Laura A. Koutsky, PhD
Professor of Epidemiology
School of Public Health
University of Washington
Seattle, Washington
Cervical cancer is the second most common cancer in women worldwide, with the majority of cases (about 80%) occurring in developing nations. In the US and other developed nations, cervical cancer is no longer a leading cause of cancer death. This is because these women undergo routine Pap screening and are treated if the precancerous condition known as cervical intraepithelial neoplasia (CIN) is diagnosed. A diagnosis of CIN, which is usually caused by the human papillomavirus (HPV), however, can cause some women significant psychological distress, and, if untreated, can lead to cervical cancer. At least 15 HPV types are carcinogens that play a central role in the pathogenesis of cervical cancer and other less common cancers, including vaginal, vulvar, anal, penile, and upper aerodigestive tract cancers.
Of the estimated 60 million Pap tests performed annually in the US, 3.1 million (5%) are read as abnormal. In addition to the anxiety, distress, and negative self image an abnormal Pap test may cause, it also triggers more procedures including additional Pap and HPV DNA testing, colposcopy, biopsy, and treatment. In Australia, where the national screening policy consists of Pap testing every two years, the lifetime risk of colposcopy for a 15-year-old female is estimated to be 77%. The majority of American women continue to receive annual Pap tests and the lifetime risk of colposcopy appears to be at least as high as the Australian rate. Thus, a prophylactic vaccine to prevent HPV-related CIN and cancers would save lives, reduce the need for costly medical procedures, and ultimately provide substantial benefits to individual women and communities throughout the world.
Since HPV16 is a cause of about 50% of cervical cancers, a prophylactic vaccine trial targeted against HPV16 was undertaken to determine whether immunization would prevent persistent HPV16 infection. Women between ages 18 and 23 were randomized to receive either a placebo or 3 doses of the vaccine in a 0-, 2-, or 6-month regimen. After an average of 17.4 months following the immunization date, the incidence of persistent HPV16 infection was 41 cases in the 765 women in the placebo group compared to no cases in the 768 women in the vaccine group. Overall, the vaccine was generally well tolerated and there were no serious vaccine-related events in either the vaccine or placebo groups.
Currently, there are underway international, multicenter phase III trials of a related vaccine, one that targets HPV16 and HPV18 (which cause about 70% of cervical cancers worldwide) and HPV6 and HPV11 (which cause about 90% of genital warts). An interim analysis will likely occur in a few years. If the results show high efficacy for preventing HPV16 or 18-related high grade CIN and HPV6 or 11-related genital warts, the vaccine might be commercially available shortly thereafter. Another international, multicenter phase III trial is examining a different HPV 16 and 18 vaccine; encouraging results from a phase II trial of this vaccine have been reported.
As these phase III prophylactic HPV vaccine trials proceed, there is a growing sense of optimism that within a decade, HPV immunization will reduce the number of women who require colopscopy, biopsy, and treatment for CIN and cancer. By fostering collaborations between industry, governments, and charitable organizations, HPV vaccines will ultimately reach women who need them most--those who by virtue of geography or finances do not have access to Pap tests, diagnostic procedures, or effective treatments. Important issues to be addressed in the coming years include vaccine efficacy in men, long-term durability of protection after immunization, integration of HPV vaccines into on-going Pap screening programs, and public education.
