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

Project Narrative Cervical cancer (CC) remains a significant problem worldwide and women living with HIV (WWH) have higher rates than the general population. Women living with perinatally transmitted HIV (WWPHIV) seem to be especially vulnerable even if they have received the HPV vaccine. This study will examine HPV vaccine effectiveness and will examine several tests to see which ones are best to screen HPV vaccinated and unvaccinated WWH including WWH so that no woman with cancer will be missed and at the same time, to make sure there are few false positives tests (that is they have a positive test but no disease).