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Liver Biopsies Indicate Persistent Inflammation and Fibrosis in HCV Antibody Positive People with Undetectable HCV RNA

People who carry antibodies indicating exposure to hepatitis C virus (HCV), but who have undetectable plasma HCV viral load, are generally considered to have inactive disease. Likewise, continued undetectable plasma HCV RNA 24 months after completion of interferon-based therapy is usually regarded as a cure.

But hidden HCV in the liver -- even in the absence of detectable virus in the blood -- may still lead to liver disease progression, according to a study published in the December 2008 issue of Hepatology.

It is unclear whether HCV has been eradicated or persists at a low level in HCV antibody positive HCV RNA negative individuals, the study authors noted as background, and the natural history of the disease and liver histology in such individuals are not well characterized.

Matthew Hoare and colleagues from the U.K. studied 172 HCV antibody positive but plasma HCV RNA negative individuals who underwent diagnostic liver biopsies between 1992 and 2000. A total of 102 patients who had any possible causes of liver injury other than HCV were excluded. The remaining 70 participants were analyzed after a median 7 (range 5-12) years of follow-up.

A single pathologist scored biopsy samples according to the Ishak scoring criteria. Characterization of inflammatory infiltrate in selected patients was done using a novel semi-quantitative technique, and results were compared with those of patients with detectable HCV RNA and HCV antibody negative healthy control subjects.


  • 4 of the 70 patients (5.7%) became HCV RNA positive during follow-up.
  • 66 patients (94.3%) remained HCV RNA negative.
  • 5 patients (7.5%) had normal liver biopsies.
  • 54 of the patients with abnormal biopsies (82%) had liver fibrosis, including 16 (24%) with moderate to advanced (stage 2 or 3) fibrosis.

Biopsies from patients with undetectable plasma HCV RNA revealed expanded portal tracts with fewer CD4 cells and more CD8 cells than healthy HCV negative control subjects, but indistinguishable from patients with detectable plasma HCV RNA.

Lobular CD4 staining was absent in control subjects, but present in patients with both undetectable and detectable plasma HCV RNA (more marked in the latter).

"Non-viremic HCV antibody positive patients have a liver biopsy that is usually abnormal," the study authors conclude. "Fibrosis was present in most with similar inflammatory infiltrate to viremic cases."

The added that, "The presence of a CD8 rich inflammatory infiltrate suggests an ongoing immune response in the liver, supporting the view that HCV may persist in the liver in the majority of HCV RNA negative cases."

Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK; Department of Pathology, University of Cambridge, Cambridge, UK; Clinical Microbiology and Public Health Laboratory, Health Protection Agency, Addenbrooke's Hospital, Cambridge, UK; Medical Research Council (MRC) Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK.

M Hoare, WT Gelson, SM Rushbrook, and others. Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection. Hepatology. 48(6): 1737-1745. December 2008. (Abstract).

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