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
Antepartum Care
HIV-Infected Women Who have Never Received Antiretroviral Drugs (Naive)
(Last updated:9/14/2011)
Panel’s Recommendations:
• HIV-infected pregnant women who meet standard criteria for initiation of antiretroviral therapy (ART) per adult antiretroviral (ARV) treatment guidelines should receive standard potent combination ART as recommended for nonpregnant adults, taking into account what is known about the use of specific drugs in pregnancy and the risk of teratogenicity (Table 5) (AI).
o For women who require immediate initiation of therapy for their own health, treatment should be started as soon as possible, including in the first trimester (AII). (Note that the use of efavirenz should be avoided during the first trimester.)
• A three-drug combination ARV regimen for prophylaxis of perinatal transmission also is recommended for HIV-infected pregnant women who do not require treatment for their own health (AII).
o Consideration can be given to delaying initiation of prophylaxis until after the first trimester (BIII) in women who are receiving ARV drugs solely for prevention of perinatal transmission, but earlier initiation of therapy may be more effective in reducing in utero transmission.
• ARV regimens should include a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone that includes one or more NRTIs with high levels of transplacental passage, if possible, to provide pre-exposure prophylaxis to the infant (AIII).
• If HIV RNA is above the threshold for resistance testing (i.e., >500–1,000 copies/mL), ARV drug-resistance studies should be performed before starting the ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) (AI). If HIV is diagnosed late in pregnancy, the ARV drug regimen should be initiated pending results of resistance testing (BIII).
• Nevirapine can be used as a component of the ARV drug regimen for pregnant women with CD4 cell counts ≤250 cells/mm3. In pregnant women with CD4 cell counts >250 cells/mm3, however, nevirapine should be used only if the benefit clearly outweighs the risk because the drug is associated with an increased risk of hepatic toxicity (AII). |
Pregnant women with HIV infection should receive standard clinical, immunologic, and virologic evaluation. Decisions about the need for initiation of therapy should be based on the standard guidelines for nonpregnant adults [1].
HIV-Infected Pregnant Women Not on Antiretroviral Therapy and Who Need Antiretroviral Treatment for Their Own Health
Any HIV-infected pregnant woman who meets standard criteria for initiation of ART as per ARV guidelines in nonpregnant adults should receive potent combination ART, generally consisting of NRTIs plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI), with continuation of therapy postpartum. Treatment should be started as soon as possible—including in the first trimester—for women who require immediate initiation of therapy for their own health because the potential benefit of treatment for the mother outweighs potential risks to the fetus. The regimen generally should be chosen from among those shown to be effective in nonpregnant adults, taking into account what is known about use of the drugs during pregnancy and risk of teratogenicity (see General Principles Regarding Use of Antiretroviral Drugs during Pregnancy) [1].
A review of a large database of nevirapine studies indicated that women with CD4 counts >250 cells/mm3 have an increased risk of developing symptomatic, often rash-associated, nevirapine-related hepatotoxicity that can be severe, life threatening, and in some cases fatal [2-3]. A more recent study involving 820 women in Kenya, Zambia, and Thailand, however, did not find an association between CD4 count and development of hepatotoxicity [4]. Rash and liver toxicity were associated with elevated baseline liver transaminases but not with CD4 count; all deaths from hepatic toxicity occurred in women with CD4 counts <100 cells/mm3 at baseline. In women with CD4 counts >250 cells/mm3, nevirapine should be used as a component of a combination regimen only when the benefit clearly outweighs the risk. If nevirapine is used, frequent and careful monitoring of transaminase levels is required, particularly during the first 18 weeks of treatment (see Nevirapine and Hepatic/Rash Toxicity). Transaminase levels should be checked in women who develop a rash while receiving nevirapine. Nevirapine should be stopped immediately in women who develop signs or symptoms of hepatitis.
HIV-Infected Pregnant Women Not on Antiretroviral Therapy Who Require Antiretroviral Prophylaxis Solely to Prevent Perinatal Transmission of HIV
HIV-infected pregnant women should be counseled regarding the benefits of ARV drugs for prevention of perinatal transmission even when initiation of ART for maternal health is not recommended or is considered optional on the basis of current guidelines for treatment of nonpregnant persons [1]. Although such women are at low risk of clinical disease progression if ARV treatment is delayed, use of an ARV regimen that successfully reduces plasma HIV RNA to undetectable levels substantially lowers the risk of perinatal transmission of HIV and lessens the need for consideration of elective cesarean delivery as an intervention to reduce risk of transmission.
The fetus is 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 of pregnancy who do not require immediate initiation of therapy for their own health may consider delaying initiation of ARV drugs until after 12 weeks of gestation. This decision should be carefully considered by the health care provider and the woman. Their discussion should encompass an assessment of the woman’s health status, the benefits and risks to her of delaying initiation of ARV drugs for several weeks, the fact that most perinatal transmission of HIV events occur late in pregnancy or during delivery, and the possibility that early control of viral replication may be important in preventing the smaller proportion of earlier in utero transmission. In a recent French study, lack of early and sustained control of maternal viral load appeared strongly associated with residual perinatal transmission of HIV [5]. 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 of gestation. Among women starting ARV drugs during pregnancy, the gestational age at initiation of therapy did not differ between groups (30 weeks), but viral load decreased earlier in the nontransmitters. These data suggest that early and sustained control of HIV viral replication is associated with decreasing residual risk of transmission and favor initiating ARV drugs as early in pregnancy as possible for all women.
ARV prophylaxis is recommended for all pregnant women with HIV infection, 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 assured [6-8]. The mechanism by which ARV drugs reduce perinatal HIV transmission 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 [9-13]. Additional mechanisms of protection include pre-exposure prophylaxis and post-exposure prophylaxis of the infant. With pre-exposure prophylaxis, 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. With post-exposure prophylaxis, ARV drugs are administered to the infant after birth. Transplacental passage is excellent with zidovudine but may be variable with many other ARV drugs (Table 4). Therefore, whenever possible, combination ARV drug regimens initiated during pregnancy should include zidovudine or another NRTI with high transplacental passage, such as lamivudine, emtricitabine, stavudine, tenofovir, or abacavir (see Table 5) [14-17].
All pregnant women with HIV infection should be counseled about and offered combination ARV regimens containing at least three drugs for prevention of perinatal transmission of HIV. In an analysis of perinatal transmission in 5,151 HIV-infected women between 2000 and 2006 in the United Kingdom and Ireland, the overall mother-to-child 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 [18]. Transmission rates were 0.7% for women receiving a triple-ARV drug regimen combined with a planned cesarean delivery or with planned vaginal delivery and 0.5% in 464 women who received single-drug prophylaxis with zidovudine combined with a planned cesarean delivery (as recommended in the British HIV Association guidelines for women with HIV RNA levels <10,000 copies/mL and wild-type virus who do not require treatment for their own health) [19], not significantly different between groups. 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.
A combination regimen including two NRTIs and either an NNRTI or a PI (the latter with or without low-dose ritonavir) would be the preferred prophylactic regimen for ARV-naive women receiving drugs solely for prevention of transmission, as discussed in Recommendations for Use of Antiretroviral Drugs during Pregnancy. A study in Botswana compared a PI-based triple-drug regimen to a triple-NRTI (zidovudine/lamivudine/abacavir) combination regimen for prevention of transmission in breastfeeding women with CD4 counts ≥200 cellsmm3 [20]. Both regimens had similar rates of viral suppression by delivery (96% receiving the PI regimen and 93% receiving the triple-NRTI regimen had HIV RNA <400 copies/mL) and perinatal transmission (0.4% and 1.4%, respectively, not significantly different). Thus, for women who plan to discontinue prophylaxis following delivery, a triple-NRTI regimen also can be considered. If using abacavir, testing for HLA-B*5701, which identifies patients at risk of abacavir hypersensitivity reactions [21-22], should be performed and the results documented as negative before abacavir is started.
Some women may wish to restrict fetal exposure to ARV drugs while reducing the risk of HIV transmission to the infant. 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., HIV RNA <1,000 copies/mL) on no ARV drugs. Time-limited administration of zidovudine during the second and third trimesters of pregnancy is less likely to induce the 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 [23-24].
Following delivery, considerations regarding continuation of the ARV regimen for treatment of the mother are the same as for other nonpregnant adults (see General Principles for Use of Antiretroviral Drugs during Pregnancy).
References
1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2011:1-174. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
2. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. Sep 2003;34 Suppl 1:S21-33.
3. Boehringer-Ingelheim Pharmaceuticals Inc. Viramune drug label. March 25, 2011.
4. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count >/=250 cells/muL among women in Zambia, Thailand and Kenya. HIV Med. Nov 2010;11(10):650-660.
5. 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. Feb 15 2010;50(4):585-596.
6. 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. Apr 15 2002;29(5):484-494.
7. 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. Aug 5 1999;341(6):385-393.
8. 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. Aug 5 1999;341(6):394-402.
9. 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. Feb 15 2001;183(4):539-545.
10. 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. Nov 12 1998;339(20):1409-1414.
11. 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. Sep 13 2003;362(9387):859-868.
12. Petra Study Team. 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. Apr 6 2002;359(9313):1178-1186.
13. 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. Mar 1 2003;187(5):725-735.
14. 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. Mar 2009;53(3):1067-1073.
15. 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. Feb 2009;85(2):182-189.
16. 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. Jul 2001;41(7):732-741.
17. 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. Dec 15 2004;190(12):2167-2174.
18. 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. May 11 2008;22(8):973-981.
19. Hawkins D, Blott M, Clayden P, et al. Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission of HIV. HIV Med. Jul 2005;6 Suppl 2:107-148.
20. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. Jun 17 2010;362(24):2282-2294.
21. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. Feb 7 2008;358(6):568-579.
22. Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. Apr 1 2008;46(7):1111-1118.
23. 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. Aug 2008;9(7):448-451.
24. 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. Dec 5 2003;17(18):2665-2667.