HPV Infections May Return to Haunt Older Women

Reactivation of latent human papillomavirus (HPV) infection in older women could obscure an age-related increase in HPV detection at menopause, data from a prospective cohort study suggested.

The age-specific prevalence of 14 high-risk HPV genotypes decreased in women with fewer than 5 lifetime sexual partners but not women with five or more partners, as reported online in Journal of Infectious Diseases.

The population-attributable risk (PAR) associated with five or more lifetime sexual partners was three times greater in older women. However, older women had a fourfold lower PAR associated with a new sexual partner than younger women.

Taken together, the findings suggest that the low probability of HPV infection in women who became sexually active before the sexual revolution of the 1960s and ‘70s could be obscuring an age-related increase in the rate of HPV reactivation, according to Patti E. Gravitt, PhD, of the Johns Hopkins School of Public Health, and colleagues.

“Our data raise the possibility that reactivation risk may increase around age 50 years and contribute to a larger fraction of HPV detection at older ages, compared with new acquisition,” Gravitt and colleagues wrote of their findings. “Long-term follow-up of previously highly exposed women who will transition through menopause in the next decade is urgently needed to accurately estimate the potential risk of postmenopausal invasive cervical cancer in the U.S. Baby Boom population and guide prevention strategies,” they concluded. The absence of a second peak in HPV prevalence at menopause in the U.S. has led to speculation that few older women have new sexual partners and are not at risk of reactivating infection acquired decades earlier. To investigate the validity of the speculation, Gravitt and colleagues studied an older HPV screening population in the Baltimore area. From March 2008 through March 2011 they recruited women ages 35 to 60 who were attending clinics for routine gynecologic assessment. Eligible women had an intact cervix, no plans to become pregnant, no history of organ transplantation, and documented HIV seronegativity. The baseline evaluation consisted of a gynecologic examination (including testing for genotype-specific HPV) and a questionnaire that elicited information about social and demographic status, reproductive and menstrual history, medication use (including hormonal therapies), and past and current sexual history. Statistical analysis was completed for 882 women, mean age 47. Whites constituted 74% of the population, more than half had a college degree, more than 90% had a history of hormonal contraceptive use (including 22% current users), and 8% reported a history of hormone replacement therapy. All of the women had a history of Pap smear, 49% had a history of an abnormal Pap test, 21.5% had a history of colposcopy, and 19% had a history of cervical intraepithelial neoplasia. Fewer than 5% of the study population had current abnormal cervical cytology. Data on sexual history revealed a significant trend toward a higher number of lifetime sexual partners among the younger women (P=0.009). About 3% of the participants (mostly younger women) reported a new sex partner within the previous 6 months. The proportion of women reporting no sexual activity within the previous 6 months increased with age, ranging from 12% of women 35 to 39 and 33% of those 55 to 60. The prevalence of any HPV and high-risk HPV (as defined by genotypes) had an inverse association with age (P=0.002 and P<0.001, respectively). The 24 women who reported a new sexual partner within 6 months had the highest prevalence of HPV (OR 11.5) and high-risk HPV (OR 12.5). Rates were not increased among sexually active women who reported no new sexual partners within the past 6 months. Among women with fewer than five lifetime sexual partners, the prevalence of any HPV and high-risk HPV decreased as age increased. Women with five or more lifetime sex partners were presumed to have an increased risk of HPV reactivation. In that subgroup, the prevalence of HPV and high-risk HPV declined during ages 35 to 40, increased in women 40 to 54, and then decreased among those ages 55 to 60 (P=0.01 for interaction between age and number of sex partners). The PAR for any HPV and for high-risk HPV associated with five or more lifetime sex partners was 62.3% and 87%, respectively, among older women, compared with 37% and 28%, respectively, among younger women. The PAR associated with a new sex partner was 28% among women 35 to 49 and 7.7% in the older age group. "The older women in our study, who experienced sexual debut at the beginning of the US. sexual revolution of the 1960s and 1970s, had a lower lifetime risk of HPV infection, as demonstrated by a lower self-reported lifetime number of sex partners," the authors wrote in their discussion. "When we stratified by the lifetime number of sex partners as a crude measure of past probability of HPV infection (and thus risk of reactivation), HPV prevalence declined with age only among women with fewer than five lifetime sex partners." The findings have substantial epidemiologic, behavioral, and clinical implications, according to the authors of an accompanying editorial. "Older women should not be told that detection of HPV always indicates a new infection, but rather that detection of HPV could result from an infection acquired many years ago," wrote Darron R. Brown, MD, and Bree Weaver, MD, of Indiana University in Indianapolis. "Further research is needed to help better understand the natural history of HPV infection in older women and to understand the importance of HPV persistence and reactivation in all women." Limitations of the study, identified by the authors, included a well-educated population of women who underwent routine screening and thus may not be representative of the general population and absence of information about whether HPV represented new, persistent, or reactivation infection. Thus, the authors consider the study "hypothesis-generating."

The study was supported by the National Cancer Institute. Gravitt and colleagues had no relevant disclosures. Brown disclosed relationships with Merck.
## Primary source: Journal of Infectious Diseases Source reference: Gravitt PE, et al “A cohort effect of the sexual revolution may be masking an increase in human papillomavirus detection at menopause in the United States” J Infect Dis 2012; DOI: 10.1093/infdis/jis660.

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