Despite major advances in testing and treating HIV, including highly effective oral pre-exposure prophylaxis, there were 1.7 million new cases of HIV in 2019.  Fifty-nine percent of these occurred in sub-Saharan Africa, where a high proportion of newly infected individuals are women. In order to see if facilitating PrEP delivery decreased HIV transmission in these areas, a flexible care delivery model of PreP for high-risk individuals was tested in 16 rural communities in Kenya and Uganda. The study paired community HIV testing with same-day access to PrEP in HIV-negative high-risk individuals, as well as follow-up appointments at week 4, week 12 and every 12 weeks thereafter until week 144.  Location of follow-up visits, care, and PrEP refills was flexibly scheduled at local areas including homes, nearby schools, or community locations to facilitate follow-up and adherence.

Overall, 79% of individuals who started PrEP adhered to the program and follow-up visits.  In 8 of the 16 communities, data from those who started PrEP was compared to data from people with similar demographic and risk profiles from the year before PrEP was available. In women, incidence of HIV was 76% lower in women and 74% in the overall population among individuals who initiated PrEP compared to control groups who did not.  These finding suggest that this intervention strategy including access to PrEP in conjunction with existing testing, treatment and prevention sites can reduce HIV spread in these rural settings, especially when scaled up to meet the community’s needs through a flexible care delivery model.

Reference: Koss et al. HIV incidence after pre-exposure prophylaxis initiation among women and men at elevated HIV risk: A population-based study in rural Kenya and Uganda. PLoS Medicine. 2021 Feb 9; 18(2): e1003492.

Although the spread of HIV has slowed down thanks to risk-reduction measures, prevention efforts, and oral antiretroviral preexposure prophylaxis (PrEP), there are more than 1.5 million new cases of the human immunodeficiency virus (HIV) each year worldwide. The Antibody Mediated Prevention trials included two clinical trial cohorts, to test the ability of the monoclonal antibody VRC01 to prevent HIV acquisition. The study enrolled participants from three different continents, including at-risk cisgender men and transgender people and at-risk women in sub-Saharan Africa. Participants were healthy, HIV-uninfected adults 18-40 years old randomly assigned to receive either the VRCO1 antibody or a placebo 8 weeks at a time for a total of 10 infusions over the course of 20 months.

Researchers found that, although the VRC01 antibody did not prevent overall HIV-1 transmission, VRC01 treatment was linked to lower risk of acquisition of HIV-1 isolates that had in vitro sensitivity to the antibody. For women in sub-Saharan Africa who were at risk for HIV-1 infection and were exposed to subtype C variants, VRC-01 demonstrated 75% protection against this group of viruses. This was also the case at other sites, including at-risk persons in South America, Switzerland, and the United States who were as­signed male sex at birth or were transgender, and who were exposed to subtype B variants.  These findings support that pre-exposure prophylaxis using broadly neutralizing antibodies can be a promising strategy to prevent HIV spread. 

Reference: Corey L et al. Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition. N Engl J Med. 2021 Mar 18;384(11):1003-1014.

Although pregnant people are at higher risk for severe COVID-19, pregnant volunteers were not included in the initial clinical trials to evaluate the efficacy of vaccines against SARS-CoV-2 infection, which causes COVID-19. To address the gap in knowledge about COVID-19 vaccination during pregnancy, NIAID-supported researchers enrolled 131 individuals of reproductive age, including 84 pregnant, 31 lactating, and 16 nonpregnant individuals in a cohort study to evaluate the immune response generated by the COVID-19 messenger RNA vaccines. Researchers compared the immune responses in individuals who were pregnant and vaccinated with vaccinated non-pregnant participants, and with the immune responses of those who had been naturally infected with COVID-19 while pregnant. Results showed that vaccine-induced antibody responses were equal between pregnant and lactating individuals compared with nonpregnant participants. Antibody levels after vaccination were significantly higher than those induced by natural infection during pregnancy. Vaccine-generated antibodies were also present in all umbilical cord blood and breastmilk samples. Thus, messenger RNA vaccines induced robust immunity in pregnant and lactating individuals, and this immunity was transferred to newborns via the placenta and breastmilk.

Reference: Gray KJ, Bordt EA, Atyeo C, et al. Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol 2021; 225: 303.e1-17.

Plasmodium falciparum, the parasite that causes malaria, creates a significant burden of morbidity and mortality around the world. In pregnant women, P falciparum- infected red blood cells (iRBCs) collect in vascular spaces of the placenta by binding to chondroitin sulfate A (CSA). This sequestration of iRBCs can result in inflammatory responses, which can lead to many adverse pregnancy outcomes such as severe maternal anemia, fetal growth retardation, premature delivery, maternal and/or perinatal mortality.

In pregnant women, VAR2CSA, a parasite protein, binds to CSA and has been shown to facilitate placental sequestration of iRBCs.  In addition, several other genes are upregulated in maternal parasites, including Plasmodium falciparum chondroitin sulfate A ligand (PfCSA-L).  These proteins serve as promising targets for the development of placental malaria interventions.

This study showed that PfCSA-L binds both placental CSA and VAR2CSA and is co-expressed on the iRBC surface. Examination of plasma from East African children, men, and women revealed significant differences in antibody levels to PfCSA-L between the groups.  Additionally, plasma from women who had multiple pregnancies potently blocked binding of PfCSA-L to CSA while plasma from men and women with their first pregnancy did not.  Taken together with data from previous studies, this data suggests PfCSA-L could be a promising target for the development of malaria vaccines.

Keitany et al. An Invariant Protein That Colocalizes With VAR2CSA on Plasmodium falciparum-Infected Red Cells Binds to Chondroitin Sulfate A. The Journal of Infectious Diseases, 2021, jiab550.

Viral suppression of HIV during pregnancy is important for both maternal health and prevention of mother-to-child transmission. Antiretroviral therapy (ART) is an effective method to manage HIV, but rigorous studies on the safety and efficacy of different ART regimens in pregnant women have been limited. To address this, a recent phase 3 trial was conducted to compare three ART regimens: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate.

This randomized controlled, phase 3 clinical trial was conducted across 22 clinical research sites in 9 countries across the world. Pregnant women with confirmed HIV-1 infection were randomly assigned to one of the three ART regimens. The study showed that when started during pregnancy, dolutegravir-containing regimens were superior at suppressing viral RNA levels at delivery compared with the efavirenz, emtricitabine, and tenofovir disoproxil fumarate regimen. Additionally, the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of adverse pregnancy outcomes and neonatal deaths.

These results support the WHO recommendation for use of dolutegravir in all populations, including pregnant women, and highlights a preference for the use of tenofovir alafenamide fumarate in combination with dolutegravir and emtricitabine over the other combinations. The findings of this study support efforts to reduce mortality, adverse outcomes, and transmission of HIV to the fetus through optimization of safe and effective ART regimens in pregnant individuals.   

Lockman et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial.  Lancet. 2021 Apr 3;397(10281):1276-1292.

For pregnant women living with HIV, antiretroviral treatment (ART) is recommended to treat the infection in the mother and prevent mother-to-child HIV transmission. However, pregnancy may affect the way antiretroviral drugs are metabolized and may result in rendering the drug less effective. Studies that address the pharmacokinetics (rates of distribution, absorption, metabolism, and excretion) of drugs in pregnant women are critical to ensure the most appropriate dose is prescribed for maximum protection of mother and child.

This study evaluated the pharmacokinetics and safety of the combination of two antiretroviral drugs—darunavir and cobicistat—among pregnant women with HIV in the United States. Pregnant women in their second and third trimester taking daily darunavir and cobicistat were enrolled and followed up to twelve weeks after delivery, along with their infants. To assess drug pharmacokinetics over time, study participants underwent intensive sampling for a 24-hour period, starting just prior to taking their daily dose of ART. This 24-hour assessment occurred once during the second trimester, the third trimester, and post-delivery, to compare how the drugs were processed at different stages of pregnancy. Infants enrolled in the study were screened four times after birth on a harmonized schedule. Researchers found that both darunavir and cobicistat levels were much lower during the second and third trimesters when compared to postpartum levels. Additionally, the data revealed that transfer of these drugs across the placenta is limited.

The findings of this study suggest that standard darunavir and cobicistat dosing during pregnancy results in significantly lower exposure to the drug, which may increase the risk of treatment failure and mother-to-child transmission and should be avoided during pregnancy.

Reference: Momper et al. Pharmacokinetics of darunavir and cobicistat in pregnant and postpartum women with HIV, AIDS: July 1, 2021 - Volume 35 - Issue 8 - p 1191-1199.

Since 2015, Zika Virus (ZIKV) has caused several outbreaks, with more than one million estimated cases occurring in North and South America. Pregnant women infected with ZIKV can transmit it to their unborn child, which can lead to miscarriage and microcephaly, a condition in which the baby’s head is much smaller than expected standard size.  Currently, there are no approved treatments available to address the public health impact of this disease. Previous studies have shown that favipiravir and ribavirin can inhibit ZIKV replication in vitro and provide protection against disease in some animal models.  In particular, favipiravir has been shown to be effective against several RNA viruses in different animal models of infection.  In this study, researchers conducted a study to assess the effectiveness of favipiravir and ribavirin in a mouse model of ZIKV infection.

When comparing favipiravir, ribarvirin, and a combination of the two to protect mice against lethal ZIKV challenge, researchers discovered that only favipiravir was effective against ZIKV infection. Protection from lethality with favipiravir was significantly different between male and female mice, with survival rates at 25% and 87%, respectively. These findings suggest that sex may be a variable in the efficacy of favipiravir against ZIKV and underscores the importance of using animal models of both sexes in preclinical models for medical countermeasures.  Further studies are required to define the underlying mechanisms of the sex differences associated with favipiravir treatment, as well as if it is a viable option as an intervention for other similar viral infections.

Reference: Matz et al. Favipiravir (T-705) Protects IFNAR−/− Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner, Microorganisms, 9(6), 1178.

Tuberculosis (TB) has a significant impact on maternal and infant health and is one of the leading causes of maternal death worldwide. Pregnant and postpartum women with latent TB are at a higher risk of developing active TB and pregnancy complications due to TB infection can result in babies with low birth weight, premature birth, and stillbirth. Additionally, maternal TB more than doubles the risk of mother-to-child transmission of HIV and significantly increases the death rate for all children in the household. Hence, prevention of active TB during pregnancy is a critical public health concern.

One treatment regimen for TB prevention is a 3 month course of weekly isoniazid and rifapentine, referred to as 3HP. When compared to other treatment options for TB prevention, 3HP’s shorter treatment duration allows for better adherence and has fewer associated adverse events, including in people living with HIV. Given the success of 3HP in nonpregnant women, the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) network initiated a study to determine the safety of this regimen for use in pregnant women with latent TB and understand how pregnancy impacts the pharmacokinetics (rates of distribution, absorption, metabolism, and excretion) of this combination of drugs in women with and without HIV.

The IMPAACT 2001 study enrolled women in their 2nd and 3rd trimesters in Haiti, Kenya, Malawi, Thailand, and Zimbabwe. These women were provided treatment during their study visits and were monitored throughout the study. Additionally, their babies were monitored for 24 weeks after birth. The results of this small study suggest that 3HP is well-tolerated and safe in pregnant women. While there were some differences in the pharmacokinetics of the drugs between women with or without HIV, all study participants achieved levels that were indicative of prevention and no women or infants developed active TB. These results pave the way for larger studies that are powered to address maternal safety, increase diversity in study participants, and understand the influence of antiretroviral therapy on the TB drug levels in pregnant women living with HIV.

Reference: Mathad et al. Pharmacokinetics and Safety of 3 Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women, Clinical Infectious Diseases, 2021;, ciab665.