The Next Steps in Cervical Screening

Abstract

Cervical cancer is fourth most common cancer among women with four-fifths of the global burden in low- and middle-income countries (LMICs). Persistent infection with one of the high-risk types of human papillomaviruses (HPV), particularly HPV 16/18, is the central cause of cervical neoplasia. Progress in developing feasible, alternative screening methods in LMICs and HPV vaccines have further improved cervical cancer prevention prospects. While existing screening programs in high-income countries should be re-organized, in view of the downstream effects of national HPV vaccination programs, LMICs should introduce national programs to vaccinate single year cohorts of girls aged 9–13 years with two or three doses and screen 30–35-year-old women with HPV testing to pragmatically decrease their high disease burden.

Keywords

cervix cancer cytology HPV testing HPV vaccination natural history precancerous lesions prevention screening VIA

Cervical cancer is the fourth most common cancer in the world with a high incidence and mortality in low- and middle-income countries (LMIC) in sub-Saharan Africa, Central and South America, Asia and Oceania. Of the estimated 528,000 new cases and 267,000 cervical cancer deaths in the world, LMICs account for 445,000 new cases and 230,000 deaths [1]. Lack of effective prevention and screening programs or existing suboptimally performing cytology screening programs, high prevalence of HPV infection in the general populations and of HIV infection in certain populations have been responsible for the high burden of cervical cancer in LMICs. The knowledge that persistent infection with one of the oncogenic human papillomaviruses (HPV) is the necessary cause for cervical cancer has led to innovative disease control strategies for prevention and early detection that may lead to potential elimination of cervical cancer.

HPV vaccination to prevent HPV 16 and 18 infections has been introduced as part of national immunization programs (NIPs) in more than 60 countries including some LMICs at national or subnational levels, and eventually HPV vaccination will be implemented in more countries. New HPV vaccines that will target a wide spectrum of cancer-causing HPV infections will have even more impact on preventing HPV infections than the currently available vaccines. In due course, widespread HPV vaccination will have a telling impact on the incidence and prevalence of cancer causing HPV infections leading to lower frequency of precancerous lesions. Cervical screening programs will need to adapt in the post HPV vaccination era to maintain their efficiency and effectiveness to further reduce cervical cancer risk and their eventual elimination in a cost-effective manner. This task is now becoming more urgent given the relatively rapid impact of the HPV vaccination in real-world settings as seen in Australia, Denmark and other countries [2 –9]. The observed stability on the HPV type distribution in cervical cancer specimens over 70 years from 1940 to 2007 predicts a high and stable impact of HPV vaccination in reducing the cervical cancer burden in future vaccinated generations [10].

Australia was the first country to introduce HPV vaccination as part of its NIP in April 2007, the first country to offer it to boys in 2014 and the first country to conduct a comprehensive review of cervical screening to adapt to the post HPV vaccination scenario [2,6,9,11]. In this chapter, we briefly review how cervical cancer screening programs need to cost-effectively adapt over the next few years both in LMICs as well as in high-income countries in the context of increasing primary prevention initiatives and new developments in the way that one can screen for cervical cancer.

HPV infection & cervical cancer

Cervical cancer is a rare long-term outcome of a common persistent infection with one of the high-risk HPV types such as HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68. Persistent high-risk HPV infection is a necessary cause for cervical precancerous lesions and cancer and HPV 16 and 18 are associated with 70–75% of the cervical cancer cases across the world [12]. HPV viral DNA integration in cervical cancer cells and the reduction in high-grade cervical intraepithelial neoplasia (CIN3), following HPV vaccination, support the causal role of HPV infection.

Early age at first sexual intercourse and at first child birth and more lifetime sexual partners are the main risk factors for genital HPV infection in women [13]. The life-time probability of ever being infected with HPV is as high as 80–90% and peak HPV acquisition occurs in adolescence and early adulthood. However, 90% of the infections become undetectable within 2 years of acquisition. In 5–10% of women the infection may persist leading to a high risk for cervical cancer. Since only a small proportion of HPV infected women ever progress to invasive cancer, other factors such as the type and duration of HPV infection, immunocompromised states such as HIV infection, poor nutritional status and smoking may be involved in cervical carcinogenesis. HPV 16 and 18 are more likely to persist than other high-risk HPV infections, which often resolve spontaneously. HIV-infected women suffer from a high frequency of incident, persistent and progressive HPV infection. Antiretroviral therapy (ART) has no impact on the high risk of HPV infection and the cumulative incidence of cervical cancer among HIV-infected women. Increased survival of HIV-infected women on ART in a moderately immunocompromised state increases the risk and the development of cervical neoplasia.

Factors such as multiparity, early age at first full-term pregnancy, long term use of oral contraceptives, poor sanitation and hygiene, co-infection with other agents (e.g., herpes simplex virus 2, chlamidia trochomatis) and smoking may modulate the progression of HPV infection to cervical neoplasia and are associated with an increased risk of cervical cancer [14 –18]. Multiparity explains the highest proportion of cervical cancer among HPV-infected women. A general decline in parity to some extent accounts for the declining trends in cervical cancer incidence seen in countries with no screening programs. Male circumcision and barrier protection during sexual intercourse may reduce the risk of HPV infection and cervical cancer [19].

Natural history of cervical neoplasia

The natural history of cervical cancer involves four distinct stages namely HPV infection of the metaplastic epithelium of the transformation zone (TZ), long-term HPV infection persistence, clonal progression of HPV infected epithelium to high-grade cervical cancer precursor lesions (CIN3) and progression of CIN3 to invasive cancer [20]. The fact that it takes over 2–3 decades from the time of HPV infection to cancer occurrence facilitates decisions on appropriate age-groups to screen and optimal frequency of screening.

HPV infection is ubiquitous among women of reproductive age and the peak of HPV infection is seen in women below 25 years of age followed by a decline that plateaus around 30–35 years and in some developing countries a second peak is observed in women between 45 and 50 years. Since the rate of incident infections decline steadily with age, infections acquired at a young age contribute to most cervical cancers. Among HPV-infected women, the most important determinant of cancer risk is persistence, particularly HPV 16 persistence. A minority of women may demonstrate minor cellular abnormalities, such atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL) or atypical glandular cells of undetermined significance (AGUS), on cytology or CIN1 on histology within months or years following incident and transient HPV infections. In a great majority (>80%), infection clears within 2 years and the low-grade lesions resolve [20].

Persistent HPV infections may progress to high-grade squamous intraepithelial lesions (HSIL) or CIN2 and 3 or adenocarcinoma in situ (AIS). Around 70% of CIN2 lesions in women under 25 years, and 40–50% in older women, regress. CIN3 is considered as the real precursor of cervical cancer, although 20–30% of these regress. The peak of CIN3 is observed between 25 and 35 years of age. The time between getting infected with HPV and developing CIN3 is shorter than the time between CIN3 developing into invasive cancer. Repeated HPV positivity conveys substantially more risk of CIN3 than a single HPV-positive test. Among women testing positive at two HPV tests 2-years apart, 19.3% had an absolute risk of CIN3 or worse lesions (CIN 3+) at 12 years; for HPV 16, the risk of CIN 3 + at 3, 5 and 12 years of follow-up were 8.9, 23.8 and 47.4%, respectively [20]. Around 10–20% of untreated CIN3/AIS lesions may progress to invasive cancer in 5 years and 40–50% of untreated CIN3 progress within 30 years, whereas less than 1% of adequately treated CIN3/AIS progress to cancer [21 –24].

The risk of CIN3 or worse lesions and cervical cancer is extremely low for several years following one or two negative HPV tests [25,26]. The group of HPV-negative women included those once positive, but whose infections cleared, and those who never acquired HPV infection, however, it is not possible to distinguish between the above groups due to lack of accurate serology. The low risk of CIN3 or worse lesions in HPV-negative women indicates that infections, once cleared, rarely reappear and do not cause substantial CIN3 lesions.

Histologically, the most frequent type of cervical cancer is squamous cell carcinoma arising from squamous intraepithelial precursor lesions accounting for 80–90% of cases in different regions of the world; adenocarcinoma (AC) and its subtypes developing from glandular precursor lesions account for 10–20% of cases [27]. Rare types of cervical cancers include adenoid cystic carcinoma, adenoid basal and small cell carcinoma and carcinosarcoma, which do not have any known precursor lesions; other rare cervical cancers include sarcoma, melanoma and primary lymphoma.

Prevention

The fact that high-risk HPV infections cause almost all cervical cancers have led to two new approaches for cervical cancer prevention: HPV vaccination to prevent infections in younger women (<18 years old) and HPV testing in older women (≥30 years old). Primary prevention of cervical cancer is based on healthy life styles, improved socio-economic status, awareness, empowerment of women with education and better social status, male circumcision, improved hygiene and HPV vaccination. The slow decline in cervical cancer incidence in many LMICs without screening programs is due to socio-economic development, improvements in education and awareness, better sanitation and increasing family planning practices.

Prophylactic HPV vaccination with the currently available vaccines is a major strategy for cervical cancer prevention. The currently available quadrivalent vaccine targets oncogenic HPV 16 and 18 types as well as 6 and 11; the bivalent vaccine targets HPV 16 and 18. Efficacy against vaccine HPV-type related CIN3 in HPV-naïve populations in Phase III clinical trials exceeded 99% [28].

HPV vaccination has the potential to prevent 70% of cervical cancers in adequately vaccinated populations and 75–80% cases if the cross-protection is taken into account. The evidence on safety and efficacy strongly supports the introduction of HPV vaccination in NIPs. More than 200 million vaccine doses have been used so far with excellent safety and tolerability profiles. Mild-to-moderate injection-site symptoms, headache and fatigue were the most common adverse events following HPV vaccination.

HPV vaccination is currently part of the NIP in 62 countries targeting pre-adolescent and adolescent girls and ‘catch up’ immunization of older cohorts with variable upper age limits (Figure 1). Decisions by governments to implement HPV vaccination in NIPs, which involved substantial investment, have in part been based on findings from cost–effectiveness studies. The major barriers for HPV vaccination include high costs of the vaccine, significant antivaccine propaganda, political and media frenzies spreading misinformation and exaggerated adverse event coverage, and the logistics of finding suitable health service platforms and vaccinating pre-adolescent and adolescent girls. Government commitment, procuring HPV vaccines at affordable prices through tiered pricing, Global Alliance for Vaccines and Immunization (GAVI) Alliance and negotiated pricing, education of the community at large, awareness about the safety and efficacy are critical to introduce HPV vaccination in NIPs in LMICs. Among the LMICs, Bhutan, Malaysia, Uzbekistan, Fiji, Rwanda, South Africa, Zambia, Uganda, Panama, Mexico, Brazil, Chile, Argentina, Colombia, Peru, Uruguay and Paraguay have implemented HPV vaccination as part of NIP with very high coverage of the target populations (>90% third dose coverage) and excellent safety profile [29 –31]. In fact, ten LMICs (nine in sub-Saharan Africa, i.e., Ghana, Kenya, Madagascar, Malawi, Mozambique, Niger, Sierra Leone, Tanzania and Zimbabwe as well as Laos in Asia) have introduced HPV vaccination demonstration projects supported by GAVI, as a prelude to future national programs (Figure 1). Uganda, Rwanda and Uzbekistan are currently receiving support from GAVI alliance for HPV vaccination in their wider NIP. The introduction of HPV vaccination as part of NIPs in some LMICs has happened in spite of antivaccination campaigns in different countries [32 –34].

Figure 1.

World map showing countries with HPV vaccination implemented as part of the national immunization programs or as GAVI-assisted demonstration projects.

Emerging evidence from evaluation of HPV vaccination programs around the world has shown that the number of young people with vaccine targeted HPV infections and the frequency of precancerous lesions and genital warts among vaccinated cohorts is falling and protection is expected to be long term [7,8,35 –37]. In April 2007, Australia introduced quadrivalent HPV vaccination for 12–13-year-old girls through schools in their NIP followed by a catch-up vaccination for 13–26-year-olds via schools, community-based programs and general practices during July–December 2009. Third dose coverage among the 12–13-year-old primary target group exceeded a modest 70% reflecting a real world setting. A significant decline in the prevalence of HPV types 16/18/6/11 after introduction of a national HPV vaccination program in Australia [36]. Further evidence of vaccine effectiveness have emerged since then as indicated by the 77% fall in prevalence of HPV vaccine-related infections, 90% reduction in genital warts and 48% reduction in CIN3/AIS lesions in the vaccine targeted age-group [6,35]. The rapid drop in HPV prevalence in Australia corresponds to the previous model-based projections on the effects of vaccination [38].

A statistically significant decline in the risk for HPV16/18 associated CIN2 and 3 lesions among vaccinated women has been reported in a preliminary study in the USA [39]. Long-term, population-based cancer registry follow-up of 874 vaccinated, 875 placebo-vaccinated and an unvaccinated cohort of 15,719 women in Finland found no cases of CIN3 or cervical cancer among the vaccinees, three cases of CIN3 among the placebo vaccinated women (incidence rate = 87.1 per 100,000), and 59 cases of CIN3 and three cancer cases among the unvaccinated women (incidence rate = 93.8 per 100,000) [37]. In a program of routine national surveillance following HPV vaccination in Scotland, a significant decline in HPV 16 and 18 prevalence was demonstrated among HPV vaccinated women (prevalence = 150/1100 [13.6%]) compared with unvaccinated women (prevalence = 1018/3418 [29.5%]) was found in a cross-sectional study involving 1000 women aged 20–21 years recruited annually during 2009–2012 [8].

Six years from the introduction of HPV vaccination in Denmark in 2006, the risk of atypia or worse lesions and CIN 2 and 3 lesions have significantly declined among vaccinated women; there is a 44% reduction in CIN2–3 lesions among vaccinated cohorts of women born during 1991–1992 and a 73% reduction in CIN 2–3 lesions in the 1993–94 birth cohorts [7]. Although there was no information on the HPV types responsible for the detected cervical lesions, the lower risk among vaccinated women seems to be due to a reduced risk for HPV16/18 lesions. These early findings are instructive to encourage LMICs to roll out HPV vaccination programs to prevent cervical cancer.

Reduced number of doses from the current three-dose schedule will lower costs, ease logistics of vaccine delivery, increase accessibility and improve compliance with vaccine schedules. The two doses may be administered over a 2-year period, with the interval between the first and second doses being of at least 6 months. Whereas most countries use the three-dose schedule, a two-dose regimen is being used in some countries such as Canada, Chile, Colombia, Mexico, South Africa and Switzerland. England will switch over to a two-dose schedule from September 2014 onwards; the guidelines in the UK for switching over to two-dose regimen suggest that the first dose can be given at any time during school year 8 (12–13-year-old girls) followed by a minimum of 6 months and a maximum of 24 months between doses; for operational purposes a 12-month gap between the first and second doses has been recommended. The use of the two-dose regime in the above countries is based on the recent research evidence that immunogenicity following two doses in adolescent girls is noninferior to that following a three-dose course in the age-group where efficacy against persistent infection and precancerous lesions has been demonstrated [40 –45]. Based on findings that immunogenicity of two doses is comparable to three doses in 9–4-year-old girls, the European Medical Agency and ten countries in Central and North America, Africa and Asia have licensed the use of two-dose regimes.

Future perspective for screening in LMICs

It is well established that screening asymptomatic, apparently healthy women with cervical screening tests such as conventional cytology (Pap smear), liquid-based cytology, HPV testing and visual inspection with acetic acid (VIA) and treating detected precancerous lesions can effectively prevent cervical cancer. High-income countries have integrated large-scale cytology screening in public health services and have achieved high cumulative coverage rates by screening women at frequent intervals of 2–5 years, investigating screen-positive women with colposcopy, directed biopsies and treating those detected with CIN2–3 and AIS leading to substantial declines in cervical cancer incidence and mortality [46]. However, most LMICs do not have the capacity to initiate and sustain quality-assured cytology screening programs in view of the underdeveloped health services, several competing priorities, lack of resources and variable commitment to provide preventive health care; they are largely unsuccessful in reducing cervical cancer mortality in some LMICs where they exist [47,48]. The high risk of cervical cancer, the inability to introduce quality-assured cytology screening and the need for affordable and simple tests have led to the evaluation of innovative approaches for cervical cancer prevention in LMICs.

VIA is the most widely evaluated alternative test in LMICs which allows a single visit ‘see and treat’ approach. It is a point of care screening test in low-resource settings given the limited consumable and infrastructure requirements, immediate results allowing further investigations and treatment in the same sitting and the ease with which the providers can be trained, despite the variation in accuracy and reproducibility due to the subjective nature of the test; realistic sensitivity and specificity of a single, quality-assured VIA in detecting CIN2–3 lesions is around 50 and 85%, respectively [48]. VIA involves naked eye visualization of cervix under bright light 1 min after the application of 5% acetic acid; detection of dense acetowhitening in the cervix abutting the squamocolumnar junction constitutes a positive test outcome [49]. Visual inspection with Lugol's iodine may be used as an adjunctive test following VIA to assess equivocal VIA results or to assess if the acetowhite lesions turn yellow after iodine application. The accuracy of VIA in detecting CIN2–3 lesions in postmenopausal women is not satisfactory due to the inability to visualize the TZ adequately. However, VIA performs better in HIV-infected women than in the general population due to the increased prevalence of large high-grade lesions [50,51].

In two randomized trials in India, VIA screening was associated with 30–35% reduction in cervical cancer mortality [52,53]. The safety, acceptability and effectiveness of a single visit ‘screen and treat’ approach in which VIA-positive women who eligible for cryotherapy are treated in the same sitting has been well established [54,55]. Women with cryotherapy ineligible precancerous lesions may be referred for excisional methods such as loop electrosurgical excision procedure for diagnosis and treatment. The single-visit approach represents a major innovation for scaling-up cervical cancer screening in LMICs and has been adopted by many countries in sub-Saharan Africa and Asia [48]. Despite all its limitations, implementation of VIA screening in LMICs will facilitate the building up of infrastructure and human resources that may facilitate the introduction of affordable HPV tests in future [48]. VIA-based ‘screen-and-treat’ has been implemented through HIV care services in sub-Saharan African countries [53] and in more than 20 provinces in Thailand.

HPV testing, the most reproducible of all cervical screening tests, involves detecting HPV DNA or mRNA in cervical cells collected by pelvic examination or by self-sampling. Since only a negligible minority of women have ever been screened in LMICs, collecting cervical samples by pelvic examination is preferable as it provides an opportunity to visually inspect cervix for cancer. HPV testing is more sensitive, but less specific than cytology for the detection of precancerous lesions and cancer. The accuracy of HPV testing in detecting CIN2+ lesions exceeds 90% and CIN3+ exceeds 95%; although the specificity was lower than cytology, the difference was not always significant [56]. Lower cumulative incidence of CIN3+ lesions or cancer has been reported in women aged 30 years or above who were HPV-negative compared with cytology-negative women [26,56,57]. A pooled 53% reduction in CIN3+ lesions was found in HPV-negative women compared with cytology-negative women at enrollment in four randomized trials; moreover, in three trials, the detection rate of cervical cancer at round 2 was 87% lower in HPV-negative women at recruitment [57]. Following a single round of HPV testing, a significant 53% reduction in the incidence of advanced cancer (stage II+) and a 48% reduction in cervical cancer mortality was observed compared with the control arm with routine care [26]. It is evident that HPV testing is more effective than cytology screening as a primary screening test for women aged 30 years and above and the screening intervals for HPV-negative women can be extended to 5 years or more; a recent WHO Guidance note even recommends a 10-year interval (WHO 2013). Management of women testing positive for HPV poses complexities, but VIA may be used for triage for treatment or referral in a two-visit ‘screen and treat’ approach [48]. Reflex cytology testing or genotyping for HPV 16 or 18 can be used to triage HPV-positive women where such capacity exists.

Cost–effectiveness studies in settings such as rural China suggest that primary careHPV screening compares favorably to VIA screening [58]. However, there are still considerable challenges in introducing HPV-based screening programs and in fulfilling the promise of a feasible point-of-care HPV screening test in many LMICs unless more affordable and rapid HPV tests become widely available. Even the currently available careHPV test has limitations in these contexts in view of the costs and the need for high-volume screening. In spite of these limitations, HPV testing is the promise of the future in all settings given the fact that widespread HPV vaccination will significantly reduce HPV infections and CIN lesions and HPV testing will be the most suitable screening test in such a scenario. A pragmatic way of introducing HPV testing in such a scenario will be to offer it once to women aged 30 or 35 years in LMICs and, if resources permit, repeating it at 10-year intervals, with the eventual wider availability of affordable and rapid HPV tests. Primary care practitioners in LMICs may prescribe HPV testing for women aged 30 years and above if such tests are afford-ably available in their setting; women with a negative test may be advised a repeat test after 5–10 years and those with a positive test may be triaged with VIA in a screen and treat approach or cytology or colposcopy.

It is important to ensure that screen-positive women be followed up with diagnosis and treatment, irrespective of the screening test used. The most clinically effective and cost-effective methods for reducing cervical cancer incidence are those that limit the number of visits required for screening and treatment implying a single visit approach is preferred in LMICs. Recently it was estimated that US$59 million would be required to purchase treatment if cryotherapy is to be placed at every screening facility in 23 high-risk sub-Saharan African countries and the cost per women screened ranged from US$3 to $15 and the cost per woman treated varied between $28 to $71 [59,60]. The aim of treatment of screen-positive women (in a ‘screen- and-treat’ setting) or of women with confirmed CIN is to prevent their progression to cancer by destroying or removing the entire TZ. Women with confirmed CIN1 may be followed over a 2-year period and treated if it persists or progresses; alternatively women aged 30 years and above with CIN 1 in LMICs may be treated if there is a high probability of losing them for follow-up. Treatment of young women and adolescents with any grade of CIN should be discouraged to avoid increased pregnancy-related risks. Therefore, to avoid detection and treatment of CIN in young women, screening should only commence in women over 30 in LMICs. In settings with capacity for colposcopy and histology, a ‘see-and-treat’ approach may be used where cryotherapy or cold coagulation may be offered during a colposcopy visit after taking biopsies, with histology available aposteriori, providing histological assessment of the lesion(s) treated [54].

While HPV vaccination trials have not been done widely in high-risk Asian and African populations the role of alternative tests in cervical cancer screening has been more widely addressed in these populations. A number of evaluations of HPV vaccination of pre-adolescent girls in developed and developing countries, especially low-income countries, have universally found this intervention to be cost-effective, even in the context of existing screening programs in developed countries, whereas the cost–effectiveness in LMICs is heavily influenced by the unit cost of the vaccine [61,62]. Cost–effectiveness studies also indicate that introduction of vaccination in countries without national HPV vaccination at present would prevent substantially more cases of cervical cancer than in countries with such programs [62]. Although studies differ in their conclusions about the optimal age for catch-up vaccination, a catch-up round for young adolescent girls (12–15 years) whose future access to screening is uncertain in LMICs is worth considering and 16–20% of HPV 16/18 protection from vaccination is attributed to catch up vaccination strategy [63,64].

Although the best blend of vaccination and screening is not obvious, a pragmatic way of integrating HPV vaccination and screening in LMICs is to provide HPV vaccination to a single year cohort of girls between 9–13 years of age (e.g., 11-year-old girls) with two or three doses and to provide at least a single round of cervical screening with HPV testing for women aged 30–35 years; if resources permit, catch up vaccination of 13–15-year-old girls or 13–18-year-old girls may be carried out and screening may be repeated after 10 years. While HPV vaccination will result in generation of successive cohorts of women at low risk of HPV infection and cervical cancer as vaccination proceeds over time, the single round of screening at 30–35 years will reduce the risk of cervical cancer deaths among targeted women not yet protected by HPV vaccination. As both the programs progress over two decades and more, the target population for screening will eventually comprise of increasing proportions of vaccinated women and the role of screening will essentially be to reduce the risk among vaccine nonparticipants and those who have failed vaccination either through breakthrough infections or because of lesions caused by vaccine nonincluded types (most likely in those who were vaccinated by current vaccines rather than the next generation vaccines aiming to protect against 80–90% of cervical cancers). The timing of the effect of vaccination on cervical screening will be country-specific and will depend on any catch-up vaccination, variation in coverage, the impact of herd immunity (often not considered and not always evaluated in most cost–effectiveness studies) and the age at which screening starts. The above strategy ensures at least a low intensity screening program that is commensurate with the health services resources is introduced to begin with, which will eventually turn out to be a more cost-effective way of screening in the context of a long-standing HPV vaccination program, taking into account its probable downstream impact.

Conclusion & future perspective

Cervical cancer screening in high-income developed countries mostly rely on conventional cytology or liquid-based cytology although recently at least six countries (Finland, France, Italy, Sweden, Spain, Netherlands) in the EU have begun to implement primary HPV testing in cervical cancer screening though most of these are still in planning or piloting stages. The screening programs are organized or opportunistic, but more commonly are a mix of both types of programs. Whereas organized programs, as in Nordic countries, rely on active invitation of the target population with systematic monitoring and quality assurance, opportunistic programs lack monitoring and quality control. Even today, in many countries in the EU, where the European Commission recommends organized programs and has formulated guideline, there are large variations in screening policies and opportunistic screening is the only or main way to access screening; coverage of the screening tests taken within organized screening in EU ranges between 10 and 79% [65]. In Italy, for instance, almost half of the target women aged 25–64 years are screened opportunistically rather than in organized programs [66]. The targeted age-range and the frequency at which it is repeated vary between countries. For instance, the target age-range and screening intervals are respectively 30–60 years and 5 years in The Netherlands, whereas it is 15 years and above and annual screening in Luxembourg [65]. In the Australian National Cervical Screening Program, these are currently 18–69 years and 2 years [34]. It is estimated that almost 65 million smears are taken and US$6 billion is spent in the USA, whereas Australia spends around AU$220 million annually for cervical screening [67,68]. However, the current model of cervical cancer screening in high-income countries cannot continue for long in the light of implementation of HPV vaccination programs, costs incurred and logistics involved. Studies indicate that if screening remains unchanged in developed countries, it will be less cost-effective in vaccinated compared with unvaccinated women [69].

As described earlier, HPV vaccination of pre-adolescent girls and catch-up vaccination of adolescents and young women has been introduced in developed countries since 2007. HPV vaccination has been found to be cost-effective even in the context of existing screening programs; however, catch-up vaccination over the age of 18 years has been found to be less cost-effective and studies differ in their conclusions about the optimal age for catch-up vaccination [69]. It may take approximately two decades for these programs to have an impact on the frequency of cervical precancerous lesions and at least four decades for the downstream impact on cervical cancer [70]. Since peak incidence of cervical cancer is observed in the fifth and sixth decades, health gains in terms of cervical cancer prevention are likely to be observed several decades from now. On the other hand, cervical screening programs deal with detecting and treating cervical precancerous lesions by frequently repeated screening tests beginning in the third decade of life in most developed countries, with the high frequency of low-grade lesions in cytology (due to high frequency of HPV infections in young women) driving triaging and treatment demands of a screening program.

The existing screening programs will need to take into account the population-level downstream effects of HPV vaccination in terms of reduced HPV infection frequency in future. A number of new considerations should be taken into account as new vaccinated cohorts reach screening age and the changing dynamics of the cost–effectiveness equation. These include new screening strategies in populations of mixed vaccination status, delaying the starting age of screening to 25 or 30 years, increasing the screening intervals to 5 or 7 or 10 years, using HPV testing as primary screening test and new methods of triaging HPV-positive women such as reflex liquid-based cytology or HPV genotyping for HPV types 16 and 18. In addition, careful consideration should be given to any disparities in vaccination and screening uptakes, introduction of new generation of HPV vaccines such as the nonavalent vaccine, potential effects of vaccination on trends in screening participation and compliance to post screening management algorithms.

Executive summary

Global burden of cervical cancer

Cervical cancer is the fourth most common cancer globally with estimated 528,000 new cases and 267,000 deaths.

Four-fifths of the global burden occur in low- and middle-income countries (LMICs) where effective prevention and early detection programs are lacking.

HPV infection & cervical carcinogenesis

Cervical cancer is a rare long-term outcome of a common infection with one of the high-risk human papillomaviruses (HPV) types such as HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68, with HPV 16 and 18 being responsible for 70–75% of the cervical cancer cases globally.

Peak HPV acquisition occurs in adolescence and early adulthood with a life-time probability of ever being infected as high as 80–90%.

Approximately 90% of the incident HPV infections become undetectable within 2 years of acquisition, with infection persisting in 5–10% of women conferring a high risk for cervical cancer.

Prevention of HPV infection will prevent cervical precancerous lesions and cancer and other HPV-related cancers.

Natural history of cervical neoplasia

The natural history of cervical cancer involves HPV infection of cervical cells, HPV infection persistence, clonal progression of HPV infected cells to high-grade cervical cancer precursor lesions (CIN3) or adenocarcinoma in situ (AIS) and their progression to invasive cancer over 2–3 decades.

Around 10–50% of untreated CIN3/AIS lesions may progress to invasive cancer over 5–30 years, whereas only less than 1 % of adequately treated CIN3/AIS progress to cancer.

Prevention of cervical cancer

Efficacy of current vaccines against HPV 16/18 related CIN3 in HPV-naïve populations in Phase III clinical trials exceeded 99%.

The evidence on safety and efficacy strongly supports the introduction of HPV vaccination in national immunization programs (NIPs).

HPV vaccination has been introduced in NIPs in at least 62 countries and GAVI assisted HPV vaccination demonstration projects have been introduced in ten LMICs.

Based on research findings that immunogenicity of two doses of current HPV vaccines is comparable to three doses in 9–14-year-old girls, two-dose vaccination has been implemented in NIPs in Canada, Colombia, Chile, Switzerland, Mexico and South Africa and England.

Future perspectives for screening in LMICs

Most LMICs do not have the capacity to initiate and sustain quality-assured cytology screening programs.

Screening tests with visual inspection with acetic acid (VIA) and single visit ‘screen-and-treat’ approach have proved feasible, safe and effective in reducing cervical cancer burden in research settings.

HPV testing has proved as accurate, effective and highly reproducible alternative screening method with a high negative predictive value in women above the age of 30 years.

A pragmatic way of integrating HPV vaccination and screening in LMICs is to provide vaccination to a single year cohort of girls between 9 and 13 years of age and to provide at least a single round of HPV screening for women aged 30–35 years.

While HPV vaccination will result in cohorts of women at low risk of HPV infection and cervical cancer, the low-intensity screening will constitute a cost-effective way of screening when downstream effects vaccination occur, in addition to reducing the risk of cervical cancer deaths among a proportion of women not yet protected by HPV vaccination.

Future perspective for screening in high-income countries

The existing cytology screening programs should be reorganized as population-level downstream effects of HPV vaccination become evident and the target population for screening will increasingly comprise of vaccinated women.

Screening programs should switch over from cytology to HPV testing as primary screening test and consider new methods to triage HPV-positive women using cytology or HPV genotyping, increasing the starting age of screening to 25 or 30 years and increasing screening intervals to 5, 7 or even 10 years.

The reorganization should carefully consider any disparities in vaccination and screening uptakes, introduction of new generation of HPV vaccines such as the nonavalent vaccine, potential effects of vaccination on trends in screening participation and compliance to post screening management algorithms.

Just as Australia was the first country to introduce HPV vaccination in NIP in 2007, it is also the first high-income country to consider cervical screening policy changes as above in the post HPV vaccination era.

Since a large proportion of high-grade CIN are caused by HPV 16 and 18, preventing these by HPV vaccination will lead to significant reduction in the frequency of high-grade lesions. There will be fewer abnormal findings on cytology leading to a diagnosis high-grade CIN and the positive predictive value of an abnormal cytology for predicting CIN 3 or worse lesions will substantially decline, leaving behind at most some insignificant cytological abnormalities in this scenario [71]. Currently, colposcopy is the most widely used triaging investigation for cytology-positive women in developed countries. The above scenario following long-standing HPV vaccination will further challenge colposcopic interpretation of cervical findings.

As the HPV vaccination programs gain momentum and coverage, one needs to consider to raise the age of starting screening, the use of more objective primary screening tests such as HPV testing, increase the screening intervals and adapt suitable management algorithms. Cost–effectiveness analyses support raising the age of initiating cervical screening to 24 years [72]. Recently the medical services advisory committee (MSAC) of Australia recommended the Australian Government that a ‘new’ cervical cancer screening test, namely HPV testing should replace the current Pap smear in the Australian National Cervical Cancer Screening program [11]. It has recommended 5-yearly cervical screening using a primary HPV test with partial HPV genotyping and reflex liquid-based cytology triage, for HPV vaccinated and unvaccinated women 25–69 years of age, with exit testing of women 70–74 years of age, in the context of revisiting how cervical screening might be reorganized in the aftermath of HPV vaccination introduction. It is anticipated the above changes may be implemented after 2016. In the postvaccination scenario, HPV testing based, low-intensity screening with raised age at initiating screening and few screening rounds at wide intervals such as 7 or 10 years seems to be the most suitable option for screening in all countries.

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.

Footnotes

Acknowledgements

The authors gratefully acknowledge E Bayle, K Guinot and S Montigny for their assistance in the preparation of this manuscript.

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