Trial Information

Safety and Efficacy of Two Screen-and-Treat Approaches for the Prevention of Cervical Cancer

Participants and Clinical Examinations: Unscreened, non-pregnant women 35-65 years of age
are enrolled at three closely located clinical sites in Khayelitsha, South Africa. All women
provide informed consent, receive counseling for confidential HIV serotesting, a
questionnaire, a pregnancy test if not postmenopausal, anonymous HIV serotesting, and a
vaginal speculum examination by nurses trained in visual inspection of the cervix with
acetic acid (VIA). Cervical specimens are obtained for testing for N. gonorrhea, Chlamydia
trachomatis and high-risk types of HPV, and cytology. The cervix is washed with 5% acetic
acid and inspected for gross abnormalities or areas of acetowhitening and a 35 mm.
photograph taken. Women with significant cervicitis or vulvovaginitis are treated using the
syndromic approach. N. gonorrhea or Chlamydia trachomatis positive women receive appropriate
therapy. A positive VIA examination is defined as any acetowhite lesion and no attempt is
made to differentiate the acetowhitening of metaplasia from CIN. Women with lesions
suspicious for cancer, large acetowhite lesions extending over 70% of the cervix or into
endocervical canal, and 374 unsuitable for cryotherapy due to severe atrophy, polyps, cervix
distorted, cervix not adequately visualized are excluded. These women are referred to
colposcopy.

Women are asked to return 2-6 days later for randomization to either: (1) HPV arm in which
all HPV DNA positive women receive cryotherapy; (2) VIA arm in which all VIA positive women
receive cryotherapy; and (3) a delayed evaluation arm in which women are followed untreated,
irrespective of HPV or VIA status. Randomization is done at a patient level using a
computer-generated randomization schedule with arm assignments provided to the clinics in
sealed envelopes. Cryotherapy is performed by a nurse using N2O and a cryosurgical unit
(Wallach Surgical Devices, Orange, CT) using two 3-minute freezes. Cytology results are not
available at the time of cryotherapy. Both treated and untreated women are asked to return
at 4 weeks for a questionnaire.

At 6 months, colposcopy is done by a physician blinded to arm and clinical information. All
acetowhite lesions are biopsied and all have an endocervical curettage. Women with CIN 2+
are treated with LEEP. Examinations in women who became pregnant during the study are
postponed until three months post-partum. Blood for anonymous HIV serotesting is obtained.
All women who were HPV or VIA-positive at enrollment and a subset who were HPV and
VIA-negative (all women enrolled in 2002) are scheduled for repeat colposcopy at 12 months,
24 months and 36 months post-randomization. At these visits, cervical samples are collected
and colposcopy and biopsy if indicated is performed.

Laboratory Testing: HPV testing is done using the Hybrid Capture 2 HPV DNA assay and
high-risk probe mixture (Digene Corporation, Gaithersburg, MD) at the University of Cape
Town. Biopsies are processed at Columbia University and blindly evaluated by a single
pathologist.