S- Editor Liu Y L- Editor Kumar M E- Editor Wang HF
Published online Jun 7, 2007. doi: 10.3748/wjg.v13.i21.3020
Revised: April 3, 2007
Accepted: April 16, 2007
Published online: June 7, 2007
- Citation: Dahari H, Perelson AS. Hepatitis C virus RNA kinetics: Drug efficacy and the rate of HCV-infected cells loss. World J Gastroenterol 2007; 13(21): 3020-3021
- URL: https://www.wjgnet.com/1007-9327/full/v13/i21/3020.htm
- DOI: https://dx.doi.org/10.3748/wjg.v13.i21.3020
We read the study by Medeiros-Filho et al 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 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 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 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), 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 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 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). 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.
|1.||Medeiros-Filho JE, de Carvalho Mello IM, Pinho JR, Neumann AU, de Mello Malta F, da Silva LC, Carrilho FJ. Differences in viral kinetics between genotypes 1 and 3 of hepatitis C virus and between cirrhotic and non-cirrhotic patients during antiviral therapy. World J Gastroenterol. 2006;12:7271-7277. [PubMed] [Cited in This Article: ]|
|2.||Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282:103-107. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1595] [Cited by in F6Publishing: 1656] [Article Influence: 63.8] [Reference Citation Analysis (0)]|
|3.||Perelson AS, Herrmann E, Micol F, Zeuzem S. New kinetic models for the hepatitis C virus. Hepatology. 2005;42:749-754. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 114] [Cited by in F6Publishing: 102] [Article Influence: 6.3] [Reference Citation Analysis (0)]|
|4.||Dahari H, Ribeiro RM, Perelson AS. Triphasic decline of hepatitis C virus RNA during antiviral therapy. Hepatology. 2007;46:16-21. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 93] [Cited by in F6Publishing: 90] [Article Influence: 5.8] [Reference Citation Analysis (0)]|
|5.||Dahari H, Lo A, Ribeiro RM, Perelson AS. Modeling hepatitis C virus dynamics: Liver regeneration and critical drug efficacy. J Theor Biol. 2007;247:371-381. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 121] [Cited by in F6Publishing: 98] [Article Influence: 7.6] [Reference Citation Analysis (0)]|