Antiretroviral Therapy (ART) in Pregnant Women With HIV Infection
Updated: Jun 23, 2020
Author: Madhu Chhanda Choudhary, MD; Chief Editor: Michael Stuart Bronze, MD
Overview of HIV Antiretroviral Therapy (ART) in Pregnancy
Antiretroviral therapy (ART) during pregnancy should focus on the reduction of perinatal transmission and the treatment of maternal human immunodeficiency virus (HIV) disease.[1] ART can reduce perinatal transmission by several mechanisms, including lowering maternal antepartum viral load and preexposure and postexposure prophylaxis of the infant. Therefore, for prevention of perinatal transmission of HIV, combined antepartum, intrapartum, and infant antiretroviral prophylaxis is recommended.[1] Combination drug regimens are considered the standard of care for treatment of HIV infection and for prevention of perinatal HIV transmission.[2]
Clinical Data on HIV Antiretroviral Therapy (ART) in Pregnancy
The Pediatric AIDS Clinical Trials Group 076 (PACTG 076) clinical trial showed that the administration of zidovudine (AZT, ZDV) to a pregnant woman and her infant could reduce the risk of perinatal transmission by nearly 70%.[3] Subsequent trials and observational studies have shown combination antiretroviral prophylaxis administered to the mother antenatally is associated with reduced perinatal transmission rates of less than 2%.[1, 2] Additional trials have also identified simple regimens that are effective in reducing perinatal transmission in resource-limited countries. From these study results, we can better understand the use of antiretroviral drugs in resource-limited and resource-rich countries.[4, 5]
These clinical trials have provided the following guiding principles:
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The probability of HIV transmission is directly correlated with the viral load, especially the viral load at the time of delivery.
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Regardless of HIV viral load and CD4 count, all HIV-infected pregnant women should be offered antiretroviral therapy (ART) to reduce perinatal transmission.
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Elective cesarean delivery reduces the risk of perinatal transmission and should be offered at week 38 if the viral load is likely to exceed 1000 copies/mL at delivery; there is no benefit if the viral load is less than 1000 copies/mL or when the procedure is done after rupture of membranes.
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Combination ART is more effective than a single-drug regimen in reducing perinatal transmission.
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Longer duration of antepartum antiretroviral prophylaxis is more effective than shorter duration.
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Antiretroviral drugs reduce perinatal transmission by several methods, accounting for the recommendation for a combination antepartum, intrapartum, and infant ART.
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In women who are already receiving ART, the regimen needs to be reviewed for its adequacy in controlling HIV, its teratogenic potential, its pharmacologic effects, and patient tolerance during pregnancy.
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In the absence of antepartum ART, intrapartum antiretroviral drugs should be administered in combination with infant antiretroviral prophylaxis to reduce the risk of perinatal transmission.
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Four weeks of zidovudine prophylaxis should be given to infants born to mothers with suppressed viremia during pregnancy. Six weeks of combination ART should be administered to infants born to mothers who did not receive antepartum care or did not have a sustained viral response during pregnancy.
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Breastfeeding is not recommended in women with HIV infection in the United States.
[1]
Factors for HIV Antiretroviral Therapy (ART) Selection in Pregnancy
Antiretroviral therapy (ART) should be selected based on specific factors, including the following:
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Comorbidities, especially hepatitis B coinfection
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Patient adherence and convenience of therapy
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Potential for adverse drug effects on the mother and drug interactions
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Results of genotypic resistance testing
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Safety and pharmacokinetic data in pregnancy
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Potential teratogenic effects on the fetus and other adverse effects on the fetus or newborn
Recommendations for HIV Antiretroviral Therapy (ART) in Pregnant Treatment-Naive Patients
HIV antiretroviral drug resistance testing should be performed prior to initiating antiretroviral therapy (ART) and should be performed if the woman is receiving ART with virologic failure (defined as an HIV viral load >200 copies/mL but may be unsuccessful with an HIV viral load from 200-1000 copies/mL).
If a woman with HIV infection presents late in pregnancy, ART should be initiated immediately, before availability of resistance testing.
Initiate treatment as soon as possible, including in the first trimester.
The preferred initial regimen in pregnancy is a backbone of dual nucleoside analogue reverse transcriptase inhibitors (NRTI) with either ritonavir-boosted protease inhibitor (PI) or an integrase Inhibitor.
Three-drug ART has reduced maternal-fetal HIV transmission rate to less than 2%. However, the safest and most efficacious combination is not yet clear.[6]
Preferred Regimens for HIV Antiretroviral Therapy (ART) in Pregnancy
Preferred regimens have demonstrated optimal efficacy and durability with acceptable toxicity and ease of use. No evidence of teratogenic effects on the fetus or established association with teratogenic or clinically significant adverse outcomes for the mother, fetus, or newborn are present.[1]
Two-NRTI backbone
Regimens include the following:
Protease inhibitor̶based regimens
Regimens include the following:
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Atazanavir (ATV) is recommended to be combined with low-dose
ritonavir (RTV): ATV 300 mg
plus RTV 100 mg PO daily as a single daily dose; some experts increase ATV/RTV dose to 400/100 mg daily during second and third trimester; manufacturer recommends dose increase in pregnancy if combined with tenofovir or H2 blocker in treatment-experienced patients and with efavirenz in treatment-naive patients
[8]
or
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Darunavir (DRV) 600 mg combined with 100 mg RTV twice daily
[9] : Once-daily dosing achieves low darunavir trough in pregnancy and should not be used, especially in treatment-experienced patients.
Integrase inhibitor regimen
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Raltegravir (RAL) 400 mg twice daily
[10] : No data on use of once-daily raltegravir 600-mg HD formulation in pregnancy; rapid reduction in viral load potentially useful if present late in pregnancy; hepatic enzyme elevation has occurred when used in late pregnancy
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Dolutegravir (DTG) 50 mg daily: Preferred during acute HIV infection and in ART-naive pregnant women who present late in care owing to rapid reduction in viral load and lower rates of INSTI resistance. DTG use in very early pregnancy has been associated with a small but statistically significant increase in neural tube defect.
[11, 12]
Alternative Regimens for HIV Antiretroviral Therapy (ART) in Pregnancy
Alternative regimens are designated as alternatives for initial therapy in pregnant women when clinical trial data in adults show efficacy but one or more of the following conditions apply:[1]
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Limited experience in pregnancy
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Lack of data on teratogenic effects on the fetus
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Dosing, formulation, administration, or interaction issues for that drug or regimen
NRTI backbone
Zidovudine with lamivudine (300 mg ZDV/150 mg 3TC) twice a day: Combination with most experience in pregnancy; can cause hematological toxicity
Protease inhibitor̶based regimen
Lopinavir (LPV) 400 mg plus ritonavir (RTV) 100 mg PO twice a day if no lopinavir-associated mutations: Insufficient data for any dosage recommendations in the presence of any lopinavir-associated resistance substitution;[13] some clinicians increase dose to 600 mg/150 mg twice a day in second and third trimester of pregnancy; once-daily LPV/RTV dosing is not recommended during pregnancy; oral solution should not be used in pregnancy because of its high alcohol content
Non-nucleoside reverse transcriptase inhibitors̶based regimen
Regimens include the following:
Recommendations for Pregnant HIV-Infected Women Receiving Antiretroviral Therapy (ART)
In general, women who are receiving ART for HIV infection should continue the same regimen during pregnancy, if it is well tolerated and yields effective HIV virologic suppression.[15]
The following regimens require changes during pregnancy:
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If the regimen contains stavudine, didanosine, or full-dose ritonavir, a regimen change is strongly considered.
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Cobicistat-boosted elvitegravir: Compared with paired postpartum data, elvitegravir AUC was 24% lower in the second trimester and 44% lower in the third trimester, while cobicistat AUC was 44% and 59% lower in second and third trimester, respectively. Elvitegravir/cobicistat (EVG/c) is not recommended for initial use in pregnancy. Women who become pregnant while taking EVG/c should be offered an alternate regimen. If an EVG/c regimen is continued, the viral load should be monitored frequently, and therapeutic drug monitoring, if available, may be useful.
[16]
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Cobicistat-boosted darunavir is not recommended for use during pregnancy, as mean darunavir minimum concentrations (C
min) were approximately 90% lower during the second and third trimester compared with postpartum levels. Therefore, darunavir/cobicistat (DRV/c) is not recommended during pregnancy. An alternative regimen is recommended for individuals who become pregnant during therapy with DRV/c-containing regimen.
[17]
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There are no data on 2-drug regimens such as DTG-RPV or DTG-3TC in pregnancy. Therefore, an additional ARV agent or regimen change is recommended.
Antiretroviral Drugs of Concern During Conception and Pregnancy
Efavirenz (EFV)
There had been concerns of neural tube defect due to efavirenz exposure during conception and first trimester. However, the risk of neural tube defect associated with efavirenz appears to be similar to that in the general population; therefore, efavirenz should be continued in women who become pregnant while receiving an efavirenz-containing regimen for viral suppression.[14] The TSEPAMO study in Botswana redemonstrated the safety of efavirenz in pregnancy, with the occurrence of only one case of skeletal dysplasia in an efavirenz-exposed infant among 395 women with first-trimester exposure to efavirenz-based ART.[11]
However, the SMARTT observational cohort of HIV exposed and uninfected children found that in utero exposure to an efavirenz-containing regimen was associated with an increased risk of microcephaly. This association was more pronounced when efavirenz was combined with zidovudine as opposed to tenofovir-containing regimen.[18] In another analysis of HIV-exposed but uninfected children exposed to specific antiretrovirals in utero, a higher risk of neurological disease with efavirenz exposure was redemonstrated.[19]
Dolutegravir (DTG)
Dolutegravir (DTG) appears to be safe if started in pregnancy; however, there are concerns of preconception safety signal. The TSEPAMO study in Botswana reported neural tube defects in 4 of 426 (0.9%) babies born to women who were taking dolutegravir at the time they became pregnant, compared with a 0.1% occurrence in babies born to women who were not taking dolutegravir.[20] In an updated analysis of the TSEPAMO study, among the 1,683 deliveries in which the mother was taking dolutegravir-based ART at conception, five neural-tube defects were found (0.30% of deliveries; 95% CI, 0.13 to 0.69), compared with 15 defects among 14,792 deliveries (0.10%; 95% CI, 0.06 to 0.17) in mothers receiving non-dolutegravir ART at conception.[21] Zero neural tube defects were reported in 2,812 infants (95% CI: 0 to 0.13) born to mothers who started DTG during pregnancy.[11] Therefore, a dolutegravir-based regimen is now preferred for ART initiation during pregnancy and an alternative regimen in women of childbearing potential with counseling and shared decision-making between the clinician and patient.[1]
Tenofovir alafenamide
In the IMPAACT P1026sPK study, among women taking tenofovir alafenamide without cobicistat, tenofovir alafenamide exposure was lower in the third trimester compared with postpartum, whereas no differences were seen between pregnancy and postpartum in women taking tenofovir alafenamide with cobicistat.[22] Before tenofovir alafenamide can be recommended during pregnancy, additional safety and outcome data are needed.
Intrapartum Care
Intrapartum AZT should be administered to pregnant HIV-infected women if the HIV viral load is 1000 or more copies/mL or unknown at time of delivery, irrespective of mode of delivery.[23]
AZT 2 mg/kg IV is administered over 1 hour, then continuous infusion of 1 mg/kg/h from onset of labor to delivery.
Oral AZT, if part of the combination regimen, should be stopped while IV AZT is administered.
IV AZT is not required if the patient is receiving combination therapy and the HIV viral load is consistently less than 1000 copies/mL near time of delivery and adherence is reliable.
Questions & Answers
Author
Madhu Chhanda Choudhary, MD Associate Professor, Department of Medicine, University of Pittsburgh School of Medicine
Madhu Chhanda Choudhary, MD is a member of the following medical societies: Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Specialty Editor Board
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.
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