A mathematical model of hepatitis C virus dynamics in patients with high baseline viral loads or advanced liver disease.
OBJECTIVE
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 (epsilonc; 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 epsilonc, resulting in lower SVR rates. However, higher beta values resulted in lower bHCV-RNA levels but higher pi and (epsilonc), 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 epsilonc, reducing the chance of achieving SVR; cirrhotic patients have lower SVR rates because of large pi values, caused by increased rates of hepatocyte infection.
Dahari
Harel
H
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
Layden-Almer
Jennifer E
JE
Kallwitz
Eric
E
Ribeiro
Ruy M
RM
Cotler
Scott J
SJ
Layden
Thomas J
TJ
Perelson
Alan S
AS
D000328:Adult; D001706:Biopsy; D049109:Cell Proliferation; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000097:blood* / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D012367:RNA, Viral / Q000097:blood*; D019562:Viral Load; D014779:Virus Replication / Q000502:physiology
D012367:RNA, Viral