Population fraction of cervical neoplasia attributable to high-risk human papillomaviruses.
OBJECTIVE
The efficacy of human papillomavirus (HPV) type 16 and 18 vaccines against cervical intraepithelial neoplasia grade II (CIN2+) has been verified, but the active follow-up of studies with invasive cervical cancer or cervical intraepithelial neoplasia grade III (CIN3) as primary end points are ethically not possible. Furthermore, ongoing registry-based passive follow-up studies with invasive cervical cancer as the end point will take time.


METHODS
To evaluate the feasibility of CIN3 as a surrogate end point, we compared high-risk (hr) HPV-associated relative risk and population attributable fraction (PAF) of CIN3 and/or squamous cell carcinoma (SCC) estimated in a large serological case-cohort HPV study. Our case-cohort comprised 83 SCC and 389 CIN3 cases and a subcohort of 7862 out of 230,998 Finnish women, who at baseline were under 32 years of age and had undergone a minimum of two pregnancies within 5 years during 1983-1997.


RESULTS
PAFs of the case-cohort, approach-based, serologically defined and misclassification-corrected HPV16 and hrHPV (HPV types 16, 18, 31 and 33) exposures in the SCC samples were 61% (95% CI: 18-85) and 73% (95% CI: 13-93), respectively. Considerably lower HPV16 and hrHPV PAF estimates in CIN3 of 6% (95% CI: -19-35) and 36% (95% CI: -5-65), respectively, were obtained. A meta-analysis-derived, PCR-based, hrHPV-associated relative risk estimate of 20.3 in CIN2/3+ yielded a PAF estimate for hrHPV in CIN2/3+ of 86% (90% CI: 63-95) in our study population. The former, hrHPV serology-based CIN3 PAF estimates were biased owing to low sensitivity of HPV16 and/or HPV16/18/31/33 serology, most notably in cervical cancer precursor lesions, but the latter estimate overlapped with our hrHPV serology-based cervical cancer PAF estimate.


CONCLUSIONS
CIN3 may be a valid surrogate efficacy end point for HPV vaccination studies, but the associated causality of multiple hrHPV exposures needs to be unambigously defined.
Laukkanen
Päivi
P
National Institute for Health & Welfare, Helsinki & Oulu, Finland.
Läärä
Esa
E
Koskela
Pentti
P
Pukkala
Eero
E
Virkkunen
Hanna
H
Lehtinen
Matti
M
D000293:Adolescent; D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000821:virology*; D015331:Cohort Studies; D005260:Female; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D015201:Meta-Analysis as Topic; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology*; D053918:Papillomavirus Vaccines; D015995:Prevalence; D012042:Registries; D002583:Uterine Cervical Neoplasms / Q000821:virology*; D014764:Viral Proteins; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000821:virology*
C118863:E1 protein, Human papillomavirus type 31; D053918:Papillomavirus Vaccines; D014764:Viral Proteins