The Journal of Infectious Diseases

SUPPLEMENT ARTICLE

Molecular Point-of-Care Testing for Hepatitis C: Available

Technologies, Pipeline, and Promising Future Directions
Elena Ivanova Reipold, Sonjelle Shilton, Marco Donolato, and Marta Fernandez Suarez
FIND, The Global Alliance for Diagnostics, Geneva, Switzerland

Hepatitis C virus (HCV) remains a major public health problem, despite the availability of effective treatments. In many areas, the
ability to diagnose HCV infection at the point of care is key to scaling up access to care and treatment. To achieve this, an accurate,
easy-to-use, and affordable diagnostic tool is required—this would enable decentralized testing and the creation of one-stop centers
to eliminate gaps in the care cascade, which would help reach the millions of people with undiagnosed HCV infection in low- and
middle-income countries and high-risk populations in high-income countries. In this review, we examine the current state of point-
of-care molecular technologies, the advantages and limitations of currently available devices (both near- and true-point-of-care),
the potential of molecular testing to transform diagnostic medicine in the future, and the challenges that need to be addressed
for broader adoption of this technology in routine clinical practice.
Keywords. hepatitis C; diagnostics; point-of-care; molecular assays.

Hepatitis C virus (HCV) is a blood-borne virus transmitted chronic HCV infection in 2019, only 21% had a confirmed di­
via direct contact with infectious blood (eg, by infusions) or agnosis and only 13% were receiving treatment [4].
indirectly via contaminated materials (eg, syringe needles or Reasons for this low uptake include (1) a lack of awareness
medical equipment) [1, 2]. It is recognized by the World about HCV in the population; (2) the complexity of existing diag­
Health Organization (WHO) as a major public health problem, nostic algorithms, which involve a 2-step process of screening fol­
with an estimated 58 million people living with chronic HCV in­ lowed by separate confirmatory testing in a centralized laboratory;
fection worldwide and 290 000 people dying from HCV-related (3) limited laboratory capacity in LMICs; and (4) the prohibitive
causes every year [3–5]. High-risk populations for HCV infection costs of testing [5, 9]. As such, it is clear that the ability to diagnose
include low- and middle-income countries (LMICs), where HCV HCV infection at the point of care is an important aspect of scaling
exerts a disproportionately high burden [2, 4], and groups who up access to HCV care and treatment [5, 9]. Unfortunately, an ac­
are regularly exposed to routes of transmission, such as people curate, easy-to-use, and affordable diagnostic tool to confirm an
who inject drugs (PWID). Of the 15.6 million PWID between HCV diagnosis in decentralized settings is still lacking and urgent­
15 and 64 years of age worldwide, it is estimated that 52%–60% ly needed in LMICs to reach the large number of people with un­
are seropositive for hepatitis C [6, 7]. In addition, it is estimated diagnosed HCV infection [4, 5]. The availability of these tests
that 23% of all new HCV cases and 33% of annual HCV-related would also help reach high-risk populations in high-income coun­
deaths are among PWID [6]. tries, and potentially enable the creation of one-stop centers to
With the advent of safe and potent direct-acting antiviral eliminate gaps in the care cascade [9, 10]. To achieve this, the
regimens, HCV treatment has become easier and more effective ideal HCV point-of-care (POC) test would be one that (1) can
with a high cure rate (over 90% irrespective of HCV genotype be performed on capillary blood without any additional require­
and disease severity) after as little as 8 to 12 weeks of treatment ment for laboratory equipment; (2) is accurate (limit of detection
[5, 8]. Despite this, and despite a 2016 WHO Global Health < 3000 IU/mL and clinical sensitivity >95%); (3) integrates speci­
Sector Strategy aimed at eliminating viral hepatitis as a public men preparation; (4) has a short turnaround time (<30 minutes);
health threat by 2030 [2], low treatment rates and low diagnosis and (5) is inexpensive ($1–10 per test) [5, 11].
rates persist—of the estimated 58 million people living with In this review, we will examine the current state of POC mo­
lecular testing, its advantages and limitations, and its potential
to transform diagnostics and patient care in the future. We will
Correspondence: Elena Ivanova Reipold, PhD, FIND, 9 Chemin des Mines, 1202 Geneva, also discuss some of the challenges that need to be addressed for
Switzerland (elena.ivanova@finddx.org). broader adoption of this technology in routine clinical practice.
The Journal of Infectious Diseases® 2024;229(S3):S342–9
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases TYPES OF POINT-OF-CARE DEVICES FOR
Society of America.
This is an Open Access article distributed under the terms of the Creative Commons Attribution
MOLECULAR NUCLEIC ACID TESTING
License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distri­
bution, and reproduction in any medium, provided the original work is properly cited.
Depending on the complexity of the design, infrastructure re­
https://doi.org/10.1093/infdis/jiad463 quirements, and ease of use, POC molecular testing platforms

S342 • JID 2024:229 (Suppl 3) • Reipold et al

can be divided into 2 subcategories: near point-of-care NEAR POINT-OF-CARE ASSAYS FOR HCV DETECTION
(near-POC) platforms and true point-of-care (true-POC) plat­ The only POC tests for HCV detection currently available are
forms (Figure 1). Near-POC platforms are usually benchtop in­ on near-POC platforms (Table 1). The Cepheid GeneXpert sys­
struments that require electrical power and at least minimal tem with Mycobacterium tuberculosis detection assay was the
laboratory infrastructure. These platforms are typically operat­ first POC molecular test endorsed by WHO in 2010. Today,
ed by experienced laboratory technicians, the testing proce­ the Cepheid system incorporates a wide variety of assays, in­
dures may include one or several manual steps, and cluding an Xpert HCV Viral Load (VL) assay and an Xpert
operation may require additional equipment such as a centri­ HCV VL Fingerstick assay [13–15]. Both are sample-to-answer
fuge or calibrated pipettes. True-POC molecular tests are typi­ disposable microfluidic cartridges that contain all the necessary
cally portable, battery-operated, integrated sample-to-answer reagents, and the testing is run on the GeneXpert platform, a
testing solutions that require minimal training and mainte­ fully integrated and automated PCR-based molecular diagnos­
nance, making them well suited for use at primary healthcare tic system. The Xpert HCV VL assay is intended for use in hu­
facilities. Most of the near-POC platforms utilize thermal cy­ man plasma and serum specimens with results available in
cling to amplify target DNA or RNA sequences (polymerase 90 minutes, and the Xpert HCV VL Fingerstick assay is per­
chain reaction [PCR] amplification), which requires rapid heat­ formed using 100 μL of fingerstick capillary blood (approxi­
ing and cooling of the reaction mixture and hence a stable pow­ mately 3 drops) and has a turnaround time of 60 minutes.
er supply to operate. PCR amplification technology provides The Xpert HCV VL and Xpert HCV VL Fingerstick assays
highly accurate results; however, the complex design of the have been evaluated in a number of studies, which have dem­
platform (which includes an instrument and a disposable assay onstrated the high diagnostic accuracy, usability, and accept­
cartridge) generally results in higher costs and infrastructure ability of the testing platform [16–19]. A recent systematic
and maintenance needs. True-POC platforms are often review reported a sensitivity of 100% [95% confidence interval
based on isothermal amplification approaches that do not re­ [CI], 98%–100%) and a specificity of 97% (95% CI, 94%–98%)
quire thermal cycling, such as loop-mediated amplification for the plasma-based assay and a sensitivity of 98% (95% CI,
(LAMP), recombinase polymerase amplification (RPA), strand 95%–99%) and a specificity of 99% (95% CI, 97%–99%) for
displacement amplification (SDA), and other techniques [12]. the fingerstick blood-based assay [20]. Both assays have re­
Although these amplification methods do not provide the ceived CE-marked in vitro diagnostics (CE-IVD) clearance
same level of accuracy as PCR, the reactions can be run at a and WHO prequalification [21, 22].
constant temperature and testing can be performed on a simple The UK-based GeneDrive has also developed a qualitative
and portable low-cost device that does not require repeated cal­ HCV assay that can detect HCV RNA in 30 μL of plasma
ibration and maintenance. [23]. The GeneDrive platform has a smaller footprint than

Figure 1. Types of point-of-care (POC) technologies.

Point-of-Care Tests for HCV RNA • JID 2024:229 (Suppl 3) • S343

Table 1. Currently Available Near-POC HCV Assays

Cepheid Xpert HCV VL and Xpert

HCV VL Fingersticka GeneDrive HCV IDb Molbio Truenat HCVc

Sample type Plasma Capillary blood Plasma Plasma, capillary blood

Sensitivity, % 100 98 99 95
Specificity, % 97 99 100 99
Sample preparation Centrifugation required, all Fully integrated Centrifugation required; Centrifugation required for testing from plasma; a
subsequent steps are additional off-board sample separate device required for sample preparation (both
integrated preparation steps plasma and whole blood); pipetting steps
(several pipetting steps)
Time to result, min 110 60 Approximately 120 60
Regulatory status CE-IVD, WHO PQ CE-IVD CE-IVD India
Power supply Needs an electricity supply Needs an Needs an electricity supply Batteries
electricity
supply
Data analysis PC PC Integrated Integrated
Abbreviations: WHO PQ, World Health Organization prequalification, CE-IVD, CE-marked in vitro diagnostics.
a
https://www.cepheid.com/en/tests/Virology/Xpert-HCV-Viral-Load; https://www.cepheid.com/en/tests/Virology/Xpert-HCV-VL-Fingerstick.
b
https://supply.unicef.org/s0003968.html.
c
https://www.molbiodiagnostics.com/product_details.php?id=22.

the GeneXpert system, weighs only 500 g, and does not require throughput and resource-limited settings, the assay’s perfor­
an external computer for data analysis and readout. However, mance could be influenced by elevated cross-contamination risks,
just like the GeneXpert, the platform requires an electricity sup­ inadequate operator training, and variable environmental condi­
ply to run the test. Importantly, the HCV ID assay cartridge is tions. Consequently, it is imperative to take into account not only
not fully integrated into the system and requires several manual the reported test performance from clinical evaluations but also
steps and precise pipetting. The assay performance has been the context in which these assays are being employed.
evaluated in several studies, including studies conducted in
resource-limited settings and primary healthcare facilities
[24], which demonstrated that the assay has a sensitivity of TRUE POINT-OF-CARE TESTING PLATFORMS THAT
COULD POTENTIALLY INTEGRATE HCV ASSAYS
99% (95% CI, 98%–100%) and a specificity of 100% (95% CI,
99%–100%) [20]. Unfortunately, despite its good performance, The coronavirus disease 2019 (COVID-19) pandemic under­
the product was recently discontinued. scored the role of testing in primary care, community, and
India-based Molbio diagnostics has developed a chip-based home settings, as well as the importance of having appropriate
rapid PCR assay for qualitative detection of HCV RNA tools to conduct this testing. The market size for POC diagnos­
(Truenat HCV). The assay can be performed using the Molbio tics grew exponentially in both size and value during this period
cartridge-based automated universal extraction system, the [26], with significant investments towards the development of
Truepep AUTO. Trueprep AUTO extraction can be done from new platforms. These investments spurred innovation at a
250 μL of fingerstick whole blood (approximately 7 drops) or pace never seen before and revolutionized the true-POC tech­
500 μL of plasma or serum in less than 20 minutes. Six microliters nology landscape [27, 28]. Molecular detection methods that
of purified RNA is transferred to the Truenat HCV chip using an can now be integrated into miniaturized battery-powered plat­
automatic pipette provided with the system; the test results are forms have expanded the use of nucleic acid amplification test­
available in 35 minutes [20, 25]. Both the Truepep AUTO and ing to nonclinical settings, and even in the home. Many of the
Truenat devices are portable and have an integrated rechargeable new platforms entered the market with a single assay for detec­
battery. The assay performance has been evaluated in a multicen­ tion of severe acute respiratory syndrome coronavirus 2
ter clinical study conducted in Spain, Ukraine, Georgia, and (SARS-CoV-2) RNA from nasal swabs. As the overall demand
Thailand, which reported an overall sensitivity of 95% (95% CI, for COVID-19 testing has been declining, some companies
93%–96%) and a specificity of 99% (95% CI, 99%–100%) [20]. have struggled to sustain their operations [29], while others
It is essential to highlight that the clinical performance assess­ are working to expand their assay menu to include testing
ment of the near-POC HCV assays mentioned above was con­ for other diseases. In the majority of cases, detection of
ducted in tightly controlled environments, primarily within SARS-CoV-2 RNA from nasal swabs does not require complex
well-equipped laboratories, and executed by extensively trained sample preparation, and usually a simple chemical lysis method
research personnel. In real-world scenarios, particularly in high- is performed. However, it is yet to be established whether the

S344 • JID 2024:229 (Suppl 3) • Reipold et al

Table 2. True Point-of-Care Testing Platforms That Could Potentially Integrate HCV Assaysa

ThermoFisher Scientific,
Nuclein, DASHb Mirai Genomics, GenPadc PlusLife, Mini Dockd Acculae

Sample preparation Chemical lysis, RNA Chemical lysis, RNA filteringg Thermal and Thermal and chemical lysis
filteringf chemical lysis
Amplification method RT-qPCR Smart Amp, proprietary isothermal RHAM, proprietary isothermal RT-PCR
technology technology
Turnaround time, min 15 40 15–35 30
Tests menu, commercially SARS-CoV-2 SARS-CoV-2, SARS-CoV-2/Flu A/B SARS-CoV-2, SARS CoV-2/Flu A/B, SARS-CoV-2, Flu A/B
available mpox (RUO)
Tests in development HCV, HIV, STDs, Flu Strep A, STDs HPV, HCV, M. tuberculosis, Strep A, NA
STDs
Abbreviations: Flu, influenza; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papillomavirus; M. tuberculosis, Mycobacterium tuberculosis; RHAM, RNAse
H-dependent amplification; RT-PCR, reverse transcription polymerase chain reaction; RT-qPCR, reverse transcription quantitative polymerase chain reaction; RNA, ribonucleic acid; RUO,
research use only; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STDs, sexually transmitted diseases; Strep A, Streptococcus A; NA, information not available.
a
The technologies selected are illustrative examples to demonstrate different types of testing systems. The information about test pipeline is taken from company websites.
b
https://www.nuclein.com/technology/.
c
https://miraigenomics.com/.
d
https://www.pluslife.com/.
e
https://www.thermofisher.com/order/catalog/product/D2000.
f
Via paramagnetic particles.
g
Via columns on the cartridge.

new true-POC technologies are compatible with more complex technologies. The requirement for sample preparation and genetic
sample types such as whole blood; in some cases, an additional material extraction from blood may limit the performances of ex­
sample preparation unit may be needed [30]. Some examples of isting isothermal-based approaches, as they may lead to low spe­
technologies that employ a simple, handheld, battery-operated cificity. In this context, isothermal amplification methods
instrument with heating and/or detection functions, together combined with clustered, regularly interspaced, short palindromic
with assay-specific consumables, are listed in Table 2. These repeat (CRISPR)-based detection holds promises for improving
technologies illustrate different architectures of true-POC sys­ clinical sensitivity and specificity. CRISPR-based readouts can
tems that could be potentially used for HCV testing and several be combined with LAMP or other isothermal amplification meth­
manufacturers have an HCV assay in their development pipe­ od to increase assay specificity, mostly by reducing the signal of the
line. Examples of technologies that are sometimes described negative samples. High accuracy of HCV detection using a
as “instrument-free,” meaning that the entire platform is dis­ CRISPR-based readout combined with LAMP amplification has
posable and built to be compatible with home use and self- been recently demonstrated [33].
testing, are presented in Table 3. Currently, none of the existing As shown in Table 3, Sherlock Biosciences is an example of a
instrument-free systems have blood detection capabilities, but company working toward implementation of this approach on
they may have the potential to be used for capillary blood, and a true-POC format. Several studies have demonstrated an effec­
hence HCV testing, through addition of an external module. tive implementation of a CRISPR-based assay on a lateral flow
It is important to note that most true-POC platforms rely on iso­ strip, and this could lead to a significant cost reduction in dis­
thermal amplification. A number of research articles have reported posable tests. Furthermore, it has recently been demonstrated
the feasibility of different isothermal methods for HCV RNA that HCV RNA extracted from clinical samples can be success­
detection. Wang et al showed that reverse transcription fully detected using reverse transcriptase (RT)-LAMP amplifi­
recombinase-aided amplification can detect HCV RNA in 30 min­ cation combined with CRISPR [33].
utes [31], and Chia et al demonstrated the applicability of RPA for Biosensor-based approaches based on semiconductor tech­
HCV RNA detection [32]. Although isothermal methods were nology or micro-electro-mechanical system (MEMS) sensors
tested in laboratory settings and not on an integrated POC device, represent an alternative approach to reducing turnaround
available data can be considered as a proof-of-concept, indicating time and the overall device cost [34, 35]. Several research
that development of HCV assays on a true-POC platform using groups and companies are also exploring the potential of
isothermal methods may be possible. graphene-based sensors for POC diagnostics [36]. Cardea Bio
and Identify Sensors are developing a graphene-based biosens­
ing solution that may not require target sequence amplification
PROMISING FUTURE TECHNOLOGIES
thanks to the intrinsically high platform sensitivity. However,
The challenge of conducting affordable and accurate molecular di­ the development of robust assays over this type of platform
agnosis from blood can potentially be tackled by new upcoming has still to be fully demonstrated and will need to overcome

Point-of-Care Tests for HCV RNA • JID 2024:229 (Suppl 3) • S345

Table 3. Instrument-Free Technologies With the Potential to be Used as HCV Assaysa

Visby Medicalb Sherlock Biosciencesc Ustar PortNATd Midge Medical Minooe

Sample preparation Thermal and chemical lysis Thermal and chemical lysis Thermal and chemical lysis Thermal and chemical lysis
Amplification method RT-PCR Isothermal/CRISPR Proprietary isothermal RPA
amplification technology
Turnaround time, min 30 15 25 NA
Tests menu, commercially SARS-CoV-2, Flu A/B; STDs NA SARS-CoV-2 NA
available
Power supply Needs electricity Battery powered Battery powered Battery powered
Tests in development NA STDs, respiratory diseases HIV, CT/NG, Flu SARS-CoV-2, HIV, M. tuberculosis, Flu,
herpes virus, Ebola virus
Abbreviations: CRISPR, clustered, regularly interspaced, short palindromic repeat; CT/NG, Chlamydia trachomatis, Neisseria gonorrhea, Trichomonas vaginalis; Flu, influenza; HCV, hepatitis C
virus; HIV, human immunodeficiency virus; M. tuberculosis, Mycobacterium tuberculosis; RPA, recombinant polymerase amplification; RT-PCR, reverse transcription polymerase chain
reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STDs, sexually transmitted diseases.
a
The technologies selected are illustrative examples to demonstrate different types of testing systems. The information about test pipeline is taken from company websites.
b
https://www.visbymedical.com/sexual-health-test/.
c
https://sherlock.bio/platforms/crispr/.
d
https://en.bioustar.com/product/155.html.
e
https://www.midgemedical.com/.

various challenges, particularly related to controlling the inter­ screening and confirmatory testing, higher rates of treatment,
action of charged molecules and buffer composition to ensure and shorter turnaround times [39, 40]. Similarly, a prospective
compatibility with the sensors. study in the United States revealed that a significantly greater
proportion of HCV-seropositive PWID received viremic test­
THE ROLE OF EXISTING AND NEW HCV DIAGNOSTICS ing in a POC setting or at a harm reduction site (where venous
IN BEST PRACTICE
blood samples were collected for off-site testing) compared
It is clear that emerging HCV true-POC technologies may help with the referral of patients between sites for blood collection
further HCV elimination efforts, particularly among marginal­ and/or testing [41]. These studies, combined with the high re­
ized populations and hard-to-reach communities with limited tention rates also observed across the care cascade [41], high­
access to centralized healthcare and high loss to follow-up [4]. light the importance of conducting as much testing as
A systematic review of 45 studies has shown that using possible at a single site [42]. True-POC technologies for HCV
near-POC HCV RNA assays instead of a centralized laboratory- could enable expansion of one-stop-shop facilities and decen­
based approach improved the efficiency of HCV programs, tralization of HCV care to primary healthcare clinics, pharma­
resulting in a quicker turnaround time between testing and cies, and harm reduction sites, by enabling an expansion of
treatment (19 days vs 64–66 days) and a 32% increase in treat­ on-site HCV diagnosis to complement existing on-site
ment uptake [37]. treatment.
Employing a completely decentralized one-stop-shop model Regarding the diagnostic landscape, liver testing also needs
(where the patient only attends one low-level health facility for to be considered alongside HCV testing. This is essential in
all diagnosis and treatment needs) could further increase link­ hepatitis C as it helps determine the appropriate treatment
age to care and treatment, particularly in high-risk groups such and posttreatment follow-up. For example, the WHO recom­
as PWID and incarcerated persons. A systematic review of 142 mendation on treatment duration varies from 8 to 24 weeks,
studies, including nearly half a million patients from LMICs, dependent on the presence of compensated cirrhosis, the
showed that this approach led to successful linkage to care in HCV genotype, and the type of treatment (sofosbuvir/daclatas­
72% of PWID and 94% of incarcerated persons, compared vir or glecaprevir/pibrentasvir) [4]. There is currently no POC
with 53% and 50%, respectively, for approaches that required liver staging, therefore, even if true-POC for HCV RNA was de­
the patient to move from one health facility to another [38]. veloped, same-day treatment initiation may not be possible.
Similarly, treatment uptake was higher with full decentraliza­ Coupling true-POC HCV testing with POC liver staging could
tion compared with partial decentralization (73% vs 66% and be considered best practice—and would be in line with current
72% vs 39% for PWID and prisoners, respectively) [38]. This WHO guidelines, which recommend liver staging prior to
study supports the findings of studies in India and Malaysia, treatment initiation [4]. However, if a diagnostic and treatment
which showed that significantly fewer patients were lost to algorithm involves ruling out decompensated cirrhosis using
follow-up during the diagnostic and treatment cascade if all clinical signs, then starting treatment solely based on detection
services were provided at a single site (vs referral to a different of HCV RNA while awaiting confirmation of liver staging re­
site/hospital), resulting in reduced loss to follow-up between sults, may also be an appropriate alternative.

S346 • JID 2024:229 (Suppl 3) • Reipold et al

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