HEPATITIS C VIRAL DYNAMICS - 08/09/11
Riassunto |
Chronic hepatitis C virus (HCV) infection is present in 1% to 3% of the population in the United States. It is a slowly progressive viral disorder that can lead to liver failure and hepatocellular carcinoma.19 Chronic hepatitis C is now the leading cause for liver transplantation.19 Interferon-⍺ (IFN-⍺) has been the mainstay of therapy, although only 9% to 20% of patients have a sustained viral response following 12 months of IFN administered three times a week. The addition of ribavirin, a nucleoside analogue, to IFN treatment regimens has significantly improved sustained viral response rates both in treatment-naive patients18, 19 and in patients who have experienced relapse after IFN therapy.3 Despite this improved response rate with combination therapy, 60% of all patients treated do not have a sustained viral response, and that percentage reaches 75% in patients infected with HCV genotype 1a or 1b.18, 29 New treatment strategies with currently available or newly developed drugs are required to improve HCV eradication rates.
The impediments to improving long-term viral response rates following therapy are many. At present, there is no cell culture system for HCV. Therefore, the mechanisms for viral cell entry, replication, and release are poorly understood, so the effect of antiviral drugs on each of these steps is difficult to assess. The initial decisions regarding the dose of IFN and the dosing pattern of IFN administration (three times a week rather than daily) were not based on viral kinetic parameters and carefully designed drug efficacy studies. Until recently, there was not a basic understanding of the kinetics of HCV RNA serum levels following initiation of therapy. Also, the effect of different doses of IFN and the pattern of IFN administration on serum HCV RNA levels were not examined in a methodical manner, and the mechanism by which IFN lowers serum HCV RNA levels was not understood.
Several studies have shown that a sustained viral response rate, that is, freedom from viral infection 6 months after IFN treatment is terminated, is greater for patients in whom HCV RNA is eliminated from serum soon after initiation of therapy and who receive prolonged therapy.19 At the National Institutes of Health (NIH) Consensus Conference that dealt with HCV treatment, it was recommended that IFN therapy be stopped at 3 months if the virus persists in serum during IFN monotherapy.19 This recommendation was based on a number of studies that demonstrated that sustained virologic clearance is unlikely if HCV RNA persists after 3 months of IFN monotherapy. Whether this recommendation is still valid, particularly with combination therapy, has come under some scrutiny. Nevertheless, studies have shown that if the virus is present in serum at week 4 of therapy, it is unlikely that the patient will have a sustained virologic response.25 Of interest, Karino et al recently demonstrated that among patients who clear serum HCV RNA within 1 week of starting IFN treatment, 76% have a sustained virologic clearance.10 However, among patients who do not clear virus until week 4, only 13% have a sustained virologic response.10 These results were independent of viral genotype but were shown to be dependent on pretreatment levels of serum HCV RNA, that is, patients with lower pretreatment HCV RNA levels (< 1.0 million copies/mL) cleared virus more quickly and had a better rate of sustained virologic response. Saito et al30 recently reported that, with the use of high-dose IFN (10 million units [MU]), patients who cleared virus within 48 hours had significantly better sustained virologic response rates than those who cleared virus later in therapy. These composite results indicate that the kinetics of HCV RNA serum levels early in therapy is an important parameter to study and understand in order to improve the overall success of clearing the virus during therapy. The understanding of the dynamics and life cycle of HIV gained by applying standard mathematical models of viral infection has dramatically improved treatment strategies and overall success in lowering viral levels and in improving CD4 lymphocyte counts. Equivalent understanding of HCV kinetics could greatly improve treatment strategies for hepatitis C.
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| Address reprint requests to Thomas J. Layden, MD, University of Illinois at Chicago, Section of Digestive and Liver Diseases, 840 South Wood Street m/c 787, Chicago, IL 60612–7323 |
Vol 3 - N° 4
P. 793-810 - novembre 1999 Ritorno al numero
Articolo precedente
- PREDICTORS OF A FAVORABLE RESPONSE TO ALPHA INTERFERON THERAPY FOR HEPATITIS C
- Eleanor Barnes, George Webster, Simon Whalley, Geoffrey Dusheiko
- COMBINATION TREATMENT WITH INTERFERON AND RIBAVIRIN FOR CHRONIC HEPATITIS C
- Gary L. Davis
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