In the first section of this review, we presented the science of HPV and cervical carcinogenicity. In the second section, we outlined the technical performance of each of the cervical cancer prevention technologies. On the basis of these facts, we outlined the currently optimal design of cervical cancer prevention programs from a public health perspective. However, cervical cancer prevention is also a social and political process. In this final section, we describe the remaining uncertainties and barriers to the adoption of HPV-based screening technologies.
Integration of HPV Screening With HPV Vaccination
The thoughtful introductions of HPV screening and HPV vaccination require consideration of how they complement each other. The two licensed HPV prophylactic vaccines—Gardasil (Merck) and Cervarix (GlaxoSmithKline)—have very high and proven efficacy against new infection with HPV16 and HPV18 and the resultant CIN2 and CIN3 lesions (122
). They also confer partial protection against HPV31 (which is closely related to HPV16) and HPV45 (which is closely related to HPV18). Within the next few years, augmented prophylactic vaccines that prevent virtually all carcinogenic types of HPV infection may be licensed. The proven duration of protection of a three-dose regimen of HPV vaccination is now approaching a decade based on follow-up of vaccine trial participants. Thus, vaccination of girls before the median age of first sexual intercourse in the population would eliminate much of the peak transmission of HPV. High population coverage with an effective multivalent HPV vaccine will be the best primary preventive strategy against CIN2+, including cervical cancer. However, HPV vaccination will not help older women who are beyond the age of vaccination or women who have an HPV infection present at vaccination (124
Meanwhile, in a world of increasingly restricted health resources, cervical screening must be reduced in HPV-vaccinated populations to maximize net public health benefits. As HPV vaccination increases, carcinogenic HPV infections and their associated CIN3+ lesions will become rarer, and almost all abnormal cytological results will be ASC-US or LSIL predicting only a low risk of cancer (125
). As a matter of public health policy, we do not screen for rare diseases even in the United States. HPV vaccination will further strengthen the argument for less frequent screening than occurs in routine practice today and for accelerating the switch from increasingly ambiguous cytology to HPV testing.
Moving From Clinical Algorithms to Risk-Based Management
In the United States, clinical guidelines from professional medical organizations provide recommendations for cervical cancer screening, the management of women with an abnormal screening test, and treatment (68
). These recommendations are usually developed through consensus meetings that review the evidence and, when possible, develop evidence-based guidelines. Of note, in the United States, cervical cancer screening is often viewed as a clinician–“patient” decision, not as a public program as it is in some other countries. Clinicians and patients may view a particular level of risk and cost differently from public health planners who are faced with limited resources.
In any case, the introduction of new HPV tests with varying test performances, new biomarkers, and the HPV vaccine will eventually make clinical algorithms regarding cervical screening and management of screening abnormalities untenably complex (95
) and quickly out of date. Each round of revised algorithms will need to account for past virological, cytological, and histological test histories (27
), as well as the results of any novel tests that emerge.
Compared with branching algorithms, a properly constructed and validated risk assessment tool would be more powerful and easier to update and use for clinical decision making, even for clinician–patient discussions (95
). The estimated risk of CIN3+ (eg, if colposcopy were performed that day, or in 1 year, or at a 3-year follow-up) is the relatively objective, quantifiable outcome that scientists can provide as the basis for cost-effective clinical and public health decisions.
Initially, such risk estimates will be most helpful to clinicians in practice settings with good continuity of care and long-term medical records. Risk-based screening and management (at the clinical or population level) would be dictated by the risk range or risk band into which the risk estimate falls (). These risk bands, which would be defined by the lower and upper thresholds of each band, would be established by professional medical societies that have considered the evidence related to the benefits and potential harms for each level of intervention. Risk estimates, updated with most recent test results, would be the basis for choosing the appropriate step to take after the most recent set of tests: 1) when the woman should next be screened; 2) whether a woman should be referred immediately for a colposcopically directed biopsy; and 3) the best follow-up management strategy after biopsy. Some women at sufficiently high risk of CIN3+, for example, those with an 80% or 90% risk, may warrant immediate LEEP.
Figure 7 The use of risk bands to guide clinical decisions. Use of risk estimates simplifies a complex battery of test results over time into a single risk score on which management can be based. The probability of diagnosis of cervical intraepithelial neoplasia (more ...)
Public Health Perspective
We believe that cervical cancer prevention, with its core components of vaccination and screening, is a public health activity, not a clinical activity. We have emphasized a risk-based rather than an algorithm-based perspective, relying on a current understanding of HPV natural history and cervical carcinogenesis. Framing public health interventions in terms of well-defined risks (with CIN3 serving as the main surrogate of invasive cancer) permits very useful and focused comparative effectiveness research structured around specific risk-based questions, such as “What would be the change in programmatic effectiveness of shifting from cytology every 2 years to cotesting every 5 years?”
The public health perspective necessarily must consider costs and cost-effectiveness of cervical cancer prevention strategies, not just comparative effectiveness (ie, benefits and harms). For comparably effective benign interventions, the question is simple: “Does one approach cost less for the health care system?” However, there is usually a trade-off between cost and effectiveness, given the multiple outcomes—lives saved, morbidity, age at cancer incidence or death, economic or family impact, iatrogenic adverse events—one might consider. This trade-off forces a consideration of the societal value of preventing a cancer or cancer death. Because the proportion of women in the general population who are truly at high lifetime risk of cervical cancer is so low, a screening test must incorporate triage or follow-up before treatment to achieve the high specificity necessary for a high positive predictive value. In other words, any cervical cancer screening program must weigh the impact of false-negative screens (ie, cancer risks associated with a missed CIN2 or CIN3 lesion) vs the impact of many more false positives (ie, the harm of telling someone her result is abnormal, with adverse effects possibly including treatments that may increase the risk of subsequent premature delivery).
Determining the specific value of a single life is a social issue beyond the scope of this scientific review. Clearly, however, assigning an infinite value to a single life regardless of the financial cost, if extended broadly as a policy, will undermine any public health–oriented consideration of the opportunity for other public health benefits from the same financial investment.
Prevention of Cervical Cancer in the United States
From a scientific and public health perspective, we conclude that cervical screening intervals can be safely extended by incorporation of HPV testing. However, such a change is not likely to happen soon in the United States, where cancer prevention policies are only partly dictated by evidence regarding optimal practice. It is notable that current evidence-based guidelines for cervical cancer screening and management are being widely ignored in the United States (13
). Each interest group with input into policy, including various government agencies, has its own mandates and constraints. Much of screening practice is dictated by clinical groups; in considering clinical recommendations, we should not ignore that the economic threat to practicing gynecologists and cytopathologists inherent in reducing the amount of screening is real. Also, it is essential for all to acknowledge, when advocating an extension of screening intervals or other incremental improvements, that no prevention strategy is perfect. Demanding perfect safety would doom the rational introduction of HPV technology.
Prevention of Cervical Cancer in Low-Resource Settings
In this review, we have focused on the incorporation of HPV testing in wealthy countries like the United States. However, cervical cancer is associated with poverty even in rich countries (119
), and 90% of deaths from cervical cancer worldwide occur in developing countries (10
). Despite its high-technology roots, HPV testing will likely save far more lives in low-resource high-risk populations where no preventive health-care structure is in place (76
) than in rich nations. The high sensitivity of HPV DNA testing indicates that one or two screens in a lifetime, between approximately age 30 years and menopause, would be sufficient to make a major impact on mortality (130
). Most women (80%–90%) will test HPV negative and gain reassurance for at least 10 years that they are at low risk of cervical cancer; women who test HPV positive will be immediately treated. An expanded discussion of HPV testing for low-resource settings, including information on the first low-cost HPV test, is presented as Supplementary Material