Abstract
Hepatitis C virus (HCV) frequently causes chronic hepatitis, while spontaneous recovery from infection is infrequent. Persistence of HCV after self-limited (spontaneous) resolution of hepatitis C was rarely investigated. The current study aimed to assess incidence and robustness of HCV persistence after self-resolved hepatitis C in individuals with normal liver enzymes and undetectable virus by conventional tests. Applying high sensitivity HCV RNA detection approaches, we analyzed plasma and peripheral blood mononuclear cells (PBMC) from individuals with previous hepatitis C infection. Parallel plasma and PBMC from 24 such non-viraemic individuals followed for 0.3–14.4 (mean 6.4) years were examined. Additional samples from 9 of them were obtained 4.5–7.2 (mean 5.9) years later. RNA was extracted from 250 μl plasma and, if HCV negative, from ~5 ml after ultracentrifugation, and from ex vivo stimulated PBMC. PBMC with evidence of HCV replication from 4 individuals were treated with HCV protease inhibitor, telaprevir. HCV RNA was detected in 14/24 (58.3%) plasma and 11/23 (47.8%) PBMC obtained during the first collection. HCV RNA replicative strand was evident in 7/11 (63.6%) PBMC. Overall, 17/24 (70.8%) individuals carried HCV RNA at mean follow-up of 5.9 years. Samples collected 4.5–7.2 years later revealed HCV in 4/9 (44.4%) plasma and 5/9 (55.5%) PBMC, while 4 (80%) of these 5 PBMC demonstrated virus replicative strand. Overall, 6/9 (66.7%) individuals remained viraemic for up to 20.7 (mean 12.7) years. Telaprevir entirely eliminated HCV replication in the PBMC examined. In conclusion, our results indicate that HCV can persist long after spontaneous resolution of hepatitis C at levels undetectable by current testing. An apparently effective host immune response curtailing hepatitis appears insufficient to completely eliminate the virus. The long-term morbidity of asymptomatic HCV carriage should be examined even in individuals who achieve undetectable HCV by standard testing and their need for treatment should be assessed.
Highlights
Hepatitis C virus (HCV) is a major cause of chronic liver disease, predisposing to cirrhosis and hepatocellular carcinoma (HCC), affecting around 150 million people [1]
Additional paired plasma and peripheral blood mononuclear cells (PBMC) samples were collected from 9 individuals at a mean 5.9 years after first collection, i.e., a mean 12.7 years total follow-up (Table 1). 22/24 described risk factors for exposure to HCV, including injecting drug use (IDU) (n = 21) or multiple blood product transfusions (n = 1) (Table 1)
When the same samples were re-analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR)/nucleic acid hybridization (NAH) assay, 58.3% (14/24) and 44.4% (4/9) were HCV RNA reactive at mean follow-up 6.4 and 12.7 years (Table 2 and Fig 1)
Summary
Hepatitis C virus (HCV) is a major cause of chronic liver disease, predisposing to cirrhosis and hepatocellular carcinoma (HCC), affecting around 150 million people [1]. 15% of those infected undergo spontaneous resolution with loss of HCV RNA using conventional analyses [2]. HCV may establish low-level, asymptomatic, persistent infection (occult HCV infection or OCI), which can only be identified using methods with greater sensitivity than those used conventionally [3,4,5,6]. This has clinical relevance since trace quantities of HCV may be infectious. OCI has been identified in individuals negative for HCV RNA by conventional testing who remain asymptomatic [6,10] and following otherwise successful antiviral therapy [3,4,5,6,11]
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