Viral kinetics in hepatitis C.
Viral kinetics in hepatitis C.
复制标题
丙型肝炎的病毒动力学。
DOI：
10.1053/jhep.2003.50238
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Hoofnagle,JayH
中科院分区：
文献类型：
--
作者：
Lutchman,Glen;Hoofnagle,JayH
In the seminal article on viral kinetics in hepatitis C, Neumann et al. 1 used 3 differential equations to resolve the decrease in HCV-RNA levels during daily interferon therapy into 2 distinct phases. The first phase was the initial sharp decay in HCV-RNA levels that occurred within the first 24 hours of therapy. The researchers related this first phase decline to the antiviral “efficacy”(ε) of interferon in blocking viral production and secretion. The value of ε was calculated to vary from 0 (no blocking) to 1 (100% blocking). The second phase decline described the subsequent, more gradual decrease in HCVRNA levels, which the researchers attributed to the rate of killing or clearance of virally infected cells (δ), superimposed on ε. The differential equations also provided estimates of the spontaneous clearance of HCV RNA from serum (viral half-life) and the rate of virus production. These mathematic formulae accurately predicted both group and individual data during therapy and revealed that HCV has a high rate of replication (1012 virions/d) and short half-life in serum (1.5 to 4.6 hours), particularly in comparison with hepatitis B virus (1011/d and 24 hours) and human immunodeficiency virus (1010/d and 5.8 hours) analyzed in a similar manner. 1-4 These analyses provided insightful information, but several elements of the interpretation and conclusion are somewhat controversial. The analyses relied on several assumptions that are not always present or proven. In the analysis of ε, for instance, it was assumed that interferon exerted its full antiviral action from the onset of its first administration and that this action was constant thereafter (during the second phase). The difficulty with this is that the antiviral actions of interferon are complex and rely on induction of genes that interact with multiple intracellular pathways that have many other modulating influences. Perhaps more importantly, the pharmacokinetics of 3 times/wk standard interferon and once weekly peginterferon are such that a constant level of interferon action and viral inhibition may not occur. A second issue is the interpretation of the second phase decay in viral levels. It is difficult to believe that this is related to the death or clearance of virally infected cells. Serum alanine aminotransferase levels, the best surrogate marker for hepatocellular necrosis, usually decrease rather than increase during the second phase of viral decay. For these reasons, the second phase decline probably represents the decline in virally infected cells that occurs as a result of eradication of virus (cure of infection) in the individual hepatocytes without cell death from necrosis or apoptosis. Additionally, variations in δ among patients may represent differences in specific host T-cell responses5 or variable clearance of virus from extrahepatic sites, 6 both of which are not specifically accounted for by the original kinetic model.Regardless of these issues, viral kinetics during interferon alfa therapy provide new insights into this disease and may help optimize therapy. This issue of HEPATOL-OGY includes 2 reports on viral kinetics, both using the approaches and formulas proposed by Neumann et al., 1 and both addressing important clinical issues. Herrmann et al. 7 from Germany analyzed HCV-RNA levels from 34 patients participating in the large, multicenter, registration trial of peginterferon alfa-2a and ribavirin in chronic hepatitis C. 8 Patients received either peginterferon alfa-2a alone, peginterferon alfa-2a with ribavirin, or standard interferon alfa-2b and ribavirin. The investigators focused on 2 issues:(1) what was the effect of addition of ribavirin on decay of HCV-RNA levels during interferon therapy? and (2) were the patterns of …
