Individualized treatment for patients with low HCV load (Genotype 1): A viral kinetic approach

Authors

  • Harel Dahari,

    1. The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
    2. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory,, Los Alamos, NM, USA
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  • Scott J. Cotler

    1. The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
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  • Potential conflict of interest: Dr. Cotler is on the speakers' bureau for Genentech, Vertex, Gilead, and Bristol-Myers Squibb.

To the Editor:

Pearlman and Ehleben's elegant study[1] showed no difference in sustained virological response (SVR) rates with or without boceprevir in patients with HCV genotype-1 and low baseline viral load, LVL (<600,000 IU/mL) who were treated with pegylated-interferon-α (P) and ribavirin (R) and had undetectable HCV-RNA (<10 IU/mL) at week 4 (termed RVR). Pearlman and Ehleben's study suggests that P/R therapy is sufficient in this special population if patients are treated for 24 weeks. However, since triple therapy is expected to be more effective than P/R, the similar SVR rates observed with the two regimens suggests that cure took place much earlier than 24 or 28 weeks of treatment. Thus, treatment duration could be shortened if it were possible to predict the time to cure during the lead-in phase.

Viral kinetic analysis during P/R lead-in phase provides a potential means to individualize treatment. The approach is illustrated in Fig. 1 using the standard biphasic model.[2] In general, LVL patients with high baseline hepatitis C virus (HCV)-RNA, bHCV (e.g., 500,000 IU/mL) need faster second-phase slope of viral decline than patients with extremely low bHCV (e.g., 1,000 IU/mL) in order to reach RVR (Fig. 1, solid and dashed lines, respectively). If both patients in Fig. 1 reach HCV negativity close to week 4, the patient with low bHCV needs a much longer duration of therapy (32 weeks) in order to achieve SVR and would benefit from addition of an HCV-protease inhibitor (PI) compared to the patient with high bHCV (12 weeks). Our conservative theoretical approach suggests that the longest treatment duration needed to achieve cure could be estimated for each RVR patient based on their bHCV. Since some patients might reach HCV negativity before week 4, two additional viral-load measurements at day 2 and week 2 would provide more confidence in estimating time to cure by allowing for calculation of the first phase of decline and the second phase slope.

Figure 1.

An individualized kinetic approach for predicting the duration of P/R therapy. The original biphasic model for HCV kinetics during treatment[2] was used to generate the viral load curves in two in silico LVL patients (one with high baseline HCV-RNA, bHCV = 500,000 IU/mL and the other with low bHCV = 1,000 IU/mL) who reached viral negativity (<10 IU/mL, horizontal dashed line) just before week 4. The time of cure, or SVR (which is defined as less than one virus and HCV-infected cell in the whole body[3]), was calculated based on the analytical solutions of the original biphasic model (i.e., eqs. 7 and 8 in Dahari et al.[4]). Based on previous studies with P/R therapy we set a conservative effectiveness of P/R in blocking viral production, ε = 0.9, and virus clearance rate, c = 6/day. The second phase slope which reflects the loss/death rate of infected cells (δ) was calculated in order to reach <10 IU/mL in each patient just before week 4. P, pegylated interferon-alpha; R, ribavirin.

Pearlman and Ehleben's exciting results indicate that patients with LVL can skip the addition of PI if they achieve an RVR after a lead-in phase of 4 weeks with P/R. Our modeling data suggest that the duration of therapy and need for a PI can be further individualized by viral kinetic analysis during the P/R lead-in phase. Further studies will be needed to verify this prediction.

Acknowledgment

Supported by NIH grants R56/R01-AI078881 and P20-GM103452 and the U.S. Department of Energy contract DE-AC52-06NA25396.

  • Harel Dahari, Ph.D.1,2

  • Scott J. Cotler, M.D.1

  • 1The Program for Experimental and Theoretical Modeling

  • Division of Hepatology

  • Department of Medicine

  • Loyola University Medical Center

  • Maywood, IL

  • 2Theoretical Biology and Biophysics Group

  • Los Alamos National Laboratory

  • Los Alamos, NM

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