title: Therapeutic response to peg-IFN-alpha-2b and ribavirin in HIV/HCV co-infected African-American and Caucasian patients as a function of HCV viral kinetics and interferon pharmacodynamics.
abstract: METHODS
  In this study we sought to characterize the relationship between several pharmacokinetic and pharmacodynamic parameters and virologic responses among HIV/hepatitis C virus genotype-1 co-infected patients receiving pegylated interferon-alpha-2b (peg-IFN2b) and ribavirin. We also tried to establish the underlying mechanisms that lead to poor sustained virologic responder rates observed with African-Americans against Caucasians and compared their results with those observed in a cohort of hepatitis C virus mono-infected patients.
  
  
  RESULTS
  Among our studied population, a viral decline of more than 1.0 log at day 3 combined with viral load of less than 5.0 log IU/ml at day 28 predicted sustained virologic responders with negative predictive value 100% and positive predictive value 100%. African-Americans had significantly (P < 0.01) slower hepatitis C virus viral kinetics as compared to Caucasians. However, peg-IFN2b concentrations and pharmacokinetic parameters, peg-IFN2b(max) and peg-IFN2b half-life, were similar in both groups and did not predict sustained virologic responders. Nevertheless, the pharmacodynamic parameter EC(50), estimated from nonlinear fitting of the viral kinetics together with peg-IFN2b concentration data, showed that HIV/ hepatitis C virus co-infected African-Americans have lower sensitivity to interferon-alpha thus giving rise to slower viral decline. The combined pharmacokinetic/pharmacodynamic parameter IFN(max)/EC(90) was an excellent predictor of sustained virologic responders, thus showing the importance of maintaining peg-IFN2b levels above EC(90) to achieve successful treatment.
  
  
  CONCLUSIONS
  Further studies are needed to evaluate whether these pharmacodynamic predictions are a result of differential host response to peg-IFN2b or other viral factors conferring relative resistance to peg-IFN2b.
authors.affiliation: Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Lynn
authors.initials: L
authors.lastname: Rozenberg
authors.forename: Bart L
authors.initials: BL
authors.lastname: Haagmans
authors.forename: Avidan U
authors.initials: AU
authors.lastname: Neumann
authors.forename: Grace
authors.initials: G
authors.lastname: Chen
authors.forename: Mary
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Levy-Drummer
authors.forename: H
authors.initials: H
authors.lastname: Masur
authors.forename: Robin L
authors.initials: RL
authors.lastname: Dewar
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.forename: Marcelo
authors.initials: M
authors.lastname: Silva
authors.forename: Maria S
authors.initials: MS
authors.lastname: Viola
authors.forename: Michael A
authors.initials: MA
authors.lastname: Polis
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000328:Adult; D001741:Black or African American; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000208:ethnology / Q000378:metabolism / Q000821:virology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000208:ethnology / Q000378:metabolism / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load; D044465:White People
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b