Pharmacokinetic Study of Long-acting Antiretrovirals and Contraceptives in HIV

Official title

Pharmacokinetic Study of Long-acting Antiretrovirals and Contraceptive Options in HIV Prevention

Overview

This study is being done to understand how long-acting injectable cabotegravir (CAB-LA) used for HIV pre-exposure prophylaxis (PrEP) and hormonal contraceptive methods affect each other when used at the same time. Women who are already using CAB-LA or not using PrEP will choose to join one of several groups based on whether they use injectable contraceptive (IM DMPA), an etonogestrel implant, or no hormonal contraceptive. Participants will have study visits every 4 to 12 weeks for up to 12 or 24 weeks after starting a contraceptive method to collect blood samples and measure levels of CAB-LA and hormone concentrations. The study will compare these levels to see if taking CAB-LA changes hormone concentrations or if using hormonal contraception changes CAB-LA drug levels. Safety, side effects, satisfaction, and continuation of CAB-LA PrEP and contraceptive methods will also be evaluated.

Detailed description

Long-acting (LA) HIV pre-exposure prophylaxis (PrEP), such as injectable cabotegravir (CAB-LA), is increasingly available and has the potential to address barriers to adherence seen with daily oral PrEP. LA PrEP regimens can expand options for women and providers to individualize prevention strategies, provide a powerful prevention tool for those facing adherence challenges with oral regimens, and reduce the burden on health systems in resource-limited settings. Another major threat to women's health is unintended pregnancies, and women at risk for HIV face unique challenges in uptake and continuation of long-acting contraceptives. Use of CAB-LA may create synergy with long-acting contraceptives, fostering more consistent uptake and improved health outcomes.

This proposed research study is a prospective, non-randomized, parallel-group pharmacokinetic (PK) study among a sentinel cohort of five distinct groups of AGYW, and will leverage existing control groups. The study will be conducted in Botswana.

This study will generate critical data to guide future implementation studies integrating CAB-LA PrEP and contraceptive services. Providing an array of prevention and reproductive health options has the potential to empower women to make informed decisions, improve adherence and continuation, and inform real-world considerations for co-delivery or future co-formulations of PrEP and contraceptives.

Our central hypotheses are the following:

* CAB-LA will not adversely influence hormonal contraceptive concentrations; * Hormonal contraceptive method use will not adversely modify CAB-LA concentrations below therapeutically relevant plasma concentrations.

Primary Objectives:

* To evaluate any associations between CAB-LA exposure and hormonal contraceptive use in the three groups of IM DMPA, ETG implant, and non-hormonal method users by generating geometric mean hormone concentrations throughout 12 weeks for IM DMPA or 24 weeks for ETG implant and no hormonal method groups (Aim 1a) * To evaluate any associations between hormonal contraceptive exposure and CAB-LA use by generating geometric mean trough CAB-LA concentrations measured immediately prior to dosing of next CAB-LA (Aim 1b)

Exploratory Objectives

* To assess safety, including side effects, satisfaction, and continuation rates of both LA ART/PrEP and hormonal contraceptive method (Aim 2a) * To qualitatively explore decision-making around PrEP and contraceptive method options, study experiences with use of/switch to CAB-LA and contraceptive method (Aim 2b)

Interventions

• Drug Long-acting injectable cabotegravir (CAB-LA)
  Injectable cabotegravir 600 mg administered as long-acting HIV pre-exposure prophylaxis (PrEP).
• Other No PrEP
  No HIV pre-exposure prophylaxis administered

Primary outcome measures

• To evaluate any associations between CAB-LA exposure and hormonal contraceptive use in the three groups of IM DMPA, ETG implant, and non-hormonal method users by generating geometric mean hormone concentrations (Aim 1a) [Time frame: 0, 4, 8, 12 weeks for IM DMPA; 0, 4, 8, 12, 24 weeks for ETG implant and non-hormonal method users]
• To evaluate any associations between hormonal contraceptive exposure and CAB-LA use by generating geometric mean trough CAB-LA concentrations measured immediately prior to dosing of next CAB-LA (Aim 1b) [Time frame: Immediately prior to each scheduled CAB-LA injection]

Secondary outcome measures (4)

• Incidence of adverse events associated with CAB-LA and hormonal contraceptive methods (Aim 2a1) [Time frame: 12 and 24 weeks after contraceptive method initiation]
• Participant satisfaction with CAB-LA and hormonal contraceptive method measured by questionnaire (Aim 2a2) [Time frame: 12 and 24 weeks after contraceptive method initiation]
• Continuation rates of CAB-LA and hormonal contraceptive method (Aim 2a3) [Time frame: 12 and 24 weeks after contraceptive method initiation]
• Participants' experiences and decision-making regarding CAB-LA and contraceptive method options assessed by semi-structured interviews (Aim 2b) [Time frame: At the end of study participation or up to 12 months after study participation]

Eligibility criteria

Parent Tshireletso Study Inclusion Criteria:

• Female 18 years of age or older and willing and able to provide an informed consent
• < 14 days after delivery (calendar day of birth = day 0)
• Negative HIV screening test (conducted at the time of enrolment)
• Female <30 years old or has had < 3 prior pregnancies (Gravida 1, 2, or 3 including this pregnancy)
• Plan to stay and receive postpartum and pediatric care in the Gaborone or Molepolole region for 24 months

Parent Tshireletso Study Exclusion Criteria

• Receiving carbamazepine, phenobarbital, phenytoin, oxycarbazepine, rifampin, rifabutin, rifapentine, systemic dexamethasone (>1 dose oral/IV), or St. John's wort
• Suspected to have, recently diagnosed with, or on treatment for TB (due to interaction with rifampicin)
• Previous hypersensitivity reaction to CAB or other INSTI
• Unstable medical or psychiatric condition making it unlikely they will be able to adhere to injections every 2 months
• Plan for pediatric and post-partum care outside the government system (private clinics)
• Inflammatory skin condition that compromises the safety of the intramuscular injection
• Weight <35kg

Parent Doris Duke Study Inclusion Criteria Post-partum females included;

• if HIV-uninfected or unknown HIV status, willing to be tested for HIV
• if HIV-infected, documented to be on DTG as part of an antiretroviral treatment regimen
• maternal age >18 years,
• ability to speak English or Setswana
• intend to be available for follow up in Molepolole, Gaborone or Mochudi for 18 months post-delivery
• have access to a cell phone (including phone of friend or relative)

Parent Doris Duke Study Exclusion Criteria Post-partum females excluded if

• did not attend antenatal care or were not included in Tsepamo surveillance
• maternal age <18,
• females who do not speak English or Setswana,
• unable or unwilling to give consent
• will not be able to attend follow up at a study site
• do not have access to any cell phone for follow up calls

Additional Inclusion Criteria for this PK Study

• For DMPA and ETG implant groups, intends to initiate or continue use of DMPA or ETG implant for at least another three or six months, respectively,
• For the CAB-LA groups, have received at least three consecutive CAB injections on time, including the one administered concurrently while starting a contraceptive method,
• Willing to undergo phlebotomy every 4 weeks for the duration of the sub-study period Additional Exclusion Criteria for this PK Study

1\) Use or anticipated use of nicotine-containing products (e.g., cigarettes or hookahs) known to interact with CAB-LA for the duration of the sub-study period 2) Use within the previous 90 days, current use, or planned future concomitant use of other hormonal contraceptives, including oral contraceptive methods 3) BMI≥35 4) Has any of the following laboratory abnormalities within the last year:

• Serum ALT>5x ULN at the time of screening,
• Serum creatinine >2.5x ULN at the time of screening. 5) Has any other condition that, in the opinion of the sub-study PI/designee, would preclude informed consent, make study participation unsafe, or complicate interpretation of study outcome 6) HIV infected females on the Doris Duke parent study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

Botswana · 1 center

• Princess Marina Hospital — Bontleng

Identifiers

NCT: NCT07516548 · IRB-300013405 · R01AI155052

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗