A Mathematical Model of Hepatitis C Virus Dynamics in Patients With High Baseline Viral Loads or Advanced Liver Disease

Background & Aims: Patients with baseline hepatitis C virus-RNA levels (bHCV-RNA) > 6 log IU/mL or cirrhosis have a reduced probability of a sustained-virologic response (SVR). We examined the relation between bHCV-RNA, cirrhosis, and SVR with a mathematical model that includes the critical-drug efficacy (epsilon(c); the efficacy required for a drug to clear HCV), the infection-rate constant (beta), and the percentage of HCV-infected hepatocytes (pi). Methods: The relation between baseline factors and SVR was evaluated in 1000 in silico HCV-infected patients, generated by random assignment of realistic host and viral kinetic parameters. Model predictions were compared with clinical data from 170 noncirrhotic and 75 cirrhotic patients. Results: The ranges chosen for beta and the viral production rate (p) resulted in bHCV-RNA levels that were in agreement with the distribution observed in US patients. With these beta and p values, higher bHCV-RNA levels led to higher epsilon(c), resulting in lower SVR rates. However, higher beta values resulted in lower bHCV-RNA levels but higher pi and epsilon(c), predicting lower rates of SVR. Cirrhotic patients had lower bHCV-RNA levels than noncirrhotic patients (P = .013), and more had bHCV-RNA levels < 6 log IU/mL (P < .001). Even cirrhotic patients with lower bHCV-RNA levels had lower SVR rates. An increase in beta could explain the results observed in cirrhotic patients. Conclusions: Our model predicts that higher bHCV-RNA levels lead to higher epsilon(c), reducing the chance of achieving SVR, cirrhotic patients have lower SVR rates because of large pi values, caused by increased rates of hepatocyte infection.