Decreasing the risk of neural tube defects with dolutegravir

Dolutegravir belongs to a class of anti-HIV drugs called integrase inhibitors. In Canada and other high-income countries, dolutegravir is sold in the following formulations and under the following brand names:

• Tivicay – dolutegravir
• Dovato – dolutegravir + 3TC
• Juluca – dolutegravir + rilpivirine
• Triumeq – dolutegravir + 3TC + abacavir

An earlier alert from Botswana

Since about 2014, the Southern African country of Botswana has been collecting data on the outcome of pregnancies of HIV-positive women. The main purpose of the data collection was to be sure that the anti-HIV drug efavirenz (Sustiva and in Atripla) was safe for the fetus when it was taken at conception.

In 2016 Botswana began a shift from the use of efavirenz-based regimens for initial HIV treatment to dolutegravir-based ART. As a result, data began to accumulate about the safety of dolutegravir taken at conception or later in pregnancy.

Based on this data, researchers in Botswana found “a potential early signal” for a type of birth defect called neural tube defects. This potential early signal was associated with four infants born to a group of 426 HIV-positive mothers who had been taking dolutegravir at the time of conception. Subsequently, the World Health Organization (WHO) and regulatory agencies in Canada and other countries issued cautionary statements and guidance about the use of dolutegravir in women who were taking it and who might become pregnant or who were pregnant.

It is important to bear in mind that scientists in Botswana found “a potential early signal.” This cautionary statement and the guidance subsequently issued were intended to reduce the possibility of harm to the fetus until further data were collected and analysed. Note that animal studies prior to the licensure of dolutegravir did not find any association with an increased risk for neural tube defects.

An updated analysis

The Botswana scientists have reviewed health-related information on 119,033 infants born to HIV-positive mothers between August 15, 2014 and March 31, 2019. A total of 98 neural tube defects occurred (0.08% of births). The distribution of these neural tube defects by medication use at the time of conception was as follows:

• dolutegravir-based ART – 0.30% (five neural tube defects in 1,683 infants)
• all non-dolutegravir-based ART – 0.10% (15 neural tube defects in 14,792 infants)
• efavirenz-based ART – 0.04% (three neural tube defects in 7,959 infants)

Among the nearly 90,000 infants born to HIV-negative mothers during the study, 70 had neural tube defects (0.08%).

All but one of the birth defects associated with dolutegravir occurred prior to May 2018. This is important to note because it was in that month that the scientists became aware of the potential link between dolutegravir taken at conception and neural tube defects.

Between May 2018 and March 2019, one additional neural tube defect was found in an infant born to a mother who used dolutegravir at conception. This resulted in a proportion of 0.08% (one out of 1,257 infants).

Trends

According to Rebecca Zash, MD, who presented the findings from Botswana, dolutegravir-associated neural tube defects began to fall during the study. The initial association of dolutegravir with potential birth defects was unexpected. The subsequent decrease in the rate of neural tube defects during the study was equally unexpected and occurred before the WHO and regulatory agencies released their cautionary statements and guidance. Furthermore, Dr. Zash and colleagues have stated that the number of births “among women who were taking dolutegravir at conception continued to rise after May 2018...”

Why was there a potential association?

Scientists, regulatory agencies and ViiV Healthcare, the manufacturer of dolutegravir, never expected a potentially increased risk of birth defects of any kind associated with the use of dolutegravir at conception. As a result, they are not certain as to why the risk of neural tube defects appeared in the first place and why this risk is now decreasing in Botswana. Also, the risk has only been reported in Botswana, but not in Brazil, Cameroon or South Africa or in Canada, France or other high-income countries. Arguably, documented exposures to dolutegravir during pregnancy and monitoring for the possibility of birth defects in infants has only been done in studies in those other countries where the number of pregnant users of dolutegravir has been relatively small compared to Botswana.

There are at least two theories for the potential signal between dolutegravir and neural tube defects as advanced by scientists in Botswana:

• Low levels of the B-complex vitamin folate (the synthetic form of this is called folic acid) in the diet of women. Deficiency of folate has long been linked to increased risk of neural tube defects in studies with HIV-negative pregnant women outside of Botswana. To reduce this risk, some countries fortify flour with folic acid. Botswana does not. It is plausible that in some women high levels of dolutegravir could have occurred at the time of conception, perhaps interfering with the fetus’ access to folate and subsequently increasing the risk for birth defects. However, at this time, there is no firm evidence for this theory.
• Some women in Botswana may have genes that increase the risk for neural tube defects in the presence of dolutegravir during conception. Again, there is no firm evidence for this.

Bear in mind

The Botswana study was observational in design. Such studies cannot prove “cause and effect”; that is, they cannot prove that dolutegravir caused neural tube defects. The Botswana scientists took into account potential factors that could have had an impact on the risk of neural tube defects, specifically the following:

• diabetes
• use of anti-seizure drugs
• use of the antibiotic Bactrim/Septra (trimethoprim-sulfamethoxazole)
• obesity

However, none of these were present in mothers who used dolutegravir at conception and gave birth to infants with birth defects.

In context

The scientists in Botswana made the following statement about their findings:

“The data…suggest a potential association between dolutegravir exposure at conception and the development of neural tube defects. Although the prevalence of neural tube defects was three times as high with dolutegravir as with non-dolutegravir [ART], this represented only approximately two defects per 1,000 [births].”

Infectious disease specialists Diane Havlir, MD, and Meg Doherty, MD, have stated in an editorial in the New England Journal of Medicine that the data on dolutegravir from Botswana should not “preclude its use among women of reproductive age.” However, they also stated that more data are needed, specifically that “large-scale pharmacosurveillance studies of birth outcomes in more countries are the only way to get an answer to the actual risk of neural tube defects and other adverse birth outcomes.”

The data from Botswana also show that efavirenz used at the time of conception is not linked to an increased risk of birth defects. Efavirenz-based regimens were once widely used in high-income countries. However, use of efavirenz has been linked to an increased risk for neuro-psychiatric side effects, and, in a small proportion of people (about 1%), an increased risk for thoughts about suicide and attempted suicide.

In Canada and other high-income countries, the next step is for regulatory agencies to issue any updates to their guidance originally issued in 2018 concerning the use of dolutegravir at conception and in pregnancy. In the absence of such guidance, doctors will likely continue to use regimens for which they have experience in pregnant HIV-positive women—such as ritonavir-boosted darunavir or the older twice-daily formulation of raltegravir (Isentress). Such regimens have not been linked to an increased risk for neural tube defects.

Resource:

CATIE News: Agencies issue caution about use of dolutegravir by pregnant HIV-positive women

—Sean R. Hosein

REFERENCES:

1. Zash R, Holmes L, Diseko D, et al. Neural tube defects by antiretroviral and HIV exposure in the Tsepamo Study, Botswana. In: Proceedings and abstracts of the 10^th IAS Conference on Science, 21–24 July 2019. Mexico City, Mexico. Abstract MOAX0105LB.
2. Pereira G, Kim A, Jalil E, et al. No occurrences of neural tube defects among 382 women on dolutegravir at pregnancy conception in Brazil. In: Proceedings and abstracts of the 10th IAS Conference on Science, 21–24 July 2019. Mexico City, Mexico. Abstract MOAX0104LB.
3. Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. New England Journal of Medicine. 2019 Aug 29;381(9):827-840.
4. Raesima MM, Ogbuabo CM, Thomas V, et al. Dolutegravir use at conception – additional surveillance data from Botswana. New England Journal of Medicine. 2019 Aug 29;381(9):885-887.
5. Havlir DV, Doherty MC. Global HIV treatment – turning headwinds into tailwinds. New England Journal of Medicine. 2019 Aug 29;381(9):873-874.
6. Money D, Lee T, O’Brien C, et al. Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study. British Journal of Obstetrics and Gynaecology. 2019; in press.
7. Chouchana L, Beeker N, Treluyer JM. Is There a safety signal for dolutegravir and Integrase inhibitors during pregnancy? Journal of Acquired Immune Deficiency Sydromes. 2019 Aug 1;81(4):481-486.
8. Mandelbrot L, Ceccaldi PF, Duro D, et al. Placental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model. PLoS One. 2019 Aug 13;14(8):e0220323.