By Ahizechukwu C. Eke, MD, PhD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
Human immunodeficiency virus (HIV) infection during pregnancy carries a significant burden to healthcare systems, and continues to be of significant public health concern.1 In 2019, approximately 1.3 million of the 16.7 million women living with HIV became pregnant, with about 6,000 to 7,000 of these women living in the United States.2 It is pertinent to note that approximately 85% of these 1.3 million women who become pregnant yearly around the world receive antiretroviral therapy (ART).2 HIV in pregnancy is important because more than 90% of pediatric HIV is acquired during pregnancy or at the time of birth (perinatal transmission).2
Prior to the advent and wide use of ART, perinatal transmission of HIV to fetuses was approximately 25% to 40%. However, with therapy, the rate of perinatal transmission of HIV decreases to approximately 2%.3 The Pediatric AIDS Clinical Trials Group (PACTG 076), conducted a randomized, placebo-controlled clinical trial and the first prospective study of any ART in pregnant women, which was published in the New England Journal of Medicine in 1994. The study demonstrated that zidovudine therapy decreased perinatal HIV transmission from 25.5% in the control group (without therapy) to 8.3% in the single-dose zidovudine arm — a reduction of approximately 66%.4 Since the PACTG 076 trial was published, several randomized clinical trials have demonstrated the efficacy and safety of ART for the management of HIV during pregnancy.5
In most countries around the world, and especially in the United States, universal screening for HIV is recommended. Pregnant women are screened for HIV antibodies during the initial prenatal visit and this is repeated once or twice in the third trimester, depending on risk factors and local protocols. A rapid HIV testing during labor in women of unknown status also can be performed.6 Prior to screening, pregnant women usually are informed about the importance of an HIV screening test, the benefits to the mother and fetus, and that the HIV test is part of the standard prenatal testing algorithm. Pregnant women then have a right to refuse HIV testing after appropriate counseling (the “opt-out approach” to HIV testing).
In women who test positive for HIV antibodies for the first time during pregnancy or in women who were living with HIV before becoming pregnant, additional prenatal laboratory work at the initial prenatal visit includes HIV viral-load and CD4 count to assess HIV disease progression; a comprehensive panel to assess hepatic and renal function; complete blood count for hemoglobin concentration, and platelet and white blood cell counts to assess marrow suppression by combination ART; hepatitis A and C antibodies, and hepatitis B surface antigen; and tuberculosis testing. After initiation of ART, it is recommended to serially monitor the HIV viral load every two to four weeks until it becomes undetectable, then every trimester (if viral load remains undetectable), and at 34 to 37 weeks of gestation to determine the best mode of delivery and management of the neonate.6 An HIV genotype becomes pertinent if there is evidence of viral resistance (usually when the HIV viral load is > 500 copies/mL to 1,000 copies/mL despite optimal medication adherence and use of potent ART). In women who are taking abacavir, pharmacogenomic testing for the HLA-B*5701 gene is recommended, since women who test positive to the HLA-B*5701 gene are at a high risk for developing life-threatening reactions to abacavir. In pregnant women living with HIV who opt for diagnostic testing, such as chorionic villous sampling and amniocentesis for fetal aneuploidy testing and umbilical cord blood sampling for fetal anemia diagnosis and treatment, it is reasonable to perform these procedures if the viral load is undetectable. In women on therapy with protease inhibitors, it is reasonable to perform the oral glucose tolerance testing with the 50 mg glucose load earlier (24 weeks of gestation) because of the known association between protease inhibitors and impaired glucose tolerance.7
ART in the form of highly active antiretroviral therapy (HAART) is the cornerstone for prevention of perinatal transmission of HIV, as well as for the continued health of the pregnant mother living with HIV. The current recommended treatment is comprised of the use of two non-nucleotide reverse transcriptase inhibitors (NRTIs) in combination with HIV medications from another class.3 In the NRTI class, commonly used ART during pregnancy includes tenovir disoproxil fumarate (TDF), emtricitabine (FTC), lamivudine, and abacavir, in combination with non-nucleotide reverse transcripase inhibitors (NNRTI), such as efavirenz and rilpivirine; integrase strand inhibitors (InsTi), such as dolutegravir and raltegravir; and protease inhibitors, such as darunavir and atazanavir. Recently, the Department of Health and Human Services (DHHS) guidelines classified these ART regimens for use in pregnant women living with HIV as either “preferred” (tenofovir disoproxil fumarate/emtricitabine; abacavir/lamivudine; dolutegravir; darunavir; ritonavir-boosted darunavir; ritonavir-boosted atazanavir) or “alternative” regimens (ritonavir-boosted lopinavir; rilpivirine; efavirenz; zidovudine).8 The ideal ART to use during pregnancy would depend on several factors, including prior effective regimens, the potential for adverse maternal effects and teratogenicity with ART, hepatitis B or C co-infection, and compliance issues. Data from the Botswana Tsepamo study initially raised concerns for the association between dolutegravir and neural tube defects, but recent data demonstrated low risk for neural tube defects with dolutegravir-based regimens.9 Because of potential drug-drug interactions between darunavir and raltegravir/dolutegravir and between darunavir and tenofovir/atazanavir, therapeutic drug monitoring for women taking these medications should be considered. In women with HIV/hepatitis B co-infection, fixed-dose combinations that include TDF/lamivudine/emtricitabine are preferred. These should be taken into consideration before starting ART in naïve (not having used ART previously) or experienced (having used ART previously) women living with HIV.10
Delivery considerations are critical in pregnant women living with HIV.6 Laboratory evaluation of viral load between 34 and 36 weeks of gestation is the single most important factor that determines the optimal mode of delivery.6 Vaginal delivery is recommended at term (37w0d to 39w6d) if the HIV RNA viral load at the time of delivery is < 1,000 copies/mL and cesarean delivery at 38w0d if HIV RNA viral load is > 1,000 copies/mL.6 Intrapartum, women with a viral load > 1,000 copies/mL should receive intravenous zidovudine (2 mg/kg loading dose over one hour, then 1 mg/kg/hr continuous infusion) over two hours prior to vaginal or cesarean delivery.6 For women with a viral load < 1,000 copies/mL, although cohort studies in pregnant women living with HIV with viral loads of 50 copies/mL to 999 copies/mL have demonstrated a 1% to 2% risk of perinatal transmission, it is a reasonable practice to consider intravenous zidovudine for three hours in all women (irrespective of viral load) at the time of delivery.6 In women diagnosed with HIV for the first time during pregnancy, it is recommended that they receive 200 mg of intravenous zidovudine over three hours, a 200 mg stat dose of nevirapine, 400 mg twice daily of raltegravir, and 150 mg twice daily of lamivudine prior to delivery. Intrauterine pressure catheters, fetal scalp electrodes, and fetal scalp blood sampling should be avoided if possible because of the potential risk for perinatal HIV transmission.6 Amniotomy has been shown to be safe, since prospective cohort studies in pregnant women living with HIV with a viral load < 50 copies/mL have demonstrated no significant differences in perinatal transmission rates in women with rupture of membranes less than four hours compared to those greater than four hours (0.12% vs. 0.14%).11
After delivery, discussions about the use of safe and effective contraception in women living with HIV is important, since there are potential drug-drug interactions between some HIV medications and hormonal methods of contraception. Such drug-drug interactions can raise concerns for decreased contraceptive efficacy of hormonal contraception in women living with HIV and can increase the risk of unwanted pregnancies. The U.S. Medical Eligibility Criteria for Contraceptive Use provides guidelines for these drug-drug interactions for reference. There are no interactions between ART and intrauterine devices or depot medroxyprogesterone acetate, so these options are safe and effective for women living with HIV.12
Breastfeeding also is an issue of critical importance for women living with HIV because approximately 15% of newborns born to women living with HIV will become infected if they breastfeed for approximately 18 months to two years.5 Because of the potential for HIV transmission to the neonate, breastfeeding currently is not recommended in neonates and infants of women living with HIV (even if the viral load remains undetectable) in developed countries.
Dr. Eke is a K23 Mentored Patient-Oriented Research Career Development Recipient from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH); and a recipient of the Johns Hopkins Center for AIDS Research (CFAR) faculty grant. The content is solely the responsibility of Dr. Eke and does not necessarily represent the official views of the NIH or CFAR.
REFERENCES
- Eke AC, Olagunju A, Momper J, et al. Optimizing pharmacology studies in pregnant and lactating women using lessons from HIV: A consensus statement. Clin Pharmacol Ther 2020; Sep 15. doi: 10.1002/cpt.2048. [Online ahead of print].
- World Health Organization. HIV/AIDS. Published Nov. 30, 2020. https://www.who.int/news-room/fact-sheets/detail/hiv-aids
- Eke AC, Brooks KM, Gebreyohannes RD, et al. Tenofovir alafenamide use in pregnant and lactating women living with HIV. Expert Opin Drug Metab Toxicol 2020;16:333-342.
- Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173-1180.
- Eke AC, Olagunju A, Best BM, et al. Innovative approaches for pharmacology studies in pregnant and lactating women: A viewpoint and lessons from HIV. Clin Pharmacokinet 2020;59:1185-1194.
- [No authors listed]. ACOG Committee Opinion No. 751: Labor and Delivery Management of Women With Human Immunodeficiency Virus Infection. Obstet Gynecol 2018;132:e131-e137.
- Soepnel LM, Norris SA, Schrier VJ, et al. The association between HIV, antiretroviral therapy, and gestational diabetes mellitus. AIDS 2017;31:113-125.
- Salama E, Eke AC, Best BM, et al. Pharmacokinetic enhancement of HIV antiretroviral therapy during pregnancy. J Clin Pharmacol 2020;60:1537-1550.
- Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med 2019;381:827-840.
- Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Updated Feb. 10, 2021. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Perinatal_GL_2020.pdf
- Lathrop E, Jamieson DJ, Danel I. HIV and maternal mortality. Int J Gynaecol Obstet 2014;127:213-215.
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-103.
