In 2011, President’s Emergency Plan for AIDS Relief (PEPFAR) released a blueprint for achieving an AIDS-free generation, including the goal of eliminating new HIV infections among children by 2015.1 While the rate of mother-to-child HIV transmission (MTCT) in the United States has decreased dramatically with maternal combination antiretroviral therapy, elective cesarean when indicated, infant prophylaxis and formula feeding, MTCT continues to occur.2 Understanding the maternal and obstetric factors associated with these cases will identify areas of focus for prevention efforts.2
In the United States between 1988 and 1993, the number of infants infected through MTCT was estimated to be approximately 1630 per year.3 New perinatal HIV infections (PHIV) have since become a rare event in the United States and other resource-rich countries with report rates of MTCT of 2.2% or less.2 , 4 The Centers for Disease Control and Prevention reported that there were 47 infants infected through MTCT in the United States in 2014.5 In resource-rich settings, cases of perinatal HIV transmission are often associated with a failure of identification, treatment or management of HIV-infected pregnant women, representing missed opportunities for prevention of MTCT. We report the rate of MTCT in the contemporary US perinatal cohort of the Pediatric HIV/AIDS Cohort Study (PHACS) and describe those factors associated with perinatal HIV transmission. We were also particularly interested in our increasing population of pregnant women who themselves have PHIV. With improved perinatal and pediatric HIV care, PHIV-infected girls are now surviving into adolescence, and pregnancy among these women is becoming more common.6 However, the maternal and infant outcomes of pregnancies among PHIV women are not well described, including the rate of MTCT for pregnant women with PHIV.
MATERIALS AND METHODS
The Surveillance Monitoring of ART Toxicities Study (SMARTT) of PHACS is a US-based prospective cohort study of HIV-infected women and their infants designed to evaluate the safety to the child of in utero exposure to maternal HIV infection and antiretroviral drugs (ARVs).7 The Dynamic cohort of SMARTT opened in 2007 and enrolls approximately 250 mother–infant pairs annually at 22 clinical sites in the United States including Puerto Rico. HIV-infected pregnant women between 23 weeks gestation and 72 hours after delivery are eligible. Infants determined to be HIV-infected are discontinued from the study. We present the outcomes of all 2123 live births occurring between the start of study enrollment in 2007 and June 30, 2015 (to allow for sufficient follow-up to determine the infection status of the infants).
Maternal pregnancy and delivery history, including CD4 and HIV viral load measurements, ARV use, sexually transmitted infections (STI) and type of delivery were abstracted from the medical record. The most complicated ARV regimen used during pregnancy was reported based on the following hierarchy: combination ARV (cARV) with entry/fusion/integrase inhibitors > cARV with protease inhibitors > cARV with nonnucleoside reverse transcriptase inhibitors > cARV with only nucleoside reverse transcriptase inhibitors > non-cARV. cARV was defined as the use of 3 or more ARVs. STIs of interest included gonorrhea, chlamydia, trichomoniasis, syphilis, genital herpes, human papilloma virus, genital warts and bacterial vaginosis. Maternal route of HIV acquisition, date of first prenatal care visit and infant HIV status were obtained through chart abstraction or interview.
The rate of MTCT and the 95% confidence interval (CI) were calculated using the Poisson distribution and generalized estimating equations to account for mothers with multiple infants on study. The proportion of mothers with a last viral load during pregnancy >1000 copies/mL and last CD4 count during pregnancy <200 cells/mm3 were compared by mother’s route of infection (perinatal vs. horizontal) using similar generalized estimating equations models. These factors were not compared by infant infection status because of the small number of infected infants. Maternal demographic, pregnancy and delivery characteristics and HIV disease status were described by the infection status of the infant and the perinatal infection status of the mother.
Included in this analysis are 2123 live-born infants delivered as of June 30, 2015. Of these, 1666 (78%) were subsequently reported to be uninfected (perinatally HIV-exposed and uninfected), 448 (21%) had undetermined HIV infection status (183 lost-to-follow-up and 265 with indeterminate status at last study visit) and 9 infants were HIV infected, giving a rate of MTCT of 0.5% (95% CI: 0.2%–1.0%) among those with defined infection status (Table, Supplemental Digital Content 1, http://links.lww.com/INF/D167). The 9 infected infants were more likely to be female than the perinatally HIV-exposed and uninfected (78% vs. 49%, respectively), while the race and ethnicity of the 2 groups were similar (67% vs. 63% black/not-Hispanic and 33% vs. 31% Hispanic, respectively). Three of the 9 infected infants were preterm (<37 weeks gestation), and 1 was very preterm (<32 weeks gestation), compared with 19% and 2%, respectively, for perinatally HIV-exposed and uninfected infants.
Characteristics of transmitting and nontransmitting mothers are described in the Table (Supplemental Digital Content 1, http://links.lww.com/INF/D167). Their median age at delivery was 24.3 and 28.5 years, respectively. The transmitting mothers were more likely to have their final viral load during pregnancy >1000 copies/mL (67% vs. 11%), while the proportion with a final CD4 count <200 cells/mm3 was similar in the 2 groups (11% vs. 9%). The proportion of transmitting and nontransmitting mothers with an STI during pregnancy was similar (44% and 42%, respectively).
Of the 2123 mother–infant pairs, 232 (10.9%) included a mother with PHIV (Table 1 and Table, Supplemental Digital Content 2, http://links.lww.com/INF/D168). The rate of MTCT was 1.1% (95% CI: 0.3–4.3) among mothers with PHIV and 0.4% (95% CI: 0.2–1.0) among those with horizontally acquired HIV. Mothers with PHIV were significantly more likely to have their final viral load during pregnancy >1000 copies/mL (19% vs. 9%; P < 0.001) and their final CD4 count <200 cells/mm3 (19% vs. 8%; P < 0.001). They also started prenatal care earlier, started ARVs earlier in pregnancy, were more likely to be receiving ARVs at the time of their first viral load in pregnancy and received more complex ARV regimens, consistent with long-term use of ARVs.
Our observed rate of MTCT of 0.5% is among the lowest reported among large cohorts of infected mothers. We acknowledge that our study population represents a select group of women who were managed at research sites and were receiving care at the time of study enrollment. Hence, they should represent the best possible outcomes.
We found that the rate of MTCT among women with PHIV was nearly 3 times that of those with horizontally HIV infected. Many perinatally infected individuals are reaching reproductive age, and, as we found, perinatally infected mothers are more likely to have detectable viral loads and lower CD4+ counts than horizontally HIV-infected mothers.6 In addition, youth with PHIV have a high prevalence of resistant virus.8 Thus, it is important to recognize that this emerging at-risk population, with lifelong HIV infection and prolonged use of ART, present with more advanced HIV disease, and their care may be complicated by poor retention in care, poor ART adherence and ARV-resistant virus.
Advances in antiretroviral therapy and management of HIV-infected pregnant women have resulted in a declining rate of MTCT. A recent report from the state of Nevada demonstrated a significant decrease in the MTCT rate after implementation of an integrated program to prevent MTCT.9 Their program focused on evaluating current practices and identifying gaps in performance, which were addressed with specific interventions designed to increase access to prenatal care, receipt of prenatal and perinatal ARVs and appropriate use of cesarean section. As a result of these interventions, the MTCT rate decreased from 23% to 0%. These results suggest that MTCT can be eliminated in resource-rich countries with the identification of populations at increased risk of transmission and addressing interventions to prevent transmission.10
Cases of MTCT represent missed opportunities for prevention. A recent report of 27 cases of MTCT found that only 3 mothers had an undetectable HIV-1 viral load at delivery.11 In our cohort, maternal viral load >1000 copies/mL at delivery was the principal risk factor for MTCT and was more than twice as likely among those with PHIV. This highlights the importance of achieving virologic suppression during pregnancy.12 Pregnant women with PHIV warrant particular attention to achieve HIV viral load suppression and maintenance of CD4+ counts through the early initiation of ARVs during pregnancy and reinforcing adherence to ARVs.
A limitation of this study is that 448 infants (21%) had unknown HIV infection status. Assuming that the MTCT rate was the same for those with unknown status as for those with known status, then the overall MTCT rate would remain 0.5% (11/2123). The MTCT rate by maternal route of infection in unlikely to differ between those with and without known infant infection status.
In conclusion, we report an overall MTCT rate of 0.5%. The rate of MTCT may be higher among pregnant women with PHIV, due in part to a greater likelihood of having a detectable viral load at delivery, the strongest predictor of transmission.12 Efforts to decrease rates of transmission should focus on viral suppression during pregnancy, and women with PHIV warrant particular attention.
The authors thank the children and families for their participation in PHACS and the individuals and institutions involved in the conduct of PHACS. All authors meet authorship criteria. Conception and design of the study was performed by R.B.V.D. and K.P., and acquisition of data was performed by all authors. All authors are responsible for analysis and interpretation of data and drafting or revision of the article. The following institutions, clinical site investigators and staff participated in conducting PHACS SMARTT in 2015, in alphabetical order: Ann & Robert H. Lurie Children’s Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Anna Cintron; Children’s Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Patricia A. Garvie, James Blood; New York University School of Medicine: William Borkowsky, Sandra Deygoo, Marsha Vasserman; Rutgers - New Jersey Medical School: Arry Dieudonne, Linda Bettica; St. Jude Children’s Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera; SUNY Downstate Medical Center: Stephan Kohlhoff, Ava Dennie, Susan Bewley; Tulane University School of Medicine: Russell Van Dyke, Karen Craig, Patricia Sirois; University of Alabama, Birmingham: Marilyn Crain, Paige Hickman, Dan Marullo; University of California, San Diego: Stephen A. Spector, Kim Norris, Sharon Nichols; University of Colorado, Denver: Elizabeth McFarland, Carrie Chambers, Jenna Wallace, Emily Barr; University of Florida, Center for HIV/AIDS Research, Education and Service: Mobeen Rathore, Kristi Stowers, Saniyyah Mahmoudi, Ann Usitalo; University of Illinois, Chicago: Karen Hayani, Kenneth Rich, Lourdes Richardson, Renee Smith; University of Miami: Gwendolyn Scott, Sady Dominguez, Anai Cuadra; University of Southern California: Toni Frederick, Mariam Davtyan, Guadalupe Morales-Avendano; University of Puerto Rico School of Medicine, Medical Science Campus: Zoe M. Rodriguez, Ibet Heyer, Nydia Scalley Trifilio.
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