Preventing Human Papillomavirus Disease
Authors: Cornelia L. Trimble
Journal: Journal of Clinical Oncology (2012)

In the last half century, in high resource settings, cytologic screening has dramatically decreased the burden of squamous cervical cancers, virtually all of which are caused by tissue-specific, persistent infection with human papillomavirus (HPV). The elucidation of the infectious etiology of this disease led to a Nobel Prize in 2008 and the development of preventative vaccines that became commercially available in 2006. This development was a public health milestone; worldwide, chronic infections initiate approximately 20% of human cancers. HPVs cause more malignancies than any other virus. Like other viruses that cause human cancers, most HPV infections are asymptomatic, eventually cleared, and do not harm the host. In unvaccinated cohorts, HPV is nearly endemic: the lifetime risk of acquiring genital HPV at least once is greater than 80%. In the United States, the uptake of preventative vaccines is incomplete and is likely to remain irregular. In 2009, less than one half (44%) of eligible children had been vaccinated. Rates of vaccine completion (defined as undergoing the full series of three prophylactic vaccinations) are dismal. Among vaccine initiators in the United States, less than one in four people complete vaccination. Evidence-based recommendations for the prevention of HPV disease of the cervix are evolving toward cohort-specific strategies on the basis of the indolent biology of infection. Young people will benefit from primary prevention provided by preventive vaccination. Because preventative vaccines confer no therapeutic effect for already existing infection or established lesions, strategies to identify preinvasive disease are still sorely needed. In the United States, current screening algorithms work for persons with access to care but are expensive, cumbersome, and iterative. Until relatively recently, because algorithms that could quantify risk were not available, an abnormal test result led to significant treatment costs, including office visits, diagnostic and therapeutic procedures, and follow-up. The best characterized risk factor for the development of squamous cancers of the cervix and their precursor lesions, cervical intraepithelial neoplasia grade 3 (CIN3), is persistent infection with an oncogenic HPV genotype, most commonly type 16 or 18. Most infections are acquired shortly after sexual debut and eventually clear. Clinically detectable CIN3 lesions develop, on average, 5 to 10 years after causal infection. Although all squamous cervical cancers arise from untreated CIN3, not all CIN3 lesions progress to invasive cancer. In immune-competent persons, approximately 35% of CIN3 lesions undergo complete regression in a timeframe of 4 to 6 months. Lesions associated with HPV16 are less likely to regress than lesions associated with other HPV types. Because it is not possible to distinguish CIN3 lesions that are likely to regress from those that are not, the standard of care is excision or ablation. Excisional approaches include a loop electrocautery excision procedure or cold knife conization. The rate of recurrence is 10%. Iterative excisional procedures are associated with subsequent preterm birth. Altogether, the United States annually spends in the neighborhood of $4 billion for the prevention and treatment of lower–genital tract HPV disease. In the article that accompanies this editorial, Castle et al provide a rationale for focused screening on the basis of a quantitative test. The authors report the long-term predictive value of HPV testing in a cohort of women observed for up to 18 years. Women with a baseline prevalent infection and women with incident infections detected over the course of the study were included in the analysis. HPV detection was confirmed by using a commercially available diagnostic test that is used routinely in clinical practice. HPV detection stratified risk more accurately than cytology; persons with a baseline negative HPV test were less likely to have CIN3 or worse (CIN3 ) diagnosed than persons who had a normal pap smear. Conversely, detectable HPV DNA identified women at increased risk of subsequent CIN3 . In the face of a normal pap smear, the detection of either HPV16 or HPV18 conferred higher risk of CIN3 than the detection of other HPV genotypes. This work is important because it provides data to support risk-based screening that can be done by using tools that are already available as part of routine practice. The implication of being able to use a test that is quantitative and not subjective as a primary screening tool is that it does not need to be performed by a provider with specialized training. The use of cervical HPV detection as a primary screen in appropriate cohorts (ie, older women in whom detectable HPV DNA is more likely than in younger women to reflect a persistent infection) could provide a way to triage the use of health care services. Although HPV testing offers a predictor of risk for preinvasive cervical disease, much remains to be learned about mechanisms of viral clearance versus persistence and why some preinvasive lesions regress and others do not. Moreover, not all persistent infections cause disease. Why does HPV behave like a commensal organism in some people but cause harm in other people? The unfortunate truth is that the incidence of HPV-associated cancers in other anatomic sites for which no screening algorithms have been developed is increasing rapidly. HPV disease is not restricted to the cervix. A growing body of evidence links persistent HPV infection to squamous cancers of the vagina, vulva, anus, and oropharynx. Almost all vaginal and anal squamous cancers, and approximately 20% of squamous cancers of the vulva, are caused by HPV. The incidence of preinvasive vulvar disease attributed to HPV has increased by 411% over the past three decades, primarily in women younger than age 65 years. HPVs have been identified in one in four squamous carcinomas of the head and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 25 SEPTEMBER 1 2012