Adjuvant 5-Fluorouracil Following Thermal Ablation to Improve HPV Treatment Outcomes in Women With HIV in Kenya

WWH face up to six times higher risk of cervical cancer, a leading cause of death in this population. Cervical cancer is caused by persistent HPV infection, which can lead to cervical intraepithelial neoplasia grade 2/3 (CIN2/3), also called cervical precancer. If untreated, CIN2/3 can progress to cervical cancer. Thermal ablation (TA) is the most commonly used treatment for HPV/precancer in low- and middle-income countries, including Kenya. However, among WWH, TA has suboptimal efficacy, with only 44-66% clearing HPV or CIN2/3 at 6-12 months, compared to 83-95% in women without HIV. This highlights the need for adjuvant therapies to improve outcomes.

Studies in high-income countries suggest that off-label, self-administered intravaginal 5FU cream can improve HPV and CIN2/3 treatment outcomes in both HIV-negative and HIV-positive women. This trial will evaluate its potential as an adjuvant therapy following TA in WWH.

• 5% 5-fluorouracil Topical Cream (Drug): Starting four weeks after thermal ablation, participants will self-administer 2 g of 5FU cream intravaginally once every two weeks for 12 doses.
• Placebo Cream (Drug): Starting four weeks after thermal ablation, participants will self-administer 2g of placebo cream intravaginally once every two weeks for 12 doses.

Primary outcomes

• High-risk human papillomavirus (hrHPV) Clearance among WWH randomized to adjuvant self-administered 5FU cream versus placebo cream following Thermal ablation (TA) [Up to 24 weeks]: Vaginal samples will be collected at baseline and approximately every four weeks. Clearance of hrHPV genotypes will be assessed using Polymerase Chain Reaction (PCR)-based human papillomavirus (HPV) Deoxyribonucleic Acid (DNA) testing on these follow-up samples.

Secondary outcomes

• Adverse Event per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 [24 weeks]: Type, frequency, severity and duration of adverse events (AEs) using NCI CTCAE v5.0 will be reported. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
• Adverse Event per National Institute of Health (NIH) Division of Acquired Immunodeficiency Syndrome (AIDS) Adverse Event Grading Criteria (DAIDS) [Up to 24 weeks]: Type, frequency, severity and duration of adverse events (AEs) using per DAIDS standardized scales will be reported. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: Grade 1 indicates a mild event, Grade 2 indicates a moderate event, Grade 3 indicates a severe event, Grade 4 indicates a potentially life-threatening event, Grade 5 indicates death.
• Number of successful self-administration of the intravaginal cream by participants [Up to 24 weeks]: Number of confirmed successful self-administrations of intravaginal 5FU or placebo cream by participants.

Sex: Female, ages: 25 Years to any

Inclusion Criteria

* Women aged 25 years or older
* Known HIV-positive status
* On antiretroviral therapy (ART) for at least 60 days prior to enrollment
* Positive HPV screening test screening result
* Able to provide informed consent in English, Swahili, or Dholuo
* Agree to use dual contraception during dosing phase if of childbearing potential
* Planning to remain in study locale for duration of study (48 weeks) Exclusion Criteria
* Current pregnancy or breastfeeding
* History of anogenital cancer (cervical, vulvar, or anal)
* Current use of immunosuppressive medications
* History of total hysterectomy
* Known allergy to 5FU
* Medical comorbidity that would interfere with study participation
* Unwilling or unable to use contraception during study participation

• Chemtai Mungo, MD, MPH, Principal investigator, UNC Lineberger Comprehensive Cancer Center

NIH grants: R37CA306827