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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Pre-Exposure Prophylaxis (PrEP), Breast Feeding

Intervention / Treatment
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* Drug: Cabotegravir Injection [Apretude]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mother 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 enrollment) Mother <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 Exclusion Criteria: Receiving carbemazapine, 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 rifampin) 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 8 weeks 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAB-LA PrEP<br>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]<br>* Injection<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Botswana, Lactation, Infant PK, long acting injectable, HIV prevention, post-partum, integrase strand transfer inhibitor, cabotegravir