Pegylated arginine deiminase lowers hepatitis C viral titers and inhibits nitric oxide synthesis

Background: The arginine-degrading enzyme, arginine deiminase conjugated to polyethylene glycol (ADI-SS PEG 20 000 mw), reduces extracellular arginine, has minimal toxicity, decreases tumor burden and improves liver function in patients with chronic hepatitis C virus infection (HCV) and inoperable hepatocellular carcinoma (HCC). Reduced extracellular arginine inhibits viral replication through unknown mechanisms. It is hypothesized that ADI-SS PEG 20 000 mw reduces HCV viral titers through nitric oxide (NO)-dependent effects. Methods: The effects of ADI-SS PEG 20 000 mw (dose, 160 IU/m²; three cycles of four once-weekly i.m. injections) on HCV titers, serum NO and plasma arginine, were evaluated using archived plasma from patients with HCC and HCV and in vitro cell model measurements of HCV replication. Results: ADI-SS PEG 20 000 mw selectively inhibited HCV replication in vitro (IC₅₀ = 0.027 IU/mL). Fifteen HCC/HCV patients completed treatment. The HCV titers were reduced by up to 99% in five out of 10 (50%) HCV-serotype 1b patients (P = 0.0093). These patients also experienced significant improvements in liver function (P = 0.0091). There were concomitant reductions of plasma arginine and serum NO levels. The HCV titer was not reduced in HCV-type 2c patients. Conclusion: Reduction of extracellular arginine by ADI-SS PEG 20 000 mw in HCC patients reduces HCV viral titers and improves liver function, possibly through suppression of NO.