Home IgG and kappa free light chain CSF/serum indices: evaluating intrathecal immunoglobulin production in HIV infection in comparison with multiple sclerosis
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IgG and kappa free light chain CSF/serum indices: evaluating intrathecal immunoglobulin production in HIV infection in comparison with multiple sclerosis

  • Lars Hagberg EMAIL logo , Igal Rosenstein , Jan Lycke , Henrik Zetterberg , Aylin Yilmaz , Arvid Edén and Magnus Gisslén
Published/Copyright: April 4, 2024
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 62 Issue 10

Abstract

Objectives

To study intrathecal kappa free light chain (KFLC) synthesis in people living with HIV (PLWH) in comparison with multiple sclerosis (MS).

Methods

Cross-sectional analysis including 56 untreated and 150 well treated PLWH, and compared with 58 controls, and 223 MS patients.

Results

Elevated serum/cerebrospinal fluid (CSF) IgG and KFLC indices were observed in untreated PLWH. Seventy percent of untreated PLWH had KFLC index above 6.1, a threshold associated with clinically isolated syndrome/MS diagnosis. No association was found between KFCL index and CSF markers of neuronal injury in either PLWH or MS patients.

Conclusions

HIV-related immune system dysfunction is often associated with an elevated KFLC index akin to those observed in MS. HIV infection should be considered as a differential diagnosis for patients presenting with neurological symptoms and increased intrathecal immunoglobulin synthesis.

Keywords: kappa free light chain; multiple sclerosis; HIV; cerebrospinal fluid; intrathecal immunoglobulin; MS diagnosis

Introduction

Intrathecal IgG production and increased cerebrospinal fluid (CSF) concentrations of kappa free light chain (KFLC) are well-known characteristics in all stages of HIV infection [1], [2], [3], [4]. Free light chains are more often elevated than the IgG index [5]. Antiretroviral therapy (ART) effectively reduces the IgG index; however, residual intrathecal IgG production may persist for several years following successful treatment [6, 7]. Although CSF white blood cell counts typically normalize during effective ART [8], CSF neopterin levels, which serve as markers for gamma interferon production, exhibit a similar pattern to the IgG index, with incomplete normalization post-ART [9, 10]. The KFLC index has been less investigated in HIV infection than IgG index and CSF neopterin concentrations.

The KFLC index has been increasingly recognized for its diagnostic potential in multiple sclerosis (MS) as a quantitative alternative to IgG oligoclonal bands [11, 12]. It is, therefore, important to compare the results of this test with findings in other inflammatory central nervous system (CNS) diseases. In this study, we report on IgG and KFLC concentrations and CSF/serum indices as markers of intrathecal immunoglobulin synthesis, in both untreated and treated people living with HIV (PLWH) and compare them with concentrations we recently observed in MS patients [11]. We discuss the laboratory similarities, differences, and clinical relevance of these tests in the context of HIV infection and MS disease.

Materials and methods

Clinical data and pre-analytical sample handling

This is a retrospective cross-sectional study including 206 PLWH without CNS symptoms participating in the Gothenburg longitudinal CSF study [13] (56 with HIV and not on ART who were newly diagnosed (within weeks), and thus never treated before, 150 on successful ART), and 223 patients with MS. The MS cohort included 20 individuals with clinically/radiologically isolated syndrome, 161 with relapsing-emitting MS, 19 with primary progressive MS, and 23 with secondary progressive MS at the time of sampling. Data on the MS cohort has previously been published [11]. In addition, CSF/serum samples from 59 healthy controls including 41 males who were taking HIV pre-exposure prophylaxis (tenofovir and emtricitabine) due to risk behavior for contracting HIV [14], and 18 healthy HIV-negative volunteers were analyzed. The volunteers were recruited with economical compensation. Clinical characteristics are shown in Table 1.

Table 1:

Clinical characteristics of people living with HIV (PLWH) without antiretroviral treatment (no ART), PLWH on ART, multiple sclerosis (MS), and healthy controls.

PLWH, no ART PLWH on ART MS Controls
Number 56 150 223 59
Age, years, mean (SD) 39 (11.4) 48 (12.3) 41 (13.0) 37 (10.6)
Male/female 38/18 98/52 100/123 49/10
Years on ART, mean n/a 9.3 n/a n/a
HIV plasma, copies/mL, mean 382,000 <20a n/a n/a
HIV CSF, copies/mL, mean 36,000 <20a n/a n/a
Blood CD4, ×106/L, mean 364 658 n/a 883

  1. n/a, not applicable. aAll PLWH had viral copies below detection level (<20). SD, standard deviation.

CSF and blood samples were collected and processed using a standardized approach as previously described [13]. Cell counts, HIV RNA, and proteins were analyzed immediately after sampling, and remaining aliquots were centrifuged and frozen at − 70 °C pending further analysis.

Analyses of intrathecal immunoglobulin synthesis, inflammation, and degenerative biomarkers

Serum and CSF concentrations of KFLC were measured on an Atellica NEPH 630 instrument (Siemens) using the N Latex FLC kappa kit, following instructions by the manufacturers. The KFLC index was calculated using the equation ([CSF KFLC/serum KFLC]/[CSF albumin/serum albumin]). CSF and serum albumin and IgG concentrations were measured using the IGG-2 and ALBT2 Reagent cassettes on a Cobas c module instrument (Roche). The CSF/serum albumin ratio was calculated as (CSF albumin [mg/L]/serum albumin [g/L]), and the IgG index was calculated as ([CSF IgG/serum IgG]/[CSF albumin/serum albumin]). Neurofilament light chain protein (Nfl) was measured using an in-house enzyme-linked immunosorbent assay (ELISA), a method previously described in detail [15]. Quantitative HIV RNA was measured with Cobas Taqman v.2, Roche Diagnostic Systems (Hoffmann-La Roche, Inc, Basel, Switzerland), where 20 copies/mL was the lowest detectable level.

Statistical analysis

Descriptive statistics were performed using SPSS (IBM SPSS version 28, Chicago, IL) or Prism (version 9, GraphPad, La Jolla, California). Comparison of biomarker concentrations between subject groups were made using non-parametric methods including Mann-Whitney to compare two groups, and as well as Kruskal-Wallis with Dunn’s post hoc test to compare three or more groups. Biomarker associations were analysed using Spearman’s rank correlation.

Results

KFLC concentrations and IgG/KFCL indices in PLWH (median, 95 % confidence interval)

Serum KFCL concentrations in PLWH without ART were significantly higher (40.8 mg/L, 32.3−53.0) than in healthy controls (16.0 mg/L, 15.0−18.0), p<0.001. In parallel, CSF KFCL concentrations in PLWH without ART were also significantly higher (4.75 mg/L, 1.75−7.50) than in healthy controls (0.17 mg/L, 0.13−0.21), p<0.001. PLWH on ART had significantly lower serum and CSF KFCL concentrations (serum 20.8 mg/L, 19.0−22.0, CSF 1.05 mg/L, 0.73−1.28) than PLWH without ART (serum 40.8 mg/L, 32.3−53.0, CSF 4.75 mg/L, 1.75−7.50), p<0.001, but higher than controls (p<0.01) (Table 2).

Table 2:

Kappa free light chain (KFCL), immunoglobulin G (IgG), indices, albumin, neurofilament (NfL), neopterin concentrations in serum (S), and cerebrospinal fluid (CSF) in people living with HIV (PLWH), without antiretroviral treatment (no ART), PLWH on ART, MS patients, and healthy controls.

PLWH no ART PLWH on ART MS Controls
Number 56 150 223 59
IgG index 0.73 (0.52–1.01) 0.55 (0.48–0.69) 0.72 (0.59–1.04) 0.50 (0.47–0.53)
S-KFLC, mg/L 41 (27–72) 20 (16–26) 13 (10–16) 17.0 (12–20)
CSF – KFLC, mg/L 4.8 (1.0–15.9) 1.1 (0.4–2.8) 3.1 (1.0–6.2) 0.17 (0.10–0.28)
KFLC index 15.0 (4.8–54.3) 10.3 (4.0–32.1) 44.6 (16.4–126.2) 2.1 (1.6–3.0)
Albumin quotient 5.2 (3.3–6.3) 4.6 (3.5–6.0) 4.4 (3.2–6.0) 4.6 (3.6–5.5)
CSF NfL, ng/L 390 (250–735) 460 (288–700) 650 (400–1,280) 330 (240–570)

  1. Median values (IQR 25th–75th percentile).

When analyzing CSF/serum IgG and KFLC indices to estimate intrathecal production, we found significantly higher indices in untreated PLWH; IgG index (0.73, 0.64−0.83); KFLC index (15.0, 11.2–26.5) than in HIV-negative controls; IgG index (0.50, 0.49−0.52) and KFCL index (2.10, 1.80−2.20), p<0.001. In addition, PLWH on ART had higher IgG and KFCL indices than HIV-negative controls (p<0.01). A lower median IgG index (0.55, 0.52−0.59) was recorded in PLWH on ART than in those without (0.73, 0.68–0.81), p<0.001. However, the KFCL index in PLWH on ART was still at a rather high level (10.3, 7.60−15.0) and was not statistically different from PLWH without ART (15.0, 11.2−26.5) (Figure 1). As expected, the IgG index correlated with the KFLC index, r=0.859, p<0.0001 (Figure 2).

Figure 1: Kappa free light chain-index (KFCL) and IgG-index in people living with untreated HIV, or on effective antiretroviral treatment (ART), and patients with multiple sclerosis. Boxes show median and interquartile range with “+” denoting means; whiskers designate 5 and 95th percentiles. ns, not significant. **p<0.01, ***p<0.001, ****p<0.0001. KFCL index is given in a logarithmic ordinate and IgG index in a non-logarithmic ordinate.
Figure 1:

Kappa free light chain-index (KFCL) and IgG-index in people living with untreated HIV, or on effective antiretroviral treatment (ART), and patients with multiple sclerosis. Boxes show median and interquartile range with “+” denoting means; whiskers designate 5 and 95th percentiles. ns, not significant. **p<0.01, ***p<0.001, ****p<0.0001. KFCL index is given in a logarithmic ordinate and IgG index in a non-logarithmic ordinate.

Figure 2: Kappa free light chain index (KFCL) and IgG-index in people living with untreated HIV, or on effective antiretroviral treatment (ART), and patients with multiple sclerosis. KFCL index is given in a logarithmic ordinate and IgG index in a non-logarithmic ordinate.
Figure 2:

Kappa free light chain index (KFCL) and IgG-index in people living with untreated HIV, or on effective antiretroviral treatment (ART), and patients with multiple sclerosis. KFCL index is given in a logarithmic ordinate and IgG index in a non-logarithmic ordinate.

KFLC index and neurodegenerative CSF biomarkers

No significant difference was found in CSF NfL concentrations between PLWH with or without ART. Additionally, no significant correlation was seen between CSF NfL concentrations and the KFLC index in the PLWH groups (Table 2).

Laboratory data on PLWH compared with MS, median (95 % confidence interval)

Data from PLWH were compared with the MS patient cohort whose data were analyzed during the same period, using the same methods, and by the same laboratory. MS patients had median serum KFCL concentrations of 13.1 mg/mL (12.6−13.8) and median CSF KFCL concentrations of 2.99 mg/L (2.22−3.54). IgG index in the MS cohort was median 0.72 (0.68−0.81) with KFCL index of 44.6 (33.24−56.36). Seventy percent of untreated PLWH had a KFCL index above 6.1, which is the estimated level for the discrimination of clinically-isolated syndrome/MS diagnosis from controls [16], and 39 % had a KFCL index above the cut-off level (19.5) for high certainty of more than 2 oligoclonal CSF bands indicating MS [11]. However, the median KFLC index was significantly lower in untreated PLWH compared with MS (p<0.001) (Table 2, Figure 1). Untreated PLWH and MS patients had an IgG index of similar magnitude (Figure 1).

Oligoclonal bands and IgM index

More than 2 CSF IgG oligoclonal bands were observed in 197/223 (88.3 %) of the MS patients. The median IgM-index was 0.1 (IQR 0.06–0.19) measured on 64 MS patients. Oligoclonal bands and IgM index were not analyzed in PLWH.

Discussion

Most neurotropic microorganisms, such as borrelia burgdorferi, syphilis, various viral meningitides, and in our study HIV, generate an intrathecal immune reaction and must be considered as possible differential diagnoses to MS and other neuroinflammatory CNS diseases. In this study, we show that there is considerable overlap between MS and HIV infection regarding the pattern of intrathecal immunoglobulin production, with increased concentrations of IgG and KFCL in CSF and serum in both diseases [2]. Also, similar to MS, CSF IgG oligoclonal bands are present in all stages of HIV infection [17]. Furthermore, the favorable clinical impact of disease-specific treatments, such as ART in HIV-infection or disease-modifying treatment (DMT) in MS, were not accompanied by a normalization of the KFLC index after treatment, compared to baseline [11]. Although pre- and post-treatment KFCL index levels appeared unaffected by DMTs, it is important to note that the MS cohorts treated with DMT in the study by Rosenstein et al. were relatively small sample size and were limited solely to fingolimod and alemtuzumab treatment, potentially affecting the generalizability of the findings. By contrast, another study showed that MS treatment with very high-efficacy DMTs (alemtuzumab, natalizumab, anti-CD20 therapy, and mitoxantrone) was associated with a relatively lower intrathecal fraction of KFLC as compared to untreated controls or those with less effective DMTs (fingolimod, daclizumab) [18]. This study was limited by a cross-sectional design, a small sample size, and the fact that no significant difference was observed between the group with highly effective DMTs and those with moderately effective DMTs. The question of whether DMTs in MS influence the intrathecal synthesis of KFLC remains largely unanswered and warrants further investigation.

The potential clinical significance of low-grade intrathecal immune activation is uncertain. We found no correlation between the KFLC index and markers of axonal injury in either PLWH or MS patients, which does not lend support to the hypothesis of potential harm arising from residual increased immunoglobulin synthesis. Most intrathecally synthesized IgG in HIV infection is non-disease specific. Although HIV antigens are targeted, this specific response accounts for less than 5 % of the total intrathecal synthesis [19]. Similarly, MS patients also exhibit primarily non-specific intrathecal production of antibodies, including only low IgG levels directed against common viral epitopes [20].

In MS, the determination of an elevated KFLC index is considered a simple, quantitative method for measuring increased intrathecal immunoglobulin production, which is a hallmark of MS and has high diagnostic potential [21]. However, in most studies evaluating the KFCL index as a diagnostic biomarker in MS, the control groups consist mostly of patients with non-infectious CNS diseases [11, 22, 23]. As a result, the establishment of a cut-off value for an upper reference limit depends on the clinical question, the composition, and the study population. Our investigation highlights the importance of excluding HIV infection (and potentially other CNS infections) when determining reference KFLC index values for MS diagnostics. Notably, 70 % of untreated PLWH had a KFCL index higher than the cut-off level of 6.1, a proposed value for supporting an MS diagnosis [4, 6, 16].

The coexistence of MS and HIV is extremely rare, and only a few studies have described concomitance of MS and HIV infection. Importantly, HIV infection may present with a variety of neurological symptoms including “MS-like illness” [24]. HIV infection is easily diagnosed using a combination of antibody plus antigen tests. Our study highlights the importance of testing patients presenting with neurological symptoms for HIV, even in the case of those without apparent risk factors for HIV infection. In contrast to HIV infection, there are no MS-specific tests available for clinical use. MS diagnosis is based on a combination of clinical symptoms, MRI measures, presence of increased intrathecal immunoglobulin production as determined by CSF-specific IgG oligoclonal bands. It has been suggested that the KFLC index can improve the diagnostic arsenal for MS, particularly as it is more objective and less laborious to analyze compared to isoelectric focusing. In HIV infection, the clinical utility of measuring KFLC remains uncertain, although one report suggests that serum KFLC concentrations might be a strong and sensitive predictor of the risk of developing HIV-associated lymphomas [25].

The KFLC index has previously been shown to have significantly higher diagnostic accuracy than the IgG index in the case of MS [11, 23, 26]. It is, therefore, anticipated that in the future MS clinicians will focus on measurements of KFLC rather than IgG index alone. Furthermore, high KFLC index in MS appears to be associated with a higher risk of conversion from a clinically isolated syndrome to clinically definitive MS [27, 28], progression to expanded disability status scale ≥3 [29], and cognitive decline [30].

In clinical HIV practice, the most useful laboratory test to predict clinical outcome and treatment response is plasma viral load [31, 32]. It remains unlikely that the KFCL index has any utility for estimating disease progression. Nevertheless, the lingering intrathecal production in virologically suppressed PLWH, measured as KFLC index may have implications for understanding the pathogenesis of chronic autoimmune CNS inflammation.

In summary, our study demonstrates that HIV-related immune system dysfunction is associated with an elevated KFLC index concentration like that observed in MS disease. Although the KFCL index is lower in HIV infection than in MS, it is seen in most PLWH and in those on long term ART. Consequently, HIV infection must be differentially considered when evaluating CSF laboratory test results in patients presenting with unexplained neurological symptoms.

Corresponding author: Lars Hagberg, Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, SE 416 85 Gothenburg, Sweden; and Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden, E-mail:

Funding source: the Swedish state, under an agreement between the Swedish government and the county councils

Award Identifier / Grant number: ALF agreement ALFGBG-965885

Funding source: Edith Jacobson’s Foundation and Helena Ahlin’s Foundation. European Union’s Horizon Europe research and innovation programme under grant. agreement

  1. Research ethics: The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Regional Ethics Review Board in Gothenburg, Sweden (Ö588-01 with amendment including healthy controls T1081-18), and by the Swedish Ethical Review Agency (Dnr: 2020-06851).

  2. Informed consent: Informed consent was obtained from all individuals included in this study.

  3. Author contributions: LH, MG, and IR designed the study, examined, and collected CSF from the participants, registered the results, and contributed equally to writing the paper. JL, AY, and AE examined, and collected CSF from the participants, registered the results, and contributed to the manuscript. HZ was responsible for the laboratory analyzes and contributed to the manuscript. The author have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: LH has no competing interests. IR has received compensation for lectures from Biogen. MG has received research grants from Gilead Sciences, honoraria as a speaker, and is a DSMB committee member and/or a scientific advisor for Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer and Sanofi. HZ has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures at symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). JL has received travel support and/or lecture honoraria and has served on scientific advisory boards for Alexion, Almirall, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator-initiated study.

  5. Research funding: This work was supported by the Swedish state, under an agreement between the Swedish government and the county councils (ALF agreement ALFGBG-965885). Edith Jacobson’s Foundation and Helena Ahlin’s Foundation. European Union’s Horizon Europe research and innovation programme under grant. agreement.

  6. Data availability: The raw data can be obtained on request from the corresponding author.

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Received: 2023-09-12
Accepted: 2024-03-08
Published Online: 2024-04-04
Published in Print: 2024-09-25

© 2024 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  3. Six years of progress – highlights from the IFCC Emerging Technologies Division
  4. IFCC Papers
  5. Skin in the game: a review of single-cell and spatial transcriptomics in dermatological research
  6. Bilirubin measurements in neonates: uniform neonatal treatment can only be achieved by improved standardization
  7. Validation and verification framework and data integration of biosensors and in vitro diagnostic devices: a position statement of the IFCC Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MBHLM) and the IFCC Scientific Division
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  30. Letters to the Editor
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https://doi.org/10.1515/cclm-2023-1018
Keywords for this article
kappa free light chain; multiple sclerosis; HIV; cerebrospinal fluid; intrathecal immunoglobulin; MS diagnosis
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Six years of progress – highlights from the IFCC Emerging Technologies Division
  4. IFCC Papers
  5. Skin in the game: a review of single-cell and spatial transcriptomics in dermatological research
  6. Bilirubin measurements in neonates: uniform neonatal treatment can only be achieved by improved standardization
  7. Validation and verification framework and data integration of biosensors and in vitro diagnostic devices: a position statement of the IFCC Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MBHLM) and the IFCC Scientific Division
  8. Linearity assessment: deviation from linearity and residual of linear regression approaches
  9. HTA model for laboratory medicine technologies: overview of approaches adopted in some international agencies
  10. Considerations for applying emerging technologies in paediatric laboratory medicine
  11. A global perspective on the status of clinical metabolomics in laboratory medicine – a survey by the IFCC metabolomics working group
  12. The LEAP checklist for laboratory evaluation and analytical performance characteristics reporting of clinical measurement procedures
  13. General Clinical Chemistry and Laboratory Medicine
  14. Assessing post-analytical phase harmonization in European laboratories: a survey promoted by the EFLM Working Group on Harmonization
  15. Potential medical impact of unrecognized in vitro hypokalemia due to hemolysis: a case series
  16. Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes
  17. Targeted ultra performance liquid chromatography tandem mass spectrometry procedures for the diagnosis of inborn errors of metabolism: validation through ERNDIM external quality assessment schemes
  18. Improving protocols for α-synuclein seed amplification assays: analysis of preanalytical and analytical variables and identification of candidate parameters for seed quantification
  19. Evaluation of analytical performance of AQUIOS CL flow cytometer and method comparison with bead-based flow cytometry methods
  20. IgG and kappa free light chain CSF/serum indices: evaluating intrathecal immunoglobulin production in HIV infection in comparison with multiple sclerosis
  21. Reference Values and Biological Variations
  22. Reference intervals of circulating secretoneurin concentrations determined in a large cohort of community dwellers: the HUNT study
  23. Sharing reference intervals and monitoring patients across laboratories – findings from a likely commutable external quality assurance program
  24. Verification of bile acid determination method and establishing reference intervals for biochemical and haematological parameters in third-trimester pregnant women
  25. Confounding factors of the expression of mTBI biomarkers, S100B, GFAP and UCH-L1 in an aging population
  26. Cancer Diagnostics
  27. Exploring evolutionary trajectories in ovarian cancer patients by longitudinal analysis of ctDNA
  28. Diabetes
  29. Evaluation of effects from hemoglobin variants on HbA1c measurements by different methods
  30. Letters to the Editor
  31. Are there any reasons to use three levels of quality control materials instead of two and if so, what are the arguments?
  32. Issues for standardization of neonatal bilirubinemia: a case of delayed phototherapy initiation
  33. The routine coagulation assays plasma stability – in the wake of the new European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) biological variability database
  34. Improving HCV diagnosis following a false-negative anti-HCV result
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