Occult Hepatitis C Virus Infection in Hemodialysis Patients: Examining the Evidence
2009; Elsevier BV; Volume: 54; Issue: 1 Linguagem: Inglês
10.1053/j.ajkd.2008.12.033
ISSN1523-6838
AutoresNassim Kamar, Florence Nicot, Jacques Izopet, Lionel Rostaing,
Tópico(s)Renal Transplantation Outcomes and Treatments
ResumoThe incidence of hepatitis C virus (HCV) infection is greater in hemodialysis patients than in the general population.1Pereira B.J. Levey A.S. Hepatitis C virus infection in dialysis and renal transplantation.Kidney Int. 1997; 51: 981-999Crossref PubMed Scopus (358) Google Scholar At present, nosocomial transmission is the main cause of HCV infection in hemodialysis patients.2Izopet J. Sandres-Saune K. Kamar N. et al.Incidence of HCV infection in French hemodialysis units: A prospective study.J Med Virol. 2005; 77: 70-76Crossref PubMed Scopus (61) Google Scholar In dialysis units, testing for HCV relies on HCV serological and nucleic-acid testing of serum.3National Kidney FoundationKidney Disease: Improving Global Outcomes (KDIGO).Kidney Int Suppl. 2008; : S1-S99Google Scholar Liver enzyme levels in dialysis patients with chronic liver HCV infection often are within the normal range.4Guh J.Y. Lai Y.H. Yang C.Y. et al.Impact of decreased serum transaminase levels on the evaluation of viral hepatitis in hemodialysis patients.Nephron. 1995; 69: 459-465Crossref PubMed Scopus (119) Google Scholar, 5Fabrizi F. Lunghi G. Andrulli S. et al.Influence of hepatitis C virus (HCV) viraemia upon serum aminotransferase activity in chronic dialysis patients.Nephrol Dial Transplant. 1997; 12: 1394-1398Crossref PubMed Scopus (65) Google Scholar, 6Espinosa M. Martin-Malo A. Alvarez de Lara M.A. Soriano S. Aljama P. High ALT levels predict viremia in anti-HCV-positive HD patients if a modified normal range of ALT is applied.Clin Nephrol. 2000; 54: 151-156PubMed Google Scholar It is suggested that HCV RNA–positive patients who are candidates for kidney transplantation be treated for HCV infection.3National Kidney FoundationKidney Disease: Improving Global Outcomes (KDIGO).Kidney Int Suppl. 2008; : S1-S99Google Scholar 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.7Carreno V. Occult hepatitis C virus infection: A new form of hepatitis C.World J Gastroenterol. 2006; 12: 6922-6925PubMed Google Scholar 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.7Carreno V. Occult hepatitis C virus infection: A new form of hepatitis C.World J Gastroenterol. 2006; 12: 6922-6925PubMed Google Scholar, 8Pardo M. Lopez-Alcorocho J.M. Castillo I. Rodriguez-Inigo E. Perez-Mota A. Carreno V. Effect of anti-viral therapy for occult hepatitis C virus infection.Aliment Pharmacol Ther. 2006; 23: 1153-1159Crossref PubMed Scopus (33) Google Scholar In the absence of liver biopsies, it has been suggested to test for HCV RNA in PBMCs to identify patients with occult hepatitis.7Carreno V. Occult hepatitis C virus infection: A new form of hepatitis C.World J Gastroenterol. 2006; 12: 6922-6925PubMed Google Scholar, 9Carreno V. Bartolomé J. Castillo I. Quiroga J.A. Occult hepatitis B virus and hepatitis C virus infections.Rev Med Virol. 2008; 18: 139-157Crossref PubMed Scopus (58) Google Scholar Another potential approach has been shown by Bartolomé et al,10Bartolomé J. Lopez-Alcorocho J.M. Castillo I. et al.Ultracentrifugation of serum samples allows detection of hepatitis C virus RNA in patients with occult hepatitis C.J Virol. 2007; 81: 7710-7715Crossref PubMed Scopus (83) Google Scholar 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 al11Castillo I. Pardo M. Bartolomé 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: 7-14Crossref PubMed Scopus (229) Google Scholar detected HCV RNA in liver and PBMCs in 57% and 40%, respectively. Conversely, using an ultrasensitive real-time polymerase chain reaction assay, Halfon et al12Halfon P. Bourliere M. Ouzan D. et al.Occult hepatitis C virus infection revisited with ultrasensitive real-time PCR assay.J Clin Microbiol. 2008; 46: 2106-2108Crossref PubMed Scopus (41) Google Scholar 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. Carreno7Carreno V. Occult hepatitis C virus infection: A new form of hepatitis C.World J Gastroenterol. 2006; 12: 6922-6925PubMed Google Scholar 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 al13Pham T.N. King D. Macparland S.A. et al.Hepatitis C virus replicates in the same immune cell subsets in chronic hepatitis C and occult infection.Gastroenterology. 2008; 134: 812-822Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar 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.14Pham T.N. Michalak T.I. Occult persistence and lymphotropism of hepatitis C virus infection.World J Gastroenterol. 2008; 14: 2789-2793Crossref PubMed Scopus (32) Google Scholar Very recently, in serum antibody-positive but RNA-negative patients, Hoare et al15Hoare M. Gelson W.T. Rushbrook S.M. et al.Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection.Hepatology. 2008; 48: 1737-1745Crossref PubMed Scopus (41) Google Scholar 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.15Hoare M. Gelson W.T. Rushbrook S.M. et al.Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection.Hepatology. 2008; 48: 1737-1745Crossref PubMed Scopus (41) Google Scholar 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.15Hoare M. Gelson W.T. Rushbrook S.M. et al.Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection.Hepatology. 2008; 48: 1737-1745Crossref PubMed Scopus (41) Google Scholar However, in this study, HCV RNA was not looked for in either liver biopsy specimens or PBMCs. Finally, Fowell et al16Fowell A.J. Sheron N. Rosenberg W.M. Renal hepatitis C in the absence of detectable serum or hepatic virus.Liver Int. 2008; 28: 889-891Crossref PubMed Scopus (8) Google Scholar 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 al17Barril G. Castillo I. Arenas M.D. et al.Occult hepatitis C virus infection among hemodialysis patients.J Am Soc Nephrol. 2008; 19: 2288-2293Crossref PubMed Scopus (80) Google Scholar 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,17Barril G. Castillo I. Arenas M.D. et al.Occult hepatitis C virus infection among hemodialysis patients.J Am Soc Nephrol. 2008; 19: 2288-2293Crossref PubMed Scopus (80) Google Scholar 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 al17Barril G. Castillo I. Arenas M.D. et al.Occult hepatitis C virus infection among hemodialysis patients.J Am Soc Nephrol. 2008; 19: 2288-2293Crossref PubMed Scopus (80) Google Scholar 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.1Pereira B.J. Levey A.S. Hepatitis C virus infection in dialysis and renal transplantation.Kidney Int. 1997; 51: 981-999Crossref PubMed Scopus (358) Google Scholar 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.18Kamar N. Toupance O. Buchler M. et al.Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation.J Am Soc Nephrol. 2003; 14: 2092-2098Crossref PubMed Scopus (139) Google ScholarOne important question regarding the transmission of HCV infection is whether HCV can replicate in PBMCs. Barril et al17Barril G. Castillo I. Arenas M.D. et al.Occult hepatitis C virus infection among hemodialysis patients.J Am Soc Nephrol. 2008; 19: 2288-2293Crossref PubMed Scopus (80) Google Scholar 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. The incidence of hepatitis C virus (HCV) infection is greater in hemodialysis patients than in the general population.1Pereira B.J. Levey A.S. Hepatitis C virus infection in dialysis and renal transplantation.Kidney Int. 1997; 51: 981-999Crossref PubMed Scopus (358) Google Scholar At present, nosocomial transmission is the main cause of HCV infection in hemodialysis patients.2Izopet J. Sandres-Saune K. Kamar N. et al.Incidence of HCV infection in French hemodialysis units: A prospective study.J Med Virol. 2005; 77: 70-76Crossref PubMed Scopus (61) Google Scholar In dialysis units, testing for HCV relies on HCV serological and nucleic-acid testing of serum.3National Kidney FoundationKidney Disease: Improving Global Outcomes (KDIGO).Kidney Int Suppl. 2008; : S1-S99Google Scholar Liver enzyme levels in dialysis patients with chronic liver HCV infection often are within the normal range.4Guh J.Y. Lai Y.H. Yang C.Y. et al.Impact of decreased serum transaminase levels on the evaluation of viral hepatitis in hemodialysis patients.Nephron. 1995; 69: 459-465Crossref PubMed Scopus (119) Google Scholar, 5Fabrizi F. Lunghi G. Andrulli S. et al.Influence of hepatitis C virus (HCV) viraemia upon serum aminotransferase activity in chronic dialysis patients.Nephrol Dial Transplant. 1997; 12: 1394-1398Crossref PubMed Scopus (65) Google Scholar, 6Espinosa M. Martin-Malo A. Alvarez de Lara M.A. Soriano S. Aljama P. High ALT levels predict viremia in anti-HCV-positive HD patients if a modified normal range of ALT is applied.Clin Nephrol. 2000; 54: 151-156PubMed Google Scholar It is suggested that HCV RNA–positive patients who are candidates for kidney transplantation be treated for HCV infection.3National Kidney FoundationKidney Disease: Improving Global Outcomes (KDIGO).Kidney Int Suppl. 2008; : S1-S99Google Scholar 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.7Carreno V. Occult hepatitis C virus infection: A new form of hepatitis C.World J Gastroenterol. 2006; 12: 6922-6925PubMed Google Scholar 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.7Carreno V. Occult hepatitis C virus infection: A new form of hepatitis C.World J Gastroenterol. 2006; 12: 6922-6925PubMed Google Scholar, 8Pardo M. Lopez-Alcorocho J.M. Castillo I. Rodriguez-Inigo E. Perez-Mota A. Carreno V. Effect of anti-viral therapy for occult hepatitis C virus infection.Aliment Pharmacol Ther. 2006; 23: 1153-1159Crossref PubMed Scopus (33) Google Scholar In the absence of liver biopsies, it has been suggested to test for HCV RNA in PBMCs to identify patients with occult hepatitis.7Carreno V. Occult hepatitis C virus infection: A new form of hepatitis C.World J Gastroenterol. 2006; 12: 6922-6925PubMed Google Scholar, 9Carreno V. Bartolomé J. Castillo I. Quiroga J.A. Occult hepatitis B virus and hepatitis C virus infections.Rev Med Virol. 2008; 18: 139-157Crossref PubMed Scopus (58) Google Scholar Another potential approach has been shown by Bartolomé et al,10Bartolomé J. Lopez-Alcorocho J.M. Castillo I. et al.Ultracentrifugation of serum samples allows detection of hepatitis C virus RNA in patients with occult hepatitis C.J Virol. 2007; 81: 7710-7715Crossref PubMed Scopus (83) Google Scholar 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 al11Castillo I. Pardo M. Bartolomé 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: 7-14Crossref PubMed Scopus (229) Google Scholar detected HCV RNA in liver and PBMCs in 57% and 40%, respectively. Conversely, using an ultrasensitive real-time polymerase chain reaction assay, Halfon et al12Halfon P. Bourliere M. Ouzan D. et al.Occult hepatitis C virus infection revisited with ultrasensitive real-time PCR assay.J Clin Microbiol. 2008; 46: 2106-2108Crossref PubMed Scopus (41) Google Scholar 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. Carreno7Carreno V. Occult hepatitis C virus infection: A new form of hepatitis C.World J Gastroenterol. 2006; 12: 6922-6925PubMed Google Scholar 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 al13Pham T.N. King D. Macparland S.A. et al.Hepatitis C virus replicates in the same immune cell subsets in chronic hepatitis C and occult infection.Gastroenterology. 2008; 134: 812-822Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar 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.14Pham T.N. Michalak T.I. Occult persistence and lymphotropism of hepatitis C virus infection.World J Gastroenterol. 2008; 14: 2789-2793Crossref PubMed Scopus (32) Google Scholar Very recently, in serum antibody-positive but RNA-negative patients, Hoare et al15Hoare M. Gelson W.T. Rushbrook S.M. et al.Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection.Hepatology. 2008; 48: 1737-1745Crossref PubMed Scopus (41) Google Scholar 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.15Hoare M. Gelson W.T. Rushbrook S.M. et al.Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection.Hepatology. 2008; 48: 1737-1745Crossref PubMed Scopus (41) Google Scholar 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.15Hoare M. Gelson W.T. Rushbrook S.M. et al.Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection.Hepatology. 2008; 48: 1737-1745Crossref PubMed Scopus (41) Google Scholar However, in this study, HCV RNA was not looked for in either liver biopsy specimens or PBMCs. Finally, Fowell et al16Fowell A.J. Sheron N. Rosenberg W.M. Renal hepatitis C in the absence of detectable serum or hepatic virus.Liver Int. 2008; 28: 889-891Crossref PubMed Scopus (8) Google Scholar 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 al17Barril G. Castillo I. Arenas M.D. et al.Occult hepatitis C virus infection among hemodialysis patients.J Am Soc Nephrol. 2008; 19: 2288-2293Crossref PubMed Scopus (80) Google Scholar 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,17Barril G. Castillo I. Arenas M.D. et al.Occult hepatitis C virus infection among hemodialysis patients.J Am Soc Nephrol. 2008; 19: 2288-2293Crossref PubMed Scopus (80) Google Scholar 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 al17Barril G. Castillo I. Arenas M.D. et al.Occult hepatitis C virus infection among hemodialysis patients.J Am Soc Nephrol. 2008; 19: 2288-2293Crossref PubMed Scopus (80) Google Scholar 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.1Pereira B.J. Levey A.S. Hepatitis C virus infection in dialysis and renal transplantation.Kidney Int. 1997; 51: 981-999Crossref PubMed Scopus (358) Google Scholar 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.18Kamar N. Toupance O. Buchler M. et al.Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation.J Am Soc Nephrol. 2003; 14: 2092-2098Crossref PubMed Scopus (139) Google Scholar One important question regarding the transmission of HCV infection is whether HCV can replicate in PBMCs. Barril et al17Barril G. Castillo I. Arenas M.D. et al.Occult hepatitis C virus infection among hemodialysis patients.J Am Soc Nephrol. 2008; 19: 2288-2293Crossref PubMed Scopus (80) Google Scholar 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. Financial Disclosure: None. Evidence of Occult Hepatitis C Virus Infection in Hemodialysis PatientsAmerican Journal of Kidney DiseasesVol. 54Issue 5PreviewWe write in response to the editorial by Kamar et al1 that mentioned our study of occult hepatitis C virus (HCV) in hemodialysis patients.2 First, we tested for occult HCV infection only in selected patients with abnormal liver enzyme values. So, contrary to the assertion of the authors, occult HCV may exist in patients with normal alanine aminotransferase. Second, a liver biopsy performed in 1 patient with occult HCV showed cholestasis, and liver cirrhosis was seen by laparoscopy in another patient. Full-Text PDF In Reply to ‘Evidence of Occult Hepatitis C Virus Infection in Hemodialysis Patients'American Journal of Kidney DiseasesVol. 54Issue 5PreviewWe read with interest the letter from Barril et al1 commenting on our editorial,2 in which we had suggested an absence of occult hepatitis C virus (HCV) infection in hemodialysis patients. Unfortunately, in their comments, the authors have not provided any additional convincing data, and many questions remain unanswered from their previous study, which reported that 45% of hemodialysis patients with elevated liver-enzyme levels of unknown cause had occult HCV infection, inducing an unusually high mortality rate. Full-Text PDF
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