title: Comparative efficacy, pharmacokinetic, pharmacodynamic activity, and interferon stimulated gene expression of different interferon formulations in HIV/HCV genotype-1 infected patients.
abstract: The effect of different formulations of interferon on therapeutic response in patients coinfected with HIV and HCV is unclear. In this study, the safety, tolerability, viral kinetics (VK) modeling and host responses among HIV/HCV coinfected patients treated with pegylated-IFN or albinterferon alfa-2b (AlbIFN) with weight-based ribavirin were compared. Three trials treated 57 HIV/HCV coinfected genotype-1 patients with PegIFN alfa-2b (1.5 µg/kg/week) (n = 30), PegIFN alfa-2a (180 µg/week) (n = 10), and AlbIFN (900 µg/q2week) (n = 17) in combination with weight-based ribavirin (RBV). HCV RNA, safety labs, and interferon stimulated gene expression (ISG) was evaluated. Adverse events were documented at all study visits. HCV viral kinetics using a full pharmacokinetic/pharmacodynamic model was also evaluated. Baseline patient characteristics were similar across the three studies. All three formulations exhibited comparable safety and tolerability profiles and efficacy. VK/PK/PD parameters for all three studies as measured by mean efficiency and rate of infected cell loss were similar between the three groups. Host responses (ISG expression and immune activation markers) were similar among the three groups. All three regimens induced significant ISG at week 4 (P < 0.05) and ISG expression strongly correlated with therapeutic response (r = 0.65; P < 0.01). In summary, a comprehensive analysis of responses to three different interferon formulations in HIV/HCV coinfected patients demonstrated similar effects. Notably, interferon-based therapy results in a blunted host response followed by modest antiviral effect in HIV/HCV coinfected patients. This suggests that future treatment options that do not rely on host immune responses such as direct antiviral agents would be particularly beneficial in these difficult to treat patients.
authors.affiliation: LIR, NIAID, NIH, Maryland; Clinical Research Directorate/CMRP, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland.
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bon
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Seerat
authors.initials: S
authors.lastname: Poonia
authors.forename: Bhavana
authors.initials: B
authors.lastname: Shivakumar
authors.forename: Shu Yi
authors.initials: SY
authors.lastname: Cai
authors.forename: Brad
authors.initials: B
authors.lastname: Wood
authors.forename: Bart
authors.initials: B
authors.lastname: Haagmans
authors.forename: Richard
authors.initials: R
authors.lastname: Lempicki
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.forename: Michael
authors.initials: M
authors.lastname: Sneller
authors.forename: Michael
authors.initials: M
authors.lastname: Polis
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D015658:HIV Infections / Q000150:complications*; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D012254:Ribavirin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a
keywords: HCV; HIV; IFN-activity; ISGs; pharmacokinetic/pharmacodynamic