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
Recommendations for Use of Antiretroviral Drugs During Pregnancy
Pregnant Women Living with HIV Who Have Never Received Antiretroviral Drugs (Antiretroviral Naive)
Last Updated: December 15, 2016; Last Reviewed: December 15, 2016
|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
Pregnant women living with HIV infection should receive standard clinical, immunologic, and virologic evaluation. They should be counseled about and offered combination antiretroviral therapy (ART) containing at least three drugs for their own health and for the prevention of perinatal transmission of HIV, consistent with the principles of treatment for non-pregnant adults.1 Use of an ART regimen that successfully reduces plasma HIV RNA to undetectable levels substantially lowers the risk of perinatal transmission of HIV, lessens the need for consideration of elective cesarean delivery as an intervention to reduce risk of transmission, and reduces risk of antiretroviral (ARV) drug resistance in the mother. In an analysis of perinatal transmission in a total of 12,486 infants delivered by women living with HIV between 2000 and 2011 in the United Kingdom and Ireland, the overall perinatal transmission rate declined from 2.1% in 2000–2001 to 0.46% in 2010–2011. The transmission risk was significantly lower (0.09%) in women with viral loads <50 copies/mL compared with a risk of 1.0% in women with viral loads of 50–399 copies/mL, regardless of the type of ARV regimen or mode of delivery.2 The continued decline in perinatal transmission rates was attributed to the increasing number of women on ART at the time of conception and reductions in the proportion of women either initiating ART late in pregnancy or never receiving ART prior to delivery. Similar data from Canada in 1,707 pregnant women living with HIV followed between 1997 and 2010 showed perinatal transmission was 1% in all mothers receiving ART and 0.4% if more than 4 weeks of ART was received.3
ARV drug-resistance testing should be performed before starting an ARV regimen if plasma HIV RNA levels are above the threshold for resistance testing (i.e., >500 to 1,000 copies/mL). For details regarding genotypic and phenotypic resistance testing, see Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (Adult and Adolescent Guidelines). Given the association of earlier viral suppression with lower risk of transmission as discussed above, during pregnancy, ART should be initiated as soon as HIV is diagnosed without waiting for the results of resistance testing, with modification of the regimen, if required, when test results return. A PI-based ART regimen generally should be considered when the results of resistance testing are not available to inform selection of ARVs because clinically significant resistance to protease inhibitors (PI) is less common than resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in ARV-naive individuals.
Table 6 outlines the ARV regimens that are preferred for treatment of pregnant women living with HIV who have never received ARV drugs. These recommendations are based on available data indicating acceptable toxicity profiles, ease of use, pharmacokinetic data in pregnancy, and lack of evidence of teratogenic effects or established adverse outcomes for mother, fetus or newborn in addition to optimal ARV efficacy and durability. Preferred regimens include a dual nucleoside reverse transcriptase inhibitor (NRTI) combination (abacavir/lamivudine or tenofovir disoproxil fumarate [TDF]/emtricitabine or lamivudine) in combination with either a ritonavir-boosted PI (atazanavir/ritonavir or darunavir/ritonavir) or an integrase inhibitor (raltegravir). Alternative regimens include those demonstrated to be effective in adults but with more limited data on use in pregnancy, lack of or incomplete data on teratogenicity, and dosing, formulation, toxicity or interaction issues. Selection of these regimens should be based on individual patient characteristics and needs (see Table 8).
Susceptibility of fetuses to the potential teratogenic effects of drugs is dependent on multiple factors, including the gestational age of the fetus at exposure (see the Teratogenicity section). Although fetal effects of ARV drugs are not fully known, in general, reports of birth defects in fetuses/infants of women enrolled in observational studies who receive ARV regimens during pregnancy have been reassuring. There have been no differences in the rates of birth defects for first-trimester compared with either later gestational exposures or with rates reported in the general population.4-7 The decision about when to initiate ART should be carefully considered by health care providers and their patients. The discussion should include an assessment of a woman’s health status and the benefits and risks to her health and the potential risks and benefits to the fetus.
Although most perinatal transmission events occur late in pregnancy or during delivery, recent analyses suggest that early control of viral replication may be important in preventing transmission. In the prospective multicenter French Perinatal Cohort, maternal viral load at delivery and timing of ART initiation were both independently associated with perinatal transmission rate. The perinatal transmission rate increased from 0.2% for women starting ART before conception to 0.4%, 0.9% and 2.2% for those starting in the first, second, or third trimester (respectively). Regardless of when ART was initiated, the perinatal transmission rate was higher for women with viral loads of 50 to 400 copies/mL near delivery than for those with <50 copies mL.8 In an earlier publication involving the same cohort, lack of early and sustained control of maternal viral load appeared strongly associated with residual perinatal transmission of HIV.9 That study evaluated risk factors for perinatal transmission in women with HIV RNA <500 copies/mL at the time of delivery; overall HIV transmission was 0.5%. Women who transmitted were less likely to have received ARV drugs at the time of conception than nontransmitters and were less likely to have HIV RNA <500 copies/mL at 14, 28, and 32 weeks’ gestation. By multivariate analysis, plasma viral load at 30 weeks’ gestation was significantly associated with transmission. Among women starting ARV drugs during pregnancy, the gestational age at initiation of therapy did not differ between groups (30 weeks), but viral load tended to decrease earlier in the nontransmitters, although this was not statistically significant. The number of patients initiating therapy during pregnancy was too small to assess whether initiation of ARV drugs in the first trimester was associated with lower rates of transmission. These data suggest that early and sustained control of HIV viral replication is associated with decreasing residual risk of transmission and favor initiating ART sufficiently early in ARV-naive women to suppress viral replication by the third trimester. Other studies have demonstrated that baseline viral load is significantly associated with the likelihood of viral suppression by delivery, and thus, prompt initiation of ART would be particularly important in pregnant women who have high baseline viral loads.10-12 However, the potential benefits of earlier initiation of ART must be balanced against the unknown long-term outcome of first-trimester ARV exposure to the fetus.
ART is recommended for all pregnant women living with HIV, regardless of viral load. Although rates of perinatal transmission are low in women with undetectable or low HIV RNA levels, there is no threshold below which lack of transmission can be ensured.13-15 The mechanism by which ARV drugs reduce perinatal transmission of HIV is multifactorial. Although lowering maternal antenatal viral load is an important component of prevention in women with higher viral load, ARV prophylaxis is effective even in women with low viral load.16-20 Additional mechanisms of protection include pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis of the infant. With PrEP, passage of the ARV drug across the placenta results in presence of drug levels sufficient for inhibition of viral replication in the fetus, particularly during the birth process when there is intensive viral exposure. Therefore, whenever possible, ART regimens initiated during pregnancy should include an NRTI with high transplacental passage, such as lamivudine, emtricitabine, tenofovir, or abacavir (see Table 8).21-24 With post-exposure prophylaxis, ARV drugs are administered to the infant after birth.
The use of zidovudine monotherapy during pregnancy is no longer recommended because of the clear health benefit of ART to the mother and for the prevention of perinatal transmission of HIV. In the past, use of zidovudine alone during pregnancy for prophylaxis of perinatal transmission was considered to be an option for women with low viral loads (i.e., <1,000 copies/mL) on no ARV drugs. Zidovudine single-drug prophylaxis is still recommended in the British HIV Association guidelines for women with CD4 T lymphocyte counts >350 cells/mm3 and HIV RNA levels <10,000 copies/mL and wild-type virus who do not require treatment for their own health.25
All pregnant women living with HIV infection should be counseled that ART is recommended, regardless of viral load, to optimally reduce the risk of perinatal transmission. However, after counseling, women’s choices to use or not use ARV drugs during pregnancy should be respected.
Raltegravir has been suggested for use in late pregnancy in women who have high viral loads because of its ability to rapidly suppress viral load (approximately 2-log copies/mL decrease by Week 2 of therapy).26-29 Two recent case series have reported the effect of adding raltegravir to ART regimens. In one, 4 women diagnosed with HIV infection in the third trimester experienced a mean viral load decline per week of 1.12 log after raltegravir was added to a standard ARV regimen.30 In the second publication, raltegravir was either initiated as part of a combination ARV regimen in nine ARV-naive women or added to an existing ARV regimen in five women who conceived on ART but had persistent viremia. Raltegravir was initiated at a gestational age of 34 weeks or later.31 The median exposure time to raltegravir was 17 days and the mean viral load decline was 2.6 log. Although no raltegravir-related adverse effects were noted in these reports, marked elevations in hepatic transaminases were reported in a single pregnant woman living with HIV when raltegravir was added to an ARV regimen.32 Because the efficacy and safety of this approach has only been described in anecdotal reports, it cannot be routinely recommended at this time for women who are ARV-naive.
The ART regimen initiated during pregnancy can be modified after delivery to include simplified regimens that were not used in pregnancy because pregnancy safety data were insufficient. Decisions regarding continuation of an ARV regimen or which specific ARV agents to use should be made by women in consultation with their HIV care providers, taking into account current recommendations and life circumstances (see General Principles Regarding Use of Antiretroviral Drugs during Pregnancy).
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2014. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed July 13, 2016.
- Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011. AIDS. 2014;28(7):1049-1057. Available at http://www.ncbi.nlm.nih.gov/pubmed/24566097.
- Forbes JC, Alimenti AM, Singer J, et al. A national review of vertical HIV transmission. AIDS. 2012;26(6):757-763. Available at http://www.ncbi.nlm.nih.gov/pubmed/22210635.
- daCosta TP, Machado ES, et al. Malformations among HIV vertically exposed newborns—results from a Brazilian cohort study. Presented at: 6th IAS Conference on HIV Pathogenesis and Treatment and Prevention. 2011. Rome, Italy.
- Watts DH, Huang S, Culnane M, et al. Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication. J Perinat Med. 2011;39(2):163-170. Available at http://www.ncbi.nlm.nih.gov/pubmed/21142844.
- Knapp KM, Brogly SB, Muenz DG, et al. Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012;31(2):164-170. Available at http://www.ncbi.nlm.nih.gov/pubmed/21983213.
- Floridia M, Mastroiacovo P, Tamburrini E, et al. Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001–2011. BJOG. 2013;120(12):1466-1475. Available at http://www.ncbi.nlm.nih.gov/pubmed/23721372.
- Mandelbrot L, Tubiana R, Le Chenadec J, et al. No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception. Clin Infect Dis. 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26197844.
- 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.
- Read PJ, Mandalia S, Khan P, et al. When should HAART be initiated in pregnancy to achieve an undetectable HIV viral load by delivery? AIDS. 2012;26(9):1095-1103. Available at http://www.ncbi.nlm.nih.gov/pubmed/22441248.
- Katz IT, Shapiro R, Li D, et al. Risk factors for detectable HIV-1 RNA at delivery among women receiving highly active antiretroviral therapy in the women and infants transmission study. J Acquir Immune Defic Syndr. 2010;54(1):27-34. Available at http://www.ncbi.nlm.nih.gov/pubmed/20065861.
- Aziz N, Sokoloff A, Kornak J, et al. Time to viral load suppression in antiretroviral-naive and -experienced HIV-infected pregnant women on highly active antiretroviral therapy: implications for pregnant women presenting late in gestation. BJOG. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23924192.
- 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.
- Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. 1999;341(6):385-393. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432323.
- Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med. 1999;341(6):394-402. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432324.
- Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml. J Infect Dis. 2001;183(4):539-545. Available at http://www.ncbi.nlm.nih.gov/pubmed/11170978.
- Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med. 1998;339(20):1409-1414. Available at http://www.ncbi.nlm.nih.gov/pubmed/9811915.
- 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.
- 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.
- de Ruiter A, Taylor GP, Clayden P, et al. British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review). HIV Med. 2014;15 Suppl 4:1-77. Available at http://www.ncbi.nlm.nih.gov/pubmed/25604045.
- Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007;369(9569):1261-1269. Available at http://www.ncbi.nlm.nih.gov/pubmed/17434401.
- Papendorp SG, van den Berk GE. Preoperative use of raltegravir-containing regimen as induction therapy: very rapid decline of HIV-1 viral load. AIDS. 2009;23(6):739. Available at http://www.ncbi.nlm.nih.gov/pubmed/19279447.
- Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy. J Antimicrob Chemother. 2010;65(9):2050-2052. Available at http://www.ncbi.nlm.nih.gov/pubmed/20630894.
- McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women. AIDS. 2010;24(15):2416-2418. Available at http://www.ncbi.nlm.nih.gov/pubmed/20827058.
- Westling K, Pettersson K, Kaldma A, Naver L. Rapid decline in HIV viral load when introducing raltegravir-containing antiretroviral treatment late in pregnancy. AIDS Patient Care STDS. 2012;26(12):714-717. Available at http://www.ncbi.nlm.nih.gov/pubmed/23101466.
- Nobrega I, Travassos AG, Haguihara T, Amorim F, Brites C. Short communication: Use of raltegravir in late-presenting HIV-infected pregnant women. AIDS Res Hum Retroviruses. 2013;29(11):1451-1454. Available at http://www.ncbi.nlm.nih.gov/pubmed/23731224.
- Renet S, Closon A, Brochet MS, Bussieres JF, Boucher M. Increase in Transaminase Levels Following the Use of Raltegravir in a Woman With a High HIV Viral Load at 35 Weeks of Pregnancy. J Obstet Gynaecol Can. 2013;35(1):68-72. Available at http://www.ncbi.nlm.nih.gov/pubmed/23343800.