Occult hepatitis C: How convincing are the current data?

Welker, Martin-Walter; Zeuzem, Stefan

doi:10.1002/hep.22706

Cited by 86 publications

(93 citation statements)

References 147 publications

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We read with interest the review by Welker and Zeuzem on occult hepatitis C virus (HCV) infection and also the reply by Carreno et al 1,2 The latter reported in their answer to Welker and Zeuzem that HCV can replicate in patients with occult HCV infection. Because this conclusion would have substantial consequences for patients considered cured of their HCV infection, as well as for the health care system, the data must be interpreted most carefully.

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mentioning

confidence: 96%

The myth of occult hepatitis C infection

Halfon¹,

Martinot‐Peignoux²,

Cacoub³

2009

Hepatology

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We read with interest the review by Welker and Zeuzem on occult hepatitis C virus (HCV) infection and also the reply by Carreno et al. 1,2 The latter reported in their answer to Welker and Zeuzem that HCV can replicate in patients with occult HCV infection. Because this conclusion would have substantial consequences for patients considered cured of their HCV infection, as well as for the health care system, the data must be interpreted most carefully. They reported two studies that "unconvincingly failed to detect occult HCV infection in cryptogenic hepatitis because of several concerns with the methodology employed." 3,4 We would like to correct Carreno et al. on these two important points. In the first study published by Tanari et al., it was shown that the ability for HCV RNA detection is more sensitive in whole blood instead of peripheral blood mononuclear cells (PBMCs), due to circulation of the infectious virus in patient sera in the form of triglyceriderich particles which is present in the whole blood and not in PBMCs. 5 In the second study, we looked for the so-called "occult hepatitis C", in a different population of patients and controls, including patients with long-term normal alanine aminotransferase level, by using an original ultrasensitive validated real-time polymerase chain reaction (PCR) method. We failed to find any occult hepatitis C. 4 Moreover, we would like to underscore that for a long time, Carreno et al. reported the same results on the same cohort of patients. 6 The method proposed used PBMCs from a patient chronically infected with HCV for RNA isolation and HCV RNA detection. Serial dilutions of the isolated RNA cannot be a gold standard due to the limit of detection of HCV RNA by an in-house reverse transcription PCR method. PBMCs from our patients were subjected to HCV RNA transcription-mediated amplification assays without any HCV RNA detectable using this high sensitivity assay. 6 The second issue addressed is related to the concept of the presence of HCV RNA in the liver in the absence of HCV RNA detected in PBMCs. Carreno et al. suggested that negativity for HCV-RNA in PBMC does not exclude the existence of occult HCV infection because the gold standard method to identify this occult infection is by detection of viral RNA in liver cells. To address this question, Maylin et al. recently assessed the presence of residual HCV RNA in serum, liver, and PBMCs using TMA (sensitivity Ͻ9.6 IU/mL) in a long-term follow-up study of patients infected with chronic hepatitis C who achieved a sustained virological response after interferon-based treatment. 6 A total of 114 patients had a posttreatment liver tissue and 156 had PBMCs. Serum HCV RNA remained undetectable (1300 samples), indicating that none of the patients had a relapse. HCV RNA was detectable in 2 of 114 (1.7%) liver specimens, and in none of 156 PBMC specimens. These authors strongly suggest that SVR may be considered to show eradication of HCV infection. 7 This latest observation was confirmed by another recent study with a ...

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mentioning

confidence: 96%

The myth of occult hepatitis C infection

Halfon¹,

Martinot‐Peignoux²,

Cacoub³

2009

Hepatology

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“…3,4 The reason that HCV-RNA is not detectable in the serum of OCI patients is unknown. It has been proposed that the number of circulating viral particles is too low to be detected by conventional molecular techniques.…”

Section: Dear Editorsmentioning

confidence: 99%

“…2 The second form is characterized by negativity for both anti-HCV and HCV-RNA in serum, although still displaying elevated levels of serum aminotransferases. 3,4 The reason that HCV-RNA is not detectable in the serum of OCI patients is unknown. It has been proposed that the number of circulating viral particles is too low to be detected by conventional molecular techniques.…”

Section: When To Search For Occult Infection After Eradication Of Hepmentioning

confidence: 99%

When to Search for Occult Infection After Eradication of Hepatitis C?

Marco

Pellicano

2017

Gastroenterology

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Dear Editors:We read with great interest the article by Elmasry et al on the detection of occult hepatitis C virus (HCV) infection (OCI) in patients with abnormal levels of serum aminotransferases despite a sustained virologic response (SVR), after treatment with direct-acting antiviral (DAA) agents for HCV reinfection, after liver transplantation. 1 OCI is characterized by 2 immune-viral/clinically distinct forms. The first is characterized by anti-HCV positivity but undetectable HCV-RNA in serum, and normal levels of serum aminotransferases. Individuals with this form have been labelled as having "secondary OCI" and are characterized by the presence of HCV-RNA in peripheral blood mononuclear cells and in the liver. They have a residual persistent HCV infection despite spontaneous or therapy-induced SVR.2 The second form is characterized by negativity for both anti-HCV and HCV-RNA in serum, although still displaying elevated levels of serum aminotransferases. 3,4 The reason that HCV-RNA is not detectable in the serum of OCI patients is unknown. It has been proposed that the number of circulating viral particles is too low to be detected by conventional molecular techniques.5 Although several authors have described this new form of infection with emerging implications in different clinical scenarios, 6 few data are available in the setting of liver transplantation.The results from Elmasry et al are very interesting. The authors found that 5 of 9 subjects with SVR, who were also biochemical nonresponders, had OCI. Consequently, they proposed that this group should receive an additional course of antiviral therapy.1 Considering that at the moment the prevalence of patients with OCI remains unclear, the proposal to treat patients who, after antiviral therapy, still have abnormal liver function tests and OCI, needs to be studied further. We think that the search for OCI and its treatment should also be justified in patients treated for HCV before liver transplantation 7 who maintain abnormal liver function tests despite achieving a SVR. This could limit the risk of viral recurrence after surgery. LAURA DE MARCO Conflicts of interestThe authors disclose no conflicts. Among the 9 patients in whom serum alanine aminotransferase (ALT) levels did not normalize despite a sustained virologic response (SVR) 12 weeks after therapy with direct-acting antiviral (DAA) agents for posttransplant recurrent hepatitis C virus (HCV) infection, positive-and negative-strand HCV-RNA were detected in 5 patients (55%): 4 (44%) in liver tissue, 2 (22%) in peripheral blood monocytes, and 1 in both. Notably, all 5 patients with the occult HCV infection (OCI) had the unfavorable (TT) genotype for rs12979860 near the interleukin-28B gene. The authors proposed that further investigations in subjects with normal ALT are necessary to determine whether OCI can cause the abnormal ALT levels. We obtained liver biopsy specimens from 25 patients (mean age, 63 ± 11 years; 9 men and 16 women) without a history of liver transplantation or the use of im...

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“…1 If clinically significant replication of HCV takes place in patients with "occult" HCV infection and sustained virologic response (SVR) after interferon-alfa (IFN)-based antiviral therapy for chronic HCV infection, high rates of late virologic relapse may be expected. However, late virologic relapse rates are overall very low in patients with SVR, irrespective of whether their immune system is impaired or not.…”

Section: Replymentioning

confidence: 99%