What will it take to refute the possible safety signal for dolutegravir and neural tube defects?

In May 2018, regulatory authorities released cautionary statements about the possible association between neural tube defects (NTDs) and dolutegravir (DTG)-based antiretroviral therapy (ART) exposure at conception, based on data from the Tsepamo study in Botswana which reported four NTDs among 426 pregnancies exposed to DTG at conception, compared with 11 among 11 300 who were exposed to ART at conception that did not contain DTG (Zash et al. NEJM 2019;379:979–81). Given the small number of events from a single study, more data are needed to confirm or refute this association. Difficulty finding these additional data highlights limitations of existing pharmacovigilance systems and challenges of combining disparate sources of data to understand rare but important events. Money et al. (BJOG 2019;126:1338–45) report on birth defects among infants born to HIV-infected women in Canada from 2007 to 2017. During this 10-year period, there were 69 exposures to DTG at conception; no NTDs were identified. In Canada, a country with mandated grain folate fortification, overall NTD prevalence is 4 per 10 000 births. Given this low NTD prevalence and only 69 exposures to DTG at conception, the Money study has approximately 8% power to detect a ten-fold NTD increase with DTG conception exposure. Power is further reduced because of lack of birth defect ascertainment among stillbirths or pregnancy terminations; in Botswana, where termination of pregnancy is not legal, 25% of NTDs were detected in stillborn infants. Since May 2018, the Money et al. study is among the largest to evaluate NTDs with DTG exposure, but the chance of a false-negative result (type 2 error) remains >90%. Given low overall NTD prevalence, negative results from small studies provide insufficient evidence to refute the signal. Future meta-analyses may improve power, but uncertainty will remain because of methodological variability, incomplete outcome ascertainment, and differences between countries in preconception folate repletion and baseline NTD prevalence. Outside of Botswana, accrual of sufficient data to confirm or refute the signal will take time. Expanding pharmacovigilance in low-resource settings with high HIV prevalence, where the majority of fetal ART exposures occur, is essential as DTG is further rolled-out and new drugs become available. Ongoing uncertainly about the NTD signal makes ART treatment decisions more challenging but does not necessarily preclude DTG use among women of reproductive potential. DTG-based ART has many advantages (Vitoria et al. AIDS 2018;32:1551–61), and modelling suggests large public health benefits of DTG use in low- and middle-income countries when weighed against small possible absolute NTD risks (Dugdale et al. Ann Intern Med 2019;170:614–25). With the exception of efavirenz, there are insufficient data on the safety of conception exposure to acceptable DTG alternatives, including other integrase inhibitors, protease inhibitors such as darunavir and atazanavir, and newer non-nucleoside reverse transcriptase inhibitors such as rilpivirine and doravirine. A focus on expanding pharmacovigilance systems, improving comprehensive sexual and reproductive health service access, and developing effective risk communication to assist informed, patient-centred treatment choices will benefit people living with HIV, whether the signal is ultimately confirmed or refuted. Additionally, although it is not yet known whether folate could mitigate the possible DTG-associated NTD risk, implementation of folate food fortification and pre-conception folate supplementation in settings where these important interventions are lacking would benefit persons living both with and without HIV (Kancherla. Birth Defects Res 2018;110:965). RMZ reports grants from NIH/NICHD during the conduct of the study. There are no other potential conflicts of interest. A completed disclosure of interests form is available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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