterferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy. Antivir Ther 2006;11: Bain VG, Kaita KD, Yoshida EM, et al. A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol 2006;44: McHutchison J, Zeuzem S, Benhamou Y, et al. Interim antiviral and safety data with albumin interferon alfa-2b combined with ribavirin in a phase 2b study conducted in patients with genotype 1, IFN-naïve, chronic hepatitis C infection. Hepatology 2006; 44(Suppl 1):abstr Nelson D, Rustgi V, Balan V, et al. Sustained virologic response rates with albumin interferon alfa-2b in combination with ribavirin in non-responders to prior interferon therapy: interim results from a phase 2 study. Hepatology 2006; 44(Suppl 1):abstr Puri P, Sanyal AJ. Role of obesity, insulin resistance, and steatosis in hepatitis C virus infection. Clin Liver Dis 2006;10: Patel K, Zekry A, McHutchison JG. Steatosis and chronic hepatitis C virus infection: mechanisms and significance. Clin Liver Dis 2005;9: Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002;23: Leandro G, Mangia A, Hui J, et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a metaanalysis of individual patient data. Gastroenterology 2006;130: Conjeevaram HS, Kleiner DE, Everhart JE, et al. Virahep-C Study Arm. race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology 2007;45: Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28: Pazienza V, Clement S, Pugnale P, et al. The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. Hepatology 2007;45: Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol 2007; 102: C a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140: Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. 23. Waris G, Felmlee DJ, Negro F, et al. Hepatitis C virus induces Lancet 2001;358: proteolytic cleavage of sterol regulatory element binding proteins 6. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and and stimulates their phosphorylation via oxidative stress. J Virol ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;81: ;352: von Wagner M, Huber M, Berg T, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; Address requests for reprints to: Vincent G. Bain, MD, Professor of 129: Medicine, Director, Liver Unit, Zeidler Ledcor Center, University of 8. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a andalberta, 130 University Campus, Edmonton, Alberta, Canada T6G 2X8. ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med vince.bain@ualberta.ca; fax: ;357: This study was supported by Human Genome Sciences, Rockville, 9. Osborn BL, Olsen HS, Nardelli B, et al. Pharmacokinetic andmaryland, and Novartis Pharma AG, Basel, Switzerland. Drs Bain, Kaita, pharmacodynamic studies of a human serum albumin-interferonalpha fusion protein in cynomolgus monkeys. J Pharmacol Exp research support from Human Genome Sciences, Inc, Rockville, Mary- Marotta, Yoshida, Swain, Bailey, Patel, and McHutchison have received Ther 2002;303: land, and Novartis Pharma AG, Basel, Switzerland. Drs Cronin, Pulkstenis, 10. Liu C, Zhu H, Subramanian GM, et al. Anti-hepatitis C virusand Subramanian are employees of Human Genome Sciences. Bioactivity of albinterferon alfa-2b in cell culture. Hepatol Res 2007; Science Communications, New York, NY, provided editorial support 37: funded by Human Genome Sciences and Novartis Pharma AG.