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 Women
HIV-Infected Pregnant Women Who Have Never Received Antiretroviral Drugs (Antiretroviral Naive)
(Last updated:3/28/2014; last reviewed:3/28/2014)
- All HIV-infected pregnant women should receive a potent combination antiretroviral (ARV) regimen to reduce the risk of perinatal transmission of HIV (AI). The choice of regimen should take into account current adult treatment guidelines, what is known about the use of specific drugs in pregnancy, and the risk of teratogenicity (see Table 6 and Table 7).
- The decision as to whether to start the regimen in the first trimester or delay until 12 weeks’ gestation will depend on CD4 T lymphocyte count, HIV RNA levels, and maternal conditions (e.g., nausea and vomiting) (AIII). Earlier initiation of a combination ARV regimen may be more effective in reducing transmission, but benefits must be weighed against potential fetal effects of first-trimester drug exposure.
- ARV drug-resistance studies should be performed before starting the ARV regimen if HIV RNA is above the threshold for resistance testing (i.e., >500 to 1,000 copies/mL) unless drug-resistance studies have already been performed (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) (AI). If HIV is diagnosed later in pregnancy, the ARV regimen should be initiated promptly without waiting for the results of resistance testing (BIII).
- If there is no evidence of resistance, combination ARV regimens that are preferred for the treatment of antiretroviral-naive HIV-infected pregnant women include: a dual nucleoside reverse transcriptase inhibitor combination (abacavir/lamivudine, tenofovir/emtricitabine or lamivudine, or zidovudine/lamivudine) and either a ritonavir-boosted protease inhibitor (ritonavir-boosted atazanavir or ritonavir-boosted lopinavir) or a non-nucleoside reverse transcriptase inhibitor (efavirenz initiated after 8 weeks of pregnancy) (see Table 6) (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
Pregnant women with HIV infection should receive standard clinical, immunologic, and virologic evaluation. They should be counseled about and offered combination antiretroviral therapy (cART) containing at least 3 drugs for their own health and for prevention of perinatal transmission of HIV, consistent with the principles of treatment for non-pregnant adults.1 Use of a cART 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 ARV drug resistance in the mother. In an analysis of perinatal transmission in 5,151 HIV-infected women between 2000 and 2006 in the United Kingdom and Ireland, the overall perinatal transmission rate was 1.2%. A transmission rate of 0.8% was seen in women on ARV drugs for at least the last 14 days of pregnancy, regardless of the type of ARV regimen or mode of delivery.2 After adjustment for viral load, mode of delivery, and sex of the infant, longer duration of use of ARV drugs was associated with reduced transmission rates. Similar data from Canada in 1,707 HIV-infected pregnant women followed between 1997 and 2010 showed perinatal transmission was 1% in mothers receiving cART, and 0.4% if more than 4 weeks of cART 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 (that is, >500 to 1,000 copies/mL) unless drug-resistance testing has already been performed. For details regarding genotypic and phenotypic resistance testing, see Adult and Adolescent Antiretroviral Guidelines. Given the association of earlier viral suppression with lower risk of transmission as discussed above, if HIV is diagnosed in the second half of pregnancy, the ARV regimen should be initiated promptly without waiting for the results of resistance testing, with modification of the regimen, if required, when test results return. Because clinically significant resistance to protease inhibitors (PI) is less common than resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in ARV-naive individuals, a PI-based cART regimen generally should be considered in this situation.
Table 6 outlines the ARV regimens that are preferred for treatment of HIV-infected pregnant women who have never received ARV drugs, 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 dual nucleoside reverse transcriptase inhibitor (NRTI) combinations include abacavir/lamivudine, tenofovir/emtricitabine or lamivudine, or zidovudine/lamivudine in combination with either a ritonavir-boosted PI (ritonavir-boosted atazanavir or ritonavir-boosted lopinavir) or an NNRTI (efavirenz initiated after 8 weeks of pregnancy). 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 7).
Fetuses are most susceptible to the potential teratogenic effects of drugs during the first trimester and the risks of ARV drug exposure during that period are not fully known. Therefore, women in the first trimester who do not require immediate initiation of therapy for symptomatic HIV infection can consider delaying initiation of ARV drugs until after 12 weeks’ gestation. This decision 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 of delaying initiation of ARV drugs for several weeks.
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 a French study, lack of early and sustained control of maternal viral load appeared strongly associated with residual perinatal transmission of HIV.4 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 were 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 cART 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 cART would be particularly important in HIV-infected pregnant women who have high baseline viral loads.5,6 However, the potential benefits of earlier initiation of cART must be balanced against the unknown long-term outcome of first-trimester ARV exposure to the fetus.
A cART regimen is recommended for all HIV-infected pregnant women, 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.7-9 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.10-14 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, cART regimens initiated during pregnancy should include zidovudine or another NRTI with high transplacental passage, such as lamivudine, emtricitabine, tenofovir, or abacavir (see Table 7).15-18 With post-exposure prophylaxis, ARV drugs are administered to the infant after birth.
Some women may wish to restrict fetal exposure to ARV drugs while reducing the risk of HIV transmission to their infants. Use of zidovudine alone during pregnancy for prophylaxis of perinatal transmission is not optimal, but it could be an option for women with low viral loads (i.e., <1,000 copies/mL) on no ARV drugs. In the U.K. study discussed above, transmission rates were 0.7% for women receiving a triple-ARV drug regimen combined with planned cesarean delivery or with planned vaginal delivery and 0.5% in 464 women with HIV RNA levels <10,000 copies/mL who received single-drug prophylaxis with zidovudine combined with planned cesarean delivery, not significantly different between groups. Zidovudine single-drug prophylaxis is 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.19 Time-limited administration of zidovudine during the second and third trimesters is less likely to induce development of resistance in women with low viral loads than in those with higher viral loads. This lower rate of resistance is likely because of the low level of viral replication and the short duration of exposure.20,21 Women’s choices after counseling 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).22-25 A recent publication reported the effect of adding raltegravir to a standard ARV regimen in 4 women diagnosed with HIV infection in the third trimester.26 The median viral load at presentation was 271,000 copies/mL and the mean viral load decline per week was 1.12 log (usually not seen until after 1–2 months of standard cART). Although no raltegravir-related side effects were noted in these reports, marked elevations in hepatic transaminases were reported in a single HIV-infected pregnant woman when raltegravir was added to an ARV regimen.27 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 cART 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. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
- Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS. 2008;22(8):973-981. Available at http://www.ncbi.nlm.nih.gov/pubmed/18453857.
- 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.
- 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.
- 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.
- Taylor GP, Clayden P, Dhar J, et al. British HIV Association guidelines for the management of HIV infection in pregnant women 2012. HIV Med. 2012;13 Suppl 2:87-157. Available at http://www.ncbi.nlm.nih.gov/pubmed/22830373.
- Read P, Costelloe S, Mullen J, et al. New mutations associated with resistance not detected following zidovudine monotherapy in pregnancy when used in accordance with British HIV Association guidelines. HIV Med. 2008;9(7):448-451. Available at http://www.ncbi.nlm.nih.gov/pubmed/18840150.
- Larbalestier N, Mullen J, O'Shea S, et al. Drug resistance is uncommon in pregnant women with low viral loads taking zidovudine monotherapy to prevent perinatal HIV transmission. AIDS. 2003;17(18):2665-2667. Available at http://www.ncbi.nlm.nih.gov/pubmed/14685064.
- 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.
- 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.