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Antiretroviral selection and management in pregnant women with HIV in resource-rich settings

Antiretroviral selection and management in pregnant women with HIV in resource-rich settings
Authors:
Brenna L Hughes, MD, MSc
Susan Cu-Uvin, MD
Section Editor:
Lynne M Mofenson, MD
Deputy Editor:
Milana Bogorodskaya, MD
Literature review current through: Nov 2022. | This topic last updated: Sep 08, 2022.

INTRODUCTION — The management of the pregnant woman with human immunodeficiency virus (HIV) infection has evolved significantly over the past 25 years in light of advancements in drug development and a greater understanding of the prevention of vertical HIV transmission (transmission of HIV during pregnancy, labor and delivery, and breastfeeding). In the United States and Europe, the risk of HIV transmission from mother to infant has declined to historically low levels with the use of antiretroviral medications [1,2]. Contributions to this successful prevention effort include universal testing of pregnant women for HIV infection, life-long antiretroviral therapy (ART) administration to all individuals infected with HIV including pregnant women, the use of cesarean delivery (when appropriate), appropriate infant antiretroviral prophylaxis management, and avoidance of breastfeeding, when feasible. (See "Prenatal evaluation of women with HIV in resource-rich settings".)

This topic will address ART in the pregnant woman with HIV in resource-rich settings. In the United States, the Department of Health and Human Services publishes guidelines on the evaluation and management of pregnant women with HIV, which are updated on an ongoing basis [3]. Our recommendations below are largely consistent with these guidelines. Many newer drug regimens recommended as preferred agents for nonpregnant adults have not yet been studied in pregnancy. Thus, recommended regimens for initiation of therapy are different from those for nonpregnant adults. These recommendations change regularly as safety and efficacy data become available.

Other guidelines that are relevant to resource-rich settings include those from the American College of Obstetricians and Gynecologists, the British HIV Association, and the European AIDS Clinical Society [4-6]. Links to these and other expert guidelines can be found in the society guideline links section below. (See 'Society guideline links' below.)

Information regarding antepartum evaluation and teratogenicity and the pharmacokinetics of individual agents during pregnancy is found elsewhere. (See "Prenatal evaluation of women with HIV in resource-rich settings" and "Safety and dosing of antiretroviral medications in pregnancy".)

Discussion of the intrapartum and infant antiretroviral management in resource-rich settings is also found elsewhere. (See "Intrapartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings".)

Information regarding the management of the pregnant female with HIV in resource-limited settings and the prevention of HIV transmission during breastfeeding is found elsewhere. (See "Prevention of vertical HIV transmission in resource-limited settings" and "Prevention of HIV transmission during breastfeeding in resource-limited settings".)

RATIONALE FOR MATERNAL ART — The use of antiretroviral therapy (ART) during pregnancy involves two separate but related goals: reduction of vertical transmission and treatment of maternal HIV disease [3]. All pregnant women with HIV should receive ART, regardless of CD4 cell count or plasma HIV viral load, to prevent vertical transmission and to treat their HIV infection. The combination of maternal antepartum, maternal intrapartum, and infant prophylaxis is recommended to maximize infant pre-exposure and postexposure prophylaxis and suppress maternal viral load below the limit of detection throughout pregnancy to decrease the risk of transmission. In resource-rich countries, with widespread use of ART during pregnancy, the incidence of vertical transmission of HIV is estimated at less than 1 percent [1-3,7-12].

HIV viremia and risk of infant infection — In general, the risk of vertical transmission declines with decreasing levels of maternal HIV ribonucleic acid (RNA) (eg, <1000 copies/mL) although there is still some element of risk even at low RNA levels [12,13].

In a prospective cohort study, HIV RNA levels were serially measured in 1542 women with HIV who gave birth from 1990 to 2000 to assess the relationship between plasma viremia, the type of therapeutic intervention, and the risk of HIV vertical transmission [1]. The risk of HIV transmission declined with lower levels of maternal viremia at delivery. HIV transmission rates ranged from 1 percent for patients with a nondetectable viral load (<400 copies/mL) compared with 23 percent for those with a viral load >30,000 copies/mL. Even at low levels of viremia, the risk decreases with further reductions. In a study of 14,630 women with HIV who were receiving antepartum ART in France between 2000 and 2017, vertical transmission rates were higher among those first initiating ART during pregnancy (73/7448; 0.99 percent) compared with those on ART at conception (9/6316; 0.14 percent) [12]. Among women on ART at conception, the rate of vertical transmission was 2.42 percent (8/330) in women with viral load at delivery >400 copies/mL, 0.20 percent (1/504) for those with viral load 50 to 399 copies/mL, and 0 percent (0/5,482) for women with viral load under 50 copies/mL.

These data support the use of ART with the goal of full viral suppression to decrease the risk of vertical HIV transmission [14]. These data also highlight the fact that women with a very low viral load can still transmit HIV to their infants, although the risk is low. This residual risk may be related to the presence of detectable HIV in the genital secretions. Thus, ART is recommended in all pregnant women for the prevention of vertical transmission, regardless of the mother’s viral load.

Efficacy of ART in preventing transmission — Numerous studies have documented the efficacy of antiretroviral use in decreasing the risk of mother to child HIV transmission. In 1994, acquired immunodeficiency syndrome (AIDS) Clinical Trial 076 evaluated the safety and efficacy of zidovudine prophylaxis in preventing vertical transmission among 477 pregnant women with HIV [15]. Zidovudine was administered during the antepartum and intrapartum period to the mother and in the infant for the first six weeks of life. Women who were randomly assigned to the intervention arm had a significantly lower risk of transmitting HIV infection to their newborn (25 versus 8 percent) with minimal toxic side effects.

After this landmark trial conducted in the United States and France, many subsequent clinical studies of HIV vertical transmission have been performed in resource-limited settings to determine if lower-cost medications could be used or if alternative strategies could be as effective. Much of these data are not directly applicable to resource-rich countries due to varying HIV genotypes, patient populations, and infant feeding practices. However, illustrative concepts have emerged from these clinical trials that are also instructive for management of patients in resource-rich settings (see "Prevention of vertical HIV transmission in resource-limited settings", section on 'Maternal antiretroviral therapy'):

A combination regimen is more effective in reducing HIV transmission than a single-drug regimen [16,17].

A three-part strategy (ie, antepartum, intrapartum, and infant prophylaxis) is more effective than giving medications only during the intrapartum and/or postpartum periods [18,19].

Starting ART before or earlier in pregnancy is more effective in reducing vertical transmission than starting late in pregnancy [12,20,21]. (See 'When to initiate ART during pregnancy' below.)

A summary of the clinical trials is available online through the Department of Health and Human Services [3].

WHEN TO INITIATE ART DURING PREGNANCY — Many pregnant women who are known to have HIV will already be taking antiretroviral therapy (ART). For treatment-naïve women, earlier initiation of ART is associated with increased likelihood of viral suppression by the time of delivery and decreased risk of transmission [12,21-24]. Thus, we recommend initiation of ART as soon as HIV is diagnosed in a pregnant woman or as soon as pregnancy is diagnosed in untreated women with an established HIV diagnosis.

Drug resistance testing is indicated prior to ART initiation for all individuals with detectable virus, but ART should be initiated as soon as possible without delaying until availability of those results; regimen should be adjusted after results return if necessary. (See 'Drug resistance testing' below and 'ART selection and management' below.)

For pregnant women who are not yet on ART, the rate of virologic control after initiation of ART appears comparable to that in nonpregnant women. As an example, in a study of 519 treatment-naïve pregnant women initiating ART, 93 percent had achieved a HIV viral level <400 copies/mL by the third month of therapy [25]. Available data additionally suggest that earlier initiation of ART is associated with increased likelihood of viral suppression by the time of delivery [21,23,24]. In a cohort of 671 ART-naïve pregnant women in the United States who initiated ART during pregnancy, a detectable viral load (>400 copies/mL) at delivery was documented in 13 percent and was associated with antiretroviral initiation at a later gestational age [24]. Twenty-four percent of women who initiated the regimen during the third trimester had a detectable viral load.

Accordingly, earlier ART initiation is associated with a lower risk of vertical transmission [12,22]. A study of 14,630 women who received antepartum ART in France between 2000 and 2017, the rate of vertical transmission was 0.14 percent among women receiving ART at conception and 0.52 percent, 0.75 percent, and 1.67 percent for women initiating ART in the first, second, or third trimester, respectively. No transmission occurred among 5482 infants born to women who received ART before conception, continued ART throughout pregnancy, and had a viral load <50 copies/mL at delivery [12].

Some women may prefer delaying ART until after completion of the first trimester, when the fetus is less susceptible to the potential teratogenic effects of medications, but we recommend not delaying ART given the established safety of ART. Moreover, later initiation of ART is less effective in reducing in utero transmission of HIV [21] and if ART is delayed beyond 28 weeks gestation, HIV RNA may not be fully suppressed by the time of delivery, leading to an increased risk of vertical transmission [20].

ART SELECTION AND MANAGEMENT

General principles — In pregnant women, antiretroviral regimen selection should take into account the resistance profile of the virus, the safety and efficacy of the drugs in the mother and fetus, the convenience and adherence potential of the regimen, the potential for drug interactions with other medications, and pharmacokinetic data in pregnancy. For women initiating antiretroviral therapy (ART) during pregnancy, regimen selection is similar to that for nonpregnant patients, with the exception that certain agents that are preferred in the general population with HIV may not be preferred in pregnancy because of limited clinical experience and/or lack of pharmacokinetic data to inform appropriate dosing during pregnancy. (See 'Preferred antiretroviral agents for those who are treatment-naïve' below.)

Treatment-experienced women on a suppressive antiretroviral regimen can usually continue it even if the agents are not specifically preferred during pregnancy, unless the regimen contains agents that either have poor safety or uncertain pharmacokinetic profiles in pregnancy. (See 'On ART with viral suppression' below.)

For both treatment-naïve and treatment-experienced women, it is important to be aware that pharmacokinetic changes in pregnancy may require increased dosing, more frequent dosing, or boosting of certain medications, especially protease inhibitors. (See 'Selecting the third drug' below and "Safety and dosing of antiretroviral medications in pregnancy", section on 'Protease inhibitors'.)

Decisions about the choice of antiretroviral drugs during pregnancy should be made by the woman following discussion with her health care provider of the potential benefits and risks of each regimen. Guidelines produced by the United States Department of Health and Human Services are updated regularly and include preferred regimens in pregnancy. Clinicians in the United States wishing to discuss management options can call the National Perinatal HIV Consultation and Referral Service at the University of California, San Francisco: 1-888-448-8765.

Selection of ART regimens in nonpregnant individuals with HIV is discussed elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Drug resistance testing — If HIV RNA is detectable on the baseline blood test, drug resistance testing should be performed to inform the optimal selection of an antiretroviral regimen [3]. ART should be initiated in pregnant women prior to receiving the results of the resistance testing; if necessary, the regimen can be subsequently modified based on the results of the resistance assay. This is particularly important if the mother presents late for care, as the risk of transmission is associated with the duration of antenatal ART and level of viral suppression at delivery. (See 'When to initiate ART during pregnancy' above.)

Clinicians should be aware that drug resistance testing may not be feasible if the viral load is low (eg, <500 to 1000 copies/mL). (See "Overview of HIV drug resistance testing assays".)

Approach by patient population

Preferred antiretroviral agents for those who are treatment-naïve — Selecting a regimen that will be active against the patient’s virus based on the resistance profile is the primary objective. Within that constraint, we generally favor a regimen consisting of a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone with an integrase inhibitor or a protease inhibitor as a third drug, using agents with a documented history of safety in pregnancy (table 1). Other factors that inform the regimen selection are patient factors such as adherence potential, tolerability, other comorbidities, and pharmacokinetic data in pregnancy. Some of the preferred regimens in nonpregnant adults lack data on pharmacokinetics during pregnancy; hence, preferred regimens for pregnant women differ somewhat from those for the general adult population with HIV.

The following describes our approach to regimen selection for a pregnant woman without evidence or suspicion of drug resistance, for whom a preferred NRTI combination backbone with a third preferred agent is appropriate. It is important to note that this is one approach, and there may be other appropriate reasons to choose a particular preferred agent over another.

Selecting the NRTI backbone — The preferred nucleoside reverse transcriptase inhibitor (NRTI) combinations in pregnancy include tenofovir alafenamide-emtricitabine (TAF-FTC), tenofovir alafenamide plus lamivudine (TAF-3TC), tenofovir disoproxil fumarate-emtricitabine (TDF-FTC), lamivudine-tenofovir disoproxil fumarate (TDF-3TC), or abacavir-lamivudine (ABC-3TC). We generally use TAF-FTC unless there is significant concern for excessive gestational weight gain, in which case a TDF-containing combination can be used. Because abacavir-lamivudine should only be used in patients who are negative for the HLA-B5701 allele and testing may take several days to obtain the result, this regimen is less desirable. Additionally, this combination should not be used with ritonavir-boosted atazanavir or efavirenz if the baseline viral load is >100,000 copies/mL because of a higher risk of virologic failure. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Abacavir'.)

For women with hepatitis B virus coinfection, a TAF- or TDF-containing combination is preferred because of its activity against hepatitis B virus. Patients who have hepatitis B virus coinfection and significant renal impairment should receive the TAF-containing combination. If neither tenofovir formulation can be used, consultation with an expert in treating hepatitis B virus is warranted.

Data in pregnant women have shown both TAF and TDF to be safe [26,27]. TAF is associated with less renal and bone toxicity than TDF in the general population. TDF should be used with caution in the setting of renal insufficiency because of its association with renal toxicity.

In general, TAF is preferred over TDF due to similar efficacy and less toxicity with TAF in pregnant patients. In a study of 643 pregnant women who were randomized to three different ART regimens (dolutegravir plus TAF-FTC, dolutegravir plus TDF-FTC, or efavirenz plus TDF-FTC), there was no difference in viral suppression between the three groups but the TAF-FTC group was associated with fewer adverse birth outcomes compared with TDF-FTC [26]. However, more women in the TAF-FTC group had high gestational weight gain, which could lead to adverse birth outcomes in certain patients.

Although concerns have been raised [28] regarding a possible increased risk of very preterm birth and neonatal death with TDF when combined with lopinavir-ritonavir based on a trial conducted in Africa, we do not feel that the trial results are clear enough to stop using TDF as a preferred NRTI in pregnancy and are reassured by observational data on TDF use. Our stance is consistent with that of the British HIV Association and the United States Department of Health and Human Services Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission [3,29]. However, due to concerns about a potential increase in TDF levels with concomitant lopinavir-ritonavir, we avoid initiating TDF with lopinavir-ritonavir during pregnancy. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Tenofovir disoproxil fumarate'.)

Selecting the third drug — Preferred third drugs for initiation in treatment-naïve pregnant women include an integrase inhibitor or a boosted protease inhibitor (table 1). For most women, we suggest the integrase inhibitor dolutegravir.

Integrase inhibitors

DolutegravirDolutegravir has high and durable virologic potency, it leads to more rapid viral decline than efavirenz with a similar safety profile during pregnancy [26,30], it is dosed once daily, and it is better tolerated than protease inhibitors. Although there had been concern about neural tube defects associated with preconception dolutegravir, updated data indicate that the risk is not statistically different than with non-dolutegravir-based regimens [31]. Rates of stillbirth, neonatal death, small for gestational age, and preterm birth with dolutegravir-based regimens, started before or during pregnancy, are comparable with other antiretroviral regimens [32-34]. These data are discussed in detail elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Dolutegravir'.)

Dolutegravir’s high barrier to resistance and rapidity of virologic control make it a preferred option for patients with acute HIV or with detectable viremia late in pregnancy. As an example, in two randomized trials, starting dolutegravir-based ART in the second or third trimester resulted in more rapid and more frequent virologic suppression compared with efavirenz-based ART [26,30].

The approach to the use of dolutegravir in nonpregnant individuals of childbearing potential is discussed elsewhere. (See "HIV and women", section on 'Individuals of childbearing potential'.)

Raltegravir − The other preferred integrase inhibitor, raltegravir, is also associated with rapid decline in viral load but must be administered twice daily in pregnancy (the once daily dose is not recommended during pregnancy) and has a lower barrier to resistance than dolutegravir. Also, it is not a preferred agent in women who present with acute HIV infection during pregnancy.

Data on the integrase inhibitor raltegravir during pregnancy are limited but increasing and generally reassuring [35-37]. Raltegravir is an attractive option if drug interactions or toxicity preclude the use of other preferred agents. Additionally, because it can rapidly reduce viral load, raltegravir has been used in several case reports of women who presented late in pregnancy [37-41]. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Raltegravir'.)

Protease inhibitorsAtazanavir plus ritonavir and darunavir plus ritonavir are the preferred protease inhibitors; there is the most clinical experience with this class of drug, but each may have some drawbacks. Atazanavir plus ritonavir is administered once daily and thus minimizes problems with adherence; however, it can cause asymptomatic maternal indirect hyperbilirubinemia. Darunavir plus ritonavir is well tolerated during pregnancy but must be given twice daily.

Ritonavir-boosted atazanavir – This combination is administered once daily. Given pharmacokinetic changes during pregnancy, an increased dose during the second and third trimesters may be warranted for certain women, such as treatment-experienced women or those receiving concomitant tenofovir. Gastrointestinal side effects may also be seen with the use of this regimen, but since there is not a need for increased dosing in the first trimester, this may be a preferred regimen for women with early pregnancy nausea and vomiting. Atazanavir plus ritonavir should not be used in a patient requiring proton pump inhibitors. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Atazanavir'.)

Ritonavir-boosted darunavir – This combination is administered as 600 mg darunavir plus 100 mg ritonavir, each twice daily during pregnancy. Because of low trough levels with once-daily dosing, twice-daily dosing of darunavir is recommended during pregnancy, especially for treatment-experienced patients. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Darunavir'.)

These protease inhibitors can also be boosted with cobicistat in nonpregnant populations, but the pharmacokinetics and safety of protease inhibitor and cobicistat combinations in pregnancy have not been extensively studied. Available data suggest decrease in both cobicistat and protease inhibitor drug levels in the second and third trimester [42-44]. Because of concern for decreased drug levels with cobicistat-boosted regimens, they are not recommended for routine use during pregnancy. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Cobicistat'.)

Protease inhibitor use during pregnancy has not been clearly associated with gestational diabetes. Nevertheless, some experts consider protease inhibitor exposure a risk factor for glucose intolerance and thus screen for it earlier in women on a protease inhibitor-containing regimen. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Gestational diabetes'.)

There are conflicting data regarding the risk of preterm birth with protease inhibitor use in pregnancy, with some studies suggesting an increased risk; for women who are at very high risk of preterm birth, such as those with a history of multiple spontaneous preterm births, we may avoid protease inhibitor-containing regimens if other effective regimens are available. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Preterm birth'.)

For patients who cannot use one of the preferred agents (table 1), alternative third drugs include efavirenz, oral rilpivirine, and lopinavir-ritonavir. (See 'Alternative agents' below.)

Bictegravir is not recommended for use during pregnancy due to limited data on appropriate dosing and safety. (See 'Agents with insufficient data' below.)

Cobicistat-boosted regimens (including elvitegravir-cobicistat) are not recommended because of concerns for decreased drug levels during pregnancy [42,43,45]. (See 'Not recommended' below.)

On ART with viral suppression — With few exceptions, women who have achieved viral suppression on antiretroviral therapy (ART) that was initiated before pregnancy should continue their current regimen during pregnancy, provided that they tolerate it, even if the agents are not one of the preferred antiretroviral drugs for use during pregnancy. Certain agents, in particular protease inhibitors, may warrant dosing changes during pregnancy to compensate for pharmacokinetic changes during that time. (See 'Selecting the third drug' above.)

Certain antiretroviral regimens warrant particular consideration:

Two-drug regimens – Although evidence supporting two-drug regimens (eg, dolutegravir-lamivudine) in the general population has grown, data in pregnancy remain limited. If a woman is virally suppressed on such a regimen, we closely monitor the viral load during pregnancy; alternatively, the regimen can be switched to a three-drug regimen.

Injectable cabotegravir-rilpivirine regimen – Data on the use of this regimen during pregnancy is limited. We agree with the United States Department of Health and Human Services (DHHS) Antiretroviral Guidelines Panel's recommendation that women taking the injectable regimen switch to a preferred oral regimen for the duration of the pregnancy [3]. Initiation of the oral regimen should occur within four weeks of the last cabotegravir and rilpivirine intramuscular doses.  

Cobicistat-boosted regimens (eg, elvitegravir-cobicistat or darunavir-cobicistat) – Because of data suggesting decreased drug levels during pregnancy and an associated risk of loss of virologic suppression, these agents are not recommended for initiation during pregnancy, pending further data [3,42-45]. The optimal management of women who become pregnant while on a suppressive cobicistat-containing regimen is uncertain. We generally suggest continuation of the regimen with frequent viral load monitoring (eg, every month); if loss of viral suppression occurs, then a switch to a more potent regimen is recommended. Alternatively, the woman could be switched to a different regimen for the duration of pregnancy, choosing among preferred and alternative agents for use in pregnancy and guided by the treatment history and results of prior resistance testing. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Cobicistat'.)

Dolutegravir-containing regimens – We agree with the United States DHHS Antiretroviral Guidelines Panel's recommendation that pregnant women already receiving dolutegravir continue the same regimen [3]. Although initially there was a signal suggesting a small increased risk of neural tube defects with maternal dolutegravir use at the time of conception, accumulation of more data demonstrated no difference in risk of neural tube defects between the use of dolutegravir-based and non-dolutegravir-based ART regimens at time of conception. The data on dolutegravir and risk of neural tube defects are discussed in detail elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Dolutegravir'.)

Although there had been concern about a potential risk of neural tube defects with efavirenz, enough reassuring data on first-trimester efavirenz exposures have accumulated that recommendations from expert groups do not restrict efavirenz use in pregnancy [3,46,47]. Women who become pregnant while on a suppressive efavirenz-containing regimen should continue it. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Efavirenz'.)

On ART without viral suppression — Women who have not yet achieved viral suppression on antiretroviral therapy (ART) initiated prior to pregnancy should be evaluated for reasons for virologic failure. In this case, the clinician must begin by asking the patient about their level of drug adherence. Nonadherence can result in incomplete viral suppression merely due to the lack of adequate drug level, even in the absence of drug resistance.

Drug resistance testing is also essential in this situation, and a new ART regimen should be tailored to the individual woman based on her resistance profile and individual medication tolerability. In such cases, agents that are not considered preferred antiretrovirals in pregnancy may be warranted (see 'Nonpreferred antiretroviral agents' below). Consultation with an expert in the management of drug-resistant HIV is recommended in such cases. If resistance to the current drugs in the ART regimen is not detected and suboptimal adherence is felt to have contributed to the failure to achieve viral suppression, a once-daily regimen would be particularly desirable. Alternatively, the original regimen could be continued along with intensive adherence counseling.  

The virologic response must be monitored carefully. Women who do not show an appropriate virologic response require a repeat resistance panel test.

The general approach to individuals with HIV who have not been able to achieve viral suppression on ART is discussed in detail elsewhere. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Treatment experienced but not currently on ART — It is important to obtain a history of all prior antiretroviral drug exposure and results of prior resistance testing (if done previously) in women who have a history of antiretroviral therapy (ART) in the past. Past antiretroviral history and results of drug resistance testing should be used to guide the choice of ART regimen. In such cases, agents that are not considered preferred antiretrovirals in pregnancy may be warranted because of documented or presumed drug resistance. (See 'Nonpreferred antiretroviral agents' below.)

The virologic response must be monitored carefully. Women who do not show an appropriate virologic response require a repeat resistance panel test and should have careful assessment for adherence. If adherence appears adequate, they should also have a consultation with a clinician experienced in antiretroviral drug resistance. The recommended next-line therapy will vary based on the individual patient’s prior exposure and drug resistance profile. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Detectable viremia late in pregnancy — Women with a high viral load who present and/or initiate ART late in pregnancy (eg, after 28 weeks) may be at increased risk of transmission if viral suppression cannot be achieved by the time of delivery. For ART-naïve women presenting to care late in pregnancy, we recommend initiation of integrase-inhibitor-based ART. For women who have detectable viremia late in pregnancy while on ART that does not contain an integrase inhibitor, we suggest adjusting the regimen to one that contains an integrase inhibitor if the treatment history and drug resistance testing allow. Use of an integrase inhibitor (eg, dolutegravir, raltegravir) may reduce viral load more rapidly and thereby decrease transmission risk. Initiation of a regimen should not be delayed while awaiting results of drug resistance testing.

In a randomized trial (DolPHIN-1) that included 60 Ugandan and South African ART-naïve women presenting in the third trimester of pregnancy, initiation of dolutegravir-containing ART resulted in a faster rate of viral suppression compared with efavirenz-containing ART (median time to <50 copies/mL 32 versus 72 days) [48]. In a similar but larger trial (DolPHIN-2) that included 268 pregnant women with HIV, viral suppression at delivery was higher with dolutegravir than efavirenz (in 74 versus 43 percent of women) [30,48]. Similarly, in a trial of 408 pregnant women, initiation of raltegravir-based ART after 20 weeks gestation resulted in a shorter median time to viral load <200 copies/mL (8 versus 15 days) and a higher rate of viral suppression at delivery (92 versus 64 percent) compared with efavirenz-based ART [49].

The intrapartum management of women with detectable viremia late in pregnancy and management of their infants are discussed elsewhere. (See "Intrapartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings".)

NONPREFERRED ANTIRETROVIRAL AGENTS

Alternative agents — Alternative agents include those that have proven virologic efficacy or have been well-studied in pregnancy but otherwise have certain drawbacks [3]:

Zidovudine-lamivudine – Despite extensive experience and trial data demonstrating its safety in pregnancy and efficacy in reducing the risk of vertical HIV transmission [15], this combination is an alternative agent because of associated adverse effects (eg, anemia, headache) and the need for twice-daily dosing. Some but not all studies have suggested an increased risk of congenital heart defects with zidovudine exposure, and the clinical significance of this is unclear as many of the reported defects were ventricular septal defects detected by fetal ultrasound that can undergo spontaneous closure postnatally in many children [50,51]. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Zidovudine'.)

Efavirenz – This is an alternative, once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) for use with a dual-NRTI backbone. Drawbacks to this agent include a risk for exacerbation of mental health disorders and central nervous system symptoms. The risks of central nervous system symptoms may detract from its use in women with a history of such symptoms. It also has significant drug-drug interactions with methadone, which may require altered methadone dosing if a patient initiates efavirenz during pregnancy. Although there has been concern about a potential risk of neural tube defects with efavirenz, enough reassuring data on first-trimester efavirenz exposures have accumulated so that recommendations from expert groups do not restrict efavirenz use in pregnancy [3,46,47]. It can be a useful agent for women who want a once-daily one-pill regimen and cannot take an integrase inhibitor.

Oral rilpivirine – This is an alternative NNRTI for use with a dual NRTI backbone during pregnancy, although data in pregnancy remain relatively limited. Its advantage is that it is coformulated in a single-pill once daily combination regimen with tenofovir and emtricitabine. Rilpivirine should not be used in individuals with baseline HIV viral load >100,000 copies/mL or CD4 cell count <200 cells/microL. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Rilpivirine'.)

Agents with insufficient data — There are many medications in the HIV armamentarium that have not been well evaluated in the pregnant patient. Occasionally these agents may be needed if the patient is infected with a drug resistant virus or has other reasons that preclude the use of agents with more data during pregnancy. In such cases, use of agents with less data in pregnancy may be warranted for maternal health reasons. Women who become pregnant on such regimens and are virologically suppressed should continue their regimen during pregnancy. The risks and benefits of such an approach need to be conveyed to the patient.

Although it is commonly used for HIV treatment in the general population, there are insufficient data for routine use of bictegravir in pregnancy. Other agents for which there are minimal data in pregnancy include doravirine, ibalizumab, and fostemsavir. As noted, women who are virologically suppressed on regimens with these drugs and become pregnant may continue their regimen during pregnancy.

Not recommended — Cobicistat-containing regimens (eg, elvitegravir-cobicistat, darunavir-cobicistat, and atazanavir-cobicistat) have not been extensively evaluated in pregnancy, but they are not recommended for initiation during pregnancy because of emerging data suggesting a decrease in drug levels during the third trimester with an associated risk of loss of virologic suppression [42-45]. Women who become pregnant while suppressed on a cobicistat-containing regimen can continue to take it but should have plasma viral loads checked more frequently (every one to two months) during pregnancy. (See 'On ART with viral suppression' above.)

Two-drug regimens (eg, dolutegravir-lamivudine) are not recommended for initiation during pregnancy [3]. Those who become pregnant while suppressed on a two-drug regimen can continue to take it but should have plasma viral loads checked more frequently (every one to two months) during pregnancy. (See 'On ART with viral suppression' above.)

Injectable cabotegravir and rilpivirine are not recommended for use in pregnancy due to insufficient data [3]. In those who are virally suppressed on the injectable regimen at time of conception, we favor switching to a preferred oral regimen for the remainder of pregnancy. (See 'On ART with viral suppression' above.)

There is extensive experience with lopinavir-ritonavir during pregnancy, but because of the need for twice-daily dosing during pregnancy and adverse effects, it is not recommended for use during pregnancy except under special circumstances [3]. Women who become pregnant while on a fully suppressive regimen that contains lopinavir-ritonavir can continue to take it.

Other agents that are not recommended (except under special circumstances) include etravirine, maraviroc, and enfuvirtide.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in pregnant women" and "Society guideline links: HIV infection in infants and children".)

SUMMARY AND RECOMMENDATIONS

Introduction − In the United States and Europe, the risk of HIV transmission from mother to infant has declined to historically low levels with the use of antiretroviral medications. The combined use of maternal antepartum, maternal intrapartum, and infant antiretroviral prophylaxis maximizes infant pre-exposure and postexposure prophylaxis to decrease the risk of HIV acquisition. (See 'Introduction' above.)

Rationale for maternal ART − Fully suppressive antiretroviral therapy (ART) for pregnant women has two separate but related purposes: reduction of vertical transmission and treatment of maternal HIV disease. All pregnant women with HIV should receive combination ART, regardless of CD4 cell count or plasma HIV RNA copy number. (See 'Rationale for maternal ART' above and 'HIV viremia and risk of infant infection' above and 'Efficacy of ART in preventing transmission' above.)

When to initiate ART − For treatment-naïve pregnant women, we recommend prompt initiation of ART regardless of gestational age (Grade 1B). Earlier initiation of an antiretroviral regimen is associated with increased likelihood of viral suppression by the time of delivery and thus decreased risk of transmission. (See 'When to initiate ART during pregnancy' above.)

General principles of selecting an ART regimen − Selecting a regimen that is active against the patient’s virus based on the resistance profile is the primary objective. Within that constraint, we generally favor agents with a documented history of safety in pregnancy (table 1). Other factors that inform the regimen selection are patient factors such as adherence potential, tolerability, other comorbidities, and pharmacokinetic data in pregnancy. (See 'General principles' above.)

Preferred ART regimen for those who are treatment-naïve − Treatment-naïve pregnant woman should be started on a regimen that consists of a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone with either a protease inhibitor or integrase inhibitor as a third drug (table 1).

In general, we suggest tenofovir alafenamide with emtricitabine as the NRTI backbone and dolutegravir as the third drug (Grade 2C).

Lamivudine is a reasonable alternative to emtricitabine, although it is not available in a single-pill coformulation with tenofovir alafenamide. Tenofovir disoproxil fumarate is a reasonable alternative to tenofovir alafenamide if there is concern for excessive weight gain during pregnancy or if tenofovir alafenamide is not available.

The individual agents should be chosen from those that are preferred in pregnancy because of their substantial clinical use and demonstrated efficacy during pregnancy. ART should be initiated after obtaining resistance testing while awaiting results and can be adjusted after results of a resistance profile of the virus are obtained, if applicable. (See 'Preferred antiretroviral agents for those who are treatment-naïve' above.)

Approach to those on ART with viral suppression − Treatment-experienced women on a virologically suppressive ART regimen that they tolerate can usually continue that regimen, even if the individual agents are not preferred in pregnancy. However, there are additional considerations for certain regimens (see 'On ART with viral suppression' above):

We suggest that patients who become pregnant while receiving dolutegravir not stop therapy (Grade 2C) since dolutegravir does not appear to be associated with increased risk of neural tube defects compared with non-dolutegravir based regimens.

For patients who become pregnant while virologically suppressed on a cobicistat-containing regimen (eg, elvitegravir-cobicistat or darunavir-cobicistat), we suggest continuing the regimen with frequent monitoring of viral levels throughout pregnancy (Grade 2C). If loss of virologic control occurs, we switch to a more potent regimen. The alternative is to switch up front to a different regimen for the duration of pregnancy. The concern is for possible low drug levels and the potential for virologic failure during pregnancy.

Approach to those not on ART or those without viral suppression − In treatment-experienced women who are either not on an antiretroviral regimen or are on a failing regimen, antiretroviral selection will be mainly guided by the history of prior antiretroviral drug exposure and results of previous and current resistance testing. In such cases, use of agents that are not preferred in pregnancy may be warranted. (See 'On ART without viral suppression' above and 'Treatment experienced but not currently on ART' above.)

Approach to those presenting late in pregnancy − For ART-naïve women who first present late in pregnancy (eg, after 28 weeks gestation), we recommend an integrase-inhibitor-containing regimen (Grade 1B). These agents can lead to rapid decrease in viral load and resultant viral suppression, ideally by the time of delivery. (See 'Detectable viremia late in pregnancy' above.)

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