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  IAS 2019: Conference on HIV Pathogenesis
Treatment and Prevention
Mexico City
July 21-24 2019
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Neural Tube Defect Rate 0.40% With Dolutegravir
in Pregnancy--But Data Still Slim

  10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City
Mark Mascolini
Neural tube birth defects occurred at a rate of 0.40% when pregnant women took periconception dolutegravir, compared with an overall periconception prevalence of 0.03% for any antiretroviral therapy [1]. But the dolutegravir result from the Antiretroviral Pregnancy Registry (APR) remains tentative because of the small number of women taking the integrase inhibitor during pregnancy, only 248.
Concern about neural tube defect risk when pregnant women take dolutegravir arose when the Tsepamo birth surveillance study in Botswana suggested such a link in May 2018 [2,3]. The finding stirred debate about dolutegravir use by HIV-positive women who may become pregnant. Neural tube defects affect the brain, spine, or spinal cord and notably include spina bifida and anencephaly.
To improve understanding of this issue, the APR Steering Committee charted prevalence of central nervous system (CNS) defects, neural tube defects, and encephalocele in the APR by antiretroviral drug class and individual drugs. The APR considers encephalocele separately from neural tube defect because it may occur slightly after neural tube closure. This analysis included data through January 2019.
The APR has collected voluntarily submitted reports on women taking antiretrovirals during pregnancy since 1989 [4]. The international registry includes 160 antiretrovirals--57 brands and 103 generics. For CNS and neural tube defects, 75% of reports come from the US and Canada, 8% from Europe, 7% from Africa, 6% from South America, and 4% from Asia.
Among 20,727 pregnancy outcomes including 19,287 live births, the APR has logged 536 birth defect cases (2.8%). There were 51 CNS defects, including 8 neural tube defects (0.04%) and 1 encephalocele. Among 8546 pregnancies with periconception antiretroviral exposure (from 2 weeks before conception through up to 28 days after conception), there were 241 birth defect cases (2.8%) and 23 CNS defects, including 3 neural tube defects.
For periconception ART, neural tube defect prevalence came to 0.03% (3 cases) for any ART, 0.04% for any nucleoside/nucleotide (0.10% for abacavir), 0.03% for any protease inhibitor (0.09% for atazanavir), 0.04% for any nonnucleoside (0.10% for efavirenz), 0.14% (1 case) for any integrase inhibitor, and 0.40% (1 case in 248 births) for dolutegravir (0 for elvitegravir or raltegravir). The 1 dolutegravir case was anencephaly. The APR recorded no cases of encephalocele. The Botswana study listed 4 neural tube defects with periconception dolutegravir in 426 pregnancies (0.94%) [2].
The researchers noted that most birth defect cases in the APR come from the United States, where national food folic acid fortification lowers neural tube defect risk by one third to two thirds in the general population. They proposed that "the number of pregnancies enrolled in the APR with integrase inhibitor periconception exposure [is] currently insufficient to rule out or confirm any potential association with neural tube defect." They noted that ruling out a 3-fold increase in a rare event like neural tube defect requires about 2000 preconception exposures, about 8 times more than recorded so far for dolutegravir.
1. Mofenson LM, Vannappagari V, Scheuerle AE, 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 (IAS 2019), July 21-24, 2019, Mexico City. Abstract TUAB0101.
2. AIDSinfo. Recommendations regarding the use of dolutegravir in adults and adolescents with HIV who are pregnant or of child-bearing potential. May 30, 2018. http://www.natap.org/2018/HIV/053018_01.htm
3. Alcorn K. Neural tube defects and integrase inhibitors: still waiting for stronger evidence. aidsmap.com. March 7, 2019. http://www.aidsmap.com/page/3464458/ 4. Antiretroviral Pregnancy Registry. www.APRegistry.com. SM_APR@INCResearch.com.