Appendix D: Review of Clinical Trials of Antiretroviral Interventions to Prevent Perinatal HIV Transmission

Updated Reviewed

June 02, 2023: This Appendix was last reviewed in 2018 and no longer reflects the latest Panel recommendations. It has been maintained in the Guidelines to provide a resource for historical context of clinical trials to advance the prevention of perinatal HIV transmission.

One of the major achievements in HIV research was the demonstration by the PACTG 076 clinical trial that administering zidovudine to pregnant women and their infants could reduce the risk of perinatal transmission by nearly 70%.1 Following the results of PACTG 076, researchers began to explore the development of shorter, less expensive prophylactic regimens that are more applicable in resource-constrained settings. In addition, multiple studies have tried to determine the optimal regimens for reducing the risk of postnatal transmission during breastfeeding. More recently, in the context of recommendations for universal antiretroviral therapy (ART), studies have also explored the efficacy of universal ART during pregnancy and breastfeeding. This Appendix provides a table summarizing the results of major studies of antiretroviral (ARV) interventions used to prevent perinatal transmission (see Supplemental Table 1) and a brief discussion of lessons learned. In many cases, a direct comparison of results from these trials is not possible because the studies involved diverse patient populations from different geographic locations, with differing viral subtypes and infant feeding practices. However, some generalizations are relevant to understanding the use of ARV drugs for prevention of perinatal transmission in both resource-limited and resource-rich countries. Furthermore, these studies have provided critical information elucidating the risks, timing, and mechanisms of perinatal transmission.

ART is more effective antenatally in reducing perinatal transmission than a single-drug prophylactic regimen.

ARV drugs are highly effective at preventing perinatal transmission, even in women living with advanced HIV.2,3 Efficacy has been demonstrated for a number of short-course ARV regimens, including zidovudine alone, zidovudine plus lamivudine, single-dose nevirapine, and single-dose nevirapine combined with either short-course zidovudine or zidovudine/lamivudine.4-13 In general, combination regimens are more effective than single-drug regimens in reducing the risk of perinatal transmission. In addition, administering ARV drugs during the antepartum, intrapartum, and postpartum periods is a more effective approach for preventing perinatal transmission than administering ARV drugs during only the antepartum and intrapartum periods or the intrapartum and postpartum periods.5,14,15

Almost all trials in resource-limited countries have included oral intrapartum prophylaxis, with varying durations of maternal antenatal and/or infant (and sometimes maternal) postpartum prophylaxis. Regimens with antenatal components, including those starting as late as 36 weeks’ gestation, can reduce the risk of perinatal transmission, even when these regimens are lacking an infant prophylaxis component.10-12 However, longer-duration antenatal zidovudine prophylaxis that begins at 28 weeks’ gestation is more effective than shorter-duration zidovudine prophylaxis that begins at 35 weeks’ gestation.13 The Perinatal HIV Prevention Trial (PHPT)-5 trial demonstrated that women who received <8 weeks of prophylaxis during pregnancy had a significantly greater risk of perinatal transmission than women who received longer durations of prophylaxis.16 The European National Study of HIV in Pregnancy and Childhood demonstrated that each additional week of an antenatal, triple-drug regimen corresponded to a 10% reduction in risk of transmission.17 More prolonged infant post-exposure prophylaxis does not appear to substitute for longer-duration maternal ARV prophylaxis.13

The Promoting Maternal and Infant Survival Everywhere (PROMISE) study was a large randomized clinical trial that demonstrated the superiority of ART over zidovudine-based prophylaxis for prevention of in utero transmission in women with CD4 T lymphocyte (CD4) cell counts >350 cells/mm3.18 Pregnant women were randomized to one of three study arms:

  • Zidovudine plus single-dose nevirapine at delivery plus postpartum tenofovir disoproxil fumarate (TDF)/emtricitabine tail
  • Zidovudine plus lamivudine plus lopinavir/ritonavir (LPV/r)
  • TDF plus emtricitabine plus LPV/r

The rate of perinatal transmission through 1 week of life was significantly lower among women receiving ART (0.5%, 9 infections among 1,710 infants) than among those randomized to receive zidovudine plus single-dose nevirapine plus postpartum TDF/emtricitabine tail (1.8%, 25 infections among 1,386 infants).

Regimens that do not include maternal ARV therapy during pregnancy have been evaluated because some women may lack antenatal care and present for prenatal care for the first time when they go into labor. Regimens that include only intrapartum and postpartum drug administration also have been shown to be effective in reducing the risk of perinatal transmission.4-6 However, without continued infant post-exposure prophylaxis, intrapartum pre-exposure prophylaxis alone with nucleoside reverse transcriptase inhibitor drugs (zidovudine/lamivudine) is not effective in reducing the risk of transmission.5 The South African Intrapartum Nevirapine Trial (SAINT) trial demonstrated that intrapartum/postpartum zidovudine/lamivudine and single-dose intrapartum/newborn nevirapine are similar in efficacy and safety.6

Combination infant ARV prophylaxis is recommended in the United States for infants at high risk for HIV acquisition.

Delayed maternal HIV diagnosis or delayed presentation for pregnancy care may result in missing the opportunity to provide maternal ARV drugs during pregnancy or labor. In the absence of maternal therapy, the standard infant prophylaxis regimen of 6 weeks of zidovudine was effective in reducing the risk of HIV transmission compared with no prophylaxis, based on epidemiological data in resource-rich countries.19 A trial in Malawi in breastfeeding infants demonstrated that adding 1 week of zidovudine therapy to infant single-dose nevirapine reduced risk of transmission by 36% compared with infant single-dose nevirapine alone.7

To define the optimal infant prophylaxis regimen in the absence of maternal antepartum ARV drug administration in a formula-fed population of infants such as in the United States, the NICHD-HPTN 040/P1043 (NCT00099359) clinical trial compared three infant ARV regimens in formula-fed infants born to mothers who did not receive ARV drugs during the current pregnancy:

  • Standard 6 weeks of zidovudine alone
  • 6 weeks of zidovudine plus three doses of nevirapine given in the first week of life (first dose given within 48 hours of birth, second dose given 48 hours after first dose, third dose given 96 hours after second dose)
  • 6 weeks of zidovudine plus lamivudine and nelfinavir given from birth through age 2 weeks.20

The study demonstrated that both the dual- and triple-combination regimens reduced the risk of intrapartum transmission by approximately 50% compared with infant prophylaxis with zidovudine alone, although there was more hematologic toxicity with the triple regimen (see Supplemental Table 1). Based on these data, combination ARV prophylaxis is now recommended in the United States for infants born to women who are at increased risk for transmission (see Antiretroviral Management of Newborns with Perinatal HIV Exposure or Perinatal HIV).

Single-dose intrapartum nevirapine is not recommended for women in the United States who are receiving standard recommended antenatal ARV prophylaxis.

PACTG 316 (a clinical trial conducted in the United States, Europe, Brazil, and the Bahamas) demonstrated that adding single-dose nevirapine to combination antenatal ARV prophylaxis for non-breastfeeding women with very low viral loads at the time of delivery did not offer significant benefit.21 Thus, adding single-dose intrapartum nevirapine is not recommended for women in the United States who are receiving standard recommended antenatal ARV prophylaxis (see Intrapartum Antiretroviral Therapy/Prophylaxis).

Breastfeeding by women with HIV infection is not recommended in the United States.

Breastfeeding by women living with HIV (including those receiving ARV drugs) is not recommended in the United States, where replacement feeding is affordable, feasible, acceptable, sustainable, and safe, and the risk of infant mortality due to diarrheal and respiratory infections is low.22

Clinical trials in resource-limited settings have demonstrated that both infant prophylaxis (daily infant nevirapine, lamivudine, and LPV/r) during breastfeeding and maternal triple-drug prophylaxis during breastfeeding decrease the risk of postnatal infection (see Supplemental Table 1).2,23-31 The PROMISE trial was a large, randomized clinical trial that demonstrated that daily infant nevirapine and maternal ART have similar safety and efficacy for prevention of perinatal transmission during breastfeeding in women with CD4 cell counts ≥350 cells/mm3.18,32 At 6 to 14 days postpartum, the study randomized participants to receive either infant nevirapine or maternal ART until 18 months after delivery or breastfeeding cessation. The rates of perinatal transmission were similar (0.58%, 5 infections among 1,211 infants receiving nevirapine vs. 0.57%, 7 infections among 1,219 infants whose mothers received ART), both strategies were safe, and infant HIV-1–free survival was high across both arms (97.7% with infant nevirapine vs. 97.1% with maternal ART at 24 months).

Hypothetically, maternal triple-drug prophylaxis may be less effective than infant prophylaxis if the maternal regimen is first started postpartum or late in pregnancy, because it takes several weeks to months to achieve full viral suppression in breast milk.27,33 Importantly, although prophylaxis significantly lowers the risk of postnatal infection, neither infant nor maternal postpartum ARV prophylaxis eliminates the risk of HIV transmission through breast milk. Therefore, breastfeeding is not recommended for women living in the United States (including those receiving combination ARV drug regimens).22 Finally, both infant nevirapine prophylaxis and maternal ART during breastfeeding may be associated with the development of ARV drug resistance in infants who acquire HIV despite prophylaxis; multiclass drug resistance has been described in breastfeeding infants with HIV despite maternal triple-drug prophylaxis.34-38

Supplemental Table 1. Results of Major Studies on Antiretroviral Interventions to Prevent Perinatal HIV Transmission

Supplemental Table 1. Results of Major Studies on Antiretroviral Interventions to Prevent Perinatal HIV Transmission


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Supplemental Table 1. Results of Major Studies on Antiretroviral Interventions to Prevent Perinatal HIV Transmission

Supplemental Table 1. Results of Major Studies on Antiretroviral Interventions to Prevent Perinatal HIV Transmission

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