Despite the success of cervical cancer control programs in high income countries, where extensive high quality screening has been in place for decades, the disease is still a leading cause of cancer death among women in low and middle-income countries (LMIC), where 90% of the disease occurs. Large disparities in access to medical services, in particular screening, explain this situation. Repeated screening of a large fraction of women with cervical cytology and referral to colposcopy and treatment of cervical cancer precursors has been the basis of most screening programs. However, it has proven extremely difficult to successfully implement such programs in developing countries.

Recent developments in the understanding of the etiology and natural history of cervical cancer have resulted in very promising new prevention tools, representing a tremendous opportunity for developing countries. The availability of safe and effective vaccines against the major HPV genotypes promises to dramatically reduce infection, precancer and eventually invasive cancer. More than 70 countries have already established national programs for adolescent women, but the areas that need it most are still lagging behind in implementation of vaccination (1).

The challenges and limitations of HPV screening For secondary prevention, the main development is the availability of highly accurate and reproducible HPV DNA or RNA methods that permit detection of cervical neoplasia with higher sensitivity than cytology. Consequently, its high negative predictive value for disease development in the following years allows extension of the screening intervals to 5 or more years. Even one HPV test with proper follow-up has been shown to reduce cervical cancer mortality. The availability of new strategies may be an opportunity for countries to organize screening programs assuring proper coverage of the population, ideally in population-based (organized) screenings to assure true coverage of at least 80% (distributed over the number of years in the screening interval). Even more importantly, programs need to guarantee proper follow-up and treatment of all lesions detected according to the specified protocols, including referral and treatment of advanced cancer and palliative care when required.

Laboratory technician in a screening site in Honduras.

The problem with testing for HPV infection, the etiologic agent of cervical cancer, is that only a few women who have HPV infections have or will develop pre-cancerous disease in the future; the vast majority of cervical HPV infections, regardless of age and HPV type, regress spontaneously. Therefore, the specificity of the test is sub-optimal and there is a need to define cost-effective clinical management strategies for HPV positive women, to assure that all those who require an intervention to prevent cervical cancer are treated appropriately, avoiding excessive and costly referrals and reducing potential overtreatment. The decision has to take into account the resources available, and the feasibility of proper follow-up and the women’s preferences.

Managing HPV positive women
The most radical approach is to treat with ablative procedures all HPV positive women over 30 years of age, proposed as one of the alternatives in the recent WHO recommendations². This option may be considered for areas with limited resources where colposcopy and pathology are not available or difficult to access, and where repeated visits or follow-up are impractical. In El Salvador and other Central American countries, this approach is being used with treatment of about 10% of women. Treating all HPV positive women evidently results in treatment of many women who do not have current disease, possibly up to 80% of those treated, but it also treats a number of women who will develop disease in the future, particularly those who already harbor persistent infections. In addition, ablation of the transformation zone might destroy the specialized cells where cervical cancer originates and thus potentially prevent future disease, although this needs further research³. The main problem is that this alternative requires setting up treatment facilities for large numbers of women and the logistics for ablative treatment are more difficult than previously thought. New simplified treatment methods promise to solve many of these problems. Another problem is that in some areas (e.g., some locations in Africa) the fraction of HPV positive women is very large even in women over 30, particularly among HIV positive women. The program has reported good compliance and has been shown to be cost effective⁴. In the context of high prevalence and high frequency of multiple infections with oncogenic HPV types of limited malignant potential, one of the options is to design tests detecting a more restricted group of HPV types. This requires further investigation. One of the key issues for success in developing countries is the reduction of the number of visits. Thus the ideal method would be a self-administered diagnostic method providing immediate results followed by treatment with oral or topical medication or a therapeutic vaccine. There are important initiatives to investigate these alternatives but in the meantime access to organized high quality screening, with a solid assurance to follow-up all abnormalities detected and provision of treatment as needed, regardless of the screening and triage methods is essential to curb the unacceptable burden of this devastating disease.

The triage choice
In order to reduce overtreatment, we have to include some form of triage, taking into account that, unless the specimen for triage is collected at the same time as the HPV test, it may require additional visits and produce loss to follow-up. The traditional method used in cytology-based screening programs is referring all HPV positive women to colposcopy, biopsy and treatment of histologically confirmed lesions. This is very costly and requires multiple visits, infrastructure and equipment often unavailable in low resource settings. Furthermore, colposcopy is a method of suboptimal sensitivity that requires extensive training of highly specialized staff and quality assurance⁷.

Cytology
Another triage method, currently in use in several ongoing screening programs is cytology, with referral to colposcopy (or potentially treatment) of all women with abnormalities (usually ASCUS +). The reduction in workload, the knowledge of the presence of HPV by the cytotechnologist and the increase in the frequency of lesions among HPV positive women are expected to improve the performance of cytology. This method is likely to be effective in areas where cytology is well established but it remains to be proven its value in other locations. The protocol for clinical management of HPV positive, cytology negative women remains unresolved and their follow-up is likely to produce losses to follow-up.

HPV typing
Another alternative for triage is referring to colposcopy or treatment only women with the most carcinogenic genotypes (i.e., HPV 16, 18, 45 or other combinations). This approach has been shown to be at least as sensitive as cytology but by design misses lesions associated with other HPV types. A combination of genotyping with cytology is promising in some settings.

Visual inspection
Visual inspection with acetic acid, considered a useful alternative as a primary screening method in settings where other approaches are not available has also been proposed as a triage method and is included in the WHO recommendations4, but there are very limited data on its performance as a triage method in the context of an HPV based screening program.

Molecular biomarkers
There are a series of molecular methods that have shown promise, particularly if they can be done in the same specimen used for HPV detection, including detection of P16/Ki67 in exfoliated cells and detection of E6 oncoproteins.

A synthesis of the advantages and disadvantages of these alternatives are summarized in Table 1

References

1. Bruni, L., M. Diaz, L. Barrionuevo-Rosas, et al., Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. Lancet Glob Health, 2016. 4(7): p. e453-63.
4. WHO, Guidelines for screening and treatment of precancerous lesions for cervical cancer prevention. WHO guidelines. 2013. www.who.int/reproductivehealth/publications/cancers/screening_and_treatment_of_precancerous_lesions/en/
5. Herfs, M., Y. Yamamoto, A. Laury, et al., A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc. Natl. Acad. Sci. U. S. A, 2012. 109(26): p. 10516-10521.
6. Campos, N.G., M. Maza, K. Alfaro, et al., The comparative and cost-effectiveness of HPV-based cervical cancer screening algorithms in El Salvador. Int J Cancer, 2015. 137(4): p. 893-902.
7. Stoler, M.H., M.D. Vichnin, A. Ferenczy, et al., The accuracy of colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials. Int. J. Cancer, 2011. 128(6): p. 1354-1362.