Viral kinetics in hepatitis C or hepatitis C/human immunodeficiency virus-infected patients

Abstract

Background and aims: Kinetic modeling of hepatitis C virus (HCV) response to interferon (IFN)-based therapy provides insights into factors associated with treatment outcomes. HCV/human immunodeficiency virus (HIV)-co-infected patients show lower response rates vs. HCV-monoinfected patients. Reasons for this remain unclear. This study evaluated kinetic parameters and treatment responses in co-infected vs monoinfected patients.

Methods: Co-infected patients were randomized within a US multicenter trial (ACTG 5071) to receive pegylated-interferon (PEG-IFN) alfa-2a + ribavirin vs. IFN alfa-2a + ribavirin. Monoinfected controls were matched prospectively for treatment, genotype, age, sex, race, and histology. Quantitative HCV-RNA testing was performed at hours 0, 6, 12, 24, 48, and 72; days 7, 10, 14, 28, and 56; and weeks 12, 24, 48, and 72.

Results: Twelve HCV/HIV-co-infected and 15 HCV-monoinfected patients underwent viral kinetic sampling. Among HIV-positive patients the mean CD4(+) count was 325 cells/mm(3). Seventy-five percent of patients were genotype 1. The HCV-RNA level was undetectable at 72 weeks in 25% and 40% of co-infected and monoinfected patients, respectively. Phase 1/2 declines, free virus clearance rate, and infected hepatocyte death rate were not affected by co-infection status but differed by treatment. Efficiency (epsilon) > or = 90% at 60 hours was associated with viral clearance ( P = .02). Modeling with pooled parameters suggests baseline viral load is a key factor in time to response in this cohort. Predicted clearance time increased by 28% in co-infected patients.

Conclusions: Co-infection status did not affect key kinetic parameters. Among kinetic parameters, efficiency was associated significantly with viral clearance. Co-infected patients may require longer treatment duration than monoinfected patients given their generally higher baseline viral loads.

Figures

Figure 1

Panel of model fit and observed viral loads over time for HCV/HIV co-infected patients with convergence. Viral load (log10 IU/mL) is shown on the y-axis. Days are shown on the x-axis. Dots represent observed values, solid line represents model fits. Fitted values are shown through the time points used in the model for each individual patient. (14 days for patients in this panel). The lower limit of assay detection is represented by the thin solid line at log10(600) IU/mL.

Figure 2

Panel of model fit and observed viral loads over time for HCV monoinfected patients with convergence. Viral load (log 10 IU/mL) is shown on the y-axis. Days are shown on the x-axis. Dots represent observed values, solid line represents model fits. Fitted values are shown through the time points used in the model for each individual patient. For patients C03 and C10, using data from days 28 and 56 allowed much improved parameter estimation. The lower limit of assay detection is represented by the thin solid line at log10(600) IU/mL.

Figure 2

Panel of model fit and observed viral loads over time for HCV monoinfected patients with convergence. Viral load (log 10 IU/mL) is shown on the y-axis. Days are shown on the x-axis. Dots represent observed values, solid line represents model fits. Fitted values are shown through the time points used in the model for each individual patient. For patients C03 and C10, using data from days 28 and 56 allowed much improved parameter estimation. The lower limit of assay detection is represented by the thin solid line at log10(600) IU/mL.

Figure 3

HCV/HIV co-infected patients without model convergence. Viral load (log 10 IU/mL) is shown on the y-axis. Days are shown on the x-axis. Only observed values are shown. The lower limit of assay detection is represented by the thin solid line at log10(600) IU/mL.

Figure 4

HCV-monoinfected patients without model convergence. Viral load (log 10 IU/mL) is shown on y-axis. Days are shown on the x-axis. Only observed values are shown. The lower limit of assay detection is represented by the thin solid line at log10(600) IU/mL.

Figure 5

(A, B) Graphs using median kinetic parameters from genotype 1 patients to show delayed clearance in co-infected patients: all parameters (∈, c, δ, V0, t0) were calculated from the median pooled values of the study population for whom the model converged and who had viral clearance. The estimated V0 was 6.86 log10 IU/mL for co-infected and 5.88 log10 IU/mL for monoinfected patients. T0 was 11.39 vs. 11.26 hours for co-infected and monoinfected patients, respectively; c was 33.20 and 22.67/day, respectively; δ was .11 and .10/day, respectively; and ∈ was .76 and .81, respectively. These parameters were used to calculate λ1 and λ2 and the resulting pooled model fits. Solid line represents co-infected patients, dashed line represents monoinfected patients. The lower limit of assay detection is represented by the thin solid line at log10(600) IU/mL. (A) Early viral clearance (through 7 days). (B) Extension of model estimation through clearance (90 days). There is an approximately 20-day differential for predicted time to clearance between co-infected and monoinfected patients.