Risk of Adverse Pregnancy Outcomes with TDF-FTC-ATV/r Similar or Lower Than Other ART Regimens

*Updated on 4/27/2018 at 11:14 AM EST

New research coming in from the Harvard T.H. Chan School of Public Health suggests that there is no difference of risk for preterm birth and early infant death between 3 antiretroviral regimens taken by pregnant women with HIV, including a regimen that has raised safety concerns in a past trial.

Through the use of antiretroviral medication, pregnant mothers with HIV are able to reduce the risk of passing their infection on to their unborn baby to 2% or lower. These drug regimens work by preventing the virus from replicating, which reduces viral load in the body.

Some of the medications pass from pregnant women to their unborn children across the placenta, thus, protecting the baby from infection. In general, these medications are safe to use during pregnancy. However, a past study referred to as the PROMISE trial, raised safety concerns regarding one triple-drug regimen: tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r).

For the PROMISE trial, investigators assessed the safety of 2 triple-drug regimens—zidovudine, lamivudine, and ritonavir-boosted lopinavir (AZT-3TC-LPV/r) and TDF-FTC-LPV/r—in women living in sub-Saharan Africa and India. They concluded that the first regimen was safer than the second, as it showed lower rates of severe adverse pregnancy outcomes, which included very low birth weight, premature delivery, stillbirth, and other serious birth defects. Additionally, they found that there were fewer infant deaths within the first 14 days with use of the first regimen compared with the second.

As the World Health Organization (WHO) recommends a TDF-FTC-based regimen to be taken daily as first-line therapy for all adults infected with HIV, including pregnant women, researchers from Harvard Chan set out to take a closer look at the two regimens that had been studied in the PROMISE trial as well as a regimen which combined TDF-FTC with another protease inhibitor called ritonavir-boosted atazanavir (ATV/r), according to a recent press release.

"The PROMISE trial left open questions as to whether their results can be replicated in other cohorts of HIV-infected pregnant women such as those in the United States and whether the increased risk of severe adverse pregnancy outcomes observed with the TDF-based regimen in PROMISE held for TDF-based regimens with other protease inhibitors such as atazanavir," senior author of the study, Kunjal Patel, DSc, MPH, a senior research scientist in the Center for Biostatistics in AIDS Research (CBAR) at Harvard Chan told Contagion^®. "These open questions inspired us to conduct this study."

For their study, the researchers looked at data from the Surveillance Monitoring for ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) and the P1025 study of the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network. Specifically, they looked at 1621 mothers who began taking 1 of the 3 drug regimen combinations either before or during pregnancy and compared the risk of adverse birth outcomes among infants who had been exposed to the regimens in utero.

“We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g),” the authors write. “Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding.”

The authors note that in total, there were 4646 birth outcomes, and not many infants or fetuses had been exposed to the TDF-FTC-LPV/r regimen (128, or 2.8%) as the initial regimen during gestation compared with the other 2 regimens, TDF-FTC-ATV/r (539, or 11.6%) and ZDV-3TC-LPV/r (954 or 20.5%).

One of the biggest takeaways from the study? "When comparing the combination regimens studied in PROMISE in a US cohort of HIV-infected pregnant women, we found no difference in risks of adverse pregnancy outcomes with the TDF-based regimen with LPV/r and the ZDV-based regimen with LPV," Dr. Patel told Contagion^®. "We should note, however, that we observed low rates of severe adverse events in our cohort which limited our ability to look at the difference in rates of these severe events by our regimens of interest." She added that for the TDF-based regimen that is more commonly used in the United States, which is with ATV, "the risks of adverse pregnancy outcomes were similar or lower than the other regimens of interest."

The TDF-FTC-LPV/r regimen, which was of concern in the PROMISE trial, is not commonly used among pregnant women living with HIV in the United States. Taking into consideration the PROMISE results regarding the risks for severe adverse pregnancy outcomes, it's reasonable to limit the use of this regimen as alternatives are available.

Our results support the current US guidelines for use of specific antiretroviral agents in pregnancy which note TDF-FTC as a preferred two NRTI-backbone," Dr. Patel concluded. "We all want our interventions to prevent perinatal HIV transmission to be effective and safe for both mother and child in the long-term so given the PROMISE results about risks for severe adverse pregnancy outcomes with TDF-FTC-LPV/r, limiting the use of this regimen is reasonable given available alternatives."