Trial Information

HPV Testing to Improve Cervical Cancer Screening in the Mississippi Delta (Mississippi Delta Project)

Background: Cytology screening programs have effectively reduced cervical cancer incidence
and mortality in the U.S. by greater than 75%. However, these programs requiring repeated
clinician-administered Pap smears do not adequately cover medically-underserved populations.
Based partly on HREB/DCEG etiologic research, we now know that carcinogenic types of human
papillomavirus (HPV) cause virtually all cases of cervical cancer. Supported by our
translational work with DCP, HPV DNA testing is already approved by the FDA as an adjunctive
screening modality to cytology in this country and as a primary screening modality to
cytology in this country and as a primary screening modality internationally. A validated
screening program of HPV DNA testing of self-collected cervicovaginal specimens would permit
wider coverage screening than cytology in the populations underserved by cytology-based
testing like the Mississippi Delta region.

Objective: To assess the technical feasibility (i.e. non-inferiority or equivalence to
cytology for detection of cervical precancer and cancer) of cervical cancer screening based
on self-collection and HPV DNA testing of cervicovaginal specimens from women aged greater
than or equal to 30 years old who live in the Mississippi Delta.

Methods: One thousand women will be enrolled during 18 months, including 500 attending
colposcopy due to cytologic abnormality, 250 women who regularly attend a screening clinic,
and 250 unscreened women who have not had a Pap smear within the last 3 years (according
to current screening guidelines) but recruited to attend a screening. Three clinical
specimens will be collected from each woman. A cervicovaginal specimen (for HPV testing) and
a cervical specimen (for cytology and HPV testing) will be collected from each woman by the
physician. At the time of the clinic visit women will be give a kit for self-collection of a
second cervicovaginal specimen (for HPV testing) to be returned by mail within two weeks.
All three specimens from each woman will be tested by two clinical DNA tests that use
pooled-probes for detection of carcinogenic HPV: an FDA-approved signal amplification test
(Hybrid Capture 2 from Digene) and a new DNA amplification test (AMPLICOR from Roche)
currently in clinical trials. Specimens will also be tested retrospectively by a research
PCR asay that detects 37 HPV types, which will help us evaluate the performance of the two
clinical HPV tests. Women attending their screening visit who test positive by cytology
(atypical squamous cells of undetermined significance or worse) or for carcinogenic HPV will
be referred to colposcopy along with a random sample of HPV negative, cytologic negative
women (n equals 100).

Analysis: We will compare the clinical performance of HPV DNA testing of self-collected
specimens to that of cytology (at a threshold of atypical squamous cells of unknown
significance (ASCUS) or more severe) for detection of histologically confirmed cervical
intraepithelial neoplasia grade 2 (CIN2) or more severe (greater than or equal to CIN2).
Cytology results will be based on standard-of-care cytology screening for women attending
the screening visit and repeat cytology for women attending colposcopy. An estimated 150
cases of greater than or equal to CIN2 will be identified. This is an equivalence study,
where we wish to reject the null hypothesis that HPV self-testing is greater than 10% less
sensitive than cytology. Assuming cytology has a 75% sensitivity for greater than or equal
to CIN2, a sample size of 150 subjects has 84% power (alpha=0.05) (one-sided non-inferiority
or equivalence test of correlated proportions) to rule out a 10% decrement in sensitivity
for self-collection with HPV DNA testing compared with cytology will guide whether the new
technique could be broadly introduced for cervical cancer screening.