Alter

Bossi

Chevaliez

Contreras

Hyon-Suk Kim

Kiely

Kondili

Oethinger

Sugitani

The Korean Journal of Internal Medicine

English

PubMed

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Anti-HCV Signal-to-Cutoff Ratio in Predicting Hepatitis C Viremia

김현숙

Yonsei University Medical Library Open Access Repository

Anti-HCV Signal-to-Cutoff Ratio in Predicting Hepatitis C ViremiaHyon-Suk KimDepartment of Laboratory Medicine, Yonsei University College of Medicine, Seoul, KoreaHepatitis C virus (HCV) is one of the major etiologicagents of chronic liver diseases. Early and effectivescreening test of HCV was developed since the virus wasfirst identified in 1989. The screening test of HCV is anti-HCV antibody test by immunoassays and the infectionstatus is confirmed by recombinant immunoblot assay(RIBA) and nucleic acid testing of HCV.Anti-HCV test was firstly developed by enzyme-linkedimmunosorbent assay which has relatively goodsensitivity and specificity. Recently, it has been replacedby automated chemiluminescent immunoassay (CLIA)because of laboratory automation trend and advantages ofits improved sensitivity and specificity. But, sometimesthe screening immunoassays have been too muchimproved their sensitivities. Especially among populationswith low (<10%) prevalence of HCV infection, assays foranti-HCV antibodies show high false-positive rates [1].This is particularly problematic in asymptomatic personswith no clinical information available or in those who arebeing tested for the first time and in determining the needfor postexposure follow-up. Therefore, positive results forHCV antibody screening tests require confirmation withother more specific supplementary tests such as RIBA or anucleic acid test [2]. However, some laboratories lack an establishedlaboratory standard for such supplemental testing or lackunderstanding of performance and interpretation of thescreening and supplemental HCV tests. The high cost ofthe supplemental tests also makes them unavailable inmany laboratories. One of the simple methods is sampleSignal-to-Cutoff (S/CO) ratio of anti-HCV immunoassay.So the Center for Disease Control and Prevention (CDC)published guidelines that recommended supplementaltests to be based on anti-HCV assay S/CO ratios [2].Generally, the S/CO value of more than 1 is regarded aspositive in CLIA test. However, owing to improvement inthe sensitivity of HCV tests, it is suggested that moreaccurate standard for reflecting positive HCV infection isneeded. Thus, establishing optimal S/CO ratio isprerequisite for avoiding unnecessary further HCV testswhich are currently adopted for increasing the reliabilityof diagnosis. In this regard, S/CO ratio is thought to betterreflect HCV infection status of patients.However, significant value of S/CO ratio determiningtrue infection status seems to be different from companyto company. Thus, the difference in the ratio fromreagents should be taken into account when judging HCVviremia.According to the CDC guideline, reflex supplementaltesting may be limited to screening test-positive patientswith average S/CO ratios <3.8, as anti-HCV positivesamples with average S/CO ratios ≥3.8 would be highlypredictive of the RIBA positivity (≥95%) [2]. Other studieshave also evaluated the clinical significance of low S/COratios and found good correlation between S/CO ratio ofanti-HCV and HCV viremia [3-8]. Some studies evensuggested the elimination of reflex supplemental testing insamples with low S/CO ratio in order to save costs andreduce unnecessary testing [5,8]. These time and costsaving efforts have been reflected in another way in thestudy by Seo et al. They evaluated the utility of low S/COratio in predicting HCV viremia and in deciding whetherto opt for qualitative or quantitative HCV RNA test in aHCV antibody positive patient. The authors suggest theuse of qualitative HCV RNA testing in patients with anti-HCV S/CO ratio <10.9 and quantitative HCV RNA testingin patients with anti-HCV ≥10.9. This is a novel approachto reduce time and cost of diagnosis, but unfortunately,DOI: 10.3904/kjim.2009.24.4.299EDITORIALCorrespondence to Hyon-Suk Kim, M.D.Department of Laboratory Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea   Tel: 82-2-2228-2443, Fax: 82-2-364-1583, E-mail: kimhs54@yuhs.acEDITORIALSee Article on Page 302-308300 The Korean Journal of Internal Medicine Vol. 24, No. 4, December 2009may not yet be universally applicable. The authors of this article Seo et al. have based theircutoff point for the S/CO ratio on results from Abbottsecond-generation anti-HCV enzyme immunoassay, socutoff points with other enzyme immunoassays orchemiluminescence immunoassays should be furtherevaluated for application in other laboratory settings. Inaddition, anti-HCV titer may decrease with spontaneousHCV resolution or clearance after therapy [9]. In this case,low anti-HCV S/CO ratio may not automatically require aqualitative RNA testing and clinicians must be aware ofsuch influence on serologic testing. As mentioned in thediscussion, the study may be subjected to selection biasdue to the inclusion and exclusion criteria and may not bequite applicable in patients with chronic hepatitis or HCVresolution with or without therapy. Furthermore, theauthors have discussed that the lower detection limit ofthe HCV qualitative test may possibly have misclassifiedthe patients and influenced the results. With developmentof transcription mediated amplification assays, thesensitivity of qualitative assays has been improved to havea lower detectable limit of 5 IU/mL [10]. This may beanother factor influencing the clinical application of theS/CO ratio.Although the CDC and others have examined thecorrelation of S/CO ratio and RIBA results, the high costand indeterminate results not infrequently seen in thegray zone of anti-HCV titer may render the RIBA assayobsolete as supplemental verification test [11]. The VitrosAnti-HCV assay has been approved by the Food and DrugAdministration and an S/CO ratio of 8.0 was set as thescreening test positive value to determine the need forreflex supplemental tests. But, a study performed in mylaboratory, the cutoff of S/CO ratios were as follows:Elecsys assay, ≥200 (95.7%); Architect assay, ≥3 (94.9%);Vitros assay, ≥7.0 (95.7%); Access assay, ≥3 (94.7%) [6].Details of the four automated CLIA reagents were theElecsys Anti-HCV assay on the Cobas e 411 analyzer(Roche Diagnostics, Mannheim, Germany), the ArchitectAnti-HCV assay on the Architect i2000 system (AbbottLaboratories, Abbott Park, IL, USA), the Vitros Anti-HCVassay on the Vitros ECiQ Immunodiagnostic System(Ortho-Clinical Diagnostics, Raritan, NJ, USA), and theAccess HCV Ab PLUS assay (Bio-Rad Laboratories,Redmond, WA, USA) on the UniCel DxI 800 analyzer(Beckman-Coulter, Fullerton, CA, USA).Nucleic acid tests with improved sensitivity maysupplant former diagnostic tools, but remain expensiveand unavailable in many clinical settings. A guidance forthe optimal diagnostic approach is necessary and maybe found in the S/CO ratio of HCV antibody screeningtest, but further evaluation is needed for broader clinicalapplication. Because many commercial reagents are onthe market and accurate correlation studies with clinicalconditions are needed. The paper of Seo et al. showed that S/CO ratio isvaluable in determining HCV viremia. Furthermore, theyproposed the critical level of S/CO which may helpdiscriminate the occasions when HCV RNA quantitativeor qualitative test are needed. These results may beapplicable effectively to detect HCV viremia for users ofthe same test method. Although their results arepromising in terms of setting-up new index for HCVviremia, further studies are needed to each laboratory todevelop their own index for their diagnostic methods. Inaddition, optimization of follow-up setting for theirstudies is expected. (Korean J Intern Med 2009;24:299-301)REFERENCES1. Sugitani M, Inchauspe G, Shindo M, Prince AM. Sensitivity ofserological assays to identify blood donors with hepatitis Cviremia. Lancet 1992;340:249-250.2. Alter MJ, Kuhnert WL, Finelli L; Centers for Disease Control andPrevention. Guidelines for laboratory testing and result reportingof antibody to hepatitis C virus. Centers for Disease Control andPrevention. MMWR Recomm Rep. 2003;7;52(RR-3):1-13.3. Ren FR, Lv QS, Zhuang H, et al. Significance of the signal-to-cutoff ratios of anti-hepatitis C virus enzyme immunoassays inscreening of Chinese blood donors. Transfusion 2005;45:1816-1822. 4. Bossi V, Galli C. Quantitative signal of anti-HCV by an automatedassay predicts viremia in a population at high prevalence ofhepatitis C virus infection. J Clin Virol 2004;30:45-49.5. Contreras AM, Tornero-Romo CM, Toribio JG, et al. Very lowhepatitis C antibody levels predict false-positive results and avoidsupplemental testing. Transfusion 2008;48:2540-2548.6. Kim S, Kim JH, Yoon S, et al. Clinical performance evaluation offour automated chemiluminescence immunoassays for hepatitisC virus antibody detection. J Clin Microbiol 2008;46:3919-3923. 7. Kim YK, Kim BH, Jin ES, et al. Positive predictability andpredictive factors of the third generation anti-hepatitis C virus(HCV) ELISA test for HCV infection. Korean J Gastroenterol2005;45:181-188.8. Oethinger M, Mayo DR, Falcone J, Barua PK, Griffith BP.Efficiency of the ortho VITROS assay for detection of hepatitis Cvirus-specific antibodies increased by elimination of supplementaltesting of samples with very low sample-to-cutoff ratios. J ClinMicrobiol 2005;43:2477-2480.9. Kondili LA, Chionne P, Costantino A, et al. Infection rate andspontaneous seroreversion of anti-hepatitis C virus during thenatural course of hepatitis C virus infection in the generalpopulation. Gut 2002;50:693-696.  10. Chevaliez S, Pawlotsky JM. How to use virological tools foroptimal management of chronic hepatitis C. Liver Int 2009;29Suppl 1:9-14. 11. Kiely P, Wilson D. Results of HCV screening of volunteer blooddonors with a chemiluminescent immunoassay and a second- orthird-generation EIA: overlap of false-positive reactivity and itsimpact on donor management. Transfusion 2000;40:580-584.Kim HS. Anti-HCV signal-to-cutoff ratio    301

Anti-HCV signal-to-cutoff ratio in predicting hepatitis C viremia

Centers for Disease Control and Prevention. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. Centers for Disease Control and Prevention. MMWR Recomm Rep.

Clinical performance evaluation of four automated chemiluminescence immunoassays for hepatitis C virus antibody detection.

Efficiency of the ortho VITROS assay for detection of hepatitis Cvirus-specific antibodies increased by elimination of supplemental testing of samples with very low sample-to-cutoff ratios.

How to use virological tools for optimal management of chronic hepatitis C. Liver Int 2009;29 Suppl

Infection rate and spontaneous seroreversion of anti-hepatitis C virus during the natural course of hepatitis C virus infection in the general population.

Positive predictability and predictive factors of the third generation anti-hepatitis C virus (HCV) ELISA test for HCV infection.

Quantitative signal of anti-HCV by an automated assay predicts viremia in a population at high prevalence of hepatitis C virus infection.

Sensitivity of serological assays to identify blood donors with hepatitis C viremia. Lancet

Significance of the signal-tocutoff ratios of anti-hepatitis C virus enzyme immunoassays in screening of Chinese blood donors. Transfusion 2005;45:1816-

Very low hepatitis C antibody levels predict false-positive results and avoid supplemental testing.

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Anti-HCV Signal-to-Cutoff Ratio in Predicting Hepatitis C Viremia

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