Letters To The Editor Open Access
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World J Gastroenterol. Jun 7, 2007; 13(21): 3020-3021
Published online Jun 7, 2007. doi: 10.3748/wjg.v13.i21.3020
Hepatitis C virus RNA kinetics: Drug efficacy and the rate of HCV-infected cells loss
Harel Dahari, Alan S Perelson
Harel Dahari, Alan S Perelson, Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, New Mexico 87545, United States
Author contributions: All authors contributed equally to the work.
Supported by NIH grants RR06555 and P20-RR18754 and the U.S. Department of Energy under contract DE-AC52-06NA25396
Correspondence to: Alan S Perelson, Theoretical Biology and Biophysics, MS-K710, T-10, Los Alamos National, Laboratory, New Mexico 87545, United States. asp@lanl.gov
Telephone: +1-505-667-6829 Fax: +1-505-6653493
Received: March 18, 2007
Revised: April 3, 2007
Accepted: April 16, 2007
Published online: June 7, 2007



We read the study by Medeiros-Filho et al[1] with much interest. The study shed light on early HCV RNA kinetics in conjunction with liver cirrhosis, different genotypes (gen-1 vs gen-3) of HCV and sustained viral response (SVR) rates. In particular, Medeiros-Filho et al[1] showed that the HCV RNA first phase decline, under interferon-α (IFN) and ribavirin therapy, which represents the effectiveness (ε) of IFN to block viral production[2,3], was significantly larger in gen-3 cirrhotic patients (mean ε = 0.99) than gen-1 cirrhotic patients (mean ε = 0.8). In addition, in these cirrhotic patients, they found that the HCV RNA second phase decay slope in gen-3 patients was significantly faster than in gen-1 patients, and suggested that the immune response against infected HCV cells in gen-1 patients may be less potent than in gen-3 patients.

We recently introduced the notion of a critical drug efficacy εc, such that if the drug efficacy, ε, is higher than the critical drug efficacy, i.e., ε > εc, then viral levels will continually decline on therapy, while if ε < εc, then viral loads will initially decline but ultimately stabilize at a steady state level lower than baseline (i.e., exhibit a flat phase)[4,5]. We have shown that the flat phase may be a simple consequence of liver homeostasis in which proliferation of hepatocytes compensates for the loss of infected cells, hence observing a flat phase does not imply a poor or absent immune response.

In light of these predictions, the interpretation of Medeiros-Filho et al[1] on the difference in viral kinetics between gen-1 and gen-3 in cirrhotic patients needs to be further addressed. First, if ε < εc, then following the first phase viral decay, the virus will reach a steady state lower than its baseline viral load very rapidly (i.e., flat phase). However, if ε is close to εc (but still ε < εc), then after the rapid viral decay phase a second slower phase of decay is predicted followed by a flat phase. Since in Medeiros-Filho et al[1] data was obtained only until d28 one can speculate that the drug efficacy in gen-1 cirrhotic patients, which are known to be difficult to treat, was lower than the critical drug efficacy (ε < εc) and that the 2nd slower phase reflects the flat phase or is just intermediate in an approach to reach a flat phase. Indeed, 4 of 7 gen-1 cirrhotic patients had a second phase slope equal to 0, which represents a flat phase, where the rest had a positive second phase decline slope but one that was lower than the predictive cut-off slope of SVR (i.e., 0.3 log IU/mL per week[1]), that may indicate an intermediate in an approach to reach the aforementioned flat phase.

Second, if ε > εc, then the viral second phase slope represents the death/loss rate of HCV-infected cells only if ε~1[4,5]. Thus, if ε in some gen-1 cirrhotic patients from Medeiros-Filho et al[1] was higher then εc, then the 2nd slope decay still does not reflect with confidence the actual death/loss rate of HCV-infected cells, since the IFN effectiveness, ε, was < 1 (mean ε = 0.8). However, in gen-3 cirrhotic patients for which the mean value of the IFN effectiveness was close to 1 (mean ε = 0.99), the second phase slope could well reflect the immune-mediated loss rate of HCV-infected cells. Thus, we argue that the mechanisms that lead to different viral kinetics between gen-1 and gen-3 cirrhotic patients may be attributed to different drug effectivenesses and not solely to the immune response against HCV-infected cells.

In conclusion, Medeiros-Filho et al[1] made an important step towards understanding why cirrhotic patients have lower SVR rates (see also review on therapy in HCV decompensated cirrhotic patients by Navasa & Forns[6]). However, we suggest that in future studies data sampling longer than d28 needs to be done in order to better capture the viral kinetic profiles in treated cirrhotic patients.


S- Editor Liu Y L- Editor Kumar M E- Editor Wang HF

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