Occult Hepatitis C Virus Infection in Hemodialysis Patients: Examining the Evidence

The incidence of hepatitis C virus (HCV) infection is greater in hemodialysis patients than in the general population.1 At present, nosocomial transmission is the main cause of HCV infection in hemodialysis patients.2 In dialysis units, testing for HCV relies on HCV serological and nucleic-acid testing of serum.3 Liver enzyme levels in dialysis patients with chronic liver HCV infection often are within the normal range.4, 5, 6 It is suggested that HCV RNA–positive patients who are candidates for kidney transplantation be treated for HCV infection.3 For patients who remain viremic despite antiviral therapy, a kidney transplant from an HCV-positive donor (with or without detectable viral RNA) can be used.

Occult HCV infection is defined as the presence of HCV RNA in the liver or peripheral-blood mononuclear cells (PBMCs) of patients whose sera samples test negative for HCV RNA, with or without the presence of anti-HCV antibodies.7 It has been suggested that patients with occult HCV infection are potentially infectious, they have a better immune response that could be the cause of milder disease compared with patients with chronic hepatitis C, and anti-HCV therapy is advisable in this setting.7, 8 In the absence of liver biopsies, it has been suggested to test for HCV RNA in PBMCs to identify patients with occult hepatitis.7, 9 Another potential approach has been shown by Bartolomé et al,10 who reported that HCV RNA can be detected in sera of patients with occult HCV infection after circulating viral particles are concentrated by using ultracentrifugation.

In patients with sera that was negative for anti-HCV antibodies and HCV RNA and who had long-standing abnormal liver test results with unknown cause, Castillo et al11 detected HCV RNA in liver and PBMCs in 57% and 40%, respectively. Conversely, using an ultrasensitive real-time polymerase chain reaction assay, Halfon et al12 failed to detect HCV RNA in PBMCs from serum HCV antibody– and RNA-negative patients with cryptogenic liver diseases, HCV-associated systemic vasculitis, or connective-tissue disease. Carreno7 detected HCV RNA in liver biopsy specimens and PBMCs from serum antibody-positive but RNA-negative patients who had persistently normal alanine aminotransferase levels. Furthermore, Pham et al13 showed that HCV RNA can persist at very low levels in serum and peripheral lymphoid cells, and an intermediate replicative form of the HCV genome can persist in PBMCs for many years after apparently complete spontaneous or antiviral therapy–induced resolution of chronic hepatitis C. More recently, the same group showed that HCV replicates in the same immune cell subsets in patients with chronic hepatitis C as in those with occult infections.14 Very recently, in serum antibody-positive but RNA-negative patients, Hoare et al15 showed that liver histological characteristics were normal in only 7.5% of cases; 92% of patients had inflammation within the liver, and 82% had fibrosis. When patients without viremia were compared with viremic patients matched for grade of inflammation and stage of fibrosis, the phenotype of inflammation infiltrates was similar in both groups and distinct from that in healthy controls.15 They concluded that the presence of CD8+-rich inflammatory infiltrates suggests an ongoing immune response in the liver, supporting the hypothesis of occult HCV infection.15 However, in this study, HCV RNA was not looked for in either liver biopsy specimens or PBMCs. Finally, Fowell et al16 detected HCV RNA in renal tissue in an anti-HCV antibody–positive patient with membranoproliferative glomerulonephritis, whereas HCV RNA was found to be negative in both serum and cryoprecipitate.

In the setting of chronic kidney disease, very recently, Barril et al17 detected the presence of genomic HCV RNA in PBMCs in 49 of 109 (45%) serum antibody- and RNA-negative hemodialysis patients with abnormal liver enzyme levels. Antigenomic HCV RNA was detected in 53% of these patients with occult “HCV infection.” This finding is of interest and may have a big impact on the management of hemodialysis patients in dialysis units, especially those with abnormal liver enzyme levels of unknown cause. However, nephrologists should be very careful in the interpretation of these results. It is unclear whether detection of genomic HCV in PBMCs is real and thus could induce liver injury and increase liver enzyme levels. In the study by Barril et al,17 genomic HCV was not looked for in hemodialysis patients with normal liver enzyme levels. We may question why occult HCV infection would induce abnormal liver enzyme levels when hemodialysis patients who have detectable serum HCV RNA replication are known to have liver enzyme levels that are mostly within the normal range. Second, the investigators did not look at liver histological characteristics in this population, and none of the studied patients developed an HCV-related liver disease. Third, 39% of patients with occult HCV infection died during length of follow-up, 12.9 ± 14.4 months. This very high proportion of deaths, which were not related to liver disease, suggests the presence of another underlying disease other than HCV infection that may be responsible for the increased enzyme levels.

In addition, the outcome of HCV infection in patients who underwent kidney transplantation in the study of Barril et al17 is also critical. Seven of these hemodialysis patients with occult HCV infection underwent kidney transplantation. It seems that serum HCV RNA remained negative after transplantation. In HCV RNA–positive patients after both kidney and liver transplantation, there is a significant increase in HCV viremia caused by losing immune control over HCV when under immunosuppressive treatment.1 Hence, it is likely that HCV RNA would be detected in serum after transplantation if it was already present in PBMCs before transplantation, particularly because antigenomic HCV RNA indicates ongoing replication. We previously reported that the treatment of HCV antibody- and RNA-positive hemodialysis patients with α-interferon can induce a complete and sustained virological response. When HCV RNA clearance occurs, no relapse was observed after kidney transplantation despite subsequent immunosuppressive treatments that included induction therapy. When assessed, HCV RNA was never detected in PBMCs.18

One important question regarding the transmission of HCV infection is whether HCV can replicate in PBMCs. Barril et al17 suggest a possible role of nosocomial transmission in the spread of occult HCV. To support this hypothesis, the investigators need to provide the proportion of hemodialysis patients with high enzyme levels in the 10 dialysis units that participated in their study, as well as the proportion of antibody- and RNA-positive patients at each center. In addition, it is useful to know whether HCV RNA–positive hemodialysis patients were undergoing hemodialysis separately from HCV RNA–negative patients, whether any of these patients had a history of HCV infection or drug abuse, and whether any had previously been treated with anti-HCV therapy. Finally, mandatory molecular analysis should be conducted based on the hypervariable region 1 of the HCV sequence (rather than the HCV core region) of all patients with occult HCV infection. The results should then be compared with those from HCV RNA–positive hemodialysis patients undergoing hemodialysis at the same dialysis center to identify the source of infection and thus eliminate any contamination.

In conclusion, to date, there is no strong evidence to support the presence of occult HCV infection in hemodialysis patients. Furthermore, there are no available data showing the virulence of this form of virus that is present in only PBMCs and not in the circulation. Additional more detailed studies are required in hemodialysis patients to determine the real prevalence of occult HCV infection in this population, its possible impact on liver histological characteristics and patient mortality, and its potential role in inducing diabetes mellitus, as well as the effect on antiviral therapy in this setting.