Integrase inhibitors and neural tube defects: more data still needed
Polly Clayden, HIV i-Base
Unsurprisingly a number of presentations at CROI 2019 focused on integrase inhibitors and neural tube defects.
If there is still anyone who missed this: last year, the Botswana Tsepamo study reported neural tube birth defects in 4/596 (0.67%) infants born to women receiving dolutegravir-based ART periconception vs 14/11,300 (0.12%) receiving periconception non-dolutegravir ART. 
Further data are still required to confirm or refute this potential safety signal. Although there have been a number of reports from small birth outcome cohorts since the Botswana data was released, these have been insufficient to alter concerns about periconception dolutegravir (or other integrase inhibitor) use. 
Reports at CROI included: data from the French National database; rates of neural tube defects in Uganda among HIV positive and negative women; data on raltegravir from its originator company; data from the Antiretroviral Pregnancy Registry; limitations of pharmacovigilance databases; and women’s choices in a cohort already receiving dolutegravir following the signal.
French Perinatal Cohort
There was no evidence of a higher birth defect rate among infants exposed to integrase inhibitors (mostly raltegravir) at conception in the French Perinatal Cohort. 
The French Perinatal Cohort, which has been running since 1986, collects data prospectively on all pregnant HIV positive women in 90 centres across the country.
There were 8126 pregnancies reported between 2008 and 2017. Of these, 808 pregnancies were exposed to integrase inhibitors: 301 exposed at conception; 183 as part of first-line ART and 324 as part of second-line had started during pregnancy.
Of 301 periconception exposures: 218 were exposed to raltegravir, 41 to dolutegravir, and 42 to elvitegravir. Birth defect rates for integrase inhibitor-exposed infants at conception did not differ significantly from those exposed during pregnancy: 5.8% (18/301) vs 2.7% (both pregnancy exposure groups 5/184 and 9/324), p=0.09.
Matched controls of pregnancies not exposed to integrase inhibitors also had similar rates of birth defects to those exposed to integrase inhibitors.
And rates of preterm birth, still birth and low birth weight were similar between exposure groups.
A report from the Makerere University–Johns Hopkins University Research Collaboration, Kampala, Uganda found neural tube defects to be common but no significant difference between rates in infants born to HIV positive or HIV negative women. 
A total of 69,766 births, at four centres, were included in this surveillance. Median maternal age was 25 years, 9.6% were HIV positive with 95.3% receiving ART, the majority efavirenz-based. Only one woman received dolutegravir in this cohort as this was not commonly available in Uganda during the study period (August 2015 to December 2017).
There were 71 neural tube defects (66 in HIV unexposed and 5 exposed infants), giving a prevalence of 10.5 (95% CI 8.3 to 13.3) vs 7.4 (95% CI 3.2 to 17.4) per 10,000 live births in HIV unexposed and exposed infants respectively: aOR 0.91 (95% CI 0.3 to 2.4), p=0.858.
The authors noted that these findings are similar to the current estimates for Africa.
Prospectively collected pregnancy outcome data on raltegravir by the originator company Merck did not suggest an association between exposure in the periconception period and neural tube defects. 
As of 31 May 2018, collected 803 prospective reports of which 443 (55%) were first trimester exposures; 295/443 were periconception exposures. There were no neural tube defects reported among this group.
There was one retrospective report of myelomeningocele among life births following periconception exposure to raltegravir.
Antiretroviral Pregnancy Registry
Too few integrase inhibitor exposed pregnancies have been reported to the Antiretroviral Pregnancy Registry (APR) to date to draw definitive conclusions about a potential association between dolutegravir and neural tube defects. 
The majority of reports to the APR and from US and Europe.
Through 31July 2018 there were 1,193 live births with an integrase exposure at any time during pregnancy, of which 604 had ongoing exposure at conception, including 174 dolutegravir, 186 elvitegravir, and 244 raltegravir live birth outcomes. There were no neural tube defects among prospective cases for any integrase inhibitor.
There were 7 neural tube defects plus 2 encephalocele cases reported to the registry retrospectively for which the denominator is unknown. Five were associated with periconception exposure to dolutegravir (4 Botswana and 1 US) and 4 raltegravir (2 periconception exposures, 1 second trimester and one unknown; 3 US and 1 UK).
Limitations of pharmacovigilance databases
An analysis of reports of neural tube defects to four pharmacovigilance databases found many limitations. [7 ] Most notably lack of a clear denominator, reporting is not systematic, there is overlap in reports for multiple drugs used in ART, duplicate cases are difficult to identify, and results differ between databases.
The analysis included reports to: 1. Food and Drug Administration FAERS database (USA) 2. World Health Organisation VigiAccess (WHO) 3. European EudraVigilance (EU) 4. UK Medicines Health Regulatory Authority (MHRA).
This revealed, out of a total of 165 neural tube cases (262 reactions) across the databases, after de-duplication, 44 remained.
Neural tube defects were reported for all drugs except bictegravir (but this is the newest drug with the smallest database). The numbers of reported neural tube cases with dolutegravir exposure were similar in the FDA and WHO databases, but no cases were reported to EU and UK MHRA.
As ART includes multiple drugs, neural tube defects could be reported for multiple drugs and by multiple sources for the same person; for example, for a single case in the FAERs database, there were 40 neural tube defect reports for the same woman who received 7 different drugs
Given widespread use and anticipated use of several new antiretrovirals worldwide, ongoing prospective follow up of pregnant women and birth surveillance studies such as Tsepamo are critical. And pregnant women should be enrolled in phase 3 trials where regulations allow, the authors wrote.
Women’s choice in Uganda
A report from a clinic in Kamala, following the introduction of dolutegravir in 2017, described choices among women of reproductive potential already receiving dolutegravir-based ART after the safety signal in May 2018. 
Of 510 women identified, 21% opted to be switched from dolutegravir (90% to efavirenz) and 79% to remain on dolutegravir. But, only 40% of these women chose effective contraceptives methods and 60% opted for condoms only/no contraceptive method.
Factors associated with switching off DTG were younger age and not using effective contraception. The authors noted that although women made informed decisions with most opting to stay on dolutegravir, effective contraception uptake was low.
Also at CROI 2019, Lynne Mofenson from Elizabeth Glaser Pediatric AIDS Foundation, gave an excellent update on antiretrovirals and birth defects.  It is worth watching the webcast.
As well as providing a tour de force of what is known (and not known) about antiretrovirals and birth defects in pregnancy, she looked at when we can expect more data on the dolutegravir signal.
By the end of March this year there will be data available on at least 1400 dolutegravir periconception exposures in the Tsepamo study.
Citing recent modelling by Schomaker et al, if there are no more defects after 1400 exposures, the confidence interval overlaps with the lower limit of non-dolutegravir exposed prevalence and the findings can be refuted. If there is 1 new defect, 2000 exposures will be needed, and with 2 new defects, 2500 exposures will be before the confidence intervals overlap.
Outside of Tsepamo, there are limited sources of data, usually from high income countries and small cohorts. Together the main ones (APR, Brazil, UK/Ireland) provide about 600 exposures but from countries with lower background rates of neural tube defects than seen in Africa and that usually use folate supplementation.
She also warned of the unreliability of pharmacovigilance databases – something we have grumbled about for some time. 
So, by the middle of this year we should have more data from Tsepamo hopefully combined with other good quality observational data – these data will be reviewed by the WHO guidelines group in July.
In the meantime, she pointed out that the risk of neural tube defects is still relatively small 1 in 1000 in general population with a potential increase to 7 in 1000 with periconception dolutegravir.
As do several of the presentations above, once again she called for data in pregnancy to be prospectively and systematically collected for new antiretrovirals.
Polly Clayden is a co-author of the study looking at pharmacovigilance databases (Abstract 746).
All references are to the programme and abstracts of the Conference on Retroviruses and Opportunistic infections (CROI) 2019, Seattle, 4–7 March 2019, unless otherwise stated.
- Clayden P. No additional neural tube defects among a further 170 preconception dolutegravir exposures in Botswana: Tsepamo study (July 2018). HTB. 3 August 2018.
- Clayden P. No additional neural tube defects with preconception dolutegravir: data from three birth outcome cohorts. HTB. 13 November 2018.
- Sibiude Jet al. No increase in birth defects in infants exposed to integrase inhibitors at conception. Poster abstract 744.
- Barlow-MoshaL et al. Neural tube defects, HIV, and antiretrovirals: birth-defect surveillance in Uganda. Poster abstract 743.
- Hala H et al. Evaluation of neural tube defects after exposure to raltegravir during pregnancy. Poster abstract 745.
- Albano JD et al. InSTI exposure and neural tube defects: data from Antiretroviral Pregnancy Registry. Poster abstract 747.
- Hill A et al. Reports of neural tube defects for 8 arts, in FDA, WHO, EMA, and UK safety databases. Poster abstract 746.
- Arnold AS et al. Ugandan clinic experience following potential teratogenicity alert for dolutegravir. Poster abstract 748.
- Mofensen L. Update on antiretroviral drugs and birth defects. Oral abstract 59.
- Clayden P. Dolutegravir preconception signal: time is up for shoddy surveillance. HTB. 11 July 2018.