In May 2018, the US Food and Drug Administration (FDA) issued a warning that serious neural tube birth defects (NTDs) had been reported in women treated with dolutegravir (DTG) during the conception period.1 The warning was based on an unplanned interim analysis by the Tsepamo Study in Botswana, which was subsequently published in the New England Journal of Medicine in July.2
The analysis assessed birth surveillance outcome data from August 2014 to May 2018 from 8 government hospitals in Botswana capturing 45% of all births.. In common with other low- and middle-income countries like Brazil, Malawi, and Nigeria, Botswana changed to a DTG-based first-line antiretroviral therapy (ART) regimen in May 2016. Data initially showed similar rates of adverse birth outcomes in pregnant women taking DTG-based ART compared with efavirenz-based ART during pregnancy.3 However, in women conceiving after initiating DTG, a higher than expected early signal of NTDs was detected in the births.
More than 99% of 89,064 births were evaluated by midwife examination with photographs or descriptions of major abnormalities. Of 426 births to mothers treated with DTG during conception, 4 (0.94%) had NTDs including encephalocele, myelomeningocele, iniencephaly, and anencephaly compared with 86 NTDs for all births (0.10%; 95% CI, 0.08 to 0.12). In the analysis, 14 NTDs were noted in 11,300 births (0.12%) to women taking non-DTG ARVs during conception and none to women who started DTG during pregnancy.
The ramifications of this finding are considerable. DTG is known to be superior to other ARVs with respect to clinical efficacy and tolerability and with a greater barrier to developing resistance. Informed decision-making in women living with HIV/AIDS depends on fully defining the nature of this risk. A letter recently published in the Lancet has highlighted the sensitivity of the rate of NTDs to further surveillance data.4 For example, a further 1000 births following dolutegravir-conception exposure without NTD will reduce the lower limit of the 95% CI to below 0.1 — the background rate in Botswana — indicating that the rate of NTDs may be no greater than chance alone.
Infectious Disease Advisor spoke to Rebecca M. Zash, MD, instructor of medicine at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, Massachusetts, and research fellow in immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, a co-investigator in one of the interim analyses3.
Infectious Disease Advisor: When do you expect there to be follow-up reporting from the Tsepamo Study to see whether the signal remains with greater numbers exposed?
Dr Zash: Our next planned analysis will be at the end of March 2019 and we will report the results as soon as possible. Our next analysis will not just include neural tube defects, but a comparison of other birth outcomes like stillbirth and preterm delivery and other birth defects.
The reason we chose that date is that it is approximately 40 weeks (the average length of gestation) after the FDA, European Medicines Agency, World Health Organization (WHO), and Botswana Ministry of Health warnings were issued. So, all women who started DTG and became pregnant before the warnings came out should deliver during this 40-week period. Since this is a surveillance study, we only capture data at the time of delivery.
Infectious Disease Advisor: The current WHO recommendation for women of childbearing age is to receive alternative ARV regimens. Do you think there will be sufficient numbers of women receiving peri-conception DTG in the Tsepamo Study to give clarity about this early signal of neural tube defects?
Dr Zash: Since the design of our study is birth outcomes surveillance, we are only capturing the data at the time of delivery. As I mentioned, for approximately 9 months after the initial warning came out from Botswana and WHO, we will be gathering data on births to women who started DTG before the warnings were out. There was no impact on treatment in these women as it came too late.
We initially projected that there would be approximately 600 more births that we could add to our analysis. However, over the last few months we were able to expand the number of sites for our study from 8 to 18, so now we think we should have at least 800 more births, for a total of >1400 total DTG-conception exposures.
However, I am not sure this will provide clarity regarding the early signal. I think if the signal continues (ie, approximately 1 in 100 neural tube defects in the DTG-conception group), this will provide quite strong evidence for an effect. However, if the signal does not continue, we may be left with some uncertainty.
For example, if none of the next 800 DTG-conception births have an NTD, the total rate of NTDs in the DTG-conception group will be approximately 3 times higher than our comparison groups, but the lower 95% CI will overlap with the upper CI in some, but not all of the comparison groups. I think in that case, it would be reassuring, but it will be helpful to see data from other settings in order to confirm that there is no effect.
Infectious Disease Advisor: The 4 cases identified had a variety of neural tube defects. Is it biologically plausible that these could all be caused by DTG?
Dr Zash: It would be unusual, but biologically plausible.
Infectious Disease Advisor: Is there data available on folate supplementation in the mothers in this study other than mothers in whose offspring the neural tube defects occurred?
Dr Zash: We collected the same data on all the mothers: the date on which they started a folate-containing supplement. In our population, all groups were similar — almost no one received folate supplementation until they were already pregnant, after initiating antenatal care, not before conception. But we do not have any way to know the true levels of pre-conception folate in any of our groups and we do not have any information on diet.
As many as 15 million people, many of whom will be women of child-bearing age, could be starting dolutegravir within the next 5 years.5 Early evidence of an increased risk for birth defects is concerning but remains to be fully established. Carefully defining the risk of using this medication during conception is crucial and depends on ongoing systematic pharmacovigilance.
1. US Food and Drug Administration (FDA) Drug Safety Communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). Silver Spring, MD: US Food and Drug Administration. Updated September 2018. Accessed October 3, 2018.
2. Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med. 2018;379(10):979-981.
3. Zash R, Jacobson DL, Diseko M, et al. Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study [published online July 6, 2018]. Lancet Global Health. doi:10.1016/S2214-109X(18)30218-3
4. Schomaker M, Davies MA, Cornell M, Ford N. Assessing the risk of dolutegravir for women of childbearing potential [published online September 1, 2018]. doi: 10.1016/S2214-109X(18)30326-7
5. Hill A, Clayden P, Thorne C, Christie R, Zash R. Safety and pharmacokinetics of dolutegravir in HIV-positive pregnant women: a systematic review. J Virus Erad. 2018;4(2):66-71.