Dolutegravir neural tube defect risk declines but still slightly higher than with other antiretrovirals
Polly Clayden, HIV i-Base
Data presented at IAS 2019, from the Tsepamo study, showed adeclining risk for dolutegravir (DTG)-associated neural tube defects (NTDs), although this remains slightly elevated compared to that with exposure to other antiretrovirals.
Datafrom Botswana (not covered by Tsepamo), Brazil and the Antiretroviral Pregnancy Registry (APR) were also shown at the conference.
World Health Organization (WHO) now recommends DTG-based ART for all and this recommendation includes women of reproductive potential. 
On 18 May 2018, WHO issued a statement following the identification of a potential safety issue with DTG related to NTDs in infants born to women who were taking DTG at the time of conception. 
The safety issue was identified at a preliminary unscheduled analysis of the ongoing Tsepamo observational study in Botswana. The analysis revealed 4 cases of NTDs out of 426 women who became pregnant while taking DTG.
July 2018 WHO guidelines recommended that women and adolescent girls of reproductive potential should use DTG with consistent and reliable contraception. And national guidelines also interpreted these results and WHO guidance with varying degrees of caution.
So, the update from Tsepamo, as well as the other studies (these represent the next three largest datasets after Tsepamo), and the revised WHO recommendations are very welcome after what has been a complicated 14 months.
The most recent update from Tsepamo, reported 5/1683 NTDs among births to women receiving DTG at conception, a rate of 0.3%.  As well as the late breaker presentation at IAS 2019, more detail can be found in the simultaneously-published paper in The New England Journal of Medicine. 
The Tsepamo birth outcomes surveillance study has been conducted by the Botswana Harvard AIDS Institute Partnership since August 2014.
It was originally designed to evaluate for NTDs with efavirenz (EFV). Secondary analyses include: all major structural malformations and other adverse birth outcomes.
Since 1 May 2018 and as of 31 March 2019 the study accrued data on an additional 29,979 deliveries including:1,257 to women on DTG at conception; 3,492 to women on non-DTG at conception; 2,172 specifically to women on EFV at conception; 1,028 to women on DTG started during pregnancy; 328 to women on non-DTG started during pregnancy; and 23,315 to HIV negative women.
Of the total study population, there were 98/119,033 NTDs, a rate of 0.08% (95% CI 0.07 to 0.10). For DTG at conception the rate was 5/1683, 0.30% (95% CI 0.13 to 0.69) and for non-DTG at conception 15/14792, 0.10% (95% CI 0.06 to 0.17).
For the other groups the rates were: EFV at conception3/7959, 0.04% (95% CI 0.01 to 0.11); DTG started during pregnancy 1/3840, 0.03% (95% CI 0.00 to 0.15); non-DTG started in pregnancy 3/5952, 0.05% (95% CI 0.02 to 0.15); and HIV negative 70/89372, 0.08% (95% CI 0.07 to 0.10).
Table 1: Neural tube defect prevalence differences by exposure
|DTG at conception vs comparison group||Prevalence difference % (95% CI)|
|Non DTG at conception||0.20 (0.01 to 0.59)|
|EFV at conception||0.26 (0.07 to 0.66)|
|DTG started in pregnancy||0.27 (0.06 to 0.67)|
|Non-DTG started in pregnancy||0.25 (0.05 to 0.64)|
|HIV negative||0.220.05 to 0.62)|
Since May 2018 the overall rate of NTDs has been lower than in previous years: 12/29,979 (0.04%) vs 98/119.033 (0.08%). But sensitivity analysis restricted to conceptions during the DTG era was similar. The investigators are looking into environmental factors to try to explain this phenomenon.
Rates of any other adverse birth outcomes since October 2016 between EFV and DTG at conception were similar: adjusted RR 0.94 (95% CI 0.86 to 1.02).
The prevalence of NTDs with DTG at conception remains higher than all other exposure groups but the estimated difference is small (0.2–0.27%). Compared with all other ART at conception, the 95% confidence interval indicates that this difference is as low as 0.01% and as high as 0.67%.
Tsepamo surveillance continues and DTG at conception exposures also continue to accrue: 240 since 31 March 2019.
Tsepamo remains the most informative dataset on which to base guidance and policy.
NTD was reported among 1/152 DTG at conception exposures at non-Tsepamo sites in Botswana. 
The Botswana Ministry of Health and Wellness expanded NTD surveillance to sites not covered by Tsepamo.
Data on all deliveries (live births and stillbirths) at 22 facilities added coverage for a further 19% of Botswana’s births (currently Tsepamo covers 72%).
Midwives identified potential NTDs before infants were discharged. A clinical geneticist (blinded to HIV status and ART exposure) reviewed suspected NTDs.
There were 3076 pregnancies: 76% among HIV negative women; 24% HIV positive women; and <1% among women with unknown HIV status.
Seventy-three per cent (n=544) of HIV positive women were on ART at conception; of these 28% (n=152) were on DTG.
This process identified 6 suspected NTDs: 1 confirmed; 2 classified as not NTDs; 2 probably NTDs; and 1 possible NTD.
Three NTDs were included in the final analysis (1 confirmed and 2 probable). One NTD was in the 152 DTG at conception pregnancies, giving a prevalence of 0.66% (95% CI 0.02 to 3.69). The other 2 were in infants born to the 2328 HIV negative mothers, giving a prevalence of 0.09% (95% CI 0.01 to 0.31).
There were none among the 381 no-DTG ART and 261 EFV ART exposures.
Although these findings suggest an increased prevalence of NTDs among infants who were DTG-exposed at conception compared to those born to HIV negative mothers, consistent with previous findings from Tsepamo, the study was only conducted for 6 months, so the numbers of pregnancies to date are small.
No neural tube defects were reported among 382 women on DTG at conception in Brazil. 
DTG was available in the public sector for first-line ART from 2017. Although the drug was restricted in pregnancy, as of May 2018 over 22,624 women between 15–49 years were on DTG in Brazil. And the NTD signal led to a national investigation.
Women who became pregnant on ART containing either DTG, EFV, or raltegravir (RAL) during the periconception period (within 8 weeks before or after the estimated date of conception) between January 2015 and May 2018 were identified retrospectively using the Brazilian ART database.
There were 1468 women included in the evaluation: 382 DTG exposures; 1115 EFV exposures; and 125 RAL exposures.
There were 2 NTDs, 1 exposed to EFV and 1 to RAL at conception and there were none among the DTG exposures.
This study was retrospective, had a large amount of missing data and was probablyunderpowered to detect a difference in exposure groups.
Antiretroviral Pregnancy Registry
One NTD was reported with 248 periconception DTG exposures in the APR through January 2019. 
Since 1989, the APR has collected prospective, voluntary, anonymised reports of women on ART during pregnancy.
For overall birth defects (prevalence 3%) 200 exposures can rule-out a 2-fold increase. But, to rule-out a 3-fold increase in a rare event like NTD (prevalence 0.1%), approximately 2,000 exposures are needed.
For the analyses, earliest timing of exposure was assigned to each drug: periconception (exposure from 2 weeks before conception through 28 days after conception ie 6 weeks estimated gestational age); later 1st trimester (after 6 weeks estimated gestational age) and 2nd/3rd trimester.
There was a total of 20,372 reports (20,727 pregnancy outcomes) of which 8546 (78%) were periconception exposures.
The overall prevalence of NTDs in 8546 periconception exposures was 0.03%. Notably, most of the reports in the APR come from North America, where there is national food folic acid fortification, which has been shown to reduce NTD risk by 36–68% in the general population.
So, this rate is consistent with the observed low NTD prevalence (0.01–0.08%) in most high-income countries with food folic acid fortification.
Among 248 DTG at conception periconception exposures there was 1NTD giving a prevalence of 0.40%, and 0.14% for the integrase inhibitor class (there were no NTDs among 268 RAL and 217 elvitegravir exposures). But this estimate is based on a single NTD in relatively small number of exposures.
It is most fortunate that Tsepamo was ongoing during the roll-out of DTG in Botswana and was able to capture this elevated rate of a rare event in a systematic way.
A denominator of 1663 DTG at conception exposures is still greater than the next three largest data sources above: 382 Brazil, 248 APR, and 152 Botswana MoH. Other publically-presented datasets range from 1 to 69 exposures. [8, 9, 10]
It is critically important that sustainable birth outcomes surveillance continues in low- and middle-income countries, including Tsepamo, the newer surveillance set up by PEPFAR in Uganda and Malawi and those under consideration for Eswatini and South Africa.
Critical too is that more ART-exposed pregnancies are reported to the APR so it can increase its numbers more swiftly and include a broader geographical scope than mostly North America.
The momentum that was gained after the first report of a potential DTG at conception safety signal must continue. And surveillance must be in place as other new antiretrovirals are rolled out. Women make up over half the HIV positive population and lack of safety data in pregnancy affects all of their access to newer drugs.
- WHO.Update of recommendations on first- and second-line antiretroviral regimens. Policy brief. July 2019.
- WHO statement on DTG. 18 May 2018.
- Zash R et al. Neural tube defects by antiretroviral and HIV exposure in the Tsepamo Study, Botswana. 10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract MOAX0105LB.
- Zash R et al. neural tube defects and antiretroviral treatment regimens in Botswana. New England Journal of Medicine, advance online publication, 22 July 2019. (Open access).
- Raesima MM et al. Addressing the safety signal with dolutegravir use at conception: Additional surveillance data from Botswana. 10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract MOAX0106LB.
- Fernandes Fonseca et al. No occurrences of neural tube defects among 382 women on dolutegravir at pregnancy conception in Brazil. 10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract MOAX0104LB.
- Mofensen M et al. Periconceptional antiretroviral exposure and central nervous system (CNS) and neural tube birth defects – data from Antiretroviral Pregnancy Registry (APR). 10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract TUAB0101.
- Clayden P. No additional neural tube defects with preconception dolutegravir: data from three birth outcome cohorts. HTB. 13 November 2019.
- Clayden P. Integrase inhibitors and neural tube defects: more data still needed. HTB. 28 March 2018.
- Zash R. Update from the Tsepamo study. 10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Symposia session TUSY0102.