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Phase 3B, randomized, open-label, safety study of dapivirine vaginal ring and oral emtricitabine 200mg/tenofovir disoproxil fumarate 300 mg tablet in breastfeeding mother-infant pairs

Title
Phase 3B, randomized, open-label, safety study of dapivirine vaginal ring and oral emtricitabine 200mg/tenofovir disoproxil fumarate 300 mg tablet in breastfeeding mother-infant pairs
Presenter
Lisa Noguchi
Authors
L. Noguchi * (1,2), M. Owor (3), B. Gati (3), E. Horne (4), N. Mgodi (5), F. Taulo (6), R. Scheckter (7), K. Bunge (8), H. Gundacker (9,10), B. Richardson (11,12), J. Piper (13), N. Chakhtoura (14), J. Balkus (15,12), MTN-043/B-PROTECTED Study Team
Institutions
(1) Jhpiego/Johns Hopkins University, Maternal Newborn Health, Washington, United States, (2) MWRI/UPMC, Microbicide Trials Network, Pittsburgh, United States, (3) Makerere University - Johns Hopkins University (MU-JHU) Research Collaboration, Kampala, Uganda, (4) Wits RHI, Shandukani Research Centre, Johannesburg, South Africa, (5) University of Zimbabwe, Clinical Trials Research Centre, Harare, Zimbabwe, (6) Queen Elizabeth Central Hospital, Obstetrics and Gynaecology, Blantyre, Malawi, (7) FHI 360, Science Facilitation, Durham, United States, (8) Magee-Womens Hospital, University of Pittsburgh Medical Center, Obstetrics and Gynecology, Pittsburgh, United States, (9) Statistical Center for HIV/AIDS Research and Prevention, Seattle, United States, (10) Fred Hutchinson Cancer Research Center, Seattle, United States, (11) University of Washington, Biostatistics and Global Health, Seattle, United States, (12) Fred Hutchinson Cancer Research Center, Division of Vaccine and Infectious Disease Research, Seattle, United States, (13) NIAID/National Institutes of Health, Division of AIDS, Bethesda, United States, (14) NICHD/National Institutes of Health, Rockville, United States, (15) University of Washington School of Public Health, Epidemiology, Seattle, United States

BACKGROUND: World Health Organization (WHO) guidance supports provision of oral pre-exposure prophylaxis (PrEP) for breastfeeding people at substantial risk of HIV acquisition. In January 2021, WHO recommended the dapivirine vaginal ring (VR) as an additional HIV prevention choice as part of combination prevention approaches. In March 2022, the VR was approved by the South African Health Products Regulatory Authority. However, data are lacking on VR safety during breastfeeding, a period of increased HIV acquisition risk.
METHODS: MTN-043 was a phase 3b, randomized, open-label trial, with 12 weeks exposure to VR or oral 200 mg emtricitabine/300mg tenofovir disoproxil fumarate tablet. Healthy, HIV-negative, exclusively breastfeeding mother-infant pairs enrolled from September 2020 to July 2021 at sites in Malawi, South Africa, Uganda, and Zimbabwe and randomized in a 3:1 ratio (VR: tablet). Adverse events (AEs) were collected throughout product exposure and two weeks following product discontinuation. Primary safety outcomes for mothers and infants included serious adverse events (SAEs) and Grade 3 or higher AEs in both arms.
RESULTS: Across sites, 197 mother-infant pairs enrolled (VR: 148, oral PrEP: 49). Median age of infants was 9 weeks. Among VR arm participants, two (1%) mothers experienced an SAE and three (2%) an AE of Grade 3 or higher; four (3%) infants experienced an SAE, and 10 (7%) an AE of Grade 3 or higher (see table). No SAEs or Grade 3 or higher events in mothers or infants were deemed related to study product.

Table. Primary safety outcomes among breastfeeding mothers and infants enrolled in MTN-043

Mothers
Infants

Serious Adverse Events
Grade 3 or Higher Adverse Events
Serious Adverse Events
Grade 3 or Higher Adverse Events

n/N
% (95% CI)
n/N
% (95% CI)
n/N
% (95% CI)
n/N
% (95% CI)
Dapivirine Vaginal Ring
2/148
1% (0, 5)
3/148
2% (0, 6)
4/148
3% (1, 7)
10/148
7% (3, 12)
FTC 200 mg/ TDF 300mg oral tablet
0/49
0% (0, 7)
2/49
4% (1, 14)
0/49
0% (0, 7)
1/49
2% (0, 11)

CONCLUSIONS: In this first evaluation of VR safety during breastfeeding, few SAEs or AEs of Grade 3 or higher occurred among mothers and infants in either study arm; most AEs were mild or moderate, and all infant AEs were unrelated to study product. This favorable safety profile, along with previous data demonstrating low drug transfer to breastmilk, support updates of WHO and other guidelines to include breastfeeding people when recommending the VR as an additional HIV prevention choice.

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