Point-of-care tests for human papillomavirus detection in uterine cervical samples: A review of advances in resource-constrained settings

Human papillomavirus (HPV) is the causative agent of cervical precancerous lesions and cancer1. Currently, there are six US-FDA-approved assays for HPV detection (DNA or RNA) for use in cervical cancer screening2. In addition, the International HPV Laboratory Network conducts proficiency testing for laboratories using commercially available HPV-based tests as well as the in-house assays3. However, the cost-intensiveness of these assays, the requirement of an extensive laboratory set-up with high-end equipment and the delay in report generation (usually due to the batch system of sample processing) have hindered the utility and application of HPV-based cervical cancer screening in the low- and low-middle income countries4. Hence, there has been a felt need for the development of cost-effective point-of-care (POC) or near-POC methods for HPV detection in cervical samples. Alongside this, there has been a growing interest in the evaluation of the self-sampling of vaginal samples for HPV-based cervical cancer screening to expand the coverage of screening. Studies have reported a comparable sensitivity across self-collected vaginal samples as well as physician-collected samples for the detection of cervical precancerous lesions56. The coupling of low-cost POC or near-POC HPV tests with self-sampling can offer the best opportunity to resource-constrained nations for cervical cancer elimination. However, a few studies have reported a lack of awareness (of cervical cancer as well as the importance of screening), social influence, religious reasons and partner’s disapproval as barriers for women not consenting to participate in self-sampling for the HPV-based cervical cancer screening7.

Over the last two decades, only a few studies have evaluated a POC test for HPV detection or described a technique that could potentially be utilized for a POC test. A recently published systematic review and meta-analysis8 evaluated the performance of two POC tests for HPV detection, careHPV™ and OncoE6 cervical test™. This analysis8 demonstrated a higher sensitivity for CIN2+ and CIN3+ lesions with care HPV™ while the specificity was better with the OncoE6 cervical test™8. However, till date, no systematic review has been performed for the POC or near-POC tests for HPV DNA or RNA detection in cervical samples. Such concise information is likely to prove useful to researchers for future directions in this field as well as to the policymakers in guiding the formulation and updation of the cervical cancer screening guidelines. This review aimed to summarize the currently available literature on POC tests for HPV-based cervical cancer screening and to briefly outline the emerging technologies in this field.

Methods

Search strategy: A systematic literature search was conducted from January 1, 2004 (after the approval of HPV tests for cervical cancer screening as a co-test) upto December 31, 2022, using the following search terms: ‘cervical cancer’, ‘human papillomavirus (HPV)’, ‘cervical cancer screening’, ‘point of care testing’, ‘evaluation’, ‘near-patient’,’ and ‘performance’. MEDLINE and Cochrane databases were searched for relevant articles. Reference lists of all the included articles were checked for additional relevant studies.

Inclusion criteria: Studies describing POC or near-POC HPV detection (DNA or RNA) for cervical cancer screening were included in this review. HPV detection tests that can be performed at the site of sample collection (generally a primary health centre in resource-constrained settings) and provide results on the same day are considered to be POC tests9. There were no restrictions in context to the type of study, population studied, sample type included or language of publication.

Exclusion criteria: Studies that described techniques not suitable for POC testing or requiring extensive laboratory set-up were excluded from the review.

The included papers were reviewed for the HPV detection method or technology described and grouped into the following categories: (i) commercially available tests, (ii) prospective candidates under trial (tests that have undergone limited testing for cervical cancer screening) and (iii) upcoming advances (technologies that are yet to be evaluated for cervical cancer screening).

Results

Commercially available point-of-care (POC) or near-point-of-care (POC) tests for human papillomavirus (HPV) detection: At the time of writing this review, there were four commercially available methods for POC HPV-based cervical cancer screening. However, none of these assays have yet received the US-FDA approval for use in cervical cancer screening.

careHPV™: The careHPV™ test was developed by Qiagen8, as a low-cost alternative for resource-constrained countries. careHPV™ is a nucleic acid hybridization test with signal amplification that requires only low cost benchtop equipment and provides a qualitative result within ~2.5 h10. Numerous studies have demonstrated the comparability of careHPV™ results with HC2, both in clinical trials with well-trained staff in a laboratory set-up and for screening the general population as well as high-risk groups in resource-constrained settings111213.

careHPV™ has also been evaluated for use in cervical cancer screening using the self-collected vaginal samples. A recent meta-analysis reported the sensitivity of careHPV™ for the detection of CIN2+ lesions using clinician-collected samples as 88.1 per cent and specificity as 83.7 per cent8. For self-collected vaginal specimens, the sensitivity of careHPV™ was 73.6 per cent while the specificity was 88 per cent for CIN2+ lesions. However, the specificity of careHPV™ for CIN2+ lesions among women living with HIV (WLHIV) reduced to 58.8 per cent, attributed to the higher number of transient HPV infections in this high-risk group. The specificity of HPV-based tests has also been linked to the prevalence of HPV infection in that a 10 per cent rise in prevalence leads to a drop in specificity by 8.4 per cent (8-8.8%)14.

For cost-effectiveness of careHPV™ in cervical cancer screening, a micro-costing study by Shi et al15 from China estimated an aggregated cost of US$ 7.49 for careHPV™ using self-sampling and US$ 7.95 for clinician-sampling. Another study by Levin et al16 showed that the unit test cost of careHPV™ for screening at a national level was US$ 8.22 compared to US$ 45.89 for HC2 test. Cost-effectiveness ratio in this study estimated that the cost per year of life saved was US$ 50 for careHPV™-based cervical cancer screening performed even once in the lifetime of a woman.

OncoE6™ cervical test: The OncoE6™ cervical test from Arbor Vita Corporation provides qualitative results of elevation of E6 oncoprotein levels for HPV16 and HPV18 with partial HPV genotyping17. OncoE6 cervical test™ is a ‘dipstick’ test where cell lysates are conjugated with monoclonal antibodies to the E6 protein of HPV16/18 over a nitrocellulose paper strip. The conjugated complex is then detected using an enzyme substrate. The test has been developed to serve as an adjunct test with other clinical evaluations but is not meant to be used as a standalone screening test18. The systematic review by Kelly et al8 reported the sensitivity of the OncoE6™ cervical test for the detection of CIN2+ lesions ranging from 31.3 to 42.4 per cent while the specificity was 99.1 to 99.4 per cent. The low sensitivity of this test has been attributed to the fact that about one-third of cervical precancerous lesions are caused by HR-HPV other than HPV16 or HPV18. Furthermore, the expression of E6 oncoprotein is linked to the potential of HPV-related lesions to progress over time. Hence, this test may miss the cervical lesions that have a lower progressive potential that do not overexpress E6 oncoprotein1920.

A study by Valdez et al19 compared OncoE6™, careHPV™ and visual inspection with acetic acid (VIA) for the detection of cervical precancerous lesions in a population-based cervical cancer screening. This study reported a better sensitivity of careHPV™ (96.5% for clinician-collected and 81.6% for collected-vaginal samples) for detecting CIN3+ lesions compared to OncoE6™ (54.4%). However, the specificity of OncoE6™ (99.1%) was higher than careHPV™ (86.9% for clinician-collected and 86.6% collected samples)19. Similar results were reported in the study by Torres et al21.

Xpert® HPV: GeneXpert® HPV is a cartridge-based test that employs nucleic acid amplification test (NAAT) for a qualitative result for 14 HR-HPV types with partial genotyping for HPV16 and HPV18/45 and can be performed on analyzers that are used for diagnosis of diseases such as tuberculosis and HIV by the same method. This assay can be performed as POC or near-POC using benchtop equipment and minimum hands-on sample preparation requirement and provides results within one hour22. This test has been validated so far only for samples collected in PreservCyt solution23.

Field evaluation by Toliman et al24 demonstrated an agreement between the HR-HPV, HPV16 and HPV18/45 detection with Xpert® HPV using self-collected samples as well as physician-collected samples. The availability of results in a short time, allowed triaging of HPV-positive women with VIA and same-day ablation therapy24. A recent large-scale study of Xpert® HPV test on self-collected vaginal samples demonstrated the sensitivity of this test to detect HSIL or worse lesions was 85.4 per cent while the specificity was 89.6 per cent with a negative predictive value of 98.9 per cent25.

Inturrisi and Berkhof26 assessed the tender-based pricing of HPV tests in Italy. Their study showed the unit price of Xpert® HPV as 33-42.3€ compared to 10.7€ for HC2 and 4.54€ for Cobas® 4800 HPV test26. The cost of the equipment may be a limiting factor in the widespread implementation of this assay for cervical cancer screening in low- and low-middle income countries. However, the cost of the assay would be significantly lower in settings where the equipment is already installed for the detection of tuberculosis or other diseases.

Truenat® HPV-HR: Truenat® HPV-HR assay has been developed by MolBio Diagnostics, India, entailing a real-time PCR-based detection of four HR-HPV types: 16, 18, 31 and 45 and providing results within one hour. A recent study27 compared this assay with the US FDA-approved HC2 method. The sensitivity and specificity of Truenat® HPV-HR were reported as 97.7 per cent and 98.9 per cent, respectively, for the detection of HR-HPV (gold standard being HC2)27. However, further studies are mandated to validate these results as well as evaluate the performance characteristics of this assay for CIN2+ or CIN3+ detection. A limitation highlighted by this study was the number of samples that can be analyzed at a time – the Truelab® Quattro allows for processing of four samples at a time which may prove to be a limiting factor in the field setting27.

Prospective candidates under trial for point-of-care (POC) HPV testing: Apart from the aforementioned commercially available tests, there are a few upcoming technologies that are in various stages of development. These tests are tabulated in Table I28293031323334353637383940.

Q- POC^TM: The Q-POC^TM analyzer has been developed by Global Good partnering with QuantuMDx (Newcastle upon Tyne, UK) as a platform involving multiplex PCR and providing results within 30 min (Table I). As per the manufacturer, the probes used in the assay offer high specificity and the estimated cost for the equipment could be about US$ 650, with each cartridge costing about US$ 6.5-2628. The Q-POC^TM HPV assay is currently being evaluated in a multi-site clinical study41.

Lab-on-Chip assays: A lab-on-chip assay is essentially a miniature device based on microfluidics that can integrate one or more tests on a single chip. This technology offers several advantages such as lower cost, compact design, ease of use, faster results, lower sample volumes, reduction of human errors and higher sensitivity for the test under consideration. However, many such assays that seem to work well in the laboratory do not lend themselves to commercialization. The ethical and regulatory issues pertaining to this new technology are yet unsettled42. In the field of HPV-based cervical cancer screening, the following lab-on-chip assays are under development:

• (i) The Biomedical Engineering Department at Boston University, USA, has developed an isothermal loop-mediated amplification (LAMP) technique with lateral flow strips as a POC testing for HPV16 (Table I). In a preliminary clinical validation, the group examined 10 cervical samples (five HPV positive and five HPV negative). There were two false positives attributed to the phenomenon of self-priming of the primers used in LAMP29.

• (ii) Wormald et al30 have developed a lab-on-chip utilizing LAMP assay (using HPV DNA and (human telomerase reverse transcriptase [hTERT] RNA) coupled with ion-sensitive field-effect transistor sensors. The investigators tested this device on 10 cervical biopsies (5 benign, 5 malignant). HPV16 DNA was detected in 4/5 of the malignant and 2/5 of the benign tissues, while HPV18 DNA was seen in 1/5 each of the malignant as well as benign tissues. hTERT messenger RNA was detected in all the malignant and none of the benign samples. These results were concordance with the standard PCR. The authors propose that this assay would be clinically applicable to cervical brush samples as well30.

• (iii) Another lab-on-chip device developed by Zhu et al31 (Table I) detects five HR-HPV types (16, 18, 31, 33, 45). The authors validated the device with 20 cervical samples, of which 16 tested positive for one of the five genotypes on the chip. This was confirmed by real-time PCR31.

• (iv) A LAMP-based nucleic acid amplification system for the detection of HPV16, 18, 39, 45 and 52 has been developed by Zhao et al32. The system was compared with quantitative PCR using HeLa cells–48 HPV-positive and 48 HPV-negative samples. The sensitivity and specificity of the LAMP assay were 100 per cent sensitive and 91.7 per cent, specific32.

• (v) Yin et al33 built a smartphone-based smart cup platform for LAMP-based detection of HPV 16, 18 and 31 DNA. As a proof of concept, 15 cervical swab samples (3 HPV positive and 12 negative) were analyzed using this device, and results showed a 100 per cent agreement with real-time PCR. However, further validation in a larger study and inclusion of other high-risk HPV types is mandated for this device33.

• (vi) Smith et al34 developed a paper-based signal amplification assay requiring a low-cost benchtop heater and involving seven steps to be performed by the user. The performance of this assay was assessed with 16 biobanked cervical swab samples (8 positive and 8 negative) showed 87.5 per cent sensitivity, 100 per cent specificity and 93.8 per cent accuracy (gold standard being careHPV™)34.

HPV genotyping 9G Membrane test: A Korean group evaluated a 9G membrane test for potential use as a POC platform in cervical cancer screening. In their validation study35, 550 cervical samples were analysed for five HR-HPV types – 16, 18, 31, 33 and 45. The results of 9G membrane test were in 100 per cent agreement with the sequencing results. Considering the PCR-based HPV detection as the gold standard, the sensitivity and specificity of the 9G membrane test were found to be 100 per cent35. This product was approved by the Korean FDA and commercialized by BMT Chip (https://www.bmtchip.com/bbs/board.php?bo_table=products_en&wr_id=7). The requirement of DNA extraction and amplification, however, might limit the current use of this assay for cervical cancer screening in field settings.

DNA-focussed digital microholography: An interesting technology – ‘DNA-focussed digital microholography’ – has been developed by Pathania et al36. The device was validated on 28 cervical samples and seven cervical biopsies, comparing the results with the reference test (Cobas® 4800 HPV test) for HPV16 and HPV18, showing a good correlation in HPV signals between pairs of cervical brush and biopsies (Pearson correlation coefficient r=0.93). A full concordance was found between the AIM-HPV assay and the Cobas® 4800 HPV test. The authors intend to improvise the device by integrating an isothermal amplification step, including other HR-HPV types and reagent lyophilization for longer storage to allow for translation into clinical practice36.

Clustered regularly interspaced short palindromic repeats (CRISPRs): (CRISPR)-based detection has shown great promise in the molecular diagnosis of various diseases. However, the technique requires expensive equipment and trained workforce. Tsou et al37 have developed a lateral flow dipstick method with HPV16/18-targeting CRISPR RNA and custom ssDNA-FAM quencher reporter. This technique was evaluated in plasma samples of 15 individuals with cervical cancer and 14 cancer-free individuals. The CRISPR-Cas12a system could detect HPV16 and HPV18 in 13/14 and 3/10 individuals with cervical cancer, respectively. However, HPV16 was also detected in 5 out of the 14 individuals who were cancer-free. This false positivity has been explained by the presence of inflammation or infection that could facilitate the viral spread into the blood circulation, and the possibility of an off-target effect of CRISPR RNA, that is the presence of sites on the RNA with partial homology37.

CRISPR/Cas12a was coupled with recombinase polymerase amplification in a fluorescence-based HPV detection system for HPV16 and HPV18 by Zhou et al38. This method, however, requires validation in a larger number of clinical samples.

The CRISPR system has been used with multiplex recombinase-aided amplification in a portable fluorescence-based assay designed by Zheng et al39. A clinical evaluation in 55 samples (7 HPV16/18 co-positive, 10 HPV16 positive, 10 HPV18 positive and 28 HPV negative) gave a sensitivity of 95 per cent and a specificity of 100 per cent39. CRISPR-based assays are not available commercially as of now.

Nanoparticle-based assays: Appidi et al40 developed a gold nanoparticle-based colorimetric assay for cervical cancer screening (C-ColAur). In this validation study, 27 of the 28 cancerous samples and 10 of the 14 normal cervical samples were identified correctly, giving a sensitivity of 96.42 per cent and specificity of 71.42 per cent, suggesting its potential utility as a screening test (Table I). Studies with a larger number of samples, including cervical precancerous lesions are, however, imperative to validate the utility of this system in cervical cancer screening.

Upcoming advances in the field of point-of-care (POC) human papillomavirus (HPV) detection: In addition to the above-mentioned advances in the field of cervical cancer screening, a few more promising methods/technologies are under development that could be accelerated to clinical evaluation in the coming years.

Paper-based devices: A ‘multiplex autonomous disposable NAAT (MAD-NAAT)’ has been developed as a POC paper-based instrument-free network device that can provide qualitative results (Table II43444546474849). The prototype has been evaluated for the detection of methicillin-resistant Staphylococcus aureus in nasal swab specimens43. This assay is intended to be evaluated for cervical HPV DNA detection, for which optimization of cervical sample preparation might be needed.

A portable battery-powered platform for one-pot amplification and detection of fluorescence has been designed by Mei et al44. This device was tested for the detection of SARS CoV-2 RNA with a limit of detection as low as 4×102 copies per ml44. This technology holds promise for HPV DNA detection. However, the manual steps, requirement of cold storage for enzymes and size of the reader are likely to make this less suitable for field settings with untrained healthcare workers.

Serum or plasma-based tests: Abviris Deutschland GmbH, Ahrensburg, Germany, has marketed a product, Prevo-Check®, a competitive immunoassay for a qualitative detection of antibodies against HPV16 L1 in serum. So far, this product has received CE-IVD for the detection of anal and oropharyngeal cancers only. A study by Blatt et al45 reported this assay to have a sensitivity, specificity and accuracy of 100 per cent for oral SCC. However, it is yet to be evaluated in screening for cervical cancer and precancerous lesions.

A compact multiplex fluorescence-based platform has been designed by Obahiagbon et al46. This platform was tested on two plasma samples – one HPV16E7 antibody positive and another negative as a proof-of-concept. Since the system is compact, field trials for the detection of HPV16 and HPV18 antibodies for cervical cancer screening may be undertaken soon.

Keyvani et al47 have used a graphene oxide-based electrochemical sensor in an integrated microfluidic assay for the detection of circulating HPV DNA (cDNA) in the plasma. However, the limit of detection of DNA by this device was higher than the average range found in individuals with cervical cancer. Hence, either an amplification step needs to be interposed or the sensitivity of the biosensor enhanced for better detection.

Other techniques: Fan et al48 used a simple, rapid and automated microchip electrophoresis (MCE) for the detection of HPV16 and HPV18. The MCE facilitates the detection of the DNA product within three minutes post amplification. The authors used CaSki cells for HPV16 DNA and HeLa cells for HPV18 DNA. The sensitivity of MCE for the detection of HPV16 and HPV18 was found to be 102 cells/ml48. The MCE detection system has not yet, however, been validated in clinical samples. There is also a need for integration of the DNA amplification with MCE to devise a complete handheld HPV detection system.

An electroanalytical biosensor utilizing the graphene oxide-DNA hybrid method was devised by Rawat et al49. This technology needs to be further refined and developed as a portable device for POC HPV DNA-based cervical cancer screening.

Other cost-effective strategies for resource-limited settings:

Urine-based human papillomavirus (HPV) detection: Urine-based detection of HR-HPV by Das et al50 in 1992 has recently garnered attention as a non-invasive and simple alternative for population-based cervical cancer screening. Urine HPV detection is based on the premise that the first-voided urine in a female contains exfoliated cells from cervical epithelial lesions which help in detecting HPV infection5051. Although studies including a recent meta-analysis demonstrate a good sensitivity and specificity for HR-HPV detection in urine samples compared to cervical samples, none of the commercially available HPV assays have so for been clinically validated for urine samples52. Adaptation of urine self-collection for POC HPV detection is a difficult task due to technical issues. A recent study53 attempted to use Xpert® HPV in urine samples from 40 women (30 from colposcopy clinic and 10 undergoing routine screening) and demonstrated a sensitivity of 66.7 per cent and a specificity of 86.7 per cent when compared with cervical samples53.

Paper smear method of cervical sample collection: In view of the non-accessibility of appropriate sample transport facilities in hard-to-reach areas, a ‘paper smear’ method of cervical sample collection was developed by Kailash et al54 where the cervical scrape is collected on a sterile Whatman 3MM filter paper cut in the size of a standard glass slide, air-dried and transported to the laboratory for PCR-based HPV detection in a single tube without extracting DNA separately. The quality and quantity of DNA extracted from this sample were shown to be comparable to those obtained from the same women and stored in phosphate-buffered saline at −70°C. This technique offers an alternative for the implementation of HPV-based cervical cancer screening in remote areas by effectively transporting samples to a reference laboratory. However, the advantages of POC or near-POC HPV testing, such as rapid results and screen-and-treat approach, are not feasible with this method.

Discussion

Cervical cancer remains a major public health concern globally, amounting to 6,04,127 new cases and the 3,41,831 deaths in year 202055. In May 2018, the World Health Organization issued a ‘Call for Action’ for cervical cancer elimination by 2030. As a part of the strategy for achieving this goal, at least 70 per cent of the eligible women should be screened using a high-performance test twice in their life (at 35 yr and 45 yr)56. Among the available modalities for cervical cancer screening, HPV DNA-based tests have shown higher sensitivity for detecting CIN2+ lesions. However, the majority of the commercially available US-FDA-approved HPV detection tests are costly with the requirement of an elaborate laboratory set up and trained workforce. These limitations have hampered the widespread utility of HPV-based cervical cancer screening in resource-constrained countries. Hence, various researchers have been attempting to develop a cost-effective, easy-to-use, rapid and efficient POC test for HPV-based cervical cancer screening.

A modelling study by Campos et al22 indicated that POCT-based cervical cancer screening with adequate linkages to treatment might be worthy of investment, especially in countries where the loss to follow up is relatively high22. Camara et al57 reported a high level of acceptability of self-collection of cervical samples for POC HPV testing by GeneXpert™ and the screen-and-treat approach in the Pacific Islands paving the way for further research on POC HPV-based tests for resource-constrained countries.

Although the field of POC tests for HPV detection has generated a significant interest, a few criteria need to be kept in mind while developing these technologies such as: (i) adequate validation process of newer tests including all the molecular steps, especially in a screening population, (ii) validation of HPV test in women who have undergone treatment for cervical precancerous lesions or cancer, (iii) validation protocol for self-collected samples and (iv) validation of HPV genotyping tests along with the decision on the comparator test58. Although careHPV™ and Xpert® HPV tests are commercially available for cervical cancer screening, their current cost imposes a limitation on their scalability for population-based screening, especially in low-resource countries8. Ideally, a test with a clinical sensitivity of 90-95 per cent and a specificity of 90-98 per cent and cost of not more than US$ 5 should be targeted for cervical cancer screening59. The traditional nucleic acid extraction and amplification techniques mandate a laboratory set up and complex instrumentation entailing high cost. The need of the hour is a test with a limited requirement of equipment and minimal sample preparation or hands-on involvement so that semi-trained healthcare providers may be able to perform the task. Technologies such as (LAMP) perform nucleic acid amplification at a single temperature (isothermal) and thus require only a simple single-temperature heater. The combination of LAMP technique with paper-based microfluidic system in assays, such as those devised as Rodriguez, Wormald, and other authors, hold promise in yielding an actual POC HPV test for resource-constrained countries. Researchers hence need to incorporate multiple HPV genotypes in the same device along with a possibility of genotyping, for HPV16, HPV18/45 and similar HPV oncogenic types.

The combination of isothermal nucleic acid amplification with the CRISPR/Cas technique may be explored to provide a simple, low-cost and portable POC testing device for HPV-based cervical cancer screening in the future.

The recent advances in the field of nanotechnology have allowed for the development of nanobiosensors for various purposes. Nanobiosensors, usually made from inert materials such as gold, work on the principle that binding of the analyte of interest to the biosensor leads to a change in the physicochemical signal that can be converted by a transducer into an electric signal60. Nanobiosensors are being developed for POC detection of various cancers such as breast and ovarian61. In the field of cervical cancer screening, gold nanoparticle-based and graphene oxide-based nanoparticles have been explored for development of rapid assays38. However, these techniques require further refinement to achieve a rapid, simple, efficient and inexpensive POC test for HPV-based screening.

The science of microfluidics has been evolving rapidly with the integration of artificial intelligence (AI), making it intelligent microfluidics. AI and machine learning can be utilized to optimize the circuit modelling of the microfluidics, fabrication and 3D printing and provide control through automation over the fluid flow, temperature, particle manipulation and so on. Nanoparticle-based sensors can also be optimized using AI. Similarly, AI and machine learning can be integrated with signal recognition and analysis for result generation in new-age diagnostic systems62. The field of HPV detection has already witnessed the advent of AI-based system developed by Pathania et al36, and this is only likely to grow and expand further.

This review highlights that, there are a few commercially available HPV detection methods suitable for POC testing and many others at various stages of development and testing to develop and validate a suitable POC test for HPV-based cervical cancer screening particularly for resource-limited countries. In our opinion, there is an imperative need for inter-group, inter-institutional and inter-country collaborations on this topic to make optimum use of the best available technology and scientific minds in devising such a test that fulfils the requirement of a cervical cancer screening modality with robust performance characteristics.