15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

RIBAVIRIN TREATMENT, BUT NOT INTERFERON PHARMACOKINETICS, IS ASSOCIATED WITH SUPPRESSION OF VIRAL REBOUNDS DURING HIGH DOSE INTERFERON-α-2a THERAPY OF HEPATITIS C INFECTION

Antivir Ther. 2006, 11:S13 (abstract no. 11)

SDW Frost¹, L Ruffini², DD Richman^1,3 and G Lake-Bakaar^4
1University of California, San Diego, California, USA; ²Department of Medicine, Veterans Affairs Medical Center, Northport, New York, USA; ³VA San Diego Healthcare System, San Diego, California, USA; ⁴Weill Medical College of Cornell University, New York, New York, USA

BACKGROUND: Hepatitis C virus (HCV) dynamics during interferon therapy are often modelled as biphasic decay following a pharmacokinetic delay. However, HCV dynamics often exhibit long delays and viral rebounds, which has resulted in the inability to obtain meaningful estimates of viral dynamics parameters for many patients, especially HIV/HCV coinfected individuals (Sherman et al. J Infect Dis. 2005 Mar 1;191(5):686-93), and individuals on interferon rather than pegylated interferon therapy (Lake-Bakaar et al. Lancet. 2002 Mar 23;359(9311):1064-5). We propose new formulations of models of HCV dynamics, and apply them to frequently sampled viral loads from individuals on high-dose interferon-α-2a therapy.

METHODS: Our model extends the model of Wu and Zhang (2002), and includes a delay term, an exponential 'phase 1' decay, and nonlinear 'phase 2' dynamics, which can capture both transient and sustained viral rebounds, modelled using cubic regression splines. Predicted viral dynamics curves were analysed using functional principal components analysis. We fitted our model to data from 16 individuals receiving daily high-dose (10 million units) interferon-α-2a therapy, either as monotherapy (n=8) or in combination with ribavirin (n=5) or ribavirin plus amantadine (n=3), for two weeks. Viral loads were obtained 1 hour before and at approximately 0, 2, 4, 6, 8, 12, 16, 20, 24, 32, and 48 hours, and then every 24 hours during therapy for up to 14 days. Models included either a delay term, or were fitted to viral load data from 8 hours onwards. Interferon-α-2a levels were measured during the first 24 hours of therapy.

RESULTS: 12/16 patients exhibited statistically significant (P<0.05) deviations from biphasic decay. The level of rebound was lower in individuals with combination therapy (P<0.05) as was attaining a sustained virological response (SVR) at 6 months after therapy (P<0.01). There were no differences by treatment arm or SVR in interferon-α-2a dynamics (peak, minimum, area under the curve; all P>0.1).

CONCLUSIONS: Viral rebounds, which may arise due to resistance to interferon, may occur even during sustained interferon levels, and are suppressed by ribavirin. Our models can fit complex viral dynamic data, with fewer convergence problems suffered by previous models, and may be important in the clinical evaluation of new antiviral agents.

2006-06-13
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