Tsepamo: 3 in 1,000 infants exposed to dolutegravir have neural tube defects
According to results from the ongoing Tsepamo study in Botswana, infants born to women who took the integrase inhibitor dolutegravir for HIV infection from conception remained at an elevated risk for neural tube defects, with three in 1,000 born with these conditions. However, the findings, which were presented at the International AIDS Society Conference in Mexico City and published in The New England Journal of Medicine, showed that the risk is significantly lower than previously estimated.
Following these results, WHO strengthened its recommendation for dolutegravir as a first-line treatment for HIV for all populations, including pregnant women and those of childbearing potential.
Early signal of safety issues
In May 2018, the FDA issued a safety alert about dolutegravir after preliminary findings from the Tsepamo study suggested that women who received the drug at the time of becoming pregnant or early in the first trimester were at a higher risk for having an infant with neural tube birth defects impacting the brain, spine and spinal cord. Rebecca Zash, MD, an assistant professor of medicine at Beth Israel Deaconess Medical Center and a research fellow in the department of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, and colleagues continued their surveillance for these birth defects across Botswana.
The researchers identified 119,477 deliveries occurring between August 2014 and March 2019. Of these births and stillbirths, 98 (0.08%; 95% CI, 0.07%-0.1%) had neural tube defects.
Among the 1,683 mothers in the study who were taking dolutegravir from conception, five of their infants had neural tube defects (0.3%; 95% CI, 0.13%-0.69%) — lower than the 0.94% prevalence initially reported back in 2018. These defects included myelomeningoceles (n = 2), anencephaly, encephalocele and iniencephaly (n = 1 each).
In comparison, 15 infants born to 14,792 mothers taking any other ART regimen from conception had neural tube defects (0.1%; 95% CI, 0.06%-0.17%). Three infants born to mothers on efavirenz from conception had neural tube defects (0.03%; 95% CI, 0.01%-0.11%). The prevalence of neural tube defects was also lower among infants born to women who began taking dolutegravir during pregnancy (n = 1 of 3,840; 0.03%; 95% CI, 0%-0.15%), and among infants born to women who did not have HIV infection (n = 70 of 89,372; 0.08%; 95% CI, 0.06%-0.10%).
Overall, children were 0.2 percentage points (95% CI, 0.01% to 0.59%) more likely to have neural tube defects when their mothers were taking dolutegravir compared with any other ART regimen from conception.
Implications of the findings
Zash and colleagues said the findings linking dolutegravir to birth defects in children were “unexpected.” A possible explanation could be folate deficiency associated with the compound.
“Folate deficiency is a well-known risk factor for neural-tube defects, and folate antagonism by dolutegravir has been investigated as a potential mechanism to explain our clinical data,” they wrote.
Additional surveillance is planned, they added.
Although dolutegravir was linked to a higher risk for neural tube defects among newborns in the Tsepamo study, findings published in Annals of Internal Medicine suggested the drug may prevent many more deaths and HIV transmissions among women than efavirenz. Researchers said the findings support a “context-specific discussion about the tradeoffs between the risks for harm and the benefits” of both treatment options.
Zash described Tsepamo as “the gold-standard study for evaluating the risk for neural tube defects and exposure to dolutegravir at conception.”
“The small risk for neural tube defects that Tsepamo found is just one piece of information regarding the use of dolutegravir in pregnancy, and it has to be weighed against the large projected benefits of dolutegravir,” she said. “Determining the best ART treatment for women of reproductive age potential is really a risk-benefit analysis, and Tsepamo has been able to quantify this particular risk.”
Zash added that there are “good data” to suggest that recommending dolutegravir to women who are already pregnant is both safe and effective.
“Given the benefits, dolutegravir should definitely be recommended for women who start ART during pregnancy,” she said. “For women who are starting ART before they get pregnant, I personally think that it is reasonable for physicians to recommend dolutegravir given the small absolute increased prevalence that we found in Tsepamo weighed against the benefits of dolutegravir, taking into account the patient’s history, preferences and values.”
In response to the Tsepamo study findings and other available evidence, WHO reaffirmed its recommendation for dolutegravir as a first-line drug.
Meg Doherty, MD, MPH, PhD, coordinator of treatment and care in the Department of HIV/AIDS at WHO, said in a press briefing that the decision was made based on the overall decreasing prevalence of neural tube defects, most of which occurred in countries that do not have folate fortification. In addition, Doherty said the recommendation is important in the context of drug resistance to nevirapine or efavirenz before starting therapy, with 12 of 18 countries reporting resistance to treatment at more than 10%.
“It is much more urgent at this point to start to reinforce the use of new regimens, including dolutegravir,” she said.
Dolutegravir was approved in the United States in 2013. It is available under the brand name Tivicay (ViiV Healthcare) and as part of fixed-dose combinations under the brand names Juluca (dolutegravir/rilpivirine, ViiV Healthcare) and Triumeq (abacavir/dolutegravir/lamivudine; ViiV Healthcare). – by Katherine Bortz
FDA. FDA Drug Safety Communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). https://www.fda.gov/drugs/drugsafety/ucm608112.htm. Accessed July 19, 2019.
UNAIDS. Botswana. https://www.unaids.org/en/regionscountries/countries/botswana. Accessed July 20, 2019.
Disclosures: Zash reports no relevant financial disclosures.