Hepatitis C virus core antigen for screening organ donors and recipients

Accepted Manuscript Hepatitis C virus core antigen for screening organ donors and recipients

Rafael Benito, Jorge Arribas, Sonia Algarate, Rocío Cebollada, M. José Gude PII: DOI: Reference:

S0732-8893(18)30038-5 https://doi.org/10.1016/j.diagmicrobio.2018.01.021 DMB 14525

To appear in: Received date: Revised date: Accepted date:

31 August 2017 25 January 2018 28 January 2018

Please cite this article as: Rafael Benito, Jorge Arribas, Sonia Algarate, Rocío Cebollada, M. José Gude , Hepatitis C virus core antigen for screening organ donors and recipients. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Dmb(2018), https://doi.org/10.1016/j.diagmicrobio.2018.01.021

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Hepatitis C virus core antigen for screening organ donors and recipients Running title: HCV-Ag assay for pretransplant evaluation Abstract word count: 150 Text Word count: 2075 a,b

PT

Rafael Benito a Department of Microbiology, University of Zaragoza, Zaragoza, Spain. b Service of Microbiology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain. Pedro Cerbuna, 12 50009-Zaragoza. Spain e-mail: [email protected] b,1

SC

RI

Jorge Arribas b Service of Microbiology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain. San Juan Bosco, 15 50009-Zaragoza, Spain e-mail: [email protected] 1 Service of Microbiology, Hospital San Jorge, Huesca, Spain. Av. Martínez de Velasco, 36 22004-Huesca, Spain a,b

MA

NU

Sonia Algarate a Department of Microbiology, University of Zaragoza, Zaragoza, Spain. b Service of Microbiology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain. Pedro Cerbuna, 12 50009-Zaragoza. Spain e-mail: [email protected] b,2

PT E

D

Rocío Cebollada b Service of Microbiology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain. San Juan Bosco, 15 50009-Zaragoza, Spain e-mail: [email protected] 2 Service of Microbiology, Hospital Ernest Lluch Martín, Calatayud, Spain. A-2, s/n 50299-Calatayud, Spain b,3

AC

CE

M. José Gude b Service of Microbiology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain. San Juan Bosco, 15 50009-Zaragoza, Spain e-mail: [email protected] 3 Service of Microbiology, Hospital Universitario A Coruña, A Coruña, Spain As Xubias, 84 15006 A Coruña, Spain Corresponding author: Dr. Rafael Benito Department of Microbiology Universidad de Zaragoza Pedro Cerbuna, 12 50009-Zaragoza Spain Phone: +34 619990331 FAX: +34 976762604 e-mail: [email protected]

1

ACCEPTED MANUSCRIPT ABSTRACT

Organ donors and recipients are routinely screened for hepatitis C virus (HCV) infection, typically via anti-HCV detection. We analyze the utility of an alternative HCV core antigen (HCVAg) quantification system, the ARCHITECT HCV Ag Assay, in this setting. We simultaneously tested 315 samples from potential organ donors and recipients using two chemiluminescent

PT

microparticle immunoassays: ARCHITECT Anti-HCV and HCV Ag (Abbott, Germany). HCV-Ag was detected in 81 of the serum samples (25.71%) and anti-HCV in 87 (27.62%). Seventy-five

RI

of the HCV-Ag–positive samples were positive for anti-HCV (92.59%). Overall concordance

SC

between the two assays was 94.29%. Of the six HCV-Ag–positive/anti-HCV–negative patients, five had HCV-Ag values <32 fmol/L and the sixth had a concentration of 477.50 fmol/L (viral

NU

load, 137,000 IU/mL). The HCV AG Assay detects HCV infections missed by the Anti-HCV Assay. Both markers should be used to screen for HCV infection in potential organ donors and

MA

recipients.

Hepatitis C HCV core antigen

AC

CE

Transplant screening

PT E

D

KEY WORDS

2

ACCEPTED MANUSCRIPT 1. Introduction Serological testing for hepatitis C virus (HCV) infection is a routine part of pretransplant evaluation and is usually urgent in the case of organ donors. Third-generation anti-HCV assays are typically used for HCV screening in this setting [Organización Nacional de Trasplantes, 2004]. However, the main disadvantage of these assays is that they can miss infected donors during the early stages of infection as they do not detect anti-HCV antibodies during the

PT

seroconversion window (a period that runs from approximately day 30 to day 70 of infection) [Glynn et al., 2005]. In addition, these assays do not distinguish between acute, chronic, and

RI

past infections and can produce false-positive or false-negative results, particularly in

SC

immunocompromised individuals [Kesli et al., 2011].

HCV antigen (Ag) is an alternative marker that is detectable during the early phase of the pre-

NU

seroconversion window, and in addition, it is not affected by immunological status. It is analyzed in human serum or plasma using the ARCHITECT HCV Ag assay for the quantitative

MA

determination of core antigen to HCV [Leary et al., 2006]. This test was introduced into the transplant evaluation protocol at our hospital in 2010. The aim of our study was to analyze the usefulness of the ARCHITECT HCV Ag Assay as a serological screening tool for HCV infection

2. Study design

PT E

D

in potential organ donors and recipients.

CE

We analyzed samples from 315 individuals included in the organ transplant program at Hospital Clínico Universitario Lozano Blesa in Zaragoza, Spain between January 2010 and June 2014.

AC

Most of the participants were evaluated for a liver transplant. The population included 239 men and 76 women. They were aged between 17 and 85 years (mean = 57, standard deviation 13), and corresponded to 81 donors, 54 recipients, and 180 potential recipients under evaluation (transplant candidates). All the samples were analyzed for anti-HCV antibodies and HCV-Ag using the ARCHITECT Anti-HCV and the ARCHITECT HCV Ag chemiluminescent microparticle immunoassays (Abbott Diagnostics, Wiesbaden, Germany), which were both run on an automated Architect i2000SR instrument. In the Anti-HCV assay, samples with sample/cutoff (S/CO) values <1.0 are considered non-reactive. In the HCV Ag assay, samples with a concentration <3 fmol/L are considered non-reactive, while those with a concentration ≥10

3

ACCEPTED MANUSCRIPT fmol/L are considered reactive. Results that fall in between these two cutoff points are considered to be in a "gray zone". Following the manufacturer’s instructions, these samples must be retested in duplicate, and the result classified as positive when one or both of the duplicates is (are) >3 fmol/L. The final value reported in such cases is the initial value.

Both anti-HCV and HCV-Ag were tested on the same instrument, following the manufacturer’s

PT

recommendations, to avoid false-positive HCV-Ag results [Morota et al., 2009]. The assay

RI

detects HCV-Ag from free viral particles and immune complexes [Medici et al., 2011].

SC

All anti-HCV-positive serum samples were additionally tested by HCV line immunoassay (LIA) (INNO-LIA HCV Score, Innogenetics, Ghent, Belgium). Finally, HCV-RNA quantification was

NU

performed using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test V2.0 in all anti-HCV-positive samples with a sufficient sample volume (50 transplant candidates,

MA

21 recipients, 1 rejected donor). All these samples were stored at -80ºC prior to analysis.

4. Results

D

Table 1 shows a summary of the HCV-Ag and anti-HCV results for the 315 samples analyzed.

PT E

HCV-Ag was detected in 81 serum samples (25.71%) from 63 transplant candidates, 17 recipients, and one rejected donor. Anti-HCV was detected in 87 samples (27.62%),

CE

corresponding to 67 transplant candidates, 19 recipients, and one rejected donor. Seventy-five of the 81 HCV-Ag–positive samples were also positive in the anti-HCV and LIA assays

AC

(92.59%). The other six samples (7.41%) were anti-HCV–negative. The concordance between the HCV Ag and anti-HCV assays was 94.29% (297/315). Table 1: Anti-HCV vs HCV-Ag HCV-Ag + HCV-Ag - TOTAL LIA+ 75 7 82 Anti HCV+ LIA0 1 1 LIA IND 0 4 4 LIA+ 0 0 0 Anti HCVLIA0 0 0 LIA NT 6 222 228 TOTAL 81 234 315 NT: Not tested

4

ACCEPTED MANUSCRIPT Six patients had a positive HCV-Ag and a negative anti-HCV result (Table 2). Five of these (three transplant candidates and two recipients) had an HCV-Ag value <31.83 fmol/L and a negative viral load test. The sixth patient (a transplant candidate) had an HCV-Ag value of 477.50 fmol/L and a viral load of 137,000 IU/mL. Four of the patients had alcoholic cirrhosis, one had autoimmune hepatitis, and one had immune tolerance after R-CHOP therapy.

477.50

NEG

0.02 137000

M 58 POS 5.18 F 43 POS 3.81 M 64 POS 31.38 S/CO: Sample/cutoff

NEG NEG NEG

0.14 0.14 0.10

NEG NEG NEG

PT

POS

Liver pretransplant evaluation, alcoholic cirrhosis. Liver recipient, alcoholic cirrhosis, deceased. Liver pretransplant evaluation, HCV cirrhosis, immune tolerance. Liver pretransplant evaluation, alcoholic cirrhosis,

RI

48

Patient status

Liver pretransplant evaluation, autoimmune hepatitis. Liver recipient, alcoholic cirrhosis.

NU

M

PCR IU/mL NEG NEG

SC

Table 2: HCV-Ag (+) /anti-HCV (-) Cases HCV-Ag Anti-HCV Sex Age Result fmol/L Result S/CO M 41 POS 3.98 NEG 0.23 M 57 POS 4.29 NEG 0.33

Twelve of the 315 samples (3.81%) were HCV-Ag–negative/anti-HCV–positive and they all had

MA

a negative viral load result (Table 3). The samples were from four liver recipients and eight candidates. Five of the transplant candidates (four of whom had alcoholic cirrhosis) had an S/CO value ≤6.03 in the anti-HCV assay and an indeterminate (n=4) or negative (n=1) LIA

D

result.

PT E

Table 3: HCV-Ag-/anti-HCV+ cases HCV-Ag Anti-HCV Sex Age Result fmol/L Result S/CO 47

NEG

2.07

POS

M

44

NEG

1.82

POS

M

57

NEG

0.00

POS

F M M

27 59 59

NEG NEG NEG

1,17 0.00 0.97

POS POS POS

F

60

NEG

2,90

POS

M M

56 50

NEG NEG

0.00 1.24

POS POS

M

56

NEG

0.00

POS

AC

CE

M

LIA

PCR

Patient status Liver recipient, IDU, HIV+, HCV+, HBV+,

11.42 POS NEG viral/alcoholic cirrhosis. 1.63 NEG NEG Liver pretransplant evaluation, alcoholic cirrhosis. Liver recipient, HCV cirrhosis, hepatocellular

14.43 POS NEG carcinoma. 1.10 IND NEG Liver pretransplant evaluation. 3.44 IND NEG Liver pre-transplant evaluation, alcoholic cirrhosis. 6.03 IND NEG Liver pretransplant evaluation, alcoholic cirrhosis. Liver pretransplant evaluation, HCV cirrhosis,

13.14 POS NEG hepatocellular carcinoma. 1.92 IND NEG Liver pretransplant evaluation, alcoholic cirrhosis. 14.71 POS NEG Liver pretransplant evaluation, alcoholic cirrhosis. Liver pretransplant evaluation, alcoholic cirrhosis,

7.27 POS NEG hepatocellular carcinoma. M 50 NEG 1.61 POS 15.27 POS NEG Liver recipient, HCV/alcoholic cirrhosis. M 50 NEG 1.42 POS 15.51 POS NEG Liver recipient, HCV/alcoholic cirrhosis. S/CO: Sample/cutoff; IDU: Intravenous drug user; IND: Indeterminate

Of the 72 sera tested by quantitative HCV NAT (Table 4), 50 were HCV-Ag–positive and HCV 4

RNA–positive; the viral load was above 10 UI/mL in 48 of the samples. Of the 22 HCV RNA–

5

ACCEPTED MANUSCRIPT negative samples, 17 were negative for both HCV-Ag and HCV RNA. The remaining five had low HCV-Ag values (3.81–31.38 fmol/L).

RI

PT

Table 4: PCR HCV vs HCV-Ag HCV-Ag+ HCV-Ag- TOTAL 4 >10 UI/ml 48 0 48 PCR+ 4 <10 UI/ml 2 0 2 PCR5 17 22 PCR NT 26 217 243 TOTAL 81 234 315 NT: Not tested

SC

5. Discussion

HCV core Ag in serum or plasma has been shown to be a useful marker of viral replication and

NU

disease progression [Lijima et al., 2008], and correlates well with HCV RNA levels [Morota et al., 2009; Mederacke et al., 2009; Ross et al., 2010; Park et al., 2010; Ottiger et al., 2013;

MA

Alonso et al., 2017]. This core antigen is also detectable in the serum of individuals during the window period of acute infection [Nübling et al., 2002; Tobler et al., 2005] and can be used to monitor response to antiviral therapy in chronically infected patients [Pradat et al., 2004;

D

Takahashi et al., 2005; Vermehren et al., 2012; Sidharthan et al., 2015; Aghemo et al., 2016;

PT E

Chevaliez et al., 2016; Freiman et al., 2016; Alonso et al., 2017].

HCV RNA quantification tests are expensive, time-consuming, and require highly trained

CE

personnel. The ARCHITECT HCV Ag Assay is cheaper, faster (40 minutes), simple to perform

AC

and has good sensitivity in samples with viral loads above 10,000 IU/mL [Tillmann HL, 2014].

We have been using the ARCHITECT HCV Ag Assay as a serological screen for the detection of HCV infection within our hospital’s organ transplant program since 2010. The overall concordance between HCV-Ag and anti-HCV results for the 315 potential organ donors and recipients analyzed in our series was high, at 94.29%. The 18 discrepant cases belonged to two distinct profiles: an HCV-Ag–positive/anti-HCV–negative profile (n=6) and an HCV-Ag– negative/anti-HCV–positive profile (n=12). Our findings are similar to other results published using the same assay [Medici et al., 2011].

6

ACCEPTED MANUSCRIPT The HCV-Ag positive/anti-HCV negative profile was detected in 6 of the 315 patients (1.90%). A similar profile has been reported for 0.6% of patients on hemodialysis and therefore at high risk of HCV infection (2/360 patients) and for 7.2% of pharmacologically immunosuppressed transplant recipients (7/97 patients) [Medici et al., 2011], confirming that seronegative HCV infections do occur. HCV infection (HCV-Ag or PCR-positive) has been reported in 0.8% (Medici et al., 2011) and 13-18% (Seiskari et al., 2011) of patients with a weak antibody response.

PT

Other authors have published data that show that “occult” HCV infection occurs in patients with altered immune responses, such as HIV-positive patients [Thomson et al., 2009] and patients

RI

on hemodialysis [Kaiser et al., 2008, Rahnavardi et al, 2008]. Furthermore, there has been a

SC

report of a “healthy” HCV carrier with negative HCV antibodies in repeated tests [Prat Arrojo et

NU

al., 2003].

Five of the six HCV-Ag–positive/anti-HCV–negative patients in our series (1.59% of the overall

MA

population and 6.17% of the HCV-Ag–positive population) had low HCV-Ag levels and a negative viral load. They corresponded to one transplant recipient and four candidates under evaluation. These results were interpreted as false positives in all cases, perhaps in relation to

D

the patients’ liver disease, and this interpretation was confirmed by patient monitoring. As

PT E

already mentioned, none of the patients was a potential donor, but had they been, they would

CE

have been rejected, even though low HCV-Ag levels suggest a false-positive result.

AC

This HCV-Ag–positive but HCV RNA (PCR)-negative or anti-HCV–negative profile had been previously described [Medici et al., 2011] in 11 patients (1.27% of 863 patients studied for HCV infection; 1.72% of 640 HCV-Ag–positive patients and 8.46% of 130 PCR–negative patients) and was interpreted as an artifact needing confirmation. In other words, further studies are necessary, as this profile may not necessarily be a false positive. In our study, we detected a similar percentage of patients with a positive HCV-Ag result (with low Ag levels) but negative HCV RNA and anti-HCV results. More studies are needed to confirm the significance of this profile, but its existence highlights the importance of being cautious when interpreting low

7

ACCEPTED MANUSCRIPT positive results in the absence of other markers. Although this profile is unlikely, its detection in an organ donor could be problematic, as it would result in unnecessary rejection.

The sixth HCV-Ag–positive/anti-HCV–negative case in our series corresponded to an immune tolerant patient who had undergone R-CHOP therapy for a non-Hodgkin B-cell lymphoma. His PCR and anti-HCV levels had been negative for the previous 5 years. This case demonstrates

PT

the usefulness of the HCV Ag Assay in immunodeficient patients, as pretransplant screening

RI

based only on anti-HCV antibodies could miss a potentially infected donor.

SC

The second discrepant profile (HCV-Ag–negative/anti-HCV–positive) was detected in 12 patients (3.81%), all of whom had a negative RNA result. Five of the samples (1.59%) had an

NU

indeterminate or negative LIA result and an anti-HCV S/CO value <7 and were classified as false positives for anti-HCV. The false-positive rate for HCV-Ag and anti-HCV was thus the

MA

same. The profile of the seven patients with a positive LIA result was interpreted as corresponding to a past infection. In our series, all the discrepant results between HCV-Ag and anti-HCV corresponded to recipients or potential recipients. Detection of this discrepancy in a

PT E

D

potential donor, however, could lead to their rejection.

The HCV-Ag Assay is known to be less sensitive than PCR in patients with a viral load below

CE

10,000 IU/mL (Tillmann HL, 2014). We did not find any HCV-RNA-positive/HCV-Ag-negative patients in our series. This profile is unlikely because untreated, chronically infected patients 4

7

AC

usually have HCV RNA levels between 10 and 10 IU/mL [Glynn et al., 2005, Medici et al., 2011; Nübling et al., 2002; Icardi et al., 2001].

The HCV Ag Assay can be used to confirm or exclude active infection in patients with a positive anti-HCV result [Medici et al., 2011; Cozzolongo et al., 2009]. It is also a useful test for patients with acute hepatitis or high-risk patients, such as those on hemodialysis [Medici et al, 2011; Kaiser et al., 2008; Icardi et al., 2001; Miedouge et al., 2010]. Moreover, our data support previous findings that it is a useful screening tool for organ recipients and donors [Tobler et al., 2005].

8

ACCEPTED MANUSCRIPT

6. Conclusions - Despite its limitations, the HCV Ag Assay is useful for screening for HCV infection in transplant programs because it is fast, easy to use, reliable, and has good sensitivity and specificity. - The HCV-Ag–positive/HCV RNA–negative profile is uncommon and should be studied in

PT

greater depth because it might not always correspond to a false-positive result.

- Because of the possibility of discrepancies between HCV-Ag and anti-HCV results, the use of

SC

RI

both markers should be contemplated in the screening of organ recipients and donors.

Acknowledgments

NU

We thank the Hospital Clínico Universitario Lozano Blesa in Zaragoza, Spain for supporting this work.

MA

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

D

Conflict of interests

PT E

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

AC

Not required.

CE

Ethics approval

References 1.

Aghemo A, Degasperi E, De Nicola S, Bono P, Orlandi A, D'Ambrosio R, et al. Quantification of Core antigen monitors efficacy of direct-acting antiviral agents in patients with chronic hepatitis C virus infection. Clin Gastroenterol Hepatol 2016;14(9):1331-6. doi:10.1016/j.cgh.2016.03.035.

9

ACCEPTED MANUSCRIPT 2.

Alonso R, Pérez-García F, López-Roa P, Alcalá L, Rodeño P, Bouza E. HCV coreantigen assay as an alternative to HCV RNA quantification: A correlation study for the assessment

of

HCV

viremia.

Enferm

Infecc

Microbiol

Clin

2017.

doi:10.1016/j.eimc.2016.11.013.

3.

Alonso R, Pérez-García F, Ampuero D, Reigadas E, Bouza E. New direct-acting

PT

antivirals for patients with chronic HCV infection: can we monitor treatment using an HCV core antigen assay? Diagn Microbiol Infect Dis 2017;87(3):243-246. doi:

SC

Chevaliez S, Feld J, Cheng K, Wedemeyer H, Sarrazin C, Maasoumy B, et al. Clinical utility

of

HCV

core

antigen

NU

4.

RI

10.1016/j.diagmicrobio.2016.11.010.

detection

and

quantification

in

the

diagnosis

MA

andmanagement of patients with chronic hepatitis C receiving an all-oral, interferon-free regimen. Antivir Ther 2016. doi:10.3851/IMP3042.

Cozzolongo R, Osella AR, Elba S, Petruzzi J, Buongiorno G, Giannuzzi V, et al.

D

5.

PT E

Epidemiology of HCV Infection in the general population: a survey in a Southern Italian

6.

CE

town. Am J Gastroenterol 2009;104:2740-2746. doi:10.1038/ajg.2009.428.

Freiman JM, Tran TM, Schumacher SG,White LF, Ongarello S, Cohn J, et al. Hepatitis

AC

C Core antigen testing for diagnosis of hepatitis C virus infection: a systematic review and meta-analysis. Ann Intern Med 2016;165(5):345-55. doi: 10.7326/M16-0065.

7.

Glynn SA, Wright DJ, Kleinman SH, HirschkornD, Tu Y, Heldebrandt C, et al. Dynamics of viremia in early hepatitis C virus infection. Transfusion 2005;45:994-1002. doi:10.1111/j.1537-2995.2005.04390.x.

10

ACCEPTED MANUSCRIPT 8.

Icardi G, Ansaldi F, Bruzzone BM, Durando P, Lee S, De Luigi C, et al. Novel approach to reduce the Hepatitis C Virus (HCV) window period: clinical evaluation of a new enzyme-linked immunosorbent assay for HCV Core antigen. J Clin Microbiol 2001;39:3110-3114. doi:10.1128/JCM.39.9.3110-3114.2001.

9.

Iijima A, Tanaka E, Kobayashi M, Yagi S, Mizokami M, Kiyosawa K. Relationship

PT

between histological prognosis of chronic hepatitis C and amount of hepatitis C virus core protein in serum. J Gastroenterol Hepatol 2008;15:311-319. doi:10.1046/j.1440-

SC

10.

RI

1746.2000.02127.x.

Kaiser T, Damerow HC, Tenckhoff S, Finger A, Boettcher I, Hafer C, et al. Kinetics of

NU

hepatitis viral RNA and HCV-antigen during dialysis sessions: evidence for differential

11.

MA

viral load reduction on dialysis. J Med Virol 2008;80:1195-1201. doi:10.1002/jmv.21190.

Kesli R, Polat H, Terzi Y, Kurtoglu MG, Uyat Y. Comparison of a newly developed automates and quantitative hepatitis C virus (HCV) core antigen test with the HCV RNA

D

assay for clinical usefulness in confirming anti-HCV results. J Clin Microbiol

Leary TP, GutierrezRA, Muerhoff AS, Birkenmeyer LG, Desai SM, Dawson GJ. A

CE

12.

PT E

2011;49:4089-4093. doi:10.1128/JCM.05292-11.

chemiluminescent, magnetic particle-based immunoassay for the detection of hepatitis

AC

C virus core antigen in human serum or plasma. J Med Virol 2006;78:1436-1440. doi:10.1002/jmv.20716.

13.

Mederacke I, Wedemeyer H, Ciesek S, Steinmann E, Raupach R, Wursthorn K, et al. Performance and clinical utility of a novel fully automated quantitative HCV-core antigen assay. J Clin Virol 2009;46:210-215. doi:10.1016/j.jcv.2009.08.014.

14.

Medici MC, Furlini G, Rodella A, Fuertes A, Monachetti A, Calderaro A, et al. Hepatitis C virus core antigen: Analytical performances, correlation with viremia and potential

11

ACCEPTED MANUSCRIPT applications of a quantitative, automated immunoassay. J Clin Virol 2011;51:260-265. doi:10.1016/j.jcv.2011.05.003.

15.

Miedouge M, Saune K, Kamar N, Rieu M, Rostaing L, Izopet J. Analytical evaluation of HCV core antigen and interest for HCV screening in haemodialysis patients. J Clin Virol

16.

PT

2010;48: 18-21. doi:10.1016/j.jcv.2010.02.012.

Morota K, Fujinami R, Kinukawa H, Machida T, Ohno K, Saegusa H, Takeda K. A new

RI

sensitive and automated chemiluminescent microparticle immunoassay for quantitative

SC

determination of hepatitis C virus core antigen. J Virol Methods 2009;157:8-14.

17.

NU

doi:10.1016/j.jviromet.2008.12.009.

Nübling CM, Unger G, Chudy M, Raia S, Löwer J. Sensitivity of HCV core antigen and

MA

HCV RNA detection in the early infection phase. Transfusion 2002;42:1037-1045. doi:10.1046/j.1537-2995.2002.00166.x.

Organización Nacional de Trasplantes de España. 2004. Criterios de selección del

D

18.

PT E

donante de órganos respecto a la transmisión de infecciones. 2ª edición. http://www.ont.es/infesp/DocumentosDeConsenso/infecciondonante.pdf,

Ottiger C, Gygli N, Huber AR. Detection limit of architect hepatitis C core antigen assay

AC

19.

CE

01.03.16).

(accessed

in correlation with HCV RNA, and renewed confirmation algorithm for reactive anti-HCV samples. J Clin Virol 2013;58:535-40. doi:10.1016/j.jcv.2013.08.028.

20.

Park Y, Lee JH, Kim BS, Kim do Y, Han KH, Kim HS. New automated hepatitis C virus (HCV) core antigen assay as an alternative to real-time PCR for HCV RNA quantification. J Clin Microbiol 2010;48:2253-6. doi: 10.1128/JCM.01856-09.

12

ACCEPTED MANUSCRIPT 21.

Pradat P, Maynard M, Buti M, Berthillon P, Picchio G, Tillmann HK, et al. The predictive value of core antigen testing for the management of hepatitis C patients receiving pegylated

interferon/ribavirin

treatment.

J

Med

Virol

2004;73:392-396.

doi:10.1002/jmv.20104.

22.

Prat Arrojo I, Ortiz Pareja M, Retamero Orta MD, Navajas Luque F, Hernandez Lama

PT

MC, Sanchez Gordo F, et al. Detection of a healthy carrier of HCV with no evidence of antibodies for over four years. Transfusion 2003;43:953-957. doi:10.1046/j.1537-

SC

23.

RI

2995.2003.00445.x.

Rahnavardi M, Hosseini Moghaddam SH, Alavian SM. Hepatitis C in hemodialysis

NU

patients: current global magnitude, natural history, diagnostic difficulties, and preventive

24.

MA

measures. Am J Nephrol 2008;28:628-640. doi:10.1159/000117573.

Ross RS, Viazov S, Salloum S, Hilgard P, Gerken G, Roggendorf M. Analytical performance characteristics and clinical utility of a novel assay for total hepatitis C virus antigen

quantification.

D

core

J

Clin

Microbiol

2010;48:1161-1168.

Seiskari T, Horsti J, Aittoniemi J. The value of HCV antigen test with reference to PCR

CE

25.

PT E

doi:10.1128/JCM.01640-09.

in confirming infection in cases with indefinite antibody test result. J Clin Virol

26.

AC

2011;51:90-91. doi:10.1016/j.jcv.2011.02.003.

Sidharthan S, Kohli A, Sims Z, Nelson A, Osinusi A, Masur H, et al. Utility of hepatitis C viral

Load

monitoring

on

direct-acting

antiviral

therapy.

Clin

Infect

Dis

2015;60(12):1743-51. doi: 10.1093/cid/civ170.

27.

Takahashi M, Saito H, Higashimoto M, Atsukawa K, Ishii H. Benefit of hepatitis C virus core antigen assay in prediction of therapeutic response to interferon and ribavirin

13

ACCEPTED MANUSCRIPT combination therapy. J Clin Microbiol 2005;43:186-191. doi:10.1128/JCM.43.1.186191.2005.

28.

Thomson EC, Nastouli E, Main J, Karayiannis P, Eliahoo J, Muir D, et al. Delayed antiHCV antibody response in HIV-positive men acutely infected with HCV. AIDS

Tillmann HL. Hepatitis C virus core antigen testing: Role in diagnosis, disease monitoring

and

treatment.

World

J

Gastroenterol

doi:

SC

10.3748/wjg.v20.i22.6701.

Tobler LH, Stramer SL, Lee SR, Baggett D, Wright D, Hirschkorn D, et al. Performance

NU

30.

2014;20:6701-6706.

RI

29.

PT

2009;23:89-93. doi:10.1097/QAD.0b013e32831940a3.

of ORTHO® HCV core antigen and trak-C™ assays for detection of viraemia in pre-

MA

seroconversion plasma and whole blood donors. Vox San 2005;89:201-207.

PT E

Vermehren J, Susser S, Berger A, Perner D, Peiffer KH, Allwinn R, et al. Clinical utility of the Architect HCV-Ag assay for early treatment monitoring in patients with chronic hepatitis

C

genotype

1

infection.

J

Clin

Virol

2012;55:17-22.

CE

doi:10.1016/j.jcv.2012.05.008.

AC

31.

D

doi:10.1111/j.1423-0410.2005.00687.x.

14

ACCEPTED MANUSCRIPT Highlights

HCV core antigen detection is a useful screening tool for organ transplant programs. It can detect HCV infections missed by anti-HCV assays. It can confirm or rule out active infection in anti-HCV positive patients.

AC

CE

PT E

D

MA

NU

SC

RI

PT

Both HCV Ag and anti-HCV assays should be used for organ transplant screening.

15