Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
General Principles Regarding Use of Antiretroviral Drugs during Pregnancy
(Last updated:3/28/2014; last reviewed:3/28/2014)
- Initial evaluation of HIV-infected pregnant women should include assessment of HIV disease status and recommendations regarding initiation of combination antiretroviral therapy (cART) or the need for any modification if currently receiving cART (AIII). The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on all aspects of perinatal HIV care.
- All pregnant HIV-infected women should receive cART to prevent perinatal transmission regardless of plasma HIV RNA copy number or CD4 T lymphocyte count (AI).
- Combined antepartum, intrapartum, and infant antiretroviral (ARV) prophylaxis is recommended because ARV drugs reduce perinatal transmission by several mechanisms, including lowering maternal antepartum viral load and providing infant pre- and post-exposure prophylaxis (AI).
- The known benefits and potential risks of ARV use during pregnancy should be discussed with all HIV-infected women (AIII).
- In counseling patients, the importance of adherence to their ARV regimens should be emphasized (AII).
- ARV drug-resistance studies should be performed before starting or modifying ARV drug regimens in women whose HIV RNA levels are above the threshold for resistance testing (i.e., >500 to 1,000 copies/mL) (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) (AIII). When HIV is diagnosed later in pregnancy, cART should be initiated promptly without waiting for results of resistance testing (BIII).
- Coordination of services among prenatal care providers, primary care and HIV specialty care providers, and when appropriate, mental health and drug abuse treatment services, and public assistance programs, is essential to ensure that infected women adhere to their ARV drug regimens (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
In addition to the standard antenatal assessments for all pregnant women, the initial evaluation of those who are HIV infected should include assessment of HIV disease status and recommendations for HIV-related medical care. This initial assessment should include the following:
- Review of prior HIV-related illnesses and past CD4 T lymphocyte (CD4) cell counts and plasma HIV RNA levels;
- Current CD4 cell count;
- Current plasma HIV RNA copy number;
- Assessment of the need for prophylaxis against opportunistic infections such as Pneumocystis jirovecii pneumonia and Mycobacterium avium complex (see Adult and Adolescent Opportunistic Infections Guidelines);
- Screening for hepatitis C virus and tuberculosis in addition to standard screening for hepatitis B virus (HBV) infection;
- Assessment of the need for immunizations per guidelines from the American College of Obstetricians and Gynecologists, with particular attention to hepatitis A, HBV, influenza, pneumococcus, and Tdap immunizations;1,2
- Complete blood cell count and renal and liver function testing;
- HLA-B*5701 testing if abacavir use is anticipated (see Table 7);
- History of prior and current antiretroviral (ARV) drug use, including prior ARV use for prevention of perinatal transmission or treatment of HIV and history of adherence problems;
- Results of prior and current HIV ARV drug-resistance studies;
- History of adverse effects or toxicities from prior ARV regimens; and
- Assessment of supportive care needs such as mental health services, substance abuse treatment, and smoking cessation.
The National Perinatal HIV Hotline
The National Perinatal HIV Hotline (1-888-448-8765) is a federally funded service providing free clinical consultation to providers caring for HIV-infected women and their infants.
HIV RNA and Transmission
ARV drugs for prevention of perinatal transmission of HIV are recommended for all pregnant women, regardless of CD4 cell counts and HIV RNA levels. Although the risk of perinatal transmission in women with undetectable plasma HIV RNA levels appears to be extremely low, transmission has been reported even in women with very low or undetectable levels of maternal HIV RNA on combination antiretroviral therapy (cART).3-5
Although there is a general correlation between viral loads in plasma and in the genital tract, discordance between blood and genital tract virus has also been reported; low-level cervico-vaginal HIV RNA and DNA shedding has been detected even in women treated with cART who have undetectable plasma viral load, particularly in the presence of genital tract coinfections.6-8
Penetration of ARV drugs into the female genital tract has been shown to vary between drugs.9-11
If exposure to HIV in the maternal genital tract during delivery is a risk factor for perinatal transmission, plasma HIV RNA levels may not always be an accurate indicator of risk.
Mechanism of Action of Antiretrovirals in Prevention of Perinatal Transmission
ARV drugs can reduce perinatal transmission through a number of mechanisms. Antenatal drug administration decreases maternal viral load in blood and genital secretions. Another mechanism of protection is infant pre-exposure prophylaxis achieved by administering ARV drugs that cross the placenta from mothers to infants and produce adequate systemic drug levels in the infants. Infant post-exposure prophylaxis is achieved by administering drugs to infants after birth, providing protection from cell-free or cell-associated virus that may have entered the fetal/infant systemic circulation during labor and delivery. The importance of the pre- and post-exposure components of prophylaxis in reducing perinatal transmission is demonstrated by the efficacy of interventions that involve administration of ARVs only during labor and/or to the newborns.12-18
Therefore, combined antepartum, intrapartum, and infant ARV prophylaxis is recommended to prevent perinatal transmission of HIV.
General Principles of Drug Selection
In general, guidelines for the use of combination antiretroviral therapy (cART) for the benefit of maternal health during pregnancy are the same as for women who are not pregnant, with some modifications based on concerns about specific drugs and limited experience during pregnancy with newer drugs.
The known benefits and known and unknown risks of ARV drug use during pregnancy should be considered and discussed with women. Results from preclinical and animal studies and available clinical information about use of the various agents during pregnancy also should be discussed (see Table 7
and Supplement: Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy
). Potential risks of these drugs should be placed into perspective by reviewing the substantial benefits of ARV drugs for maternal health and in reducing the risk of transmission of HIV to infants. Counseling of pregnant women about ARV use should be noncoercive, and providers should help them make informed decisions regarding use of ARV drugs.
Discussions with women about initiation of cART drug regimens should include information about:
- Maternal risk of disease progression and the benefits and risks of initiation of therapy for maternal health;
- Benefit of cART for preventing perinatal transmission of HIV;19
- Benefits of therapy for reducing sexual transmission to discordant partners when viral suppression is maintained;20
- The need for strict adherence to the prescribed drug regimen to avoid resistance;
- Potential adverse effects of ARV drugs for mothers, fetuses, and infants, including potential interactions with other medications the women may already be receiving; and
- The limited long-term outcome data for both women who use cART during pregnancy for prophylaxis of transmission and stop the regimen postpartum and for infants with in utero drug exposure.
Transplacental passage of ARVs is an important mechanism of infant pre-exposure prophylaxis. Thus, when selecting an ARV regimen for a pregnant woman, at least one nucleoside/nucleotide reverse transcriptase inhibitor agent with high placental transfer should be included as a component of the cART regimen (see Table 7
In women with plasma HIV RNA levels above the threshold for resistance testing (i.e., >500 to 1,000 copies/mL), ARV drug-resistance studies should be performed before starting cART. When HIV is diagnosed later in pregnancy, however, cART should be initiated promptly without waiting for results of resistance testing (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy
). Counseling should emphasize the importance of adherence to the ARV drug regimen to minimize the development of resistance.
Support services, mental health services, smoking cessation, and drug abuse treatment may be required, depending on a woman’s individual circumstances. Coordination of services among prenatal care providers, primary care and HIV specialty care providers, mental health and drug abuse treatment services, and public assistance programs is essential to ensure that infected women adhere to their ARV drug regimens.
All HIV-infected pregnant women should be started on cART during pregnancy to minimize the risk of transmission. Providers should work with women to develop long-range plans regarding continuity of medical care. Considerations regarding postpartum continuation of cART for maternal therapeutic indications are the same as for nonpregnant individuals.
Medical care of HIV-infected pregnant women requires coordination and communication between HIV specialists and obstetrical providers. General counseling should include current knowledge about risk factors for perinatal transmission. Risk of perinatal transmission of HIV has been associated with potentially modifiable factors, including cigarette smoking, illicit drug use, genital tract infections, and unprotected sexual intercourse with multiple partners during pregnancy.25-29
Besides improving maternal health, cessation of cigarette smoking and drug use, treatment of genital tract infections, and use of condoms with sexual intercourse during pregnancy may reduce risk of perinatal transmission. In addition, the Centers for Disease Control and Prevention and American Academy of Pediatrics recommends that HIV-infected women in the United States (including those receiving cART) refrain from breastfeeding to avoid postnatal transmission of HIV to their infants through breast milk30,31
and avoid premastication of food for their infants, a potential risk factor for transmission.32
- Centers for Disease Control and Prevention. Guidelines for vaccinating pregnant women. 2007. Atlanta, GA. Available at http://www.cdc.gov/vaccines/pubs/downloads/b_preg_guide.pdf.
- Centers for Disease Control and Prevention. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months—Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. Oct 21 2011;60(41):1424-1426. Available at http://www.ncbi.nlm.nih.gov/pubmed/22012116.
- Warszawski J, Tubiana R, Le Chenadec J, et al. Mother-to-child HIV transmission despite antiretroviral therapy in the ANRS French Perinatal Cohort. AIDS. 2008;22(2):289-299. Available at http://www.ncbi.nlm.nih.gov/pubmed/18097232.
- Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child transmission of HIV-1 despite a maternal viral load <500 copies/ml at delivery: a case-control study nested in the French perinatal cohort (EPF-ANRS CO1). Clin Infect Dis. 2010;50(4):585-596. Available at http://www.ncbi.nlm.nih.gov/pubmed/20070234.
- European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis. 2005;40(3):458-465. Available at http://www.ncbi.nlm.nih.gov/pubmed/15668871.
- Launay O, Tod M, Tschope I, et al. Residual HIV-1 RNA and HIV-1 DNA production in the genital tract reservoir of women treated with HAART: the prospective ANRS EP24 GYNODYN study. Antivir Ther. 2011;16(6):843-852. Available at http://www.ncbi.nlm.nih.gov/pubmed/21900716.
- Cu-Uvin S, DeLong AK, Venkatesh KK, et al. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS. 2010;24(16):2489-2497. Available at http://www.ncbi.nlm.nih.gov/pubmed/20736815.
- Henning TR, Kissinger P, Lacour N, Meyaski-Schluter M, Clark R, Amedee AM. Elevated cervical white blood cell infiltrate is associated with genital HIV detection in a longitudinal cohort of antiretroviral therapy-adherent women. J Infect Dis. 2010;202(10):1543-1552. Available at http://www.ncbi.nlm.nih.gov/pubmed/20925530.
- Yeh RF, Rezk NL, Kashuba AD, et al. Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women. Antimicrob Agents Chemother. 2009;53(6):2367-2374. Available at http://www.ncbi.nlm.nih.gov/pubmed/19307360.
- Dumond JB, Yeh RF, Patterson KB, et al. Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. AIDS. 2007;21(14):1899-1907. Available at http://www.ncbi.nlm.nih.gov/pubmed/17721097.
- Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir Ther. 2011;16(8):1149-1167. Available at http://www.ncbi.nlm.nih.gov/pubmed/22155899.
- Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet. 2003;362(9387):859-868. Available at http://www.ncbi.nlm.nih.gov/pubmed/13678973.
- Petra Study T. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet. 2002;359(9313):1178-1186. Available at http://www.ncbi.nlm.nih.gov/pubmed/11955535.
- Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis. 2003;187(5):725-735. Available at http://www.ncbi.nlm.nih.gov/pubmed/12599045.
- Taha TE, Kumwenda NI, Gibbons A, et al. Short postexposure prophylaxis in newborn babies to reduce mother-to-child transmission of HIV-1: NVAZ randomised clinical trial. Lancet. 2003;362(9391):1171-1177. Available at http://www.ncbi.nlm.nih.gov/pubmed/14568737.
- Gaillard P, Fowler MG, Dabis F, et al. Use of antiretroviral drugs to prevent HIV-1 transmission through breast-feeding: from animal studies to randomized clinical trials. J Acquir Immune Defic Syndr. 2004;35(2):178-187. Available at http://www.ncbi.nlm.nih.gov/pubmed/14722452.
- Gray GE, Urban M, Chersich MF, et al. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS. 2005;19(12):1289-1297. Available at http://www.ncbi.nlm.nih.gov/pubmed/16052084.
- Nielsen-Saines K, Watts H, Veloso VG, et al. Phase III randomized trial of the safety and efficacy of three neonatal antiretroviral postpartum regimens for the prevention of intrapartum HIV-1 transmission: NICHD HPTN 040/PACTG 1043 study results. N Engl J Med. 2012;366(25):2368-79. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716975.
- Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. 2002;29(5):484-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981365.
- Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505. Available at http://www.ncbi.nlm.nih.gov/pubmed/21767103.
- Hirt D, Urien S, Rey E, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother. 2009;53(3):1067-1073. Available at http://www.ncbi.nlm.nih.gov/pubmed/19104016.
- Hirt D, Urien S, Ekouevi DK, et al. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates (ANRS 12109). Clin Pharmacol Ther. 2009;85(2):182-189. Available at http://www.ncbi.nlm.nih.gov/pubmed/18987623.
- Moodley D, Pillay K, Naidoo K, et al. Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours. J Clin Pharmacol. 2001;41(7):732-741. Available at http://www.ncbi.nlm.nih.gov/pubmed/11452705.
- Wade NA, Unadkat JD, Huang S, et al. Pharmacokinetics and safety of stavudine in HIV-infected pregnant women and their infants: Pediatric AIDS Clinical Trials Group protocol 332. J Infect Dis. 2004;190(12):2167-2174. Available at http://www.ncbi.nlm.nih.gov/pubmed/15551216.
- Burns DN, Landesman S, Muenz LR, et al. Cigarette smoking, premature rupture of membranes and vertical transmission of HIV-1 among women with low CD4+ levels. J Acquir Immune Defic Syndr Hum Retrovirol. 1994;7(7):718-726. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7911527&dopt=Abstract.
- Turner BJ, Hauck WW, Fanning TR, Markson LE. Cigarette smoking and maternal-child HIV transmission. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14(4):327-337. Available at http://www.ncbi.nlm.nih.gov/pubmed/9111474.
- Rodriguez EM, Mofenson LM, Chang BH, et al. Association of maternal drug use during pregnancy with maternal HIV culture positivity and perinatal HIV transmission. AIDS. 1996;10(3):273-282. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8882667&dopt=Abstract.
- Bulterys M, Landesman S, Burns DN, et al. Sexual behavior and injection drug use during pregnancy and vertical transmission of HIV-1. J Acquir Immune Defic Syndr Human Retrovirol. 1997;15(1):76-82. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9215658&dopt=Abstract.
- Matheson PB, Thomas PA, Abrams EJ, et al. Heterosexual behavior during pregnancy and perinatal transmission of HIV-1. New York City Perinatal HIV Transmission Collaborative Study Group. AIDS. 1996;10(11):1249-1256. Available at http://www.ncbi.nlm.nih.gov/pubmed/8883587.
- Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1-17; quiz CE11-14. Available at http://www.ncbi.nlm.nih.gov/pubmed/16988643.
- Committee on Pediatric AIDS. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics. 2013;131 (2):391-6. Available at http://www.ncbi.nlm.nih.gov/pubmed/23359577.
- Gaur AH, Freimanis-Hance L, Dominguez K, et al. Knowledge and practice of prechewing/prewarming food by HIV-infected women. Pediatrics. 2011;127(5):e1206-1211. Available at http://www.ncbi.nlm.nih.gov/pubmed/21482608.