Background: Only clinically validated HPV assays can be accepted in cervical cancer screening. Objectives: To update the list of high-risk HPV assays that fulfil the 2009 international validation criteria (Meijer-2009). Data Sources: PubMed/Medline, Embase, Scopus, references from selected studies; published in January 2014 to August 2020. Study eligibility criteria: HPV test validation studies and primary screening studies, involving testing with an index HPV test and a comparator HPV test with reporting of disease outcome (occurrence of histologically confirmed cervical precancer; CIN2þ). Participants: Women participating in cervical cancer screening. Interventions: Testing with an index and a comparator HPV test of clinician-collected cervical specimens and assessment of disease outcome (

Given empirical evidence that the relative accuracy of HPV-testing on self- vs clinician-samples is robust across clinical settings, the VALHUDES protocol offers a framework for validation of HPV assay/self-sample device combinations that can be translated to a primary screening setting.

BACKGROUND: Women with atypical squamous cells of undetermined significance (ASC-US) can be triaged accurately with a high-risk human papillomavirus (hrHPV) test to identify those who need a referral. However, the triage of lowgrade squamous intraepithelial lesion (LSIL) with hrHPV testing has very low specificity. Overexpression of p16, with or without Ki-67, indicates neoplastic transformation of human papillomavirus-infected cervical cells and may more accurately predict underlying cervical intraepithelial neoplasia of grade 3 or worse (CIN3+). METHODS: A literature search was conducted in 3 bibliographic databases. Studies were selected if they included women with ASC-US or LSIL who were triaged with dual staining (p16/Ki-67) and/or p16 staining and, if available, with a comparator hrHPV test to detect cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or CIN3+. RESULTS: Thirty-eight studies were eligible. The sensitivity of p16 staining for CIN3+ was significantly lower than that of hrHPV DNA testing (ratio for ASC-US, 0.87; 95% confidence interval [CI], 0.78-0.97; ratio for LSIL, 0.86; 95% CI, 0.80-0.93). In contrast, the specificity of p16 staining was substantially higher with relative specificities of 1.60 (95% CI, 1.35-1.88) and 2.29 (95% CI, 2.05-2.56) for ASC-US and LSIL respectively. Dual staining was as sensitive as hrHPV DNA testing but was more specific (ratio for ASC-US, 1.65; 95% CI, 1.42-1.92; ratio for LSIL, 2.45; 95% CI, 2.17-2.77). CONCLUSIONS: This meta-analysis confirms that p16 staining and p16/Ki-67 staining are more specific for CIN2+/CIN3+ than hrHPV DNA testing. Although p16 staining is less sensitive for CIN3+ than hrHPV DNA testing, dual staining has similar sensitivity.

ObjectiveUrine self-sampling has gained increasing interest for cervical cancer screening. In contrast to analytical performance, little information is available regarding the clinical accuracy for high-risk Human Papillomavirus (hrHPV) testing on urine. MethodsVALHUDES is a diagnostic test accuracy study comparing clinical accuracy to detect high-grade cervical precancer (CIN2+) of HPV testing on self-collected compared to clinician-collected samples (NCT03064087). Disease outcome was assessed by colposcopy and histology. The Abbott RealTime High Risk HPV assay performance was evaluated on Colli-Pee collected first-void urine with cervical outcomes as comparator.3 ResultsAs no assay cut-off for urine has been clinically validated, we used the predefined cut-off for cervical samples (CN≤32). Using this cut-off, hrHPV testing was similarly sensitive (relative sensitivity 0.95; 95% CI:0.88-1.01) and specific (relative specificity 1.03; 95% CI:0.95-1.13) for detection of CIN2+ compared to testing cervical samples. In the subgroup of women of 30 years and older, similar relative sensitivity (0.97; 95% CI:0.89-1.05) and specificity (1.02; 95% CI:0.93-1.12) was found. Additionally, an exploratory cut-off (CN≤33.86) was defined which further improved sensitivity and analytical test performance. ConclusionHrHPV-DNA based PCR testing on home-collected first-void urine has similar accuracy for detecting CIN2+ compared to cervical samples taken by a clinician.

Background Interventions to reach women who do not participate regularly in screening may reduce the risk of cervical cancer. Self-collection of a vaginal specimen has been shown to increase participation. The relative clinical accuracy of human papillomavirus (HPV) testing on first-void urine (with Colli-Pee) and on vaginal self-samples versus on cervical clinician-collected samples is being investigated in the VALHUDES trial. The current study assesses attitudes and experiences regarding self-sampling among women enrolled in VALHUDES. Methods Questionnaires from 515 women (age 25–64 years [N = 498]; < 25 [N = 10], age ≥ 65 [N = 3], enrolled between December 2017 - January 2020) referred to colposcopy because of previous cervical abnormalities and enrolled in VALHUDES (NCT03064087) were analysed. Results Of the 515 participants, nearly all women confirmed that self-sampling may help in reaching under-screened women (93%). Nevertheless, 44% of the participants stated before starting collection that a clinician-collected sample is more effective than a self-collected sample. After self-sampling, the large majority of women (> 95%) declared that instructions for self-collection were clear, that collection was easy, and that they were confident about having performed the procedure correctly, for both urine and vaginal collection. However, a proportion of women found self-sampling unpleasant (9.5% [49/515] for urine collection; 18.6% [96/515] and 15.5% [80/515] for vaginal sampling with cotton swabs or plastic brushes, respectively). For their next screening round, 57% would prefer self-sampling whereas 41% opted for collection by a clinician. Among women preferring self-sampling, 53% would choose for urine collection, 38% for vaginal self-collection and 9% had no preference. Age did not modify preferences. Conclusion We conclude that both urine and vaginal self-sampling are well accepted by women, with a preference for urine sampling. Although the large majority of women are confident in their ability to perform self-sampling, four to five over ten women preferred specimen collection by a clinician. Trial registration The study VALHUDES was registered in ClinicalTrials.gov (identifier: NCT03064087).

Nasopharyngeal sampling has been the preferential collection method for SARS-CoV-2 diagnostics. Alternative sampling procedures that are less invasive and do not require a healthcare professional would be more preferable for patients and health professionals. Saliva collection has been proposed as such a possible alternative sampling procedure. We evaluated the sensitivity of SARS-CoV-2 testing on two different saliva collection devices (spitting versus swabbing) compared to nasopharyngeal swabs in over 2500 individuals that were either symptomatic or had high-risk contacts with infected individuals. We observed an overall poor sensitivity in saliva for SARS-CoV-2 detection (30.8% and 22.4% for spitting and swabbing, respectively). However, when focusing on individuals with medium to high viral load, sensitivity increased substantially (97.0% and 76.7% for spitting and swabbing, respectively), irrespective of symptomatic status. Our results suggest that saliva cannot readily replace nasopharyngeal sampling for SARS-CoV-2 diagnostics but may enable identification of cases with medium to high viral loads.

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Background: Nasopharyngeal sampling has been the standard collection method for COVID-19 testing. Due to its invasive nature and risk of contamination for health care workers who collect the sample, non-invasive and safe sampling methods like saliva, can be used alternatively. Methods: A rapid systematic search was performed in PubMed and medRxiv, with the last retrieval on June 6th, 2020. Studies were included if they compared saliva with nasopharyngeal sampling for the detection of SARS-CoV-2 RNA using the same RT-qPCR applied on both types of samples. The primary outcome of interest was the relative sensitivity of SARS-CoV-2 testing on saliva versus nasopharyngeal samples (used as the comparator test). A secondary outcome was the proportion of nasopharyngeal-positive patients that tested also positive on a saliva sample. Results: Eight studies were included comprising 1070 saliva-nasopharyngeal sample pairs allowing assessment of the first outcome. The relative sensitivity of SARS-CoV-2 testing on saliva versus nasopharyngeal samples was 0.97 (95% CI=0.92-1.02). The second outcome incorporated patient data (n=257) from four other studies (n=97 patients) pooled with four studies from the first outcome (n=160 patients). This resulted in a pooled proportion of nasopharyngeal positive cases that was also positive on saliva of 86% (95% CI=77-93%). Discussion: Saliva could potentially be considered as an alternative sampling method when compared to nasopharyngeal swabs. However, studies included in this review often were small and involved inclusion of subjects with insufficient information on clinical covariates. Most studies included patients who were symptomatic (78%, 911/1167). Therefore, additional and larger studies should be performed to verify the relative performance of saliva in the context of screening of asymptomatic populations and contact-tracing.