Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States
Lack of Viral Suppression
Last Updated: November 14, 2017; Last Reviewed: November 14, 2017
|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
Virologic suppression is defined as a confirmed HIV RNA level below the lower limits of detection of an ultrasensitive assay, and virologic failure is the inability to achieve or maintain an HIV RNA level <200 copies/mL.
Baseline HIV RNA levels have been shown to affect the time to response in both pregnant and non-pregnant individuals, with no difference in response between pregnant and non-pregnant women.1,2 HIV RNA levels should be assessed 2 to 4 weeks after an antiretroviral (ARV) drug regimen is initiated or changed to provide an initial assessment of effectiveness.3 Most patients with an adequate viral response at 24 weeks of treatment have had at least a 1 log copies/mL HIV RNA decrease within 1 to 4 weeks after starting therapy.3 Suppression of HIV RNA to undetectable levels should be achieved as rapidly as possible, because maternal antenatal HIV RNA level correlates with risk of perinatal transmission of HIV. In addition, an analysis from the Women’s Interagency HIV Study cohort found that higher viral loads were associated with an increased risk of pregnancy loss (miscarriage or stillbirth).4
Issues associated with adherence are frequently associated with lack of virologic suppression and should be assessed when viral load does not decline as expected. A systematic review and meta-analysis of adherence to antiretroviral therapy (ART) during and after pregnancy in low-, middle-, and high-income countries (27% of studies were from the United States) found that only 73.5% of pregnant women achieved adequate (>80%) ART adherence.5 Evaluation of and support for adherence during pregnancy is critical to achievement and maintenance of maximal viral suppression.
The lack of virologic suppression by late pregnancy may indicate virologic failure but may also represent inadequate time on ART. In a retrospective multicenter cohort of 378 pregnant women, 77.2% achieved HIV RNA <50 copies/mL by delivery, with success of viral suppression varying by baseline HIV RNA level. With baseline <10,000 copies/mL, gestational age at initiation did not affect success up to 26.3 weeks. With baseline >10,000 copies/mL, however, delaying initiation past 20.4 weeks significantly reduced the ability to achieve maximal suppression at delivery.1 Among 1,070 treatment-naive pregnant women with HIV participating in IMPAACT P1025, a prospective cohort study, initiation of ART at >32 weeks’ gestation was also associated with a significantly higher risk of having viral load >400 copies/mL at delivery.6 A report from the French Perinatal Cohort found no perinatal transmission among 2,651 infants born to women who were receiving ART before conception, continued ART throughout pregnancy and delivered with a plasma HIV-RNA <50 copies/mL (upper limits of confidence interval [CI] 0.1%). In the entire cohort of 8,075 mother/infant pairs followed from 2000 through 2011, HIV-RNA level and timing of ART initiation were independently associated with perinatal transmission in a logistic regression analysis.7
The response to ART may also be affected by the presence of acute HIV-1 infection. In a prospective study of serial measures of plasma HIV-RNA and CD4 lymphocyte (CD4) counts after ART initiation (non-nucleoside reverse transcriptase inhibitor-based) in 25 women with acute HIV infection and 30 women with chronic HIV infection in Kenya, mean baseline HIV viral load was similar but the rate of viral decline following ART initiation was significantly slower among women with acute HIV than those with chronic infection (after adjustment for baseline CD4 count).8 Strategies to accelerate viral decline may be considered in this situation, in consultation with HIV treatment experts (see Acute HIV Infection section).
A three-pronged approach is indicated for management of women on ART regimens who have suboptimal suppression of HIV RNA, taking into account time on treatment. The 3 steps should be:
- Assessment of adherence, tolerability, incorrect dosing, or potential problems with absorption (e.g., nausea/vomiting, lack of attention to food requirements);
- ARV drug resistance studies (if plasma HIV RNA is above the threshold for resistance testing, generally >500 copies/mL); and
- Consideration of ART regimen modification.
The role of therapeutic drug monitoring (TDM) in reducing the risk of virologic failure is still undefined.9 In a cohort of pregnant women with HIV, 66 (39%) underwent TDM.10 Comparing women who had and did not have TDM, multivariate analysis found that it was associated with medication alterations during pregnancy but was not associated with any difference in viral breakthrough during pregnancy or detectable viral load at birth; there were no transmissions in either group.
Experts in the care of ARV-experienced adults should be consulted, particularly if a change in drug regimen is necessary due to resistance or adverse effects. In certain situations, regimen simplification may be considered to promote better adherence. Other possible interventions include adherence education, treatment of comorbidities such as nausea or vomiting, and directly-observed drug administration in the home or hospital setting.11
Among 662 pregnancies followed in Italy between 2001 and 2008, treatment modification during pregnancy was independently associated with an HIV-1 RNA level >400 copies/mL in late pregnancy (adjusted odds ratio, 1.66; 95% CI, 1.07–2.57; P = 0.024), highlighting the importance of using potent and well-tolerated regimens during pregnancy to maximize effectiveness and minimize the need to modify treatment.12 These findings also highlight the importance, as much as possible, of avoiding changing effective ARV regimens in women who become pregnant on ART (see Pregnant Women Currently Receiving ART).
The integrase strand transfer inhibitor (INSTI) class of drugs has been associated with rapid viral load reduction. Raltegravir has been shown to reduce viral load by approximately 2 log copies/mL by week 2 of therapy in ART-naive patients.13,14 Because of these data, the addition of raltegravir or another INSTI in late pregnancy has been suggested for women who have high viral loads and/or in whom multiple drug-resistant mutations have resulted in incomplete suppression of viremia.15-17 However, the efficacy and safety of this approach in pregnancy have not been evaluated in clinical trials, and only case series and a retrospective cohort are available, primarily involving raltegravir.18,19 In the setting of a failing regimen related to non-adherence and/or resistance, there are concerns that the addition of a single agent may further increase risk of resistance and potential loss of future effectiveness with raltegravir. In addition, if the reason for viremia is poor adherence, it is unclear that adding a new drug to the existing regimen would improve adherence. There have been 2 reports of marked elevations in transaminase levels following introduction of a raltegravir-containing regimen in late pregnancy, with return to normal levels after raltegravir discontinuation.18,20 Furthermore, data in 19 mother-infant pairs enrolled in a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to pregnant women receiving raltegravir-based ART found that, while raltegravir readily crossed the placenta, elimination was highly variable and extremely prolonged in some infants, raising potential infant safety concerns.21 At the current time, although this approach is increasingly being used in clinical practice, data are insufficient to recommend routinely adding raltegravir alone to a regimen for women in whom ART is failing in late pregnancy.
Scheduled cesarean delivery at 38 weeks’ gestation is recommended for pregnant women living with HIV who have HIV RNA levels >1,000 copies/mL near the time of delivery (see Transmission and Mode of Delivery).22,23
- 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.
- Rachas A, Warszawski J, Le Chenadec J, et al. Does pregnancy affect the early response to cART? AIDS. 2013;27(3):357-367. Available at http://www.ncbi.nlm.nih.gov/pubmed/23079802.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2016. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
- Cates JE, Westreich D, Edmonds A, et al. The Effects of Viral Load Burden on Pregnancy Loss among HIV-Infected Women in the United States. Infect Dis Obstet Gynecol. 2015;2015:362357. Available at https://www.ncbi.nlm.nih.gov/pubmed/26582966.
- Nachega JB, Uthman OA, Anderson J, et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis. AIDS. 2012;26(16):2039-2052. Available at http://www.ncbi.nlm.nih.gov/pubmed/22951634.
- Katz IT, Leister E, Kacanek D, et al. Factors associated with lack of viral suppression at delivery among highly active antiretroviral therapy-naive women with HIV: a cohort study. Ann Intern Med. 2015;162(2):90-99. Available at https://www.ncbi.nlm.nih.gov/pubmed/25599347.
- 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.
- Drake AL, Kinuthia J, Matemo D, et al. ART response among pregnant and postpartum women with acute versus chronic HIV-1. Presented at: 22nd Conference on Retroviruses and Opportunistic Infections. 2015. Seattle, WA.
- Matsui DM. Therapeutic drug monitoring in pregnancy. Ther Drug Monit. 2012;34(5):507-511. Available at http://www.ncbi.nlm.nih.gov/pubmed/22846897.
- Whitfield T, Dessain A, Taylor K, McQuillan O, Kingston M, Ajdukiewicz K. Retrospective analysis of the associations and effectiveness of performing therapeutic drug monitoring in pregnant HIV-positive women in two large centres in Manchester. Int J STD AIDS. 2016. Available at https://www.ncbi.nlm.nih.gov/pubmed/27335118.
- McCabe CJ, Goldie SJ, Fisman DN. The cost-effectiveness of directly observed highly-active antiretroviral therapy in the third trimester in HIV-infected pregnant women. PLoS One. 2010;5(4):e10154. Available at http://www.ncbi.nlm.nih.gov/pubmed/20405011.
- Floridia M, Ravizza M, Pinnetti C, et al. Treatment change in pregnancy is a significant risk factor for detectable HIV-1 RNA in plasma at end of pregnancy. HIV Clin Trials. 2010;11(6):303-311. Available at http://www.ncbi.nlm.nih.gov/pubmed/21239358.
- Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006;43(5):509-515. Available at https://www.ncbi.nlm.nih.gov/pubmed/17133211.
- Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806. Available at http://www.ncbi.nlm.nih.gov/pubmed/19647866.
- 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.
- 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.
- Boucoiran I, Tulloch K, Pick N, et al. A case series of third-trimester raltegravir initiation: Impact on maternal HIV-1 viral load and obstetrical outcomes. Can J Infect Dis Med Microbiol. 2015;26(3):145-150. Available at http://www.ncbi.nlm.nih.gov/pubmed/26236356.
- Rahangdale L, Cates J, Potter J, et al. Integrase inhibitors in late pregnancy and rapid HIV viral load reduction. Am J Obstet Gynecol. 2016;214(3):385 e381-387. Available at http://www.ncbi.nlm.nih.gov/pubmed/26928154.
- 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. Journal of Obstetrics and Gynaecology Canada. 2013;35(1):68-72. Available at http://www.ncbi.nlm.nih.gov/pubmed/23343800.
- Clarke DF, Acosta EP, Rizk ML, et al. Raltegravir pharmacokinetics in neonates following maternal dosing. J Acquir Immune Defic Syndr. 2014;67(3):310-315. Available at http://www.ncbi.nlm.nih.gov/pubmed/25162819.
- The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. The International Perinatal HIV Group. N Engl J Med. 1999;340(13):977-987. Available at http://www.ncbi.nlm.nih.gov/pubmed/10099139.
- European Mode of Delivery C. Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. Lancet. 1999;353(9158):1035-1039. Available at http://www.ncbi.nlm.nih.gov/pubmed/10199349.