Anal Cancer Screening Study

BACKGROUND:

Human immunodeficiency virus (HIV) positive men who have sex with men (MSM) are at risk of
anal cancer that approaches the risk of cervical cancer for unscreened women living in
developing countries. There is currently no accepted method for screening HIV positive MSM
for anal precancer to reduce the morbidity and mortality due to anal cancer ; in the absence
of a standard and effective screening modality, clinics often resort to anoscopy, a
diagnostic procedure akin to colposcopy, and directed biopsies on all HIV positive MSM.

OBJECTIVE:

Evaluate the clinical performance of detecting carcinogenic human papillomavirus (HPV) DNA
and RNA, individual carcinogenic HPV genotypes, cytogenetic markers, p16(INK4a) and Ki-67
immunocytochemistry staining, anal cytology, and combinations of these biomarkers for
identifying HIV positive MSM with prevalent, 1 year cumulative, and 2 year cumulative anal
precancer and cancer (histologically-confirmed greater than or equal to AIN3) using
clinician-collected anal specimens at baseline.

ELIGIBILITY:

HIV positive MSM seeking anal cancer screening. Inclusion: 1) KPNC member; 2) documented
HIV-positive status; 3) able and mentally competent to provide written, informed consent.
Exclusion:A current diagnosis of anal cancer at enrollment.

DESIGN:

To address this need and to improve detection of anal precancer and cancer, we propose a
screening cohort study of 1,000 HIV positive MSM participating in the Kaiser Permanente
Northern California (KPNC) health maintenance program. Under written, informed consent,
participating KPNC members will respond to a self-administered risk factor questionnaire and
will undergo two anal specimen collections into liquid-based cytology (LBC) medium prior to a
digital exam and high resolution anoscopy. Subjects will be asked to self-collect at home
into the same LBC buffer and return their specimen in a prepared return envelope to evaluate
the utility of self-collection for anal cancer screening. Subjects will be followed annually
for two years to collect follow-up clinical data related to outcomes. Baseline
clinician-collected specimens will be tested in a masked fashion for the following clinical
biomarkers: 1) carcinogenic HPV DNA in aggregate and individual carcinogenic HPV genotypes;
2) carcinogenetic HPV RNA and HPV16/18 RNA; 3) cytogentic changes (3q, 5p, and 20q
amplification); and 4) p16(INK4a) and Ki-67 immunocytochemical staining. For reference,
clinician-collected specimens will be used to make LBC slides and evaluated by an expert
cytopathology laboratory. We will estimate the clinical performance (sensitivity,
specificity, positive and negative predictive values, and referral rates) for detection of
prevalently-detected, one-year cumulative, and two-year cumulative histologically-confirmed
anal precancer (anal intraepithelial neoplasia grade 3) or worse (greater than or equal to
AIN3). We will test the self-collected anal specimens by the best molecular test(s) or
combination of tests for detection of prevalently-detected greater than or equal to AIN3 as
determined from testing the clinician-collected specimens. All MSM will undergo diagnostic
procedures at all visits and independent of testing results, which will result in unbiased
disease ascertainment.

- 2.1 ELIGIBILITY CRITERIA:

Any male member of KPNC who is 1) identified as HIV positive through the Kaiser HIV
registry, 2) 18 years or older, can provide written, informed consent, and 3) is not
currently diagnosed with anal cancer (prior to enrollment).

2.2 INCLUSION CRITERIA:

HIV-positive men will be invited to participate, regardless of race and ethnicity, as
described below if they meet the eligibility criteria. Other than having been diagnosed
with anal cancer prior to enrollment, there will no other disease-based exclusions. Because
of the high fraction of HIV-positive men are in fact MSM, we will not prescreen men for
their sexual orientation.

2.3 EXCLUSION CRITERIA:

The exclusion criteria will be age less than 18, a current diagnosis of anal cancer
rendered prior to enrollment, an unwillingness or inability (evident mental incapacity to
understand the informed consent documents) to give informed consent.