Assessing the risk of dolutegravir for women of childbearing potential
Authors: Michael Schomaker, Mary-Ann Davies, Morna Cornell, Nathan Ford
Journal: The Lancet Global Health (2018)

Data from May 2018 from Botswana have suggested a potential increased risk of neural tube defects (NTDs) in infants born to women with periconception exposure to the antiretroviral drug dolutegravir.1Mofenson LM In-utero ART exposure and the need for pharmacovigilance.Lancet Glob Health. 2018; 6: e716-e717Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 2WHOhttp://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdfDate accessed: July 16, 2018Google Scholar Among 426 women exposed to dolutegravir at conception, four infants with NTDs were identified, giving a proportion of 0·94% compared with 0·10% in infants of women exposed to other antiretroviral drugs at conception.2WHOhttp://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdfDate accessed: July 16, 2018Google Scholar Prevalence of NTDs in sub-Saharan Africa among live births in general is estimated at 0·10%, and about 0·15% without folic acid fortification.3Blencowe H Kancherla V Moorthie S et al.Estimates of global and regional prevalence of neural tube defects for 2015: a systematic analysis.Ann NY Acad Sci. 2018; 1414: 31-46Crossref PubMed Scopus (127) Google Scholar, 4Zaganjor I Sekkarie A Tsang BL et al.Describing the prevalence of neural tube defects worldwide: a systematic literature review.PLoS One. 2016; 11: e0151586Crossref PubMed Scopus (247) Google Scholar Importantly, the Botswana surveillance study found no evidence of an increased risk of adverse birth outcomes, such as stillbirths, among women who initiated dolutegravir during pregnancy—ie, 8 weeks after conception.5Zash 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.Lancet Glob Health. 2018; 6: e804-e810Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar After these data were reported, WHO issued a drug safety alert advising against dolutegravir use in women of childbearing potential and committed to update guidance as more information becomes available. WHO has called for strengthened pharmacovigilance and monitoring of birth outcomes, and additional data will be made available from the Botswana study and other programmes in the coming months. As data accumulate, it will be important to confidently assess whether a given number of dolutegravir exposures and NTDs represents a level of risk that is greater than chance. One proposed approach is shown in the accompanying figure, which illustrates the lower bound of the 95% CI for the proportion of NTDs for different numbers of dolutegravir conception exposures and NTD events, compared with the expected proportion of 0·10% in women exposed to other antiretrovirals at conception. For example, the current proportion of NTDs among infants of women exposed to dolutegravir at conception is four in 426 (0·94%); the lower limit of the respective one-sided 95% CI for this proportion is 0·32%, represented by a solid black dot in the figure. This proportion is higher than the expected 0·10% expected in the general population in sub-Saharan Africa, suggesting that the findings cannot be explained by chance alone. As data on further exposures and cases of NTDs accumulate, one can recalculate the lower confidence limit and assess how close this limit is to the background NTD risk of 0·10%, or to different background risks: for instance, another 1000 cases without further diagnosed NTDs, as shown by the red triangle in the graph, would result in the lower limit of the CI crossing the background proportion, indicating that the risk associated with dolutegravir exposure might be no different to that in infants born to women exposed to other antiretroviral drugs (given the background rate, one new NTD can be expected per 1000 live births). Reliable ascertainment of both numerators and denominators will be essential. For numerators, although reliable diagnosis of NTDs is relatively straightforward, the optimal approach would be diagnosis with the investigator blinded to exposure status by use of prospectively collected data, and including other adverse birth outcomes such as stillbirths, fetal loss, and terminations due to congenital anomalies, as was done in the Botswana surveillance programme. For the denominators, all dolutegravir exposures must be captured within a given cohort, and timing of exposure (periconception) reliably assessed. A minimal assessment of potentially important confounders (eg, folate use) would be desirable. Although case reports and case series will not be informative, relatively small cohorts (eg, 20 exposures) could be pooled with other studies in a so-called living meta-analysis approach, whereby estimates are constantly updated as new data become available.7Elliott JH Turner T Clavisi O et al.Living systematic reviews: an emerging opportunity to narrow the evidence-practice gap.PLoS Medicine. 2014; 11: e1001603Crossref PubMed Scopus (292) Google Scholar Without an established mechanism of action, surveillance should include periconception exposure to other integrase inhibitors to establish if any increased NTD risk is a drug class effect. A proactive, collaborative approach is needed to provide clarity regarding the risk of dolutegravir as soon as possible. Another antiretroviral drug, efavirenz, had been contraindicated in pregnancy since 2006 after several retrospective case reports suggested an association with NTDs. Retrospective reports are not reliable for establishing risk; it took 8 years before enough data had accumulated to convince the WHO guideline panel that evidence of fetal harm was sufficiently limited and the benefits of efavirenz for pregnant women outweighed potential harms. During this delay, women with HIV in low-income and middle-income countries wishing to conceive were usually switched to nevirapine, a drug associated with greater viral failure compared with efavirenz and adverse drug reactions including serious and sometimes fatal hypersensitivity reactions. The global HIV and sexual and reproductive health community have an unprecedented opportunity to collaborate in assessing periconception dolutegravir risk as rapidly as possible. We cannot afford to delay confirmation of whether women with HIV who wish to conceive can take dolutegravir—a drug that is superior to other antiretrovirals in virtually every other regard. We declare no competing interests. MD and MS received support from the Eunice Kennedy Shriver National Institute for Child Health and Human Development for the B positive project (R01HD080465). This work is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned. In-utero ART exposure and the need for pharmacovigilanceIn 2016, the PROMISE trial demonstrated the remarkable efficacy of antiretroviral treatment (ART) during pregnancy and breastfeeding to reduce perinatal and postnatal transmission in Africa—from 37% in the absence of treatment1 to 1·1% at age 18 months—and to provide clinical benefit to the mother.2–4 ART use by pregnant women living with HIV has resulted in a paradigm shift in the paediatric HIV epidemic in the past 20 years, with a striking 80% decrease in new infant infections, down from 590 000 in 1998 to 120 000 in 2016. Full-Text PDF Open Access