PROJECT SUMMARY/ABSTRACT
The World Health Organization has set goals for cervical cancer (CC) elimination through global HPV vaccination
and cervical cancer screening (CCS). Unfortunately, neither real-world HPV vaccine effectiveness nor efficient
CCS have been established for women living with HIV (WWH) who are disproportionately affected by CC. Our
group reported that HPV-vaccinated young women living with perinatal HIV infection (WWPHIV) had very high
rates of abnormal cervical cytologic compared with HIV [-] women suggesting reduced vaccine effectiveness.
While primary HPV testing used for screening (PHS) with a triage test is the preferred method for CCS in the
general population in the U.S., the CDC has not recommended it for WWH because of the lack of scientific
support. A recent study by our group showed that PHS with triage 16/18 genotyping in WWH cut the number of
unnecessary colposcopies in half without reducing sensitivity (vs HPV/cytology co-testing); however, the positive
predictive value remained low. Furthermore, the recently FDA-approved dual immunocytochemistry staining for
p16/ki67 as well as novel biomarkers using extended HPV genotyping and DNA methylation show great promise
but are vastly understudied in WWH. We have an exceptional opportunity to examine both HPV vaccine
effectiveness and PHS screening triage strategies in WWH by partnering with the Pediatric HIV/AIDS Cohort
Study (PHACS) led, in part, by our investigative team. PHACS includes a cohort of over 2400 WWH, including
WWPHIV and WWH, horizontally (WWHH) infected, who are enrolled along with their HIV exposed children. We
estimated that 90% of the WWPHIV and 50% of the WWHH <41 years of age have received at least one HPV
dose. Among WWH, we aim to: 1) examine the effectiveness of the HPV vaccine defined by the 3-year
cumulative risk of i) vaccine-HPV types that persist 12 months or longer and, ii) histologic (h) cervical
intraepithelial neoplasia (CIN)-2+; 2a) examine and compare the sensitivity (Se), specificity (Sp), positive (PPV)
and negative predictive values (NPV) to detect hCIN-2+ immediately or in 3 years in PHS[+] women using 4
reflex strategies: (i) cytology, (ii) HPV extended genotyping, (iii) p16/Ki-67 dual staining cytology, and (iv)
HPV/host methylation levels; 2b) examine the Se, Sp, PPV, and NPV in self-collected PHS[+} samples for
hCIN2+ detection focusing on methylation and HPV genotyping triage tests since these 2 tests are suitable for
self-collected samples. We plan to screen ~810 WWH using a self-sampling kit--now a well-accepted mode for
screening-- for PHS testing (Roche Cobas) and those who PHS[+] (~570) will attend a clinical visit to have
colposcopy/biopsy and the 4 triage tests. WWH with <CIN 2+ are asked to return annually for colposcopy and
HPV genotyping for up to 3 yrs. WWH with CIN 2+ are exited. WWH PHS[-] will be asked to return in Year 2 for
rescreening. Those PHS[+] will be followed as above and PHS[-] will be asked to obtain self-collected vaginal
samples for HPV genotyping annually for 3 years. Impact. Understanding HPV vaccine effectiveness and
optimal CCS strategies in WHH will make a significant contribution to decreasing the worldwide burden of CC.
