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An individual patient data analysis of almost 25,000 pregnancies in women living with HIV has found that the rate of birth defects following exposure to efavirenz was not statistically different, and may even be lower than in infants exposed to other antiretrovirals. The analysis by Professor Begoña Martinez de Tejada of the University of Geneva and colleagues is published in the Journal of Acquired Immune Deficiency Syndromes.

“We suggest that licensed product information on efavirenz is updated and that the few remaining European guidelines that still recommend avoiding efavirenz should be reconsidered,” the authors say.

Historically, there were concerns about the use of efavirenz during pregnancy, due to findings from animal studies and a small number of case reports of neural tube defects in infants exposed to efavirenz during the first three months of gestation. With time and more data, these concerns proved to be misplaced. In 2014, a systematic review and meta-analysis of 23 studies found that treatment with efavirenz during the first three months of pregnancy did not increase the risk of birth abnormalities (relative risk 0.78, 95% confidence interval 0.56-1.08). The overall incidence of birth abnormalities in infants exposed to efavirenz was 1.6%, comparable to figures reported in the general population in many countries.

Efavirenz remains a widely used antiretroviral by women of reproductive age and by pregnant women, especially in low- and middle-income countries. Although efavirenz’s place as a preferred first-line antiretroviral was starting to be taken by dolutegravir, current concerns about birth defects following exposure to dolutegravir during the first three months of pregnancy have meant that many women have been asked to take efavirenz again or have only been offered efavirenz.

The European Pregnancy and Paediatric HIV Cohort Collaboration includes data from 24,963 pregnancies ending in singleton live births between 2002 and 2015. Cohorts in Belgium, Denmark, Germany, Ireland, Italy, the Netherlands, Poland, Romania, Spain, Sweden, Switzerland, Thailand, Ukraine and the United Kingdom provided data.

In 1200 pregnancies (4.8%), the mother received efavirenz at the time of conception or during the first three months of pregnancy; in 7537 pregnancies (30.2%) she received a non-efavirenz regimen; and in 16,226 pregnancies (65%) she did not receive antiretroviral treatment at this stage.

There were 412 infants with at least one birth abnormality, including 34 infants with two or three abnormalities. The overall prevalence was 1.7%. Limb/musculoskeletal and congenital heart defects were the most commonly reported.

Among infants exposed to efavirenz, the prevalence of birth defects (1.6%, 95% CI 0.96-2.5%) was not statistically significantly higher than among infants not exposed to any antiretrovirals (1.3%, 65% CI 1.1-1.5%) or a non-efavirenz regimen (2.4%, 95% CI 2.1-2.8%).

After adjustment for other factors that could skew the results, the risk of birth defects was 40% lower in infants exposed to efavirenz than in those exposed to other antiretrovirals, but this was not statistically significant (adjusted odds ratio 0.61, 95% confidence interval 0.36-1.03).

Among children with congenital heart defects, almost half in the non-efavirenz group and a third in the efavirenz group had also been exposed to zidovudine. Studies have had divergent findings on the question of whether heart abnormalities are associated with zidovudine exposure or not.

Pre-term birth was more common in infants with birth defects (25%) than infants without defects (11%). There was no association with low birth weight.

“Overall, our results demonstrate evidence of the safety of efavirenz when used from the start of pregnancy with no clinically relevant differences in the risk of birth defects compared with infants exposed to non-efavirenz based regimens or non-exposed to antiretroviral therapy,” Professor Martinez de Tejada concludes.

The recent report of a potential safety issue for dolutegravir, an integrase inhibitor, has raised questions about whether there may be a safety issue for other drugs in the same class. Studies of bictegravir, elvitegravir and dolutegravir reported at October’s HIV Glasgow conference were reassuring.

Further data on raltegravir (886 live-born infants exposed to the drug) and elvitegravir (31 live-born infants) have been provided by the National Study of HIV in Pregnancy and Childhood, which collects data in the UK and Ireland. Pregnancies between 2008 and 2018 were included; the antiretrovirals could have been taken during any stage of pregnancy.

Of those exposed to raltegravir, the prevalence of birth abnormalities was 2.6%, with a rate that was not statistically different among the quarter who were exposed to the drug at the time of conception (2.3%). This is consistent with the prevalence of birth defects in the general population of the UK (2.0%) and with other HIV-positive women in the cohort (2.8%).

None of the small number of infants exposed to elvitegravir had a birth abnormality.

Martinez de Tejada B et al. Birth Defects Following Exposure to Efavirenz-Based Antiretroviral Therapy at Conception/First Trimester of Pregnancy: A Multi-Cohort Analysis. Journal of Acquired Immune Deficiency Syndromes, online ahead of print, 2018. (Abstract).

Rasi V et al. Surveillance of congenital anomalies following exposure to Raltegravir or Elvitegravir during pregnancy in the UK and Ireland, 2008-2018. Journal of Acquired Immune Deficiency Syndromes, online ahead of print, 2018. (Abstract).