While antiretroviral (ARV) treatment of HIV during pregnancy is associated with adverse birth outcomes such as stillbirth and preterm delivery, some regimens are safer than others. In a recent large study of data about pregnant women in Botswana, Atripla (efavirenz/tenofovir disoproxil fumarate/emtricitabine) proved to be the safest regimen.

Researchers analyzed obstetric records at eight government hospitals in Botswana, concerning the births of 47,124 infants between August 2014 and August 2016, representing about 45 percent of all births in the African nation. Rebecca Zash, MD, of the Beth Israel Deaconess Medical Center in Boston presented findings from the study at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Rebecca Zach of Beth Israel Deaconess Medical Center at CROI 2017 in Seattle Courtesy of Benjamin Ryan

Sufficient data were available for about 47,027 (99.8 percent) of the births. The mothers of 34,615 (74 percent of the infants) were HIV negative, while the mothers of 11,932 (25 percent) were HIV positive; 479 (1 percent) of the infants had mothers of an unknown HIV status.

Among the infants with an HIV-positive mother, 5,780 (48 percent) were continuously exposed to ARV treatment from the time of conception (43 percent with Atripla (efavirenz/tenofovir disoproxil fumarate/emtricitabine)), 4,557 (38 percent) were exposed to ARVs during pregnancy beginning after conception, 1,059 (9 percent) had no antiretroviral exposure and 138 (1 percent) had an unknown timing for ARV exposure.

The researchers looked at rates of stillbirth, preterm delivery (before 37 weeks of gestation), small for gestational age at birth (below the 10th percentile) and the death of the infant within 28 days of delivery, as well as a composite of any of these outcomes.

Thirty-four percent of the babies born to HIV-positive mothers experienced one of the aforementioned negative birth outcomes, compared with 24 percent of the babies born to mothers who did not have HIV.

The researchers had data on the CD4 counts of the mothers of 25 percent of the infants who were exposed to ARVs from conception (which was a median of 500). They did not find that CD4 count influenced the risk of the composite of negative birth outcomes.

Analyzing data on single births, researchers adjusted the data for various factors and found that compared with babies born to HIV-negative mothers, those born to HIV-positive mothers had a 1.3-fold increased risk of stillbirth, a 1.5-fold increased risk of preterm delivery, a 1.5-fold increased risk of being small for gestational age, a 1.2-fold increased risk of infant death and a 1.5-fold increased risk of any of these negative birth outcomes.

Looking at single births of infants exposed to ARVs since conception, the researchers adjusted the data for various factors and found that compared with Atripla, the following regimens were associated with an increased risk of the composite of any negative birth outcome and severe negative birth outcomes by the following respective increased factors:

  • Truvada (tenofovir disoproxil fumarate/emtricitabine) and Viramune (nevirapine), 1.2-fold and 1.4-fold
  • Combivir (zidovudine/lamivudine) and Viramune, 1.3-fold and 1.7-fold
  • Truvada and Kaletra (lopinavir/ritonavir), 1.3-fold and 1.6-fold
  • Combivir and Kaletra, 1.2-fold and 1.9-fold. 

Also compared with Atripla:

  • The first three of the four preceding regimens were associated with an increased risk of small for gestational age birth by a respective factor of 1.4-fold, 1.7-fold and 1.8-fold. All four of the preceding regimens were associated with an increased risk of very small for gestational age (less than 2nd percentile), by a respective factor of 1.5-fold, 1.8-fold, 1,8-fold and 1.7-fold.
  • Combivir plus Viramune was associated with a higher risk of stillbirth, preterm delivery, very preterm delivery (before 32 weeks) and infant death by a respective factor of 2.3-fold, 1.2-fold, 1.4-fold and 1.9-fold.
  • Combivir plus Kaletra was associated with a higher risk of preterm delivery, very preterm delivery and infant death by a respective factor of 1.4-fold, 2.2-fold and 4-fold. 

All the regimens analyzed in this study include older ARVs associated with greater toxicities than the more advanced therapies now preferred in the developed world. For example, Atripla is no longer a recommended first-line therapy in the developed world; the Sustiva (efavirenz) component is associated with neuropsychiatric side effects such as intense dreams, and the Viread (tenofovir disoproxil fumarate, or TDF) component contains an older version of tenofovir that is more toxic to bones and kidneys than the updated version, tenofovir alafenamide, known as TAF (marketed as Vemlidy when used as a standalone treatment for hepatitis B virus (HBV)).

Rebecca Zash noted at CROI that while Atripla is a first-line therapy in sub-Saharan Africa, the findings of this study raise concerns about the safety of second-line therapies for use during pregnancy.

None of the ARV regimens analyzed in the study are favored for use in the United States, however. They largely include older drugs that have been upstaged in recent years as newer, less toxic drugs have come out of the pipeline.

When asked how her study’s findings may apply to U.S. women, Zash said, “What it means for the United States is that we really don’t know. There’s really a lack of [pregnancy safety] data on most of the regimens that are first-line in the U.S. Our findings for the first time show that there really could be differences between [ARV] regimens.”