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

• ClinicalTrials.gov Identifier: NCT05986084
• Recruitment Status: Recruiting
• First Posted: August 14, 2023
• Last Update Posted: February 5, 2024
• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: Botswana Harvard AIDS Institute Partnership; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); ViiV Healthcare
• Information provided by (Responsible Party): Rebecca Zash, MD, Beth Israel Deaconess Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Pre-Exposure Prophylaxis (PrEP); Breast Feeding	Drug: Cabotegravir Injection [Apretude]	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 500 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Linking HIV Prevention and Postpartum Care: Safety, Efficacy and Feasibility of Cabotegravir-LA PrEP in a High-Risk Breastfeeding Population in Botswana
• Actual Study Start Date: November 30, 2023
• Estimated Primary Completion Date: August 2027
• Estimated Study Completion Date: August 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Persistence of CAB-LA injections [ Time Frame: 24 months ]
   The % of participants continuing CAB-LA PrEP at 5 months,11 months,17 months and 24 months
2. Uptake of CAB-LA injections [ Time Frame: 24 months ]
   The % of eligible participants accepting CAB-LA PrEP
3. Adherence to CAB-LA injections [ Time Frame: 24 months ]
   The % of injection visits attended by participants
4. HIV Incidence [ Time Frame: 24 months ]
   The incidence of HIV infections will be calculated as the number of HIV infections infections identified during follow up, per person-year)
5. Composite Maternal Adverse Effects [ Time Frame: 24 months ]
   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
6. Composite Infant Adverse Effects [ Time Frame: 24 months ]
   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

Secondary Outcome Measures :

1. Maternal Cabotegravir Levels [ Time Frame: 5 months ]
   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)
2. Infant Cabotegravir Levels [ Time Frame: 5 months ]
   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)
3. Median maternal weight change [ Time Frame: 24 months ]
   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)
4. Maternal Obesity [ Time Frame: 24 months ]
   BMI >30 at 24 months
5. Maternal Diabetes [ Time Frame: 24 months ]
   New onset diabetes and pre-diabetes (HgBA1c >5.8 or diagnosis during routine care)
6. Maternal Hypertension [ Time Frame: 24 months ]
   Systolic blood pressure >140 and/or diastolic blood pressure >90 on 2 separate measurements, or diagnosis during routine care
7. Maternal Depression [ Time Frame: 24 months ]
   PHQ-9 score >9 or diagnosis of post partum depression in routine care
8. Infant HIV infection [ Time Frame: 24 months ]
   The % of infants diagnosed with HIV infection, per person-years of follow up
9. INSTI resistance among incident HIV infections [ Time Frame: 24 months ]
   The % of incident maternal and infant HIV infections found to have INSTI resistance
10. Inadequate infant growth [ Time Frame: 24 months ]
    The % of infants with Z-score >=2SD below WHO norms for length-for-age or weight-for-age
11. Infant microcephaly [ Time Frame: 24 months ]
    Infants with head circumference >=2SD below WHO norms for head-circumference for age

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Rebecca Zash, MD; 6172756630; rzash@bidmc.harvard.edu

Locations

United States, Massachusetts

Beth Israel Deaconess Medical Center; Not yet recruiting

Boston, Massachusetts, United States, 02215

Contact: Rebecca Zash, MD 617-275-6630 rzash@bidmc.harvard.edu

Principal Investigator: Rebecca Zash, MD

Botswana

Botswana Harvard AIDS Institute Partnership; Recruiting

Gaborone, Botswana

Contact: Marcella Yoseph +267 3902671 myoseph@bhp.org.bw

Contact: Joseph Makhema +267 3902671 jmakhema@bhp.org.bw

Principal Investigator: Joseph Makhema

Sub-Investigator: Emily Shava

Sub-Investigator: Marcella Yoseph

Sub-Investigator: Sikhulile Moyo

Sub-Investigator: Tendani Gaolathe

Sub-Investigator: Rodgers L Moeng

Sponsors and Collaborators

Beth Israel Deaconess Medical Center

Botswana Harvard AIDS Institute Partnership

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

ViiV Healthcare

Investigators

• Principal Investigator: Rebecca Zash, MD; Beth Israel Deaconess Medical Center

More Information

• Responsible Party: Rebecca Zash, MD, Assistant Professor of Medicine, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT05986084
• Other Study ID Numbers: 2023P000415; 5R01HD108047 ( U.S. NIH Grant/Contract )
• First Posted: August 14, 2023
• Last Update Posted: February 5, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• 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.

• 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

Keywords provided by Rebecca Zash, MD, Beth Israel Deaconess Medical Center:

Botswana; Lactation; Infant PK; long acting injectable; HIV prevention; post-partum; integrase strand transfer inhibitor; cabotegravir

Additional relevant MeSH terms:

Cabotegravir; HIV Integrase Inhibitors; Integrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents