Cabotegravir-Hormone PK/PD Interactions for HIV Prevention

The CHIPP-PrEP protocol is a phase 1, open label study to compare the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of long-acting cabotegravir injectable (CAB-LA) administration in adults aged 19 years or older. Long-acting cabotegravir (Apretude™) is an FDA-approved injectable antiretroviral medication administered every two months for HIV pre-exposure prophylaxis (PrEP). While clinical efficacy trials have demonstrated CAB-LA's effectiveness in preventing HIV infection, knowledge gaps remain regarding drug penetration into mucosal tissues where HIV transmission primarily occurs and potential drug-drug interactions with therapeutic hormone therapies. Current PK data derives predominantly from plasma measurements, which may not accurately reflect drug concentrations at actual sites of HIV exposure in rectal and genital mucosa. This study addresses these critical gaps by directly measuring CAB-LA concentrations in blood, mucosal tissues, and genital secretions across three distinct population cohorts: males not using exogenous hormones, males using therapeutic hormone therapy, and females using non-hormonal contraception. This design enables isolation of hormone effects on CAB-LA pharmacokinetics while controlling for biological sex differences.

Following successful screening, eligible participants will return for a Baseline Visit (Day 0) to complete pre-treatment evaluations. At baseline, participants will undergo laboratory assessment of circulating hormone concentrations (estradiol and testosterone), HIV antibody/antigen and RNA testing to confirm HIV-negative status, and collection of rectal biopsies (all participants) and cervical biopsies (females only) for baseline HIV explant challenge pharmacodynamic assessment. These baseline tissue samples undergo ex vivo HIV-1 challenge experiments to establish pre-treatment viral susceptibility prior to CAB-LA exposure. One week following baseline biopsy collection (Visit 1, Day 7), participants will be administered a single 3 mL intramuscular injection of 600 mg cabotegravir long-acting injectable suspension (Apretude™, ViiV Healthcare; 200 mg/mL formulation) using the recommended ventrogluteal approach by licensed clinical staff.

Biopsy Collection Visits will occur at study visits 2,4, 6, 7, and 8 (Days 7, 14, 35, 63, and 91). At these intensive study visits, blood will be collected for hormone testing (estradiol and testosterone), plasma CAB-LA concentration determination, and eGFR monitoring. Rectal fluid and cervicovaginal fluid will be collected using specialized swabs to measure mucosal drug concentrations. Rectal biopsies (all participants) and cervical biopsies (females only) will be collected using flexible sigmoidoscopy and standard gynecological techniques, respectively, for both tissue drug concentration measurement and pharmacodynamic HIV explant challenge experiments.

Interim Pharmacokinetic Visits (Visits 3 and 5 at Days 10 and 21): Blood will be collected for plasma CAB-LA concentration determination, eGFR assessment, and hormone measurements. A final safety visit (Visit 9 at Day 98) will be performed. Select concomitant medications, with particular emphasis on exogenous hormones and medications that may affect cabotegravir or hormone metabolism, will be collected on daily concomitant medication logs maintained by participants throughout the study.

Safety assessments, including history/physical, chemistry/hematology labs at screening and interim history will be performed at study visits

Inclusion criteria

• 19 years of age or older
• For persons using exogenous hormones, must be on a stable regimen for ≥6 months and remain on that regimen throughout study conduct, and exogenous hormone regimens must be prescribed and managed under the care of a healthcare professional
• For females, must be on a non-hormonal contraceptive agent, and must persist in contraceptive use for the duration of the study
• Body weight greater than 35 kg (77.2 lbs)
• HIV-1 uninfected at screening and enrollment as documented by an instrumented Ag/Ab assay and HIV-1 RNA testing
• Understand and agree to local STI reporting requirements
• Willing to abstain from additional antiretroviral agents (including PrEP agents, F/TAF and F/TDF) during the duration of the study
• Willing to abstain from insertion of anything (drug, enema, penis, or sex toy) in the rectum or vagina for 72 hours before and 72 hours after each flexible sigmoidoscopy
• Willing to refrain from aspirin and NSAID use for one week before and after each study biopsy visit
• Willing and able to use condoms for all receptive anal intercourse and receptive vaginal intercourse for the duration of study participation
• Able and willing to communicate in English
• Able and willing to provide written informed consent to take part in the study
• Able and willing to provide adequate information for locator purposes
• Availability to return for all study visits, barring unforeseen circumstances
• Agree not to participate in other research studies involving drugs and/or medical devices for the duration of the study

Exclusion criteria

• History of previous long-acting antiretroviral use, including CAB-LA and long-acting lenacapavir
• History of oral PrEP (F/TDF, F/TAF) use within the prior eight weeks
• For females, if a participant is pregnant or plans to become pregnant during study duration
• For females, if the participant is actively breastfeeding
• For females, if the participant is post-menopausal or accessing exogenous hormone replacement therapy
• For females, has irregular menstrual cycles
• Has a tattoo or other dermatological condition which may interfere with product administration or interpretation of injection site reactions
• Surgically-placed or injected buttock implants or filler, per self-report
• One or more reactive or positive HIV test results at screening or enrollment, even if HIV infection is not confirmed
• Current known HIV-infected partner(s)
• Symptoms suggestive of acute HIV seroconversion at screening and enrollment
• Known or suspected allergy to CAB-LA
• Any ≥ Grade 2 laboratory abnormality at baseline as defined by Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 - July 2017, and Addendum 3 (Rectal Grading Tables for Use in Microbicide Studies)
• Significant rectal symptom(s) as determined by medical history or by participant self-report (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, history of inflammatory bowel disease, presence of symptomatic hemorrhoids, and presence of any painful anorectal conditions that would be tender to manipulation)
• At screening or within the past 2 months: participant-reported symptoms and/or clinical or laboratory diagnosis of active rectal or genital infection requiring treatment per current CDC guidelines or symptomatic urinary tract infection (UTI). Infections requiring treatment include chlamydia (CT), gonorrhea (GC), syphilis, active HSV lesions, chancroid, genital sores or ulcers, and, if clinically indicated, genital warts. HSV seropositivity with no active genital lesions is not an exclusion criterion. (Note: if an STI apart from HIV is detected, the participant will be referred for treatment and can be retested in 30 days and re-screened once.)
• History of significant gastrointestinal bleeding
• Clinically significant cardiovascular disease, as defined by history of symptomatic arrhythmia, ischemia, or other significant cardiac disease
• Current use of warfarin or heparin or other anticoagulant medications associated with increased risk for bleeding following mucosal biopsy (e.g., daily high dose aspirin [>81 mg], NSAIDs, or Pradaxa®)
• Use of systemic or anorectal immunomodulatory medications within 4 weeks of enrollment or planned use at any time during study participation
• Per participant report, use of any rectally or vaginally administered products containing N-9 (including condoms) or investigational products within 4 weeks of enrollment, or planned use of either at any time during study participation
• Any other condition or prior therapy that, in the opinion of the investigator, would preclude informed consent, make study participation unsafe, make the individual unsuitable for the study or unable to comply with the study requirements.
• Individuals with neocervix will be excluded from giving cervical biopsies, if eligible for study participation.