Background
Cervical cancer is a leading cause of mortality among women. In 2020, an estimated 604 000 women were diagnosed with cervical cancer worldwide and about 342 000 women died from the disease. Cervical cancer is the most commonly diagnosed cancer in 23 countries and is the leading cause of cancer death in 36 countries. The vast majority of these countries are in sub-Saharan Africa, Melanesia, South America and South-Eastern Asia.
In May 2018, Dr Tedros Adhanom Ghebreyesus, Director-General of the World Health Organization (WHO), issued a call to action for the elimination of cervical cancer. In November 2020, the Director-General launched the Global Strategy to accelerate the elimination of cervical cancer, including the following targets for each of the three pillars for 2030: 90% human papillomavirus (HPV) vaccination coverage of eligible girls, 70% screening coverage with a high-performance test and 90% of women with a positive screening test or a cervical lesion managed appropriately. Following the launch of the Global Strategy, a large panel of experts met to define the key areas of focus to increase access to screening and treatment to reach the 2030 targets. One of the agreed areas of focus was to update the existing WHO recommendations for screening and treatment to prevent cervical cancer, and to simplify the algorithms.
It was decided that the updated guideline and recommendations would be developed in four phases. The output of the first phase was a large set of recommendations on screening and treatment and the clinical algorithms for the most commonly used screening and triage strategies (with a focus on HPV DNA-based screening tests) for both the general population of women (i.e. women who are presumed or confirmed to be HIV-negative) and those living with HIV. This output was recently published in the WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention, second edition (2021).1 This current guideline delivers the initial output of the second phase of the guideline update: recommendations for the use of HPV mRNA (messenger ribonucleic acid) tests for screening to detect cervical pre-cancer and prevent cervical cancer.
Two approaches to screening and treatment are distinguished:
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In the “screen-and-treat approach”, the decision to treat is based on a positive primary screening test only.
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In the “screen, triage and treat approach”, the decision to treat is based on a positive primary screening test followed by a positive second test (a “triage” test), with or without histologically confirmed diagnosis.
Human papillomavirus (HPV) E6/E7 messenger RNA detection (mRNA) is an alternative method to HPV DNA tests for HPV detection. The mRNA technologies involve detection of mRNA of E6/ E7 oncoproteins that are responsible for HPV-mediated oncogenic transformation of epithelial cells. HPV E6/E7 mRNA detection could be more specific than detection of the viral HPV DNA because HPV mRNA tests correlate with actual virus replication, which is further down the HPV pathway toward development of pre-cancer changes. Most HPV DNA tests target the 13–14 most oncogenic HPV types. The HPV mRNA tests vary; one test targets all 14 of the most oncogenic types, while others target fewer oncogenic types.
Methods
The guideline has been developed according to the WHO handbook for guideline development, second edition (2014). The Guideline Development Group (GDG) for this guideline was formed in early 2019 and, based on their clinical expertise, research, and knowledge of tests in development, initially identified 13 clinical algorithms (involving several different screening tests) for screening and treatment that could be evaluated. In the first iteration of the updated guideline,1 seven algorithms were prioritized for evaluation, and four more algorithms are addressed in this current guideline publication.
The GDG, WHO Steering Group and WHO Secretariat, methodologists and technical groups (see Annex 1) met several times to discuss the evidence pertaining to the previously established PICO (population, intervention, comparator, outcome) questions related to the priority algorithms using HPV mRNA testing. A systematic review and meta-analysis were conducted to evaluate cross-sectional and longitudinal accuracy of HPV mRNA testing in screening and treatment algorithms. We used the methods for evidence synthesis and mathematical modelling as applied in the published guideline for the first phase of this guideline update: when relevant evidence was not available in primary research, a mathematical disease model was used to estimate the risk of important outcomes (e.g. recurrence of high-grade cervical intraepithelial neoplasia [CIN], and cervical cancer) associated with the use of different screening and treatment strategies. In addition, modelling evaluated the impact and cost-effectiveness of the different screening and treatment algorithms. Systematic literature reviews were previously conducted (during the first phase of the guideline update) on acceptability, feasibility, resources and equity aspects of the use of different screening tests. Surveys were also previously conducted on the feasibility of implementation (among GDG members), and on the acceptability and values and preferences of people using these services. These existing reports were also drawn upon for the purposes of this phase of the guideline update because most reports targeted HPV tests in general and did not distinguish between HPV DNA and HPV mRNA tests. GDG meetings took place to review and assess the evidence and determine the final recommendations presented in this guideline, applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.
Summary of recommendations for the use of HPV mRNA testing to prevent cervical cancer
In this present publication, only recommendations for the use of HPV mRNA testing are presented. For other recommendations, please refer to the July 2021 publication of the WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention, second edition.
In the general population of women, HPV DNA is the recommended primary screening test, but HPV mRNA detection may also be used.
When providing HPV mRNA testing, WHO suggests:
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providing it with or without triage;
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using samples taken by the health-care provider; and
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5-year screening intervals.
This is a conditional recommendation, based on low-certainty evidence.
Remarks:
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HPV DNA is the recommended screening test. Choosing the alternative option of HPV mRNA testing implies having the capacity to provide follow-up screening at 5-year intervals.
RECOMMENDATION:
WHO suggests that HPV mRNA detection using samples taken by the health-care provider may be used as a primary screening test, either with or without triage, to prevent cervical cancer in the general population of women with regular screening every 5 years.
Note: No recommendation was made for using HPV mRNA in women living with HIV because evidence on the outcomes of using HPV mRNA detection applicable to this population was not identified.
