UNCPM 22314 - Pregnancy, Infant and Maternal Health Outcomes Study

Study Overview
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Brief Summary
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The primary purpose of this study is a prospective cohort study is to assess the safety of long-acting injectable cabotegravir (CAB-LA) and oral pre-expose prophylaxis (PrEP) (FTC/TDF or 3TC/TDF) during pregnancy and breastfeeding among pregnant women and their infants in Malawi. The main question the study aims to answer is: - Do composite adverse pregnancy events, maternal health outcomes, and/or infant health outcomes differ between individuals taking oral PrEP and those taking CAB-LA? Women receiving PrEP at the time of pregnancy diagnosis or initiating PrEP during pregnancy will enroll into a Safety Cohort where they will be closely followed up during pregnancy while optimizing their antenatal care (ANC) per the Malawi ANC package. Women will have access to either CAB-LA or oral PrEP at the start of the study and will be given an opportunity to choose one option. Women and their infants will attend a series of follow-up visits through pregnancy, birth, and the postnatal period. In addition, the study will contribute to the development of a national PrEP Pregnancy Registry which will be initially rolled out in Lilongwe and Blantyre -the two most populous cities in Malawi-before a nationwide roll out begins under the guidance of the Malawi Ministry of Health.

Detailed Description
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For the prospective safety cohort, we will enroll and follow up eligible women attending antenatal clinic and planning to deliver at Bwaila District Hospital in Lilongwe, Malawi, with the primary objective of comparing composite adverse pregnancy events (spontaneous miscarriage, stillbirth, preterm birth, or infant born small for gestational age) between women using CAB-LA and those using oral PrEP. Pregnant women assessed as being at substantial risk for HIV and eligible for PrEP per Malawi national guidelines will be included. Infants will be followed alongside their mothers. All women meeting eligibility criteria will be consented and offered PrEP (if not already taking it). Women will have access to either CAB-LA or oral PrEP and will be given an opportunity to choose one option. For the Safety Cohort, researchers will group women according to use of oral PrEP (FTC/TDF or TDF/3TC) versus injectable PrEP (CAB-LA), and according to PrEP use before or after pregnancy diagnosis as follows: Group 1a: Initiating daily oral PrEP during pregnancy Group 1b: Using daily oral PrEP at the time of pregnancy diagnosis Group 2a: Initiating injectable CAB-LA during pregnancy Group 2b: Using injectable CAB-LA at the time of pregnancy diagnosis. Follow-up contacts for the mother-infant pairs will follow the Malawi ANC package schedule of events during pregnancy, and then include a delivery/birth visit and a series of postpartum visits through week 52 (exit visit). Interim visits initiated by the study could be to repeat abnormal laboratory tests or for safety monitoring of an adverse event. Interim visits initiated by the participant could be to report an adverse event or to seek primary care. Visits will include a series of clinical and laboratory procedures to monitor and assess any pregnancy, maternal health, or infant adverse outcomes. All clinical and laboratory adverse events will be accessed and graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. These follow up visits will also optimize antenatal care per the Malawi ANC package. Clinical and sociodemographic data with be collected by the clinic staff at the UNC study site at Bwaila District Hospital. Quantitative methods will involve administration of brief behavioral surveys conducted every six months during the study follow up period. The surveys will include (but not be limited to) questions about women's attitudes and beliefs about the two PrEP options, and questions about product-related choice and preferences. Surveys will also include risk questionnaire collecting information about previous sexual activity, partners, and PrEP use over the preceding six months, as well as self-perception of HIV risk. As part of the mixed methods approach, researchers will also conduct qualitative interviews with women to further assess acceptability of oral PrEP or CAB-LA at enrollment, 6 weeks postnatal, and study exit. This component will include a series of in-depth interviews (IDIs) with a subset of women from each group, as well as IDIs with a subset of women who experience adverse obstetric outcomes and those who seroconvert while on injectable or oral PrEP. The aim is to assess whether there are changes in the perceptions and acceptability of oral PrEP or CAB-LA over the study period and explore women's views about future PrEP use during pregnancy and breastfeeding and their choices to use PrEP with subsequent pregnancies. Additionally, all women in the safety cohort will be enrolled into a PrEP in Pregnancy Registry. The registry in this study will contribute to the development of a national PrEP Pregnancy Registry and subsequent registration and longitudinal surveillance of eligible women without HIV at CAB-LA early access sites in Blantyre and Lilongwe. The registry will include all women initiating PrEP in the national program while pregnant or at the time of diagnosis of pregnancy, and those who become pregnant while on PrEP. Registry administrators (RAs) at PrEP sites, who may be community health workers, nurses or midwives working at these sites, will register pregnant women into the PrEP Pregnancy Registry as part of routine data collection. The RA's will then obtain basic health information at enrollment, and conduct a follow-up visit at or following delivery to collect pregnancy outcomes and health care provided during delivery. These activities will be conducted as part of routine care.

Official Title
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UNCPM 22314 - Evaluating the Safety of Pregnancy, Infant and Maternal Health Outcomes Among PrEP Users in Malawi

Conditions
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Pre-exposure Prophylaxis, HIV Prevention, Pregnancy Related

Intervention / Treatment
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* Drug: Initiating daily oral PrEP during pregnancy
* Drug: Already using daily oral PrEP at the time of pregnancy diagnosis
* Drug: Initiating injectable PrEP during pregnancy
* Drug: Already using injectable PrEP (CAB-LA) at the time of pregnancy diagnosis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Maternal participants: Confirmed pregnancy by urine pregnancy test or ultrasound. Aged 15 years or older PrEP-eligible by Malawi local guidelines Confirmed HIV-negative based on the local HIV testing algorithm Hepatitis B surface antigen (HBsAg) negative Weight >35 kg Provided informed consent and expressed willingness to participate in study activities with their infants. Infant participants: Infant participants will enter the study with their mother as unborn infants. There are no specific eligibility criteria for infant participation otherwise. Exclusion Criteria: Maternal participants will not be eligible to enter the prospective cohort study if any of the following conditions are identified during the screening process: Known to be living with HIV Known allergies to CAB-LA, TDF/3TC or FTC/TDF Other current significant disease process (active or chronic), substance use, or social circumstances that, in the judgment of the site investigator would make participation in the study unsafe. Intention to leave the study site's catchment area of Bwaila before scheduled study exit.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Prospective safety cohort of time and type of PrEP initiation<br>The cohort will include pregnant women assessed as being at substantial risk for HIV acquisition and eligible for PrEP per Malawi national PrEP guidelines at Bwaila District Hospital. All women meeting eligibility criteria will be consented and offered PrEP (if not already taking it). Women will have access to either CAB-LA or oral PrEP and will be given an opportunity to choose one option. We will group our women according to use of oral PrEP (FTC/TDF or TDF/3TC) versus injectable PrEP (CAB-LA), and according to PrEP use before or after pregnancy diagnosis and follow up in those groups. All women will be registered into the PrEP Pregnancy Registry as part of routine care. | Drug: Initiating daily oral PrEP during pregnancy<br>* Group 1a, will include pregnant women who initiate oral PrEP at enrollment into the study.<br>* Other names: Tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or lamivudine (3TC) (FTC/TDF or TDF/3TC);Drug: Already using daily oral PrEP at the time of pregnancy diagnosis<br>* Group 1b will include women already using daily oral PrEP at the time of pregnancy diagnosis and enrollment in the study.<br>* Other names: Tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or lamivudine (3TC) (FTC/TDF or TDF/3TC);Drug: Initiating injectable PrEP during pregnancy<br>* Group 2a will include pregnant women who initiate injectable PrEP (CAB-LA) at enrollment into the study.<br>* Other names: CAB-LA;Drug: Already using injectable PrEP (CAB-LA) at the time of pregnancy diagnosis<br>* Group 2b will include women using injectable PrEP (CAB-LA) at the time of pregnancy diagnosis.<br>* Other names: CAB-LA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of composite adverse pregnancy outcomes | Number of women with an adverse pregnancy outcome, defined as the occurrence of any one of the following events: spontaneous miscarriage (pregnancy lost before 28 weeks gestation), stillbirth (fetal death at or after 28 weeks gestation), preterm birth (number of deliveries before 37 weeks gestation), infant born small for gestational age (birth weight of less than 10th percentile for gestational age). | Enrollment through birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of women developing grade 3 or higher clinical or laboratory events | Grade 3 or higher clinical or laboratory events assessed and graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. | Enrollment through 52 weeks postpartum | 
| Number of infants developing stage 3 or higher clinical or laboratory events | Number of infants developing stage 3 or higher clinical or laboratory events, accessed and graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. | Birth through 52 weeks of life | 
| Number of infants born with congenital anomalies | Number of infants born with congenital anomalies, diagnosed with neonatal surface exam and fetal anatomic ultrasound | Birth through 52 weeks of life | 
| Number of infants who are underweight | Number of infants who are underweight, defined as weight for age z-score (WAZ) <-2, assessed at weeks 1, 6, 12, 26 and 52 weeks after birth. | Birth through 52 weeks of life | 
| Number of infants who are stunted | A child will be considered stunted if s/he has a length for age z-score (LAZ) <-2, assessed at weeks 1, 6, 12, 26 and 52 after birth. | Birth through 52 weeks of life | 
| Number of infants who have moderate or severe acute malnutrition | Malnourishment based on anthropometrics per World Health Organization (WHO) definitions. Moderate acute malnutrition defined as a weight for length z-score (WLZ) between -3 and <-2, or mid-upper arm circumference (MUAC) between 115 millimeters and <125 millimeters. Severe acute malnutrition defined as a weight for length z-score (WLZ) of < -3 or MUAC < 115 millimeters, or the presence of bilateral pitting edema, or both. Assessed at weeks 1, 6, 12, 26 and 52 after birth. | Birth through 52 weeks of life | 
| Number of infants with poor neurodevelopment outcomes | Defined as a low Caregiver-Reported Early Development Index (CREDI) and/or Mullen Scales of Early Learning (MSEL) score for age, assessed at weeks 1, 6, 12, 26 and 52 after birth | Birth through 52 weeks of life | 
| Acceptability of oral PrEP or CAB-LA | Based on analysis of in-depth interviews with approximately 50 women in the study. Content analysis to develop codebook using domains and constructs from theoretical framework for acceptability by Sekhon. Data will then be displaced on matrices using the framework to display the patterns emerging from the text. Assessed at delivery, 12 weeks postpartum, and 52 weeks postpartum | Delivery through 52 weeks postpartum | 
| Adoption of PrEP in Pregnancy Registry | Adoption will be defined as the number of targeted settings (including districts, sites, and providers) who initiated register use by the end of the study. Adoption will be assessed at 6, 12, and 24 months after register implementation. | 6 to 24 months after implementation | 
| Reach of PrEP in Pregnancy Registry | Reach will be defined as the total number of entries in the register at each site. Reach will be assessed at 6, 12, and 24 months after register implementation. | 6 to 24 months after implementation | 
| Fidelity to PrEP in Pregnancy Registry | Fidelity is defined as the number of pregnant women who have complete entries for all infant and obstetric outcomes in the register as per protocol. Fidelity will be assessed at 6, 12, and 24 months after register implementation. | 6 to 24 months after implementation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PrEP, Pregnancy, Breastfeeding, Infant health, HIV prevention, Maternal health, Eliminating mother-to-child transmission (EMTCT)