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Does HCV Ever Really Go Away?

Highly sensitive assays indicated that patients with clinical resolution of HCV continued to harbor the virus and exhibit persistent active viral replication.

Long-term follow-up of patients who have cleared hepatitis C virus (HCV), either spontaneously or after successful therapy with interferon and ribavirin, suggests that the likelihood of recurrence is low. This conclusion is based on analysis of HCV RNA assays. However, HCV RNA assays have a variable range of detection, especially at low viral levels, and no assay results can completely eliminate the possibility of the virus's presence. Some evidence suggests that HCV is not only present in blood and liver, but also may be present in cells of the lymphatic and central nervous systems. If these locations harbor virus that is undetectable by standard assays, that could have important implications for disease recurrence. HCV antibodies can persist up to 20 years after resolution of clinical infection, suggesting that the virus and its antigens may persist, but at extremely low levels.

In this elegant study, researchers isolated specimens of serum peripheral blood mononuclear cells (PBMCs) and dendritic cells from 5 patients who had spontaneously cleared HCV infection and from 11 patients who had responded to antiviral treatment. Patients had been infected for 9 to 41 years, and treated patients had been followed for 12 to 60 months after completion of therapy. Using an extremely sensitive technique (involving reverse transcription and nested PCRs, followed by southern hybridization of the amplified products to virus-specific probes), the authors achieved a sensitivity limit 10 viral genomic equivalents/mL: They identified positive-strand viral RNA in 4 of 5 patients with spontaneous clearance of the virus and in all 11 patients with therapeutic responses (in 15 of 17 serum samples, 88% positive overall). Examination of PBMCs cultured in the presence of a mitogen stimulator yielded similar results; 81% of specimens harbored detectable levels of positive viral RNA strands. Dendritic cells isolated from 7 patients indicated that 86% had positive HCV RNA strands. As evidence of active replication, the researchers also performed assays for negative RNA strands on PBMCs; 9 of 12 specimens (75%) had detectable levels of negative RNA, suggesting viral activity. Overall, all patients were found to be have detectable viral RNA either in serum, PBMCs, or both up to 60 months after completion of therapy.

Comment: All patients in this study had clinical resolution of HCV and met accepted criteria for sustained response: normalization of liver enzymes, undetectable viral RNA levels by standard assays, and improvement in histology. However, highly sensitive assays indicated that all patients continued to harbor the virus and that active viral replication persisted in about 75%. Whether such low viral levels can subsequently result in relapse of disease is unknown. Theoretically, the virus could be transmissible and could re-emerge in immunocompromised patients (e.g., post-transplant patients). Relapse rates in longitudinal studies have been as high as 8%, but whether this represents true relapse or "fresh superinfection" is uncertain. In a review of the current study, the authors mention similar findings that were recently reported by another group in which only 2 of 17 specimens were HCV RNA negative 40 to 109 months after successful interferon therapy (Hepatology 2005; 41:106).

— Kenneth D. Flora, MD

Published in Journal Watch Gastroenterology February 16, 2005

Citation(s):

Pham TN et al. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol 2004 Jun; 78:5867-74.

• Original article (Subscription may be required)
• Medline abstract (Free)

Radkowski M and Laskus T. Persistence of hepatitis C virus after successful treatment of chronic hepatitis C: Is hepatitis C infection for life? Liver Transpl 2005 Jan; 11:114-6.

• Medline abstract (Free)