Planning cervical cancer screening in the era of HPV vaccines.

CS21-02

Recent research on the safety and efficacy of candidate prophylactic vaccines against human papillomavirus (HPV) infection has shown nearly 100% efficacy in preventing persistent infections and cervical precancerous lesions. One HPV vaccine has already been licensed (Merck's Gardasil) and another will likely be available in 2007 (GSK's Cervarix). Although the future seems bright on the prevention front policy makers are strongly cautioned to avoid scaling back cervical cancer screening. The above two vaccines protect only against the two main HPV types that together cause about 75% of all cervical cancers. Although a small degree of cross-protection against other oncogenic HPVs may be expected there is also the potential for a gradual change in the distribution of HPV types in vaccinated populations, as a reflection of the vacated ecologic niches following the progressive elimination of HPVs 16 and 18 (a yet unproven phenomenon also known as type replacement). There is also the possibility that the type-specific immunity conferred by vaccination may wane over periods extending much beyond five years. Other areas of concern that will take many years to be settled via scientific evidence include the choice of the ideal ages of vaccination, whether women who have been previously exposed to HPV can be protected (recent evidence indicates that this does not happen), and whether or not men should be vaccinated to achieve herd immunity. While much is yet to be learned about these and other vaccine-related issues it is sensible to consider that existing cervical cancer prevention strategies cannot be cost-effective following the incorporation of HPV vaccination without substantial changes to existing screening policies. Even resource-rich countries will be hard pressed to absorb the high costs of vaccination without some form of streamlining or restructuring of their cervical cancer screening programs and management practices. Indeed, assuming that HPV vaccination will become an accepted approach for primary prevention of cervical cancer, it becomes essential to consider what will happen with screening practices. Implementation of HPV vaccination is likely to be a gradual and diverse process that will reflect specific health policy environments. In some countries, vaccination may be adopted as universal policy for all adolescents and young women and covered by a centrally managed health care system. In other settings, the costs of vaccination may be shared between the public sector and individuals. It is also conceivable that some countries may not opt at all for covering the costs of vaccination and may leave the decision to health care providers and their patients. Finally, some countries may not even consider vaccination due to other pressing health care priorities. Individual countries' perceptions regarding the cost-effectiveness of vaccination as a primary prevention measure will no doubt be the main deciding factor on whether or not to adopt vaccination. To be well informed, such decisions will need to consider whether or not existing screening programs are to be modified for cost-effectiveness to be reached. As a likely short-term consequence of HPV vaccination on cervical cancer screening practices we can expect that colposcopical referral may decrease to perhaps 60% or less of the existing case loads in most Western countries. A small proportion of currently referred cases are associated with low oncogenic risk HPVs, such as HPVs 6 and 11. Merck's quadrivalent vaccine, which includes the latter two types as immunogens, may thus lead to a more pronounced reduction in abnormalities than GSK's bivalent vaccine, perhaps by an extra 10% in absolute terms. Such reductions will no doubt translate into initial savings to the health care system or to individuals but may entail untoward consequences related to personnel training and degradation of performance standards in Pap cytology. The positive predictive value of Pap cytology will decline in populations with high vaccine uptake because clinically relevant lesions will become less common. Vaccination may also lead to a decline in the performance of cytology by causing a decrease in the signal (squamous abnormalities) to noise (inflammation and reactive atypias) ratio that characterizes the subjective work of reading and interpreting smears. This may in turn lead to losses in sensitivity (low abnormality rate may lead to fatigue and less conspicuous lesions to be missed) and specificity (fear of the latter may lead to more overcalls of benign abnormalities). The above reductions in case loads will be a function primarily of two factors: (i) the overall uptake of HPV vaccination by the successive cohorts of adolescents and young women targeted by vaccination, and (ii) the time it will take for protected women to reach the age when they become clients of screening. In countries without a centrally managed health care system (e.g., the US) uptake of vaccination will require much effort in educating the public and health care providers. While women may welcome HPV vaccines there may be dissent as well, mostly stemming from the parental perception that vaccination may foster permissive behaviour among adolescents. Vaccinated adolescents will reach the age of cervical cancer screening within three years after the onset of sexual activity. Therefore, the impact on screening and management case loads will be initially minimal for women vaccinated between the ages of 10 and 18 years. On the other hand, the benefits in risk reduction among young adult women receiving the vaccine will be realized almost immediately because of the short latency between the averted acquisition of HPV infection and the appearance of low grade or equivocal cervical abnormalities. It is also possible to predict the long-term impact of vaccination on screening practices . Even with high uptake, a statistically noticeable reduction of the burden of cervical cancer via HPV vaccination is unlikely to be observed for at least a decade or longer because of the latency required for averted high grade lesions to have had the time to progress to invasive disease. A paradoxical situation may arise if high vaccine uptake occurs primarily among women who will eventually be compliant with screening recommendations. If adolescents and young women who are more likely to be vaccinated are the very ones destined to become screening-compliant the reduction in equivocal and low-grade abnormalities will be seen nearly exclusively among such women. There may be initial enthusiasm with the reduction in triage and management case loads consequent to the fewer abnormalities identified on screening. However, because of their high compliance with screening these women would not be the ones destined to develop cervical cancer. On the other hand, unprotected women may be less likely to be screened and their cervical lesions will progress undetected until invasion occurs. No precancerous lesions will be averted among the latter group and cytology surveillance will be oblivious to their existence until invasive cancer develops and the attendant symptoms will then prompt the need for diagnosis. Therefore, simply making cytology screening less frequent may not be a viable strategy to achieve a cost-effective combination of vaccination and screening in light of the aforementioned potential problems that may plague Pap cytology performance in conditions of low lesion prevalence. HPV testing has the screening performance characteristics that would make it an ideal primary cervical cancer screening test in such conditions. Pap cytology should be reserved for triage settings, i.e., in assisting management of HPV positive cases because it is more likely to perform with sufficient accuracy in conditions in which lesion prevalence is high, a situation that is artificially created when the workload includes only smears from women harbouring HPV infection. Another key advantage of using HPV testing (augmented by information of genotypes) as the primary screening tool in prevention programs is the opportunity to create HPV infection registries with the provision to link test results from the same women over time, thus allowing an efficient and low-cost strategy to monitor long-term protection among vaccinated women. In conclusion, much has been achieved during the last 10 years from research on screening and prevention of cervical cancer. Progress in this area has been grounded on the recognition that HPV infection is the central, necessary cause of this important neoplastic disease. However, it is imperative that screening and preventive strategies be adapted to one another to permit cost-effective reductions in the burden of cervical cancer. As research on the subject continues to provide acceptable evidence for public health action the next 5-10 years will bring many changes in practice standards and guidelines. Cancer control specialists and primary care providers will do well to observe closely the unfolding story of cervical cancer prevention.