It has been unequivocally demonstrated that human papillomaviruses (HPVs) are necessary (but not sufficient) for the development of invasive cervical cancer (ICC). The intent of the US Food and Drug Administration-approved HPV vaccines is to prevent the development of invasive cervical cancer and precancer. The rationale for prioritizing HPV 16 and 18 in the vaccines was the data demonstrating that greater than 70% of ICCs are caused by 1 of these 2 HPV types. A recent international meta-analysis confirms that, overall, 70% of ICCs worldwide can be attributed to either HPV 16 or HPV 18.
HPV type prevalence, however, varies significantly around the world. For example, although HPV 16 and 18 (16/18) are the most common types demonstrated in ICC from all continents in the world, the HPV 16/18 proportion is higher in Europe, North America, and Oceania (range, 74%-77%) than in Africa, Asia, and South/Central America (range, 65%-70%). The most common HPV types in high-grade preinvasive cervical lesions (HSIL) are broadly similar to those in ICC, but HPV type distribution in HSIL is not entirely representative of that in ICC.
With these international data in mind, the results from the current, important, population-based study in this issue of Cancer by Niccolai et al are not surprising, although they do confirm that there is significant HPV type variability, depending on the population being studied. Whether the populations under consideration are compared by country or continent, as in most large international studies, or by socioeconomic (SEC) status, race, or even religious group may be irrelevant. The more universal and comprehensive questions are: 1) are we targeting the appropriate risk groups with the HPV vaccine, and 2) are we using the most efficient and complete HPV type profile in the vaccines being used?
The current study is unique in the United States, in that it uses a health care database that provides the investigators data regarding HPV type as well as SEC status and race in women with high-grade cervical lesions. The value of these types of databases for the purposes of public health studies such as this cannot be overstated. Currently, HPV is not a reportable sexually transmitted disease in the United States, which makes studies of HPV type prevalence in different populations difficult, and specific HPV type information is not readily available. Only databases like that used in this study allow us to learn about the spread of HPV within specific communities so that we can effectively institute methods of prevention. From a public health standpoint, these data are invaluable.
The limitation, of course, is the same as that for any study like this: the only population we can study, by virtue of the study design, is the population that is already enjoying the benefits of screening. Although race and SEC status are certainly risk factors for the development of cervical cancer and cervical cancer precursors, it is generally accepted that the screened population is not the one that shoulders the highest burden of cervical cancer and, thus, carries the highest need for vaccination and other prevention strategies. Instead, it is the unscreened and underserved population(s) that would benefit most from targeting with prevention strategies. According to national estimates in the United States, Asian and Hispanic women aged ≥21 years had a lower prevalence of having had a Papanicolaou (Pap) test in the past 3 years compared with non-Hispanic blacks and non-Hispanic whites. Regardless of the HPV type involved in disease, racial disparities in cervical cancer rates will persist in the United States because of differences in screening, follow-up, and treatment of abnormal lesions.[8-10] World wide, cervical cancer remains a leading cause of cancer death among women in economically developing countries, in large part because of a lack of access to screening.[11-13]
It is also notable that the conclusions made in the study by Niccolai et al with respect to race, SEC status, and HPV status likely cannot be generalized to other HPV-related cancers. Although cervical cancer rates are markedly elevated among most women living in low SEC status areas, no striking SEC status disparities are apparent for some of the other HPV-associated cancers among men or women. These other HPV-related cancers include 90% of anal cancers; 60% of certain oropharyngeal cancers; and 40% of vaginal, vulvar, and penile cancers. Racial and SEC patterns in these noncervical HPV-related cancers tend to be different from those observed for cervical cancer. For example, more white women are diagnosed with anal cancer than women of other races, and more black men are diagnosed with anal cancer than men of other races. In fact, anal cancer in women is highest among whites, whereas rates in men are highest among blacks. In contrast, rates of cervical and penile cancer are highest among blacks and Hispanics compared with whites and non-Hispanics, and the rate of vulvar cancer is lower among blacks and Hispanics than among whites and non-Hispanics. In addition, rates of HPV-related cancers vary by state, with rates of HPV-associated cancers combined ranging from 8.5 per 100,000 (Utah) to 16.3 per 100,000 (West Virginia) among females and from 4.9 per 100,000 (Utah) to 11.6 per 100,000 (District of Columbia) among males.
Reasons for variations in rates of noncervical HPV-associated cancers by race, ethnicity, and state are not clear but may be attributable in part to demographics, screening practices, tobacco use, or other factors related to HPV infection or persistence. The numbers suggest, however, that it is not merely the HPV type that results in the differences observed in disease prevalence but, rather, a complex interaction between all of these factors. Indeed, one reassuring fact for the cancers (other than cervical) that are associated with HPV is that they are all associated with a much higher fraction of HPV type 16. However, a very significant risk factor that will be addressed by the Patient Protection and Affordable Care Act is perhaps one of the most important: the lack of access to care. In cervical cancer, in fact, it has been demonstrated that improved access to care may erase some racial disparities.
Niccolai et al are to be congratulated for their current study, which uses an important public health database that will continue to provide us invaluable information about the prevalence and spread of HPV in select communities within the United States. However, the over-reaching question remains: are we targeting the population that is most vulnerable to the development of HPV-related diseases in general, and to ICC in particular? The answer to that question is most likely no, because we are currently unable to study or target the unscreened population of men and women who are at highest risk for developing HPV-related malignancy and, thus, have the greatest need. Ultimately, it is not the screened population that will be best served by the HPV vaccine but, instead, the unscreened population, which is most at risk for developing ICC. Data regarding HPV infection in the unscreened population are impossible to access, but it is these patients who are truly the underserved and who will bear the largest burden of cervical cancer.
Will the current HPV vaccines cover all relevant HPV types for all world-wide risk groups? Probably not, but there is significant progress being made with novel vaccine designs. A recent international meta-analysis suggests that the 6 most important HPV types in ICC after HPV types 16/18 are consistently the same in all settings: namely, HPV types 31, 33, 35, 45, 52, and 58. The nonovalent HPV vaccine currently in a phase 3 trial targets 5 of 6 of these types and, thus, may well offer protection for greater than 90% of HPV-related cancers affecting all races and SEC groups. Other vaccines in development may offer even wider spectrum coverage. Then, there remains the next most important step in eradicating HPV-related disease: the administration of the vaccine to all human beings at risk. In the United States, at least, mandating the HPV vaccine remains a political issue. And, in the world, because greater than 80% of cervical cancer cases occur in developing countries, our public health authorities must work to make the vaccine available to all men and women who are at risk for all HPV-related diseases.