BACKGROUND: Serum tumour necrosis factor-alpha (TNF-α) levels correlate negatively with hepatitis C virus (HCV) antiviral response. OBJECTIVES: To test the hypothesis that a single infliximab induction dose would positively influence on-treatment virological response and sustained virological response (SVR). METHODS: The present study was a phase IIIB, randomized, prospective, open-label pilot trial conducted at eight Canadian sites. Treatment-naive HCV genotype 1-infected patients 18 to 65 years of age with high serum TNF-α values (>300 pg/mL) were randomly assigned to receive a single pretreatment induction infliximab infusion (5 mg/kg) seven days before antiviral therapy (arm A) or no pretreatment (arm B). All patients received pegylated interferon α2b (1.5 μg/kg/week) plus weight-based ribavirin (800 mg/day to 1400 mg/day) for up to 48 weeks. RESULTS: Eighty-five patients (arm A [n=41], arm B [n=44]; 70% male) received pegylated interferon α2b. The mean age (48.1 years), race (81% white) and METAVIR fibrosis stage (F0–2 = 79%, F3–4 = 21%) were similar between groups. Infliximab was well tolerated without attributable severe adverse events; 56.5% completed the study (arm A [n=21], arm B [n=27]). Most discontinuations were due to virological failure at weeks 12 (n=20 [23.5%]) and 24 (n=7 [8.2%]) and did not differ according to group. Numerically lower proportions of infliximab recipients achieved rapid virological response (19.5% versus 36.4%), complete early virological response (43.9% versus 59.1%) and SVR (34.1% versus 52.3%). However, between-group differences did not reach statistical significance. No differences in adverse event profile or laboratory measures were noted. CONCLUSION: A single infliximab dose before pegylated-interferon α2b and ribavirin therapy did not result in greater viral decline during the first 12 weeks of HCV therapy or improved SVR.

To evaluate the impact of advanced fibrosis/cirrhosis on SVR rates in treatment-naive genotype (G) 1-infected chronic hepatitis C patients treated with weight-based PEG-IFN alfa-2b and weight-based ribavirin (RBV) in real-life clinical settings. Methods: The POWeR program was a prospective, noninterventional, observational study conducted at 138 community and academic centers in Canada. HCV G1-infected patients were treated for up to 48 weeks with PEG-IFN alfa-2b (1.5 μg/kg/wk) plus weight-based RBV (800-1200 mg/d). This ITT analysis includes G1 patients with a liver biopsy result (assigned METAVIR score of F1-F4) who received at least one treatment dose; HIV/HCV coinfected patients were excluded. SVR was defined as undetectable HCV RNA 24 weeks post-treatment. Statistical analysis was performed with Fisher exact test. Results: This ITT analysis involved 718 G1-infected HCV patients with liver biopsy specimens, 60% (432/718) with mild to moderate fibrosis (F1-F2), and 40% (286/718) with advanced fibrosis/cirrhosis (F3-F4). Baseline viral load results were available for 651/718 (91%) patients, revealing high viral load (HVL, >600,000 IU/mL) in 356/651 (55%) patients. In this ITT analysis, the SVR rate was 38% (272/718). SVR rates in patients with F1, F2, F3, and F4 fibrosis were 52%, 46%, 26%, and 18%, respectively. End-of-treatment (EOT) responses were significantly higher in patients with F1-F2 fibrosis than in those with F3-F4 advanced fibrosis/cirrhosis (59% vs 34%, P < 0.0001); corresponding SVR rates were 48% and 22% (P < 0.0001). Relapse after EOT response was higher in patients with F3-F4 than F1-F2 fibrosis (35% vs 18%, P = 0.0009). Patients with F1-F2 fibrosis and low viral load (LVL, ≤600,000 IU/mL; n = 172) achieved signifi - cantly higher SVR rates than those with F1-F2 and HVL (n = 219) (58% vs 41%, P = 0.0008); however, the effect of HVL on SVR was not apparent among patients with F3-F4 advanced fibrosis or cirrhosis (20% LVL vs 21% HVL, P = ns; n = 123 and 137, respectively). Conclusions: Advanced hepatic fibrosis clearly diminished SVR rates in treatment-naive G1 HCV patients treated with PEG-IFN alfa-2b plus weight-based RBV therapy. Advanced fibrosis/ cirrhosis superseded the impact of viral load, as HVL reduced SVR rates in patients with mild/ moderate fibrosis but not those with advanced disease. These results suggest that G1 patients with advanced fibrosis require additional therapeutic approaches, including modified dose and/ or duration of treatment, to optimize outcomes. Note: Abstract has been updated since submission.

Liver mitochondrial toxicity is a concern, particularly in HIV/hepatitis C virus (HCV) coinfection. Liver biopsies from HIV/HCV co-infected patients, 14 ON-highly active antiretroviral therapy (HAART) and nine OFF-HAART, were assessed by electron microscopy quantitative morphometric analyses. Hepatocytes tended to be larger ON-HAART than OFF-HAART (P = 0.05), but mitochondrial volume, cristae density, lipid volume, mitochondrial DNA and RNA levels were similar. We found no evidence of increased mitochondrial toxicity in individuals currently on HAART, suggesting that concomitant HAART should not delay HCV therapy.