Antiretroviral Therapy (ART) in Pregnant People With HIV Infection 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]

The Pediatric AIDS Clinical Trials Group 076 (PACTG 076) clinical trial showed that the administration of zidovudine (AZT, ZDV) to a pregnant person and their infant could reduce the risk for perinatal transmission by nearly 70%. ^[3] Subsequent trials and observational studies have shown combination antiretroviral prophylaxis administered to the pregnant individual 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:

• The probability of HIV transmission is directly correlated with the viral load, especially the viral load at the time of birth.
• Regardless of HIV viral load and CD4 count, all HIV-infected pregnant people should be offered antiretroviral therapy (ART) to reduce perinatal transmission.
• Elective cesarean delivery reduces the risk for 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.
• Combination ART is more effective than a single-drug regimen in reducing perinatal transmission.
• Longer duration of antepartum antiretroviral prophylaxis is more effective than shorter duration.
• Antiretroviral drugs reduce perinatal transmission by several methods, accounting for the recommendation for a combination antepartum, intrapartum, and infant ART.
• In people 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.
• In the absence of antepartum ART, intrapartum antiretroviral drugs should be administered in combination with infant antiretroviral prophylaxis to reduce the risk for perinatal transmission.
• Four weeks of zidovudine prophylaxis should be given to infants born to people with suppressed viremia during pregnancy. Presumptive HIV treatment with combination ART including 6 weeks of zidovudine should be administered to infants born to people who did not receive antepartum care or did not have a sustained viral response during pregnancy.
• Breastfeeding is not recommended in people with HIV infection in the United States. ^[1]

Antiretroviral therapy (ART) should be selected based on specific factors, including the following:

• Comorbidities, especially hepatitis B coinfection
• Patient adherence and convenience of therapy
• Potential for adverse drug effects on the pregnant person and drug interactions
• Results of genotypic resistance testing
• Safety and pharmacokinetic data in pregnancy
• Potential teratogenic effects on the fetus and other adverse effects on the fetus or newborn

HIV antiretroviral drug resistance testing should be performed prior to initiating antiretroviral therapy (ART) and should be performed if the pregnant person 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 an individual 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 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 pregnant person, fetus, or newborn are present. ^[1]

Two-NRTI backbone

Regimens include the following:

• Tenofovir disoproxil fumarate with emtricitabine (TDF/FTC co-formulated) or tenofovir disoproxil fumarate with lamivudine (3TC) once daily (use with caution in renal insufficiency) or
• Tenofovir alafanamide (TAF) in combination wirth emtricitabine (coformulated TAF/FTC) once a day. There are limited data but accumulating clinical experience with tolerability and viral suppression. ^[13]  Plasma TAF exposures similar in pregnant and non pregnant adults with boosted and unboosted regimens and fixed dose combination can be used. ^[14]  Prevalence of birth defects with first trimester TAF exposure in cases reported to the Antiretroviral Pregnancy Registry was similar to the prevalence rate in the US population ^[25] ​Based on this reassuring information, TAF/FTC co-formulated can be used preferentially in pregnancy and in those planning to conceive.
• Abacavir with lamivudine (ABC/3TC) once daily (only if HLA-B5701–negative); avoid combination with ritonavir-boosted atazanavir if the pretreatment HIV viral load exceeds 100,000 copies/mL. ^[7]

Protease inhibitor - based regimens

Regimens include the following:

• 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 the 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
• 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

• 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
• Dolutegravir (DTG) 50 mg daily: Preferred during acute HIV infection and in ART-naive pregnant people 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 are designated as alternatives for initial therapy in pregnant people when clinical trial data in adults show efficacy but one or more of the following conditions apply: ^[1]

• Limited experience in pregnancy
• Lack of data on teratogenic effects on the fetus
• 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 inhibitor ̶ based  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 ^[15] ; 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 inhibitors ̶ based regimen

Regimens include the following:

• Efavirenz (EFV) 600 mg PO daily: Although there are concerns of potential neural tube defects in people of childbearing age before pregnancy is detected, increasing data in pregnancy are reassuring ^[16] or
• Rilpivirine (RPV) 25 mg PO daily if pretreatment HIV viral load is less than 100,000 copies/mL and CD4 exceeds 200 cells/mm ³. Limited pregnancy data with highly variable pharmacokinetics.

In general, people 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. ^[17]  Bictegravir and Doravirine containing regimens have limited information in pregnancy but can be continued with more frequent viral load monitoring if well tolerated and suppressed on the regimen.

The following regimens require changes during pregnancy:

• If the regimen contains stavudine, didanosine, or full-dose ritonavir, a regimen change is strongly considered.
• Cobicistat-boosted elvitegravir: Compared with paired postpartum data, elvitegravir AUC was 24% lower in the second trimester and 44% lower in the third trimester, whereas 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. Individuals 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. ^[18]
• 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. ^[19]
• Cobicistat-boosted ATV or unboosted ATV is not recommended during pregnancy.
• There are no data on oral 2-drug regimens such as DTG-RPV or DTG-3TC in pregnancy. Therefore, an additional ARV agent or regimen change is recommended. An alternative suggested approach would be frequent viral load monitoring (every or every other month), if suppressed and well tolerated during pregnancy and wish to remain on the same 2-drug regimen.
• Given lack of data on use of long-acting injectable Cabotegravir (CAB) and RPV during pregnancy, change of regimen to an alternative oral regimen is recommended at this time. 

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 those who become pregnant while receiving an efavirenz-containing regimen for viral suppression. ^[16] 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 individuals 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 for microcephaly. This association was more pronounced when efavirenz was combined with zidovudine as opposed to tenofovir-containing regimen. ^[20] 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. ^[21]  Efavirenz remains a recommended alternate regimen for treatment initiation during pregnancy with shared decision making with patient and should be continued during pregnancy if the patient is already on it and virally suppressed.

Dolutegravir (DTG)

Dolutegravir (DTG) appears to be safe if started in pregnancy; however, there were concerns of preconception safety signal. The TSEPAMO study in Botswana reported neural tube defects in 4 of 426 (0.9%) babies born to people who were taking dolutegravir at the time they became pregnant, compared with a 0.1% occurrence in babies born to those who were not taking dolutegravir. ^[22] In an updated analysis of the TSEPAMO study, among the 1,683 deliveries in which the pregnant person 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 those receiving non-dolutegravir ART at conception. ^[23] Zero neural tube defects were reported in 2,812 infants (95% CI: 0 to 0.13) born to those who started DTG during pregnancy. ^[11]  In an updated analysis, the risk for infant neural tube defect was not significantly elevated when compared with non DTG based regimen exposure around the time of conception ^[28] ; therefore, a dolutegravir-based regimen is now preferred for ART initiation during pregnancy and in people of childbearing potential. ^[1]

Intrapartum AZT should be administered to pregnant HIV-infected individuals during labor if the HIV viral load is 1000 or more copies/mL or unknown at time of delivery, irrespective of the mode of delivery. ^[24]  If the HIV viral load is between 50 to 1000 copies/ml at 34-36 weeks of pregnancy or 4-6 weeks before delivery, intrapartum AZT may be considered.

AZT 2 mg/kg IV is administered over 1 hour, then as a 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.