Tshireletso: Safety, Efficacy and Feasibility of Cabotegravir-LA PrEP in a Breastfeeding Population in Botswana (Tshireletso)

Linking HIV Prevention and Postpartum Care: Safety, Efficacy and Feasibility of Cabotegravir-LA PrEP in a High-Risk Breastfeeding Population in Botswana

The goal of this this hybrid safety/implementation study is to evaluate whether using long-acting cabotegravir (CAB-LA) for HIV prevention (PrEP) is acceptable, feasible and safe in post-partum people who are breastfeeding. The main question[s] it aims to answer are:

• Will CAB-LA injections work well as a way to prevent HIV infection in post-partum people?
• Will CAB-LA injections be safe in post-partum people and their infants who will be breastfeeding?

Participants without HIV who are admitted to the maternity ward after having delivered a baby will be offered to start CAB-LA PrEP. Those who choose to participate will receive their first dose (injection) at the maternity ward and their follow up doses (injections) at their local clinic when they come for routine post-partum and pediatric care. Participants and their infants will be followed in the study for 24 months. We will be following how many people come on-time for their CAB-LA injections, how often they keep coming back, and the reasons they continue (or stop) these injections. We will also test people for HIV at all of their visits to see how many people get HIV during the study. We will also measure the levels of the medication in the blood of the post-partum people and their infants (who may be getting some of the CAB-LA in breastmilk) and evaluate to see if their is any impact of CAB-LA on the health of the post-partum person or their infants.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Feeding; Pre-Exposure Prophylaxis (PrEP)
• Intervention / Treatment: Drug: Cabotegravir Injection [Apretude]

Detailed Description

This is a hybrid implementation/safety study of long-acting cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to prevent HIV infection in a post-partum cohort in Botswana where breastfeeding is common. The investigators will enroll 500 women at risk for HIV while they are admitted to the postpartum maternity ward after delivery at government-run health care facilities in Botswana and follow them for 24 months. The study sites will be located in two districts in Botswana, Gaborone and Molepolole.

The first CAB-LA injection will occur generally before discharge from the maternity ward. Follow up injections at 1 month, and then every 2 months, will be administered at clinics where the women and their infants receive routine care (or at research study sites when needed). The investigators will will measure uptake, adherence, persistence and implementation metrics using a mixed methods approach. The investigators will evaluate factors associated with uptake, adherence and persistence using data collected on all participants via questionnaires. The investigators will also conduct in-depth interviews of eligible participants who do not want CAB-LA and also a subset of enrolled participants at enrollment, 7 months and 19 moths. At each visit The investigators will screen for HIV using 4th generation HIV ag/ab point-of care tests and report HIV incidence over 24 months. The investigators will also evaluate safety outcomes, including postpartum depression, weight gain, and infant growth and INSTI resistance in incident HIV infections. Pharmacokinetics of CAB-LA in lactation (women, infants and breastmilk) will be evaluated in 30 mother-infant pairs in a PK substudy. HIV incidence and safety outcomes will be compared with a similar cohort of participants enrolled in a separate observational study in Botswana. This separate study also enrolls at the time of delivery from the same maternity sites.

• Study Type: Interventional
• Enrollment (Estimated): 500
• Phase: Phase 4

Contacts and Locations

Study Locations

• Botswana
  • Gaborone, Botswana
    • Botswana Harvard AIDS Institute Partnership
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Receiving carbemazapine, phenobarbital, phenytoin, oxycarbazepine, rifampin, rifabutin, rifapentine, systemic dexamethasone (>1 dose oral/IV), or St. John's wort
2. Suspected to have, recently diagnosed with, or on treatment for TB (due to interaction with rifampin)
3. Previous hypersensitivity reaction to CAB or other INSTI
4. Unstable medical or psychiatric condition making it unlikely they will be able to adhere to injections every 8 weeks
5. Plan for pediatric and post-partum care outside the government system (private clinics)
6. Inflammatory skin condition that compromises the safety of the intramuscular injection
7. Weight <35kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CAB-LA PrEP; Following a negative HIV test, long-acting Cabotegravir Injection (CAB-LA) 600mg will be administered as a 3mL intramuscular (IM) injection in the gluteal muscle at enrollment, 1 month, and then every 2 months, for a maximum of 13 injections over 24 months of follow up.	Drug: Cabotegravir Injection [Apretude]; Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistence of CAB-LA injections	The % of participants continuing CAB-LA PrEP at 5 months,11 months,17 months and 24 months	24 months
Uptake of CAB-LA injections	The % of eligible participants accepting CAB-LA PrEP	24 months
Adherence to CAB-LA injections	The % of injection visits attended by participants	24 months
HIV Incidence	The incidence of HIV infections will be calculated as the number of HIV infections infections identified during follow up, per person-year)	24 months
Composite Maternal Adverse Effects	The % of participants with any of the following: grade 2 or higher DAIDS-graded adverse event, obesity (24 month BMI >30), new onset diabetes and pre-diabetes (HgBA1c >5.8 or diagnosis during routine care), hypertension (systolic >140 or diastolic >90 on 2 separate measurements, or diagnosis during routine care) and prevalence of depression (PHQ-9 score >9) or diagnosis during routine care	24 months
Composite Infant Adverse Effects	The % of infants with any of the following: incident pediatric HIV infections, Z-score >=2 standard deviations (SD) below norms for length-for-age, weight-for-age or head-circumference-for-age based on WHO growth curves at 24 months	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal Cabotegravir Levels	Paired serum and breastmilk cabotegravir levels will be assessed just before the 1-month CAB-LA injection (early trough), 1 week after the 1-month CAB-LA injection (early peak), just before the 5-month CAB-LA injection (steady state trough) and 1 week after the 5-month CAB-LA injection (steady state peak)	5 months
Infant Cabotegravir Levels	In breastfed infants, infant serum cabotegravir levels will be assessed just before the 1-month CAB-LA injection (early trough), 1 week after the 1-month CAB-LA injection (early peak), just before the 5-month CAB-LA injection (steady state trough) and 1 week after the 5-month CAB-LA injection (steady state peak)	5 months
Median maternal weight change	The investigators will describe the median change in weight over the follow up period and the median weight gain from pre-pregnancy weight (when available)	24 months
Maternal Obesity	BMI >30 at 24 months	24 months
Maternal Diabetes	New onset diabetes and pre-diabetes (HgBA1c >5.8 or diagnosis during routine care)	24 months
Maternal Hypertension	Systolic blood pressure >140 and/or diastolic blood pressure >90 on 2 separate measurements, or diagnosis during routine care	24 months
Maternal Depression	PHQ-9 score >9 or diagnosis of post partum depression in routine care	24 months
Infant HIV infection	The % of infants diagnosed with HIV infection, per person-years of follow up	24 months
INSTI resistance among incident HIV infections	The % of incident maternal and infant HIV infections found to have INSTI resistance	24 months
Inadequate infant growth	The % of infants with Z-score >=2SD below WHO norms for length-for-age or weight-for-age	24 months
Infant microcephaly	Infants with head circumference >=2SD below WHO norms for head-circumference for age	24 months

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); ViiV Healthcare; Botswana Harvard AIDS Institute Partnership
• Investigators: Principal Investigator: Rebecca Zash, MD, Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2023
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): November 30, 2027

Study Registration Dates

• First Submitted: July 27, 2023
• First Submitted That Met QC Criteria: August 3, 2023
• First Posted (Actual): August 14, 2023

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: HIV prevention; long acting injectable; Lactation; Botswana; cabotegravir; post-partum; Infant PK; integrase strand transfer inhibitor
• Additional Relevant MeSH Terms: Behavior; Feeding Behavior; Breast Feeding; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; cabotegravir
• Other Study ID Numbers: 2023P000415; 5R01HD108047 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Researchers who provide a methodologically sound proposal (approved by the Tshireletso study team) for use of the data, including for pooling of data on the safety of medications in pregnancy and lactation to achieve aims, that have ethics approval from all involved institutions. Researchers of approved proposals will need to sign a Data Use Agreement with BIDMC before receiving the data.
• IPD Sharing Time Frame: Data will be available starting 3 months after the publication of the main outcomes of the Tshireletso study and be available until the end of the funding period for this study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No