Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Recommendations for Use of Antiretroviral Drugs During Pregnancy

People with HIV Who Are Taking Antiretroviral Therapy When They Become Pregnant

People on Fully Suppressive Antiretroviral Therapy

In general, people who are already on a fully suppressive antiretroviral regimen when pregnancy occurs should continue their antiretroviral therapy (ART) regimens. The Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission (the Panel) recommends that effective ART regimens should not be changed just because the regimen includes antiretroviral (ARV) drugs that are not Preferred or Alternative for use in pregnancy. Discontinuing or altering therapy could cause an increase in viral load, leading to disease progression, a decline in immune status, and an increased risk of perinatal HIV transmission.¹ In a study from the French Perinatal cohort among 1,797 women with HIV RNA levels <50 copies/mL before 14 weeks gestation, change in ARV regimen in 411 women due to safety concerns based on existing guidelines at the time of pregnancy did not result in loss of virologic control.² However, among 662 pregnancies that were followed in Italy between 2001 and 2008, treatment modification during pregnancy was independently associated with HIV RNA level >400 copies/mL in late pregnancy (adjusted odds ratio [aOR] 1.66; 95% CI, 1.07–2.57; P = 0.024).¹ This highlights the importance of establishing potent and well-tolerated regimens prior to pregnancy, using Preferred and Alternative ARVs for use in pregnancy whenever possible, to maximize effectiveness and minimize the need for modifying treatment in pregnancy.

Regimens that involve medications that are not recommended for use in adults because of high risk for toxicity (e.g., stavudine, indinavir, didanosine, and treatment-dose ritonavir) or inferior virologic efficacy (nelfinavir) should not be continued when pregnancy occurs; fortunately, these drugs are rarely used now. In this case, these drugs should be stopped and people switched to other ARV drugs that are recommended for use in pregnancy (see Table 6. What to Start: Initial Antiretroviral Regimens During Pregnancy for People Who Are Antiretroviral-Naive and Table 7. Situation-Specific Recommendations for Use of Antiretroviral Drugs in Pregnant People and Nonpregnant People Who Are Trying to Conceive).

Physiologic changes that occur during pregnancy may result in lower levels of certain ARVs, resulting in loss of virologic control with the potential for perinatal transmission. For patients who have achieved viral suppression and become pregnant while receiving regimens with a potential increased risk of virologic failure during pregnancy due to pharmacokinetic (PK) concerns (e.g., cobicistat [COBI]-boosted regimens, oral rilpivirine) or regimens with insufficient data about dosing and/or safety in pregnancy (e.g., doravirine [DOR], oral two-drug regimens, and long-acting injectable cabotegravir/rilpivirine), clinicians need to consider whether to continue the regimen or switch to a different regimen that is recommended for use during pregnancy^3-5 (see Table 6. What to Start: Initial Antiretroviral Regimens During Pregnancy for People Who Are Antiretroviral-Naive and Table 7. Situation-Specific Recommendations for Use of Antiretroviral Drugs in Pregnant People and Nonpregnant People Who Are Trying to Conceive).

For regimens with PK concerns or those with insufficient data about dosing in pregnancy, pregnant people and clinicians may elect to continue the suppressive regimen with frequent viral load monitoring (every 1–2 months, understanding that switching may be needed later in pregnancy and that potential viral rebound may increase vertical transmission risk and lead to cesarean delivery), or they may elect to switch to a recommended oral regimen as soon as pregnancy is recognized. In these cases, the Panel emphasizes the importance of patient counseling and informed decision-making, including consideration of individual factors (such as ARV resistance or intolerance, or difficulty with adherence to other regimens) that may increase the risk of virologic failure with a switch to a new regimen. When choosing to switch any ART regimen in pregnancy in people who are already virologically suppressed, clinicians should closely monitor tolerability of the new regimen, evaluate for adverse effects, and consider more frequent viral load monitoring (i.e., every 1–2 months). For additional information, see Appendix C: Antiretroviral Counseling Guide for Health Care Providers. 

Bictegravir

PK data on bictegravir (BIC) in human pregnancy are now available from two clinical studies and a case series.^6,7 Drug levels are lower in the second and third trimesters than in nonpregnant or postpartum individuals and are reduced in later pregnancy to a greater degree for BIC than dolutegravir (DTG). However, viral suppression was generally maintained. BIC levels remained above the 95% maximal effective concentration and thus are anticipated to suppress viral load (see Bictegravir for additional information). As a result, BIC is now recommended as an Alternative ARV for use in pregnancy (see Table 7. Situation-Specific Recommendations for Use of Antiretroviral Drugs in Pregnant People and Nonpregnant People Who Are Trying to Conceive).W 

Cobicistat-Boosted Regimens

Clinicians and pregnant people should be aware that the use of atazanavir/COBI, darunavir/COBI, or elvitegravir/cobicistat (EVG/c) is associated with lower plasma drug exposures (both of COBI and of the drug being boosted) during the second and third trimesters of pregnancy due to the physiologic changes associated with pregnancy. These low drug exposures pose an increased risk of virologic failure in the second and third trimesters and potential perinatal HIV transmission. When a pregnant person presents to care on one of these regimens, providers should consider continuing the regimen with more frequent viral load monitoring (i.e., every 1–2 months) or switching to a different regimen that is recommended for use during pregnancy (see Table 6. What to Start: Initial Combination Regimens for Antiretroviral-Naive Pregnant People and Table 7. Situation-Specific Recommendations for Use of Antiretroviral Drugs in Pregnant People and Nonpregnant People Who Are Trying to Conceive).^3-5 A multicenter, retrospective study of 134 pregnant women with HIV who received elvitegravir (EVG)-containing ART at any time during pregnancy reported that 81.3% of study participants had viral suppression at delivery (HIV RNA <40 copies/mL); among 68 women who initiated EVG before pregnancy and continued receiving EVG through delivery, the rate of viral suppression at delivery was 88.2%. The perinatal HIV transmission rate was 0.8% in this study.⁸ If one of these regimens is continued, absorption should be optimized by taking the drugs with food. Pregnant people who are taking regimens that include EVG/c should take ARV drugs and prenatal vitamins ≥2 hours apart.

Doravirine

PK data on DOR in human pregnancy are available only from PK modeling data based on ex vivo studies of placental transfer.^9,10 Patients who become pregnant with viral suppression while receiving regimens with DOR should be counseled about limited available data, see Doravirine. Clinicians and patients should reach a shared decision about continuing DOR with frequent viral load monitoring (i.e., every 1–2 months) or switching to one of the Preferred or Alternative regimens.

Oral Two-Drug Regimens

Currently, no data exist on the use of oral two-drug regimens in pregnancy (e.g., DTG plus lamivudine [3TC] and DTG plus rilpivirine [RPV]). However, for both DTG/3TC and DTG/RPV, there are data in nonpregnant persons showing noninferiority when compared to a standard three-drug regimen.^11,12 The component drugs in each of the oral two-drug regimens (DTG, 3TC, RPV) have well described PK that are adequate in pregnancy, and the individual drug components are recommended as Preferred or Alternative ARV drugs by the Panel. Note that although PK data indicate that RPV plasma concentration is reduced during the second and third trimesters of pregnancy, the reduction is less than the reductions seen with the COBI-containing regimens described above, and most pregnant people will have adequate exposure. A recent observational study of 188 pregnant people on oral RPV as part of a three-drug regimen at delivery found that 182 (96.8%) had viral load <200 copies/mL.¹³ Standard RPV dosing is recommended when used as part of a three-drug regimen, and viral load should be monitored frequently (e.g., every 1–2 months; see Rilpivirine, Table 6. What to Start: Initial Antiretroviral Regimens During Pregnancy for People Who Are Antiretroviral-Naive, and Table 7. Situation-Specific Recommendations for Use of Antiretroviral Drugs in Pregnant People and Nonpregnant People Who Are Trying to Conceive.

Long-Acting Injectable Cabotegravir and Rilpivirine

Data on long-acting injectable cabotegravir (CAB) and RPV are currently limited to a small number of patients without HIV who became pregnant while enrolled in trials of long-acting injectable CAB for pre-exposure prophylaxis and stopped the medication once pregnancy was recognized, usually in the first trimester.^14-16 In these patients, the pharmacologic washout was similar in pregnant and nonpregnant adults.^14,17 No data are available about the pharmacokinetics of CAB in the second and third trimesters, with either oral or injectable formulations. While data in nonpregnant adults suggest slower washout (and thus potentially higher CAB levels) with intramuscular CAB among people with obesity,¹⁸ this may not be applicable to the weight gain that is due to pregnancy, as the volume of distribution in pregnancy differs from that in obesity. No data exist on the PK of injectable RPV in pregnancy. Prior data have shown concern for lower concentrations of oral RPV in the third trimester,¹⁹ as above. Some patients who have achieved virologic suppression on injectable CAB and RPV experienced previous challenges with oral ART, such that switching back to oral ART could increase the risk of virologic rebound. Clinicians and pregnant people should reach a shared decision about continuing this regimen with frequent viral load monitoring (every 1–2 months) or switching to one of the Preferred or Alternative three-drug ARV regimens in conjunction with an HIV expert.

When switching from long-acting injectable CAB and RPV to an oral regimen in pregnancy, the timing of the switch must take into account the long half-life of the long-acting injectable formulation (median 5.6–11.5 weeks) with persistence of the drug for up to 12 months.²⁰ When the dosing schedule is monthly, the change to an oral regimen should occur within 1 month of the last CAB and RPV injections.²¹ When the dosing schedule is every 2 months, the change to an oral regimen should occur within 2 months of the last CAB and RPV injections.^22,23 Dosing recommendations, including guidance for switching to an oral regimen, can be found in the prescribing information.^20,23 For additional information, see Optimizing Antiretroviral Therapy in the Setting of Viral Suppression and Discontinuation or Interruption of Antiretroviral Therapy in the Adult and Adolescent Antiretroviral Guidelines.

People Not on Fully Suppressive ART When Becoming Pregnant

People who are not fully suppressed and who are currently taking ART should be evaluated carefully for adherence barriers, drug–drug interactions, drug–food requirements, and HIV drug resistance, with every effort made to achieve rapid and full viral suppression through adherence interventions or medication changes (see Pregnant People Who Have Not Achieved Viral Suppression on Antiretroviral Therapy).

For pregnant people on ART, ARV drug-resistance testing should be performed prior to changing an ARV regimen if HIV RNA levels are >200 copies/mL. For people with HIV RNA levels >200 copies/mL but <500 copies/mL, drug-resistance testing may be unsuccessful but should still be considered (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy).

References

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