Urine HPV Testing: History
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Subjects: Oncology | Health Care Sciences & Services | Agriculture, Dairy & Animal Science
Contributor:
George Valasoulis

Urine HPV detection has the potential to become a most promising tool that could expand the possibilities in changing genital and cervical cancer prevention strategies as well as in the surveillance and management of genital precancer.

  • HPV
  • HPV urine
  • cervical cancer screening
  • HPV DNA
  • genotyping
  • mRNA E6 & E7
  • HPV methylation markers

1. Introduction

Despite the substantial scientific evolution in cervical cancer prevention and related infrastructures, millions of “at-risk” women miss the opportunity to detect their precancerous lesions at a curable stage by not participating in screening programs. Sometimes, this happens because a large proportion of the population is lost to cervical cancer screening due to poor resources, cultural barriers, or avoidance of a pelvic exam [1]. Additionally, sometimes these women live in low-resource settings or belong to social or religious minorities; however, a considerable percentage of cervical screening non-attenders simply feel uncomfortable with the current screening protocols and methodology, including visiting health facilities, more so during the COVID-19 pandemic, and/or trying to avoid the gynecological examination and the lithotomy position [2][3].

During the previous decades, the progressive implementation of HPV-related cervical screenings has transformed the whole paradigm in cervical cancer prevention. HPV-based molecular screening modalities proved to be highly sensitive, thus offering better protection from cervical cancer than cytology [4][5][6][7][8][9]. However, the necessity for optimizing the cost-effectiveness of screening interventions is paramount and seems now even more justified, with health systems’ resources confronted globally by unexpected groundbreaking challenges, like the COVID-19 pandemic [10]. In the quest of increasing genital and cervical screening effectiveness, suboptimal participation rates of the targeted population in screening programs represent a fundamental drawback [11]. An important immediate gain, not only in cervical cancer but also in cancer prevention as a whole, could be attained by increasing screening the attendance among women who are currently either unscreened or screened infrequently using self-sampling HPV detection methods [4][12][13][14][15][16][17], given the causative role of HPV in a plethora of cancers. Implementing sensitive screening modalities combined with easy sampling methods with minimal pain or discomfort bypassing the doctors’ visit, such as self-sampling of vaginal and urine samples, is feasible and possibly cost-effective [18].

Older and recent studies have illustrated that self-sampling is highly acceptable among women [6][12][13][14], even during pregnancy [19] or infertility work up [20]. This popularity could be partially attributed to overcoming hesitance and concerns about disclosing sexual activity history. Acceptance rates could possibly be further improved with proper communication of the procedure and documentation of its non-inferiority compared with conventional screening [6].

Persistent high-risk HPV (hrHPV) infections are the leading cause of more than 90% of cervical and anal cancers, approximately 70% of vaginal and vulvar cancers, and more than 50% of penile cancers [21]. Based on data from 2013 to 2017, about 45,300 HPV-related neoplasms occur in the United States each year: about 25,400 among women and about 19,900 among men. Cervical cancer remains the most common HPV-related disease among women, while oropharyngeal neoplasms are the most prevalent among men [22][23].

2. Recent Developments of Urine HPV Testing

Several authors have recently published their contributions in urine self-sampling. In this perspective, their early innovation with the development of a special apparatus for the scope of urine collection represented a mainstay development [24]. The pioneering group of Vorsters has repeatedly illustrated that optimizing urinary HPV DNA detection should involve: (i) use of first-void urine (FVU); (ii) prevention of human/HPV DNA degradation during extraction and storage by adding a preservative; (iii) processing of a sufficient volume of whole urine; and the (iv) use of an analytically sensitive HPV test/recovery of cell-free HPV DNA in addition to cell-associated DNA [25][26].

Additionally, the importance of HPV genotyping in HPV lesions, genital cancer, and also cervical screening with self-samples was increasingly emphasized [12][13][14][16][19][27][28][29][30][31].

A recent study by Oliveira et. al. assessed HPV16/18-E6 expression prior to the treatment of cervical lesions and evaluated the concordance between urinary, vaginal, and cervical HPV16/18-E6 and hrHPV DNA testing [32]. Overall, HPV16/18-E6 oncoprotein was detected in 30.6% of cervical samples, 20.3% of self-collected vaginal samples, and 21% of urine samples. As of clinical sensitivity, the HPV16/18-E6 oncoprotein was undetected in CIN2 cases but was detected at low rates in CIN3 cases. The clinical sensitivity of the HPV16/18-E6 oncoprotein assessment in the detection of invasive cervical cancer was 70% for cervical scrapes, 55% for self-collected vaginal samples, and 52% for urine samples. Interpreting their results, the authors suggest that E6 oncoprotein detection, which can be tested in urine samples, serves for the clinically important detection of invasive or microinvasive lesions (Table 1).

Methylation biomarkers, as suggested by Arbyn et al., represent a promising and attractive approach (Table 2) [18]. Van den Helder et al. tested a panel of five methylation markers (ASCL1, GHSR, LHX8, SST, ZIC1) in three different urine fractions: full void urine, urine sediment, and urine supernatant. Strong correlations (r > 0.60) were found between urine fractions and methylation levels, which increased significantly with aggravated severity of underlying disease in all three fractions, another clinically important result. Comparison of cancer to controls was highly significant for all markers in all fractions; however, urine sediment performed best to detect CIN3. The authors consider their results to justify the potential of CIN3 detection by urinary methylation analysis (Table 2) [33].

Table 2. Performance Characteristics of Urine HPV assessment in Colposcopy Clinic patients. Studies focusing on Colposcopy patients.

Authors Specimen HPV Biomarker & Assay Sensitivity (%) Cohen’s Kappa Coefficient (κ)
Van den Helder et al. 2020 [33] Full void urine,
urine sediment & urine supernatant s/s		 5 methylation markers
Multiplex 1 (GHSR-SST-ZIC1)Multiplex 2 (ASCL1-LHX8)		    
Lee et al. 2020 [34] Unspecified populationCervical clinician-obtained vs. urine s/s Cervical specimens: Cobas 4800™ (Roche)
Urine: Ultrasensitive nanowire assay		 HPV16: 81.3% (95% C.I. 54.4–96.0)
HPV18: 100.0% (95% C.I. 29.2–100.0)
Other hrHPV’s: 96.4% (95% C.I. 81.7–99.9)		 HPV16: 0.83 (95% C.I. 0.67–0.99)
Hpv18: 0.65 (95% C.I. 0.28–1.00)
Other hrHPV’s: 0.97 (95% C.I. 0.91–100.0)
Asciutto et al. 2018 [35] Clinician-obtained cervical cytology & mRNA HPV,
Vaginal s/s, Urine s/s.
vs. Cervical Histology (Biopsy or LEEP)		 Aptima mRNA™ (Hologic) APTIMA™ in vaginal self-samples 85.5%
APTIMA™ in urinary samples 44.8%
Cervical Clinician-obtained Cytology 81.7%
Cervical Clinician-obtained APTIMA™ 100% for HG		  
Arias et al. 2019 [36] Female arm: Cervical cytology & Cervical histology,
FVU s/s treated with proteinase K
Untreated FVU s/s		     Arm A
Untreated FVU 0.29 (0.16–0.42)
ATS-FVU 0.63 (0.52–0.73)
Arm B
Untreated FVU 0.27 (0.14–0.41)
ATS-FVU 0.42 (0.30–0.54)
Cho et al. 2020 [37] Matched urine s/s, vaginal s/s, and clinician-obtained cervical samples RealTime HR-S HPV™ Anyplex II HPV 28™ For CIN2:
Cervical samples, Realtime HR-S: 93.13% (95% CI, 87.36 to 96.81)
Cervical samples, Anyplex II: 90.08% (95% CI, 83.63 to 94.61)
Vaginal samples, Realtime HR-S: 84.73% (95% CI, 77.41 to 90.42)
Vaginal samples, Anyplex II: 78.63% (95% CI, 70.61 to 85.30)
Urine samples, Realtime HR-S: 73.28% (95% CI, 64.85 to 80.63)
Urine samples, Anyplex II: 66.41% (95% CI, 57.61 to 74.42)		  
Cadman et al. 2021 [38] Urine & Vaginal s/s [WD=Digene® Female Swab Specimen Collection Kit (Qiagen GmbH) placed in liquid specimen transport medium (STM) plus DF = Copan FLOQswab™ (Copan Diagnostics Inc) as a dry sample vs. the QT = Qvintip® kit (Aprovix AB) & the HS = HerSwab (Eve Medical) both as dry samples] hrHPV Onclarity™ (BD) Sensitivity for CIN3+ with WD: 91.2%
Sensitivity for CIN3+ with urine: 89.7%
Sensitivity for CIN3+ with DF: 88.2%
Sensitivity for CIN3+ with QT: 81.8%
Sensitivity for CIN3+ with HS: 77.4%		 Between WD & DF: kappa = 0.801, 95% CI: 0.777, 0.826
Between QT & HS: kappa = 0.753, 95% CI: 0.723, 0.779
Between urine and the 4 vaginal samples: kappa = 0.568–0.646
Pathak et al. 2014 [39] Meta-analysis of 14 studies (1443 women) confined to urine s.s.
  • Most used commercial PCR methods on FVU
  • No independent analysis for PCR vs. signal amplification methods
 Urine detection of any HPV: pooled sensitivity of 87% (95% C.I. 78% to 92%)
Urine detection of hrHPV: pooled sensitivity of 77% (68% to 84%)
Urine detection of HPV 16 & 18: pooled sensitivity of 73% (56% to 86%)
Metaregression revealed an increase in sensitivity with FVU samples compared with random or midstream (p = 0.004)		  
Arbyn et al. 2018 [18] Meta-analysis   Each hrHPV assay based on PCR was equally sensitive for CIN2+ and for CIN3+ on self-samples versus clinician samples.
The pooled sensitivity of hrHPV assays based on signal amplification was 10–16% lower on a self-sample versus a clinician sample for all self-sampling device and storage medium categories		  
Östensson et al. 2021 [40] Pretreated patients with conizationPaired urine, vaginal s/s and cervical obtained by gynaecologist Abbott RealTime High-Risk HPV PCR (Urine & Vaginal s.s, Cervical clinician-obtained)Cobas 4800™ (Roche) Cervical clinician-obtained Clinician sampled: Any HR type:100%
Clinician sampled: 16/18: 100%
Vaginal self- sampled: Any HR type:100%
Vaginal self- sampled: 16/18: 100%
Urine self- sampled: Any HR type:100%
Urine self- sampled: 16/18: 33%		 Abbott clinician kappa = 0.83
Vaginal self-sample: kappa ranged from 0.63 to 0.89
Urine self-sample: kappa ranged from 0.36 to 0.85
Ørnskov et al. 2021 [17] Paired urine, vaginal s/s and cervical obtained by gynaecologist Cobas 4800™ (Roche) Sensitivity for CIN2+ with Self-collected vaginal sample: 96%
Sensitivity for CIN2+ with Urine sample: 93%
Sensitivity for CIN2+ with Clinician-taken cervical sample: 96%
Sensitivity for CIN3+ with Self-collected vaginal sample: 97%
Sensitivity for CIN3+ with Urine sample: 95%
Sensitivity for CIN3+ with Clinician-taken cervical sample: 97%		 Between Urine and self-collected vaginal samples, kappa = 0.77, 95% CI: 0.70, 0.85
Between clinician-taken cervical samples and self-collected vaginal samples, kappa = 0.77, 95% CI: 0.70, 0.85
Between Urine and clinician-taken cervical samples, kappa = 0.66, 95% CI: 0.57, 0.74
Abbreviation: s/s = self-sampled.

Two further recent studies have also been published by a research group that developed an ultrasensitive nanowire assay [34][41]. Both studies used polyethylenimine-conjugated nanowires (PEI-NWs) and implemented HPV DNA isolation and detection strategy in urine samples. The authors consider that this assay demonstrated excellent ability to identify HPV DNA from urine specimens, as they observed an excellent agreement in the detection of high-risk HPV between paired urine and cervical samples, even with a small urine sample volume (Table 2).

2.1. mRNA E6/E7

Three recent studies have assessed the performance of the APTIMA hrHPV E6/E7mRNA assay in urine. In the study of Asciutto et al., the sensitivity of the APTIMA HPV assay in detecting HSIL/AIS/cancer for the clinician-taken cervical HPV samples was 100.0%; however, the corresponding value for urine self-sampling was a disappointing 44.8% (Table 2) [35]. In their study, Arias et al. illustrated that treatment of first void urine with Aptima Transfer Solution optimized the detection of high-risk HPV E6/E7 mRNA with the APTIMA assay (Table 2) [36]. Finally, the paper of Padhy et al. focused on the detection of hrHPV E6/E7 mRNA expression in urine samples, comparing their concordance with cervical samples including HPV 16 & 18/45 genotyping, and determining the utility in detecting ≥CIN 2 lesions. In this study, the sensitivity of urine hrHPV E6/E7 mRNA detection was 31.5%, while the specificity and PPV were above 95%. In their concluding remarks, the authors consider that using the APTIMA assay, urine hrHPV-mRNA detection is suboptimal for cervical cancer screening, but given the high specificity, it has the potential to identify high-grade lesions (≥CIN 2). The authors also point that urine hrHPV-mRNA genotyping via this modality is not beneficial in triage settings of normal or abnormal cytology to determine the need for colposcopy (Table 1) [1].

2.2. HPV DNA

A recent Danish study investigated the concordance of hrHPV positivity of home-based collected urine samples with vaginal self-samples as well as with cervical cytology samples collected by a general practitioner by using two different hrHPV DNA assays (COBAS® 4800 & GENOMICA CLART® HPV4S). Urine samples showed good concordance in hrHPV detection compared with vaginal and cervical samples when assessed with the COBAS assay and moderate with CLART. Additionally, urinary hrHPV detection by COBAS illustrated a sensitivity of 63.9% and a specificity of 96.5% compared with 51.6% and 92.4%, respectively, for CLART. While underscoring that participating individuals considered home-based urine collection as well-accepted and ranked it as the most preferred future screening procedure, the authors urge for improvement in accuracy rates of urinary hrHPV detection before urine can serve as an alternative screening option (Table 1) [42].

Another recent Korean study aimed to evaluate the diagnostic accuracy of two PCR-based hrHPV assays (Realtime HR-S and Anyplex II) on self-collected vaginal and urine samples for the detection of cervical precancer in a colposcopy population. In this study, Cho et al. conclude that despite the comparable detection performance for hrHPV and CIN2+ on self-collected vaginal samples and clinician-collected cervical samples, the performance of these two particular hrHPV tests using urine was inferior to those using clinician-collected cervical samples in terms of detecting hrHPV and CIN2+ (Table 2) [37]. In the most recent study, Cadman et al. compared the performance of four vaginal self-sampling devices, including wet and dry transport methods between themselves and an initial stream urine sample using the Becton Dickinson Onclarity assay in 600 women referred for colposcopy. Urine samples were collected with the Colli-Pee® device, and two paired vaginal self-samples were obtained subsequently, using either simple devices (a dry flocked swab (DF) and a Dacron swab (WD)), or more complicated inventions (a HerSwab (HS) and Qvintip (QT) device). Women harboring irregular colposcopic findings underwent cervical biopsies; for these patients, histology results were also available. The authors assessed for HPV positivity and user preference and confidence in the collection; they also conducted additional analyses to examine the effect of adjusting for sample cellularity and different positivity thresholds [38]. Summarizing their results, the authors did not report any significant difference for the vaginal samples in terms of hrHPV positivity rates, which were closely distributed in a narrow range (from 65.1–71.7%), while the corresponding value for urine was a comparable 76%. Agreement on the same sample between the simple devices WD and DF were high (kappa = 0.801, 95% CI: 0.777, 0.826) but lower between the more complicated QT and HS (kappa = 0.753, 95% CI: 0.723, 0.779) and lower still between urine and the four vaginal samples (kappa = 0.568–0.646), largely due to the higher positivity rate with urine. There were no statistically significant or obvious differences in genotype-specific positivity by device. The highest sensitivity for CIN3+ was obtained with a simple and cheaper device (WD = 91.2%). Women found urine easiest to collect, and they were more confident that they had obtained the sample correctly. The authors conclude that both urine and vaginal self-samples obtained with simple devices performed well and were well-received by women (Table 2) [38].

The recent study by Östensson et al. that focused on a special population of patients who had previously undergone conization is of special interest. The authors studied 531 women and utilized the Abbott RealTime High-Risk HPV assay to examine how well the HPV findings from self-sampled vaginal (VSS) and urine specimens containing transport medium correctly identified women with recurrent CIN2+ compared to samples collected by clinicians. At the first follow-up approximately six months post-treatment, all patients with recurrent CIN3 had positive HPV results by all methods. At the second follow-up approximately one-year post-treatment, all seven newly-detected CIN2/3 recurrences were associated with HPV positivity on VSS and clinician-samples. Only clinician-collected samples detected HPV positivity for the two adenocarcinoma-in-situ recurrences, which were both HPV18 positive [40]. For overall HPV results, Cohen’s kappa revealed substantial agreement between VSS and clinician sampling and moderate agreement between urine and clinician sampling. Furthermore, clinician sampling and VSS were highly concordant for HPV16. For squamous pathology, VSS appeared as sensitive as clinician sampling for HPV in predicting outcome among the studied cohort (Table 2).

Finally, in a very recent Danish cross-sectional study in colposcopy referred individuals, Ørnskov et al. compared the absolute and relative sensitivity as well as the specificity of two self-collected specimens (Urine/Self-collected vaginal samples) and a clinician-taken Cervical Sample (CS) to detect high-grade cervical intraepithelial lesions (CIN2+/CIN3+), by using the Cobas HPV assay [Cobas 4800™ (Roche, Basel, Switzerland)]. They illustrated that both urine and vaginal self-collected sampling are non-inferior to the clinician-taken CS in identifying CIN2+/CIN3+ (Table 2). Furthermore, regarding the acceptability of the screening method used, they concluded that the majority of women identified urine as the sampling method of choice, especially when they were asked about the expected preference for women not attending the screening programme [17].

This entry is adapted from the peer-reviewed paper 10.3390/cancers13071640

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