title: Modelling hepatitis C virus kinetics: the relationship between the infected cell loss rate and the final slope of viral decay.
abstract: BACKGROUND
  Patients infected with hepatitis C virus (HCV) who respond to treatment with interferon-alpha plus ribavirin exhibit biphasic or triphasic viral load decreases. While the rapid first phase is indicative of the effectiveness of therapy in blocking viral production (epsilon), the slope of the final phase (lambda), that is, the second phase in biphasic decreases and the third phase in triphasic decreases, depends on the infected cell loss rate (delta). In standard models, lambda is approximately epsilondelta when the viral clearance rate c>>delta, as has been previously estimated.
  
  
  METHODS
  The relationship among epsilon, delta, lambda and the baseline fraction of HCV-infected hepatocytes (pi) was investigated in a model that included proliferation of hepatocytes.
  
  
  RESULTS
  We found that lambda was not proportional to epsilon, but rather obeyed a complex relationship that could lead to dramatic increases in estimates of delta as epsilon increased. In particular, when epsilon<99%, lambda moderately underestimated delta in patients with a small pi, whereas delta might be up to 10-fold larger than lambda in patients with a large pi. Interestingly, when epsilon>99%, delta approximately lambda regardless of pi.
  
  
  CONCLUSIONS
  Our results indicated that in patients undergoing therapy who achieved a 2 log(10) reduction in viral load (epsilon<99%), previously estimated delta values might represent only a minimal estimate of the infected cell loss rate. Moreover, combining interferon-alpha with new antiviral agents to achieve epsilon>99% should allow for a more accurate estimate of delta in HCV RNA kinetic studies. This might be important when using viral kinetics to estimate the effect of the immune response on viral elimination and the attainment of sustained virological response.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. daharih@uic.edu
authors.forename: Harel
authors.initials: H
authors.lastname: Dahari
authors.forename: Emi
authors.initials: E
authors.lastname: Shudo
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Cotler
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Layden
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D002452:Cell Count; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008954:Models, Biological; D012367:RNA, Viral / Q000302:isolation & purification; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin