Abstract NG13: Feasibility of topical self-administered therapies to improve cervical precancer treatment outcomes among women living with HIV in low-and middle-income countries

Abstract Global trends of invasive cervical cancer (ICC) represent a dire global health inequity, with 85 percent of incident cases and 90 percent of deaths occurring in low- and middle-income countries (LMICs).1 ICC is the leading cause of cancer death among women living with HIV (WLWH) in sub-Saharan Africa, which accounts for 71% of the global burden of HIV infection, despite being home to only 12% of the global population.2 Compared to HIV-negative women, WLWH have increased incidence and persistence of human papillomavirus (HPV),3 have a shorter time from HPV infection to development of precancerous lesions,4 and have a six to eightfold increased risk of developing invasive cancer.5 In 2020, the World Health Organization (WHO) launched the 90/70/90 global strategy for cervical cancer elimination, which aims for 90% human papillomavirus (HPV) vaccination rate, 70% screening coverage, and 90% of precancerous lesions adequately treated by 2030. Current efforts towards this elimination agenda include scaling up HPV-based screening programs as well as improving access to precancer treatment using portable ablation and excisional devices in LMICs. However, among WLWH, current precancer treatment methods are limited by high rates of treatment failure. In a randomized trial of WLWH with cervical intraepithelial neoplasia grade 2/3 (CIN2/3), recurrence at 24 months was 30% in the ablation arm and 19% in the excision arm.6 These high rates of treatment failure, demonstrated in multiple studies, are driven by persistent HPV infection following treatment,7 and are highly consequential in LMICs settings follow-up mechanisms are weak. This highlights an urgent need for studies on feasible, innovative, yet accessible strategies to improve HPV clearance following precancer treatment for WLWH in LMICs. Use of self-administered topical therapies with anti-viral properties as adjunct treatment could be a feasible and highly scalable strategy to address this limitation. Several studies, have demonstrated the safety, and efficacy of 5-Flourouracil (5FU), a readily available topical drug as primary or adjuvant therapy for CIN2/3 among both HIV-positive and HIV-negative women in the U.S. In a Phase III multicenter trial of U.S WLWH with CIN2/3 randomized to self-administered intravaginal 5-Flourouracil (5FU) versus observation following standard treatment, participants in the 5FU arm had an 8% CIN2/3 recurrence rate at 18 month follow-up, compared to 31% in the observation arm (p=0.04).8 In another randomized trial of self-administered 5FU as primary treatment versus 6-month observation for CIN grade 2 (CIN2) among U.S women without HIV infection, 93% in the 5FU arm had disease regression, compared to 56% in the observation arm (p=0.01).9 In this study, 50% of participants in the 5FU arm cleared HPV at follow-up, compared to 22% in the observation arm (p<0.05). In both studies, 5-FU, used once every other week for 8 applications, was safe, with no grade 3 or 4 adverse events, and compliance and adherence to treatment was high. However, there are no studies evaluating whether self-administered therapies would be culturally acceptable to WLWH and their male partners in LMICs, or whether topical 5FU may be in this population. To fill this gap, with the support of the 2022 Victoria’s Secret Global Fund for Women’s Cancers Career Development award, in partnership with Pelotonia & the American Association for Cancer Research, using in-depth-interviews and focus group discussions, I am carrying out a mixed-methods qualitative study among WLWH with HPV and their male partners in Kenya and Malawi to investigate their perceptions towards using self-administered therapies for HPV and cervical precancer treatment, as well as perceived barriers and facilitators to uptake. Additionally, I will conduct a Phase I trial to evaluate the safety and adherence of self-administered intravaginal 5-FU following primary treatment among WLWH with CIN2/3 in Kenya. These studies will generate key preliminary data to support future randomized trials to investigate the efficacy of 5FU as adjuvant therapy to improve current precancer treatment strategies for WLWH in LMICs. References: 1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660. 2. Joshi S, Sankaranarayanan R, Muwonge R, Kulkarni V, Somanathan T, Divate U. Screening of cervical neoplasia in HIV-infected women in India. Aids. 2013;27(4):607-615. doi:10.1097/QAD.0b013e32835b1041. 3. Smith JS, Sanusi B, Swarts A, et al. A randomized clinical trial comparing cervical dysplasia treatment with cryotherapy vs loop electrosurgical excision procedure in HIV-seropositive women from Johannesburg, South Africa. Am J Obstet Gynecol. 2017;217(2):183.e1-183.e11. doi:10.1016/j.ajog.2017.03.022. 4. Denslow SA, Rositch AF, Firnhaber C, Ting J, Smith JS. Incidence and progression of cervical lesions in women with HIV: a systematic global review. Int J STD AIDS. 2014;25(3):163-177. doi:10.1177/0956462413491735. 5. Dryden-Peterson S, Bvochora-Nsingo M, Suneja G, et al. HIV infection and survival among women with cervical cancer. J Clin Oncol. 2016;34(31):3749-3757. doi:10.1200/JCO.2016.67.9613. 6. Greene SA, De Vuyst H, John-Stewart GC, et al. Effect of Cryotherapy vs Loop Electrosurgical Excision Procedure on Cervical Disease Recurrence Among Women With HIV and High-Grade Cervical Lesions in Kenya: A Randomized Clinical Trial. JAMA. 2019;322(16):1570-1579. doi:10.1001/jama.2019.14969. 7. Chung MH, De Vuyst H, Greene SA, et al. Human Papillomavirus Persistence and Association With Recurrent Cervical Intraepithelial Neoplasia After Cryotherapy vs Loop Electrosurgical Excision Procedure Among HIV-Positive Women: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. Published online August 2021. doi:10.1001/jamaoncol.2021.2683. 8. Maiman M, Watts DH, Andersen J, Clax P, Merino M, Kendall MA. Vaginal 5-fluorouracil for high-grade cervical dysplasia in human immunodeficiency virus infection: A randomized trial. Obstet Gynecol. 1999;94(6):954-961. doi:10.1016/S0029-7844(99)00407-X. 9. Rahangdale L, Lippmann QK, Garcia K, Budwit D, Smith JS, Le L Van. Topical 5-flourourcil for treamtent of cervical intraepithelial Neoplasia 2 : a Randomized Controlled Trial. Am J Obstet Gynecol. 2014;2140():314.e1-314.e8. doi:10.1016/j.ajog.2013.12.042 Citation Format: Chemtai Mungo. Feasibility of topical self-administered therapies to improve cervical precancer treatment outcomes among women living with HIV in low-and middle-income countries. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr NG13.