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What Defines Cure for HCV Infection?
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An Expert Opinion on: Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology. 2004;41(1):106-114.
Source:
http://clinicaloptions.com/hep
Adrian M. Di Bisceglie, MD, FACP
Professor of Internal Medicine, Chief of Hepatology
Saint Louis University School of Medicine &
Saint Louis University Liver Center
St. Louis, Missouri
Posting Date: February 16, 2005
The study by Radkowski and colleagues examined 17 patients who had a sustained virologic response by the now classic definition of undetectable HCV RNA at the end of therapy and for at least 6 months after. They tested serum, liver biopsy tissue, and peripheral blood mononuclear cells for the presence of hepatitis C RNA and found it in all but 2 of the 17 patients. The potential implication of this is that what we think of as the cure of hepatitis C may not really be a cure.[1,2] These findings are potentially very important, if they can be verified.
The common wisdom is that once hepatitis C is gone, it is gone. There is a host of literature supporting that belief. But 3 recent papers,[1-3] including the one by Radkowski and colleagues, deliver a similar message: virus can still be detected in nearly 100% of patients with a sustained virologic response. Additionally, in patients who were not thought to have hepatitis C but who did have persistently elevated liver enzymes, Castillo and coworkers were able to detect HCV RNA in 57% of liver biopsies.[4]
However, there is a substantial body of work countering these recent findings. McHutchison looked at hundreds of liver biopsies before and after treatment and found that 98% of them were virus negative at the end of therapy. Of the five patients who were hepatic HCV RNA positive, 2 subsequently had a relapse of their hepatitis C.[5] One has to weigh those hundreds of biopsies against the 17 in this instance and say that this information is interesting, but it needs to be confirmed independently by a different laboratory using the same samples.
Another unresolved issue is demonstration of the biological or clinical importance of this finding. There may be traces of the virus left behind that do not cause any disease. An example is if these patients are subsequently immunosuppressed--they undergo liver transplantation or receive chemotherapy for cancer--and if they have a recurrence of their hepatitis C, that would show that traces of the virus that are still detectible might potentially reactivate at some time in the future. We have seen this with hepatitis B, traces of the virus were found in the liver but not in the serum, and following liver transplantation or chemotherapy, hepatitis B infection has reemerged, presumably from sanctuary tissue. That evidence is still lacking with hepatitis C. One key difference between the 2 viruses is that hepatitis B is a DNA virus and hepatitis C is an RNA virus. We believe that DNA viruses are likely to persist longer.
At this stage I do not believe these findings will impact clinical practice. Patients with a sustained virologic response tend to have sufficient clinical benefit from therapy. The larger question comes back to what is the goal of treatment: it is not necessarily to eradicate every trace of the virus; it is to decrease the risk of progressive liver disease, liver failure, and liver cancer. What this study does reinforce is the need to continue to follow patients who have sustained virologic response to see how many of them, if any, develop complications of the disease. Further studiers are needed to see whether traces of HCV infection, as found in this study, can result in recrudescence of HCV infection.
We know that patients coinfected with HIV respond less well to therapy for hepatitis C. In light of the present study, it is appropriate to ask whether coinfected patients may be at higher risk of harboring occult infection and therefore may be more likely to experience reactivation of HCV. But none of the subjects in the study were HIV positive, so we cannot say that for sure at this stage. Finally, the suggestion that an immune component is important to controlling viremia adds hope to the notion that a preventive vaccine for hepatitis C might be possible.
References
1. Radkowski M, Gallegos-Orozco JF, Jablonska J, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology. 2005;41:106-114.
2. Feld JJ, Liang TJ. HCV persistence: cure is still a four letter word. Hepatology. 2005;41:23-25.
3. Pham TN, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol. 2004;78:5867-5874.
4. Castillo I, Pardo M, Bartolome J, et al. Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver-function tests is unknown. J Infect Dis. 2004;189:7-14.
5. McHutchison JG, Poynard T, Esteban-Mur R, et al. Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin. Hepatology. 2002;35:688-693.
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