Abstract
“…urine tests high acceptability to women could translate into gains in screening coverage in specific settings and therefore outweigh any loss in sensitivity and specificity.”
The invention of the Pap smear, and its evolution into cytology-based cervical cancer screening methods, is a true success story for preventive medicine. The National Cervical Screening Program in the UK has been estimated to save almost 5000 lives per year [1]. However, there are some dark twists in this tale. First, screening coverage in high-income countries is falling and cervical cancer incidence is rising. In recent years, a record low of under 80% of eligible women have attended screening in the UK [2]. Second, the early successes of cervical cancer screening program have not been reproduced in the resource-poor setting. Cervical cancer remains the second leading global cause of cancer deaths in women with 88% of these deaths occurring in low-income countries [3]. This story now needs a hero to overcome these problems and recent research suggests that self-testing for human papillomavirus (HPV), including urine-based testing, could be such a hero.
The barriers
Current screening program in developed countries involve a clinician-taken sample from the endocervix to identify abnormal cells indicating the presence of cervical precancer. The test requires a speculum examination and a brush to be rotated through 360° degrees at the cervical entrance.
Although emotional barriers such as embarrassment and fear are well documented in the developed world, practical reasons have been shown to better predict nonattendance at screening. These include ‘not getting round to it’, difficulty finding convenient appointments and lack of trust in the smear tests [2]. Attendance is especially low among women who have been sexually abused. Explanations stem from the parallels of gynecological examinations to abusive situations: a perceived loss of control, the implicit power disparity between the smear-taker and the patient, and the physical sensation of the examination [4].
In the developing world, visual inspection with acetic acid or visual inspection with Lugol's iodine is accepted as a more cost-effective method with acceptable accuracy [5]. Its major advantage lies in the fact that diagnosis and treatment can be completed in a single appointment, but this still incurs costs beyond the means of most women. Subsequently, cervical screening coverage in sub-Saharan Africa is consistently less than 20%, and as low as 0.4% in some rural areas [6]. Based on WHO projections, Cervical Cancer Action has predicted grave consequences if this is not addressed: “[By] 2030, cervical cancer is expected to kill over 474,000 women per year and over 95% of these deaths are expected to be in low- and middle-income countries” [7]. If a test that could be done at home proved to be accurate and cost effective, it could promote wider uptake of screening.
The role of HPV
HPV infects 80% of sexually active women at some point in their lives. Specific strains of HPV are known to be the major causal factor cervical carcinogenesis [8]. It has therefore been extensively investigated as an alternative to cytology-based screening methods. A pooled analysis of four randomized controlled trials demonstrates that the addition of HPV testing increases protection against invasive cervical cancer by 60–70% [9–13]. HPV testing alone has also been shown to be more sensitive than cytology alone in the context of primary cervical cancer screening [14]. Consequently, HPV testing has the potential to conquer the lack of trust in the smear test that some women cite as a deterrent to screening attendance and is being incorporated into several national screening program. However, the results are based on clinician-taken cervical samples and so do not overcome many of the previously outlined barriers.
Self-testing & the future
The attraction of self-testing lies in its convenience, comfort and potential cost–effectiveness [15,16]. These qualities could increase coverage of screening program and overcome current barriers in cervical screening in the developed and developing world.
“…self-testing carries important social implications by offering a practical strategy to close the health inequality gap that exists between low- and high-income countries. Cervical cancer is a preventable and treatable disease, and a continued response to women's voices will enable its elimination.”
Our recent meta-analysis, completed with strict adherence to guidelines for the conduct and reporting of systematic reviews, demonstrates that urine HPV testing can accurately detect cervical HPV [17]. For oncogenic HPV strains, we calculated a pooled sensitivity of 77% and a specificity of 88%. Metaregression demonstrated that first void urine samples increased the sensitivity of the test. The results must be interpreted with caution due to heterogeneity in testing methods and results of individual studies. Pooled estimates may have subsequently been over- or under-estimated which can have unacceptable morbidity and mortality: unnecessary invasive testing of patients through false-positive tests and missing cervical disease through false negatives. However, by confirming a high accuracy despite methodological variations, the study indicates that urine HPV testing merits further study and refinement to improve its reproducibility. Studies addressing this are ongoing. For example, collection devices that standardize volume and capture of first void urine are being evaluated, and unpublished data suggest early morning collection contains higher levels of DNA [18]. Furthermore, the urine tests high acceptability to women could translate into gains in screening coverage in specific settings and therefore outweigh any loss in sensitivity and specificity [19]. One of the major limitations of the meta-analysis is that data are not available to estimate the accuracy of urinary tests in predicting cervical intraepithelial neoplasia (CIN). CIN is the precursor to cervical cancer that the current screening program aims to detect and treat. Any cervical screening test must have a high accuracy for detecting CIN to be able to prevent cervical cancer.
In their accompanying editorial on urine-based testing, Kitchener and Owens rightly state that to determine the true value of urine-based testing an adequately powered, prospective study is necessary to compare urine sampling with vaginal self-sampling with detection of high-grade CIN as an outcome [20]. Vaginal self-sampling has been more widely explored as a self-testing option, perhaps due to its successful incorporation into chlamydia screening program. A recent meta-analysis suggests that vaginal self-sampling is good at predicting CIN: pooled sensitivity is 76% for CIN2 or worse and specificity is 86% [21]. Other outcomes that should be evaluated include the uptake and costs in different settings so that the potential role for each testing method can be determined.
Beyond technical and clinical accuracy, the practical implementation of self-testing pathways requires synergy between technical progress and social mobilization strategies, particularly in lower-income countries. There is limited research on this for urinary testing. A recent population-based cluster randomized controlled trial in Argentina demonstrated large improvements in screening coverage rates are achieved when community health workers offer vaginal self-sampling method compared with advice to attend normal screening programs (86 vs 20% engaged in cervical screening) [22]. The effect was particularly strong in women who had not had a smear test in the past 4 years. Other studies have shown similar success in developed countries [21]. Self-testing thus appears to be a feasible alternative to cytology-based screening methods in low- and high-income countries.
Final thoughts
The ongoing global research effort into self-testing methods reflects an underlying change to healthcare delivery and research. Paternalistic models of care are fading and the development of testing methods that are more acceptable to patients is an increasingly important objective. Self-testing for HPV could dramatically increase coverage of cervical cancer screening to reduce current morbidity and mortality, but further research is necessary to refine self-tests and determine the true clinical benefit of urine-based tests compared with vaginal self-sampling. Moreover, self-testing carries important social implications by offering a practical strategy to close the health inequality gap that exists between low- and high-income countries. Cervical cancer is a preventable and treatable disease, and a continued response to women's voices will enable its elimination.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.