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A Rumsfeldian discussion of HPV in mid-adult women

A Rumsfeldian discussion of HPV in mid-adult women. The known knowns , the known unknowns, and the unknown unknowns. Part 1. The known knowns. HPV is a sexually transmitted virus. SEX. Age-specific HPV prevalence. HPV prevalence peaks near age of sexual debut Declines through mid-30’s

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A Rumsfeldian discussion of HPV in mid-adult women

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  1. A Rumsfeldian discussion of HPV in mid-adult women The known knowns, the known unknowns, and the unknown unknowns.

  2. Part 1 The known knowns

  3. HPV is a sexually transmitted virus SEX

  4. Age-specific HPV prevalence • HPV prevalence peaks near age of sexual debut • Declines through mid-30’s • Suggestion of second prevalence increase around age of menopause From de Sanjose S, et al. Lancet Infect Dis 2005;7:453-459

  5. Incidence of HR-HPV also increased among cytologically normal women in Bogota, Colombia, 1993-2001 From Munoz N, et al. J Infect Disease 2004;190:2077-87

  6. Force of infection by age • Risk of new HPV detection associated with a new partner during follow-up • RR=2.4 (1.4-4.0) in women <40 years • RR=7.6 (1.6-36.2) in women ≥ 40 years From Munoz N, et al. J Infect Disease 2004;190:2077-87

  7. Is this the primary cause of new infection in older women?

  8. From Munoz N, et al. J Infect Disease 2004;190:2077-87

  9. Part 2 The known unknowns

  10. HPV is a sexually transmitted virus SEX Protective immunity?

  11. HPV? Is HPV acute, transient, latent?

  12. Age-specific ‘incidence’ by baseline serostatus Velicer C, et al. Sexually Transmitted Diseases. 2009;36:696

  13. New HPV detection in absence of sexual exposures Sexually active past 18 months Sexually inactive for 18 month Sexual behavior includes vaginal or anal penetration or oral sex with a male or female partner Strickler, et al. JNCI 2005;97:577-86

  14. Part 3 The formerly unknown unknowns?

  15. From Munoz N, et al. J Infect Disease 2004;190:2077-87

  16. Hormonal fluctuations in the years preceding the final menstrual period • Intraindividual levels of estrogen and progesterone are erratic in perimenopausal vs. pre- and post-menopausal women • Perimenopause associated with average • Increase in follicle stimulating hormone (FSH) • Increase in estrogen • Decrease in progesterone From Santoro, et al. J ClinEndocrinolMetab 1996; 81:1495-1501

  17. Staging of Reproductive Aging Workshop (STRAW) Criteria

  18. Do hormones influence immune function? • They must! • Sex differences in infectious disease risk • Sex differences in autoimmune disease • Pregnancy associated immune suppression

  19. Do menopausal hormonal fluctuations influence immune function? Incidence of shingles by age and gender per 100,000 person-years From Fleming DM, et al. Epidemiol infect 2003;132:1-5.

  20. Multivariate analysis of determinants of HPV prevalence • N=172 • Both markers of sexual exposure opportunity and hormonal status were independently associated with prevalent HPV detection in women age 40-60. • Age adjustment strengthened the association of menopausal status and HPV From Althoff KN, et al. J Womens Health 2009;18:1341-6.

  21. NCI R01CA123467

  22. The HIP Study • Enrolling women age 35-60 years from JHMI GYN clinics • Follow-up semi-annually for 2 years • Primary outcome – high risk cervical HPV infection (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) determined by PCR • Primary exposure – menopausal stage

  23. Defining menopausal stage pre peri post

  24. Serum estrogen (e2) and progesterone (p4) by day of menstrual cycle if day of cycle<50Stratified by pre (0) and peri (1) menopausal stage E2 P4

  25. Distribution of day of cycle in pre/perimenopausal women

  26. HR-HPV declines with chronologic age but increases with reproductive age

  27. Lifetime and recent sexual partner number by menopausal stage

  28. Male partner behavior? Prevalent HR-HPV infection is significantly more common among women who reported a new male sex partner in the last 6 months, HOWEVER, only ~3% of the cohort reported this exposure. Among the majority of women who reported either having no sex in the past 6 months or having sex only with their primary partner, the odds of HR-HPV were significantly increased among peri- and postmenopausal women compared to premenopausal women. Possible explanations? Differences in behavior of male sexual partner, reactivation of latent or suppressed HR-HPV, others? reactivation?

  29. While HR-HPV is strongly associated with a new sex partner in the past 6 months, prevalence of this exposure was low. • The attributable fraction of prevalent HR-HPV due to new sex partner varied from 57% in premenopausal women to 8-10% in peri- and postmenopausal women

  30. Need the alternative explanations for increase in HPV prevalence/incidence in older women be mutually exclusive? From Munoz N, et al. J Infect Disease 2004;190:2077-87

  31. Not everything that counts can be counted, and not everything that can be counted counts Einstein’s wisdom

  32. Vital Signs Prevention: Older Women Are Not Likely to Benefit From Cervical Cancer Vaccine By RONI CARYN RABIN Published: February 24, 2010 Women older than 40 are unlikely to get much benefit from the vaccine for the virus that causes cervical cancer, a new study reports. Longitudinal Study of Human Papillomavirus Persistence and Cervical Intraepithelial Neoplasia Grade 2/3: Critical Role of Duration of Infection. Rodríguez AC, Schiffman M, Herrero R, Hildesheim A, Bratti C, Sherman ME, Solomon D, Guillén D, Alfaro M, Morales J, Hutchinson M, Katki H, Cheung L, Wacholder S, Burk RD. J Natl Cancer Inst. 2010 Feb 15. [Epub ahead of print]

  33. Acknowledgements • The HIP Study Team • Anne Burke • Ray Viscidi • Wen Shen • Katie Chang • Lori Hackett • Michelle Silver • Kathryn Severson • Emily Seay • Becky Redett • The Gravitt Laboratory • Yolanda Eby • Lyn Howard • Morgan Marks • The HIP study participants • Who graciously donate their time to enhance our understanding of HPV through the life span

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