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L Kuhn (July 2022). How should we evaluate HPV test performance prior to implementation of cervical cancer screening programs in low and middle-income countries?
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It is almost 40 years since Harald zur Hausen discovered oncogenic human papillomaviruses (HPV) and the pathogenesis of HPV and how progression to cervical cancer occurs is now well-described. Numerous molecular tests to detect HPV have been developed, validated and are commercially available. Despite this remarkable progress, integration of HPV testing into cervical cancer screening programs in low- and middle-income countries (LMICs) has not been achieved. Thus, the benefits of HPV testing have not been realized in the settings where the need for these benefits is greatest.

More than 20 years ago, clinical trials were conducted in India and South Africa which demonstrated the safety and efficacy of the HPV-based screen-and-treat approach.^1,2 Despite this strong evidence, there has been little implementation of HPV-based screen-and-treat in LMICs, with exception of a few bold demonstration projects.^3,4 It is also only in the most recent iteration of World Health Organization guidelines that there is clear endorsement of HPV-based screen-and-treat. What is the reason for this disconnect? As HPV researchers, how can we design our research to be more effective to move from research breakthroughs to implementation?

Usually when we think about evaluation, our attention turns to investigation of the reliability and validity of a particular HPV test. Reliability refers to the reproducibility of a test or the extent to which a test provides the same results when it is repeated. Kappa coefficients or intraclass correlations are the usual statistics used to describe reliability. Validity refers to the accuracy of a test or the extent to which the test measures what we expect it to measure. Sensitivity and specificity are the usual statistics used to describe validity. Validity of HPV tests in the cervical cancer screening context is more subtle as the “gold standard” to which the tests are compared is itself a biomarker of the likelihood of progression to cancer, usually histologically-confirmed cervical intraepithelial neoplasia grades 2 or 3.

At the current time, and given voluminous research in this area, in most cases it would not be necessary (and would be potentially duplicative) to repeat studies of reliability and validity of particular HPV tests before implementation in a program. WHO prequalification status or other regulatory bodies’ lists could be consulted and/or prior peer-reviewed studies could be used to inform choices. To help facilitate informed integration of new HPV tests into programs, a common protocol to evaluate new tests was developed called VALGENT.⁵ This protocol benchmarks new tests to the originally available HPV tests and offers guidance for acceptable ranges of sensitivity and specificity under different circumstances as well as offering guidance on study design for new evaluations.

All HPV tests that are currently commercially available meet acceptable performance standards and thus research can focus on other parameters including ease of use. Most HPV tests are designed to be run in fairly-sophisticated laboratories and laboratory managers need to take into account what equipment is needed and the amount of technician time required. Program managers need to take into account the flow of samples from clinical sites to the laboratory and the flow of results back to clinical sites. And from a clinician and patient point of view, the laboratory-based HPV test requires a minimum of two visits – one to collect the sample and a second to receive the results. More recently, HPV tests have become available that can be run near to the point of care. Here the clinical site and laboratory are integrated. Nevertheless, program managers need to consider the equipment necessary and operator skills required as well as designing efficient flows of specimens from collection to results, to reduce undue wait times for patients. Since these tests are done at the same location where patients are seen, such tests allow for a round of screening to be completed in a single visit.



The cost of HPV tests is often invoked as an explanation for the lack of uptake of HPV tests into cervical cancer screening in LMICs. But the unit costs of an HPV test are only one component of the total cost of programs. Comprehensive cost-effectiveness analyses have demonstrated that the most important parameter driving the overall cost of a program is the number of patient visits. The screen-and-treat approach, which reduces the number of visits to a maximum of two (with the optimal being a single visit strategy) consistently outperforms other approaches in terms of cost-effectiveness.^6,7 Firstly, because costs are reduced by reducing the number of clinical encounters, and, secondly, because effectiveness is increased by reducing attrition inevitable in multi-visit strategies.^6,7 A recent analysis using current price points for HPV tests commercially-available in South Africa concluded that the HPV screen-and-treat approach was optimal from a cost-effectiveness point-of-view.⁸

How one integrates HPV testing into the cervical cancer screening cascade is critical to the success of programs. The screen-and-treat approach is the most cost-effective and evaluation should focus on practicalities. One of these considerations is how to balance sensitivity and specificity. Current HPV tests have very high sensitivity and moderate to low specificity. HPV assays which allow for quantitation of viral load and/or have the capacity for full or partial HPV typing can be used in a way which allows for a more optimal balance of sensitivity and specificity.⁹ Very high sensitivity is arguably not necessary for a single round of screening and allowing sensitivity to be reduced slightly can achieve specificity and positive predictive values more acceptable to resource-constrained settings.⁹

In conclusion, if research is to facilitate action towards more effective cervical cancer screening programs, researchers need to move beyond simply measuring the performance characteristics of HPV tests. Practicalities and ease of use in the field are critical as well as ensuring that scarce resources are used efficiently to support effective programs. HPV testing has tremendous potential to reduce the burden of suffering associated with cervical cancer in LMICs. This potential can only be realized if women have access to high-quality programs with good coverage. Research needs to be action-oriented to reach this goal.



DISCLOSURE
The Author declares no conflict of interests to disclose.


References

1. Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical cancer in rural India. The New England journal of medicine 2009; 360(14): 1385-94. Available from: https://doi.org/10.1056/nejmoa0808516

2. Denny L, Kuhn L, De Souza M, Pollack AE, Dupree W, Wright TC, Jr. Screen-and-treat approaches for cervical cancer prevention in low-resource settings: a randomized controlled trial. JAMA 2005; 294(17): 2173-81. Available from: https://doi.org/10.1001/jama.294.17.2173

3. Kunckler M, Schumacher F, Kenfack B, et al. Cervical cancer screening in a low-resource setting: a pilot study on an HPV-based screen-and-treat approach. Cancer medicine 2017; 6(7): 1752-61. Available form: https://doi.org/10.1002/cam4.1089

4. Nakalembe M, Makanga P, Kambugu A, et al. A public health approach to cervical cancer screening in Africa through community-based self-administered HPV testing and mobile treatment provision. Cancer medicine 2020; 9(22): 8701-12. Available from: https://doi.org/10.1002/cam4.3468

5. Arbyn M, Depuydt C, Benoy I, et al. VALGENT: A protocol for clinical validation of human papillomavirus assays. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 2016; 76 Suppl 1: S14-s21. Available from: https://doi.org/10.1016/j.jcv.2015.09.014

6. Goldhaber-Fiebert JD, Denny LE, De Souza M, et al. The costs of reducing loss to follow-up in South African cervical cancer screening. Cost effectiveness and resource allocation : C/E 2005; 3: 11. Available from: https://doi.org/10.1186/1478-7547-3-11

7. Goldie SJ, Kuhn L, Denny L, et al. Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness. JAMA 2001; 285(24): 3107-15. Available from: https://doi.org/10.1001/jama.285.24.3107

8. Campos NG, Lince-Deroche N, Chibwesha CJ, et al. Cost-Effectiveness of Cervical Cancer Screening in Women Living With HIV in South Africa: A Mathematical Modeling Study. JAIDS (1999) 2018; 79(2): 195-205. Available from: https://doi.org/10.1097/qai.0000000000001778

9. Kuhn L, Saidu R, Boa R, et al. Clinical evaluation of modifications to a human papillomavirus assay to optimize its utility for cervical cancer screening in low-resource settings: a diagnostic accuracy study. The Lancet Global health 2020; 8(2): e296-e304. Available from: Available from: https://doi.org/10.1016/s2214-109x(19)30527-3


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