WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention

This WHO and HRP guideline in its second edition, is designed to help countries make faster progress, more equitably, on the screening and treatment of cervical cancer. It includes some important shifts in WHO's recommended approaches to cervical screening, and includes a total of 23 recommendations and 7 good practice statements. 

1.  What are the recommendations using the "screen and treat" approach if 

A. HPV as the primary screening test is positive, and when acetic acid is placed on the cervix to determine treatment eligibility no lesion is seen, but the transformation zone (TZ) is incompletely visualized? (Type 3 TZ)

When transformation zone is not fully visible because it is endocervical (type 2 or 3 transformation zone), then the patient should be referred for colposcopy and further evaluation

The following criteria make a person eligible for ablative treatment.

There is no suspicion of invasive cancer or glandular disease (i.e. adenocarcinoma or adenocarcinoma in situ, AIS).
The transformation zone is fully visible, the whole lesion is visible, and it does not extend into the endocervix.
The lesion is type 1 transformation zone.

What to do when the patient is not eligible for ablation and colposcopy services are not available?

Interventions may be constrained by feasibility, training, programme quality-assurance and resources. In the absence of certain infrastructure, such as the availability of colposcopes, large loop excision of the transformation zone (LLETZ) or of safe surgical settings, bridging strategies may be considered in carefully selected circumstances, to extend access to treatment rather than provide no treatment. For example, ablation may be an option for a carefully chosen, small type 2 transformation zone where the probe tip will achieve complete ablation of the squamocolumnar junction epithelium – that is, where it can reach the full extent, depth and upper limit of the transformation zone – and where adequate training for selection and follow-up is available.

B. VIA is performed as the primary screening test, no lesion is seen, but the transformation zone (TZ) is incompletely visualized? (Type 3 TZ)

As above after a VIA positive screening test, eligibility for ablative treatment needs to be assessed. When transformation zone is not fully visible because it is endocervical (type 2 or 3 transformation zone), then the patient should be referred for colposcopy and further evaluation.

Note above (question 1A) the criteria to make a person eligible for ablative treatment and also what to do when the patient is not eligible for ablation and colposcopy services are not available.

2.  What are the recommendations using the "screen-triage-treat" approach if

A. HPV as the primary screening test is positive, the VIA triage test reveals no lesion, but the transformation zone is incompletely visualized? (Type 3 TZ)

The same answer will apply as above. Whether it is as screening or as triage, when the transformation zone is not fully visible, then the patient should be referred for colposcopy and further evaluation.

The same apply if the primary screening test is VIA instead of HPV, and the VIA test is indeterminant because of the Type 3 TZ.

Note above (question 1A) the criteria to make a person eligible for ablative treatment and also what to do when the patient is not eligible for ablation and colposcopy services are not available.

3.  Would the answers to the above questions differ in WLHIV?

No – Based on evidence available at the moment

4.  Given the high risk of carcinogenic HPV infections in WLHIV, their greater propensity to persist and progress to pre-cancer, and the higher rates of persistence and recurrence of pre-cancer following treatment, why is WHO recommending the "screen-triage-treat" approach instead of the "screen and treat" approach for this population of women? Screen and treat" using HPV as the primary test would allow providers the opportunity to treat "HPV positive/VIA negative" women before a visible lesion develops (prophylactic thermal ablation) and lower the risk of pre-cancer. 

The decision to recommend screen-triage-treat rather than screen and treat in women living with HIV was based on a balance of many factors. For women living with HIV, the screen-triage-treat and screen and treat approaches both prevent cervical cancer and save lives similarly (about 64% and 68% reductions, respectively). However, by using a screen-triage-treat approach, we can reduce the number of women who receive pre-cancer treatments and have pre-term deliveries than what would happen with a screen and treat approach: over the lifetime of 100 000 women, there are approximately 300 000 fewer pre-cancer treatments, which is an important consideration for the health system and implementation questions. In addition, based on data from the general population, the screen-triage-treat approach is just as cost-effective as a screen and treat approach.

Women living with HIV with HPV positive and VIA negative test are followed-up every year

5.  We have a VIA based screening system. Should we stop that or use VIA for triaging after HPV?

A rapid transition should be organized to replace VIA testing with HPV DNA testing as the primary screening modality to prevent cervical cancer. HPV DNA based screening programmes have a much higher impact in reducing cervical cancer morbidity and mortality compared to VIA based screening and are more cost-effective. They also require fewer screening visits and generate fewer precancer treatments event and associated harms, in both the general population of women and in the population of women living with HIV.

A WHO guidance on how to introduce HPV tests is available on the following link and is entitled Introducing and scaling up testing for human papillomavirus as part of a comprehensive programme for prevention and control of cervical cancer: (https://www.who.int/publications/i/item/9789240015166)

The key is implementation at scale rather than incremental approaches.

6.  What is the price of HPV tests to be considered by countries to have a cost-effective programme?

The cost-effectiveness of an HPV based programme versus a VIA or cytology based programme was demonstrated via modelling work. In the modelling, the price of HPV test considered was $8.15USD for the test alone, or $15.09USD when including additional costs (such as sample drop-off and transport, laboratory staff time, lab supplies, general administration and overhead costs).

This provides guidance to countries in considering a threshold price when discussing with test providers, in order to set up a cost-effective programme to prevent cervical cancer.

7.  What is the false positive and false negative possibility in HPV based testing?

The evidence reviews found greater sensitivity and specificity when using HPV based testing compared to VIA or cytology. For example, we considered approximate sensitivity and specificity for HPV at 98% and 85%, respectively; for VIA 60% and 79%; and, for cytology (LSIL) 70% and 96%. What this means is that in a general population with 2% incidence of CIN 2+, using HPV would incorrectly identify 15 women with CIN 2+ (false positive) but would miss no women (false negative). When using VIA, 21 women would by incorrectly identified with CIN 2+ and 1 would be missed. When using cytology, 4 would be incorrectly identified and 1 would be missed. In summary,

While these diagnostic accuracy numbers are important to consider, the WHO recommendations consider the long-term effects of different strategies on cervical cancer and mortality, screening intervals, and other factors (such as capacity, costs and acceptability by health provider and patients). Overall, HPV DNA testing has a better impact than other strategies.

8.  When should we triage after a positive HPV test for treatment?

The impact of using HPV alone in a screen and treat strategy is similar to the use of HPV test followed by triage in a screen, triage and treat strategy; it reduces cervical cancer by 46%  and 45 % , and reduce deaths by 51 % and 49 % respectively. When using HPV followed by triage, the number of pre-cancer treatment is reduced by half. The costs of HPV alone and HPV with triage were similar. The reason for this is greater treatments with HPV alone but fewer treatments with triage but greater cost of additional testing with triage.

The choice of a screen and treat strategy vs screen, triage and treat strategy (such as using VIA as a triage after a HPV DNA test), will depend on the context: the capacity of the health care system to provide triage tests compared to more treatments when not using triage, the access to services, HIV prevalence (triage is recommended), the acceptability of treating women without lesion.

9.  If HPV DNA positive and VIA positive women only are treated, do we miss women who may have underlying lesions (as indicated by HPV positivity)?

We will not miss women with an HPV DNA positive test and VIA negative test.  DNA tests do not inform on cell transformation. HPV DNA informs on the presence of the infection. Women from the general population with a positive DNA test will be followed every 2 years. Women living with HIV with a positive DNA test will be followed every year. This will allow providers to detect any transformation in time for treatment.

10.  Is it ethical to treat all women with HPV positive result? If there are no visible lesion on the cervix, how will we know the treatment area?

Ablative treatment is ethical as the patient has a positive HPV DNA tests, meaning she is infected with HPV. The probe of thermal ablation and of cryotherapy cover the transformation zone of the cervix and therefore even lesions that are not visible will been covered and treated.

At population level, the benefit of treating HPV positive women w ablation are greater than the expected adverse effects of this treatment.

11.  What are the HPV tests available?

WHO evaluate commercial available HPV tests through a pre-qualification process, and update regularly the list of HPV tests prequalified. Prequalified HPV tests can be found on the WHO list of prequalified in vitro diagnostics products: https://extranet.who.int/pqweb/vitro-diagnostics/vitro-diagnostics-lists

HPV tests under PQ assessment can be found here: https://extranet.who.int/pqweb/vitro-diagnostics/products-under-assessment

There is also the WHO technical guidance and specifications of medical devices for screening and treatment of precancerous lesions in the prevention of cervical cancer, dated 2020 ( https://apps.who.int/iris/handle/10665/331698) 

In 2019, Unitaid developed document entitled Cervical Cancer - Screening and treatment of pre-cancerous lesions for secondary prevention of cervical cancer Technology landscape, including all the technologies as of 2019 for screening, triage and treatment of cervical cancer (https://unitaid.org/assets/Cervical_Cancer_Technology-landscape-2019.pdf )

12.  How to promote HPV self-sampling? How to ensure quality of such sample collection?

Each country will have to define an adequate and adapted social media campaign to promote screening and self-sampling options for women.

HPV self-sampling is equivalent to provider collected – acceptability high in survey

More and more manufacturers are providing self-sampling commodities together with the HPV DNA tests. Better to use the ones recommended by manufacturers

13.  If a woman tests HPV positive, should the partner be informed?

This is up to the patient to decide, and it should never be mandatory. There are no ethical issues in not informing male sexual partners as currently, there are no approved treatment for HPV infection when no symptoms are present (i.e. genital wards or cancer).

However, in case of voluntary disclosure, it is important to know that:

It is not possible to know when the infection occurred. It may have been acquired very early in life, with any other sexual partner(s), including through oral sex

Nearly all sexually active people will be infected at some point in their lives

Most men do not develop symptoms of HPV infection and usually the infection goes away by itself

The probability of transmission from women to men is much lower than from men to women

Penile, oral and anal cancers are rare, and they depend on individual sexual practices. For example, anal cancer is more frequent among men who have sex with men when compared to men who only have vaginal sex.

In the case of a female sexual partners, they should be advised to go to prevention services at 30 or 25 years of age (depending on HIV status), and independently of the screening result of her partner.

Vaccination against hrHPV infection of girls between 9 and 14 years of age is the best way to protect women against this infection.  Achieving high vaccination coverage in girls (>80%) reduces the risk of HPV infection for boys.

14.  Should we do HPV tests in women attending Sexually Transmitted Infections (STIs) clinics?

Yes, if they are 30 years of age with a negative HIV test

Yes, if they are 25 years of age and above for women living with HIV

STI clinics provide an important entry point for HIV testing services (HTS) that should be prioritized. WHO recommends routinely offering HTS to all people with STIs. HTS in STI clinics is feasible, and uptake of HTS is high in these settings. (See section 5.3.1, in 2019 HTS guideline: https://www.who.int/publications/i/item/978-92-4-155058-1)

15.  If there are other STIS should we go ahead with the thermal ablation?

There is no known contraindication. However, adequate treatment for other STI must be provided.

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