Epidemiology & Natural History of HPV Infection and its Causal Relationship with

Invasive Cervical Cancer

Michael Marco, M.Phil., MPH, ID/Epi Pre-doctoral Training Fellow, CIDER, ICAP

Infectious Disease Epidemiology - P840615 April 2010

Outline

HPV prevalence in women & men Risk factors for acquiring HPV Age & HPV Limitations of HPV serologic testing & current

understanding of immunity HPV detection HPV persistence, clearance & reactivation High-risk HPV & invasive cervical cancer (ICC)

Prevalence of disease & type-specific HPV

ICC natural history: SIL & CIN ICC screening: PAP vs. HPV (measurement error)

• A DNA Virus

• Preferentially infects squamous epithelial cells

Human Papillomavirus (HPV)

CDC 2008Median Age of Sexual Debut for Girls is 17.6 years

Winer, et al. 2003

CDC 2008

(Debatable; more for progression to cancer)

Non-penetrative transmission has been documented, but is less likely

(e.g., HIV) HPV in HIV+ women (pre-and post-HAART) is worthy a separate lecture. See Steben & Franco-Duarte review

HPV Prevalence in Women Varies Markedly in-and-between Populations

Possiblyan artifact of different assays (“home brewed”) used to measure HPV?

Methodological Issues to Consider with HPV Prevalence in Men

in

CDC 2008

HPV Prevalence is Similar Among U.S. Racial/Ethnic Groups

HPV Prevalence by Age

CDC 2008

Why Does HPV Prevalence in Women Differ by Age & their Country of Origin?

High Risk HPV Prevalence Differ by Age in Women, but not Men

CDC 2008

HPV Detection With an HPV DNA test

(Hybrid Capture II (The only FDA-approved HPV Test) Can analyze residual fluid of a liquid-based

cytology specimen from a Pap smear Detects only “high risk” (hr)HPV types, but does

not identify the individual type. Only research assays (“home brewed”) offer information on the specific genotype Would be useful for determining vaccine effectiveness in

the community? Indications for use

Routine adjunct to Pap in women 30 and overManagement of ASCUS (atypical squamous cells of

undetermined significance)

Collection of HPV for DNA Amplification

X

Hybrid Capture II

What Dose HPV Persistence, Clearance & Reactivation Mean???

Persistence of hrHPV Type is a Strong Risk Factor for Precancerous Lesions

Ho, et al. NEJM 1998

Why Should We Care About HPV Infection?

From 1000 Cases of Cervical Cancer, HPV DNA was Found in 99.7%

CDC 2008

Cervical Cancer is the 3rd Leading Cancer in Women

WHO IARC, 2006

Natural History of HPV Infection and Cervical Cancer

Natural History of HPV Infection and Cervical Cancer

SIL: cytological (cells from Pap smear) CIN: histological (tissue from colposcopy)

Colposcopy +/- Biopsy are Warranted after an Abnormal Pap or Repeat hrHPV Detection

Measurement Error is Common in the Reading of Colposcopic Biopsies

Shiffman, et al. 2007

CIN can Clear Spontaneously or Regress

CIN 1 lesions spontaneously clear in 60% of the cases and rarely progresses to cancer (1%)

CIN 2 & CIN 3 lesions spontaneously clear in 30-40% of cases, however a higher percentage progress to cancer >12% if untreated

Cannot tell by the “look” of the lesions which ones will progress

CIN 2 is defined as an “intermediate diagnosis,” but is treated for safety as if it was CIN 3

Development of CIN 2 or CIN 3 are most often used as “surrogate endpoints” for invasive cervical cancer in prospective cohort studies

An immediate vs. differed treatment study for CIN 2 lesions would be beneficial, however, no IRB would approve it.

Moskowitz 2007; Woodman 2007, Wacholder 2003

Our study found that a single round of HPV testing was associated with a significant decline in the rate of advanced cervical cancers and associated deaths, as compared with the unscreened control group. By contrast, there was no significant reduction in the rate of death in either the cytologic-testing group or the VIA group, as compared with the control group. NOTE: no cancer-related deaths were observed in any of the HPV-negative women.

Shiffman & Wacholder 2009

With HPV Testing, is it Now Time to Retire the Pap?

What about HPV & the Need for Vaccination in Animals?

Dad, I am nearing my sexual debut. Can I be the first puppy to get the HPV vaccine?