No further evidence of an increased risk of infant neural tube defects related to the use of dolutegravir or other integrase inhibitors in early pregnancy has emerged in safety reviews conducted over the past few months, researchers reported at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) on Monday.
The potential risk of a harmful effect of the integrase inhibitor dolutegravir on foetal neurological development was flagged up after an increased incidence of neural tube defects was observed in the infants of mothers who had been taking dolutegravir at the time of conception in Botswana. The World Health Organization subsequently issued guidance to national treatment programmes which suggested that dolutegravir-based regimens should be avoided by women of childbearing potential unless they had adequate contraception in place.
Investigators have stressed that what was observed was a safety signal that needs to be investigated, and that more evidence is needed before investigators can say for certain that dolutegravir increases the risk of neural tube defects if taken at the time of conception or in the first trimester (first three months) of pregnancy. Further follow-up from the prospective Botswana study will be reported in March 2019.
The safety signal also raised questions about the safety of other integrase inhibitors. Raltegravir (Isentress) has been used widely in the United States and Europe since 2008 but there is no evidence that its use is associated with an increased risk of neural tube defects.
Neural tube defects occur when the development of the spinal cord, the brain and the skull is impaired during the early weeks of pregnancy. The most frequent cause of these defects is a deficiency in folate, so pregnant women are advised to take a folic acid supplement. Exposure to some drugs around the time of conception and during the early weeks of pregnancy may cause neural tube defects.
No signal for neural tube defects associated with bictegravir or elvitegravir
Gilead Sciences reported on the incidence of neural tube defects in infants born to women exposed to the integrase inhibitors elvitegravir or bictegravir during pregnancy, who took part in clinical trials of these drugs up to May 2018 or who were exposed to the drugs after licensing. A total of 630 women exposed to elvitegravir and 25 women exposed to bictegravir became pregnant. Of these, 389 were exposed to elvitegravir before conception or during the first trimester of pregnancy and 23 to bictegravir in the same period.
One neural tube defect was reported, in an infant born to a mother who had taken elvitegravir, cobicistat and tenofovir alafenamide/emtricitabine prior to conception, and who switched to raltegravir/tenofovir alafenamide/emtricitabine 48 days after her last menstrual period. An anencephaly (absence of large part of skull and brain) was detected by ultrasound scan during early pregnancy. Another case associated with the same regimen was reported after May 2018 and is still being investigated. No cases of neural tube defects were associated with exposure to bictegravir.
The investigators say that the rate of neural tube defects observed in this study is no higher than the background rate, but they cautioned that it was difficult to calculate a rate of defects because many of the reports regarding birth outcomes are retrospective and because not all pregnancies exposed to the drugs are reported.
No signal for neural tube defects associated with dolutegravir
Three retrospective analyses reported on the incidence of neural tube defects in national cohorts, either in women exposed to dolutegravir or to other integrase inhibitors.
The Canadian Perinatal HIV Surveillance Program reported on neural tube defects in 2423 infants born to mothers receiving antiretroviral therapy between 2007 and 2017, of whom 2325 were exposed to antiretroviral drugs during the first trimester of pregnancy. A total of 170 were exposed to an integrase inhibitor (80 to dolutegravir, 76 to raltegravir and 28 to elvitegravir). Two neural tube defects were reported, neither in infants exposed to dolutegravir. However, the study did find a threefold higher rate of congenital abnormalities in infants exposed to elvitegravir during the first trimester.
The Frankfurt HIV Cohort reported on the outcomes of mothers and infants exposed to integrase inhibitors during pregnancy. Two hundred and seventy-eight women in the cohort became pregnant between 2008 and 2018, of whom 52 were exposed to integrase inhibitors (48 to raltegravir, 4 to dolutegravir). No neural tube defects were observed.
The Eastern and Central European Network Group conducted a survey of dolutegravir use in 20 countries in the region, of which seven centres in six countries were able to provide detailed information about dolutegravir exposure. Four hundred and fifteen women took dolutegravir, 28 during pregnancy (24 commenced before conception and 4 after conception). No neural tube defects were reported but the investigators emphasised the importance of gathering data on other risk factors that may affect birth outcomes. In the dolutegravir-treated women, only 22 were taking folic acid supplements, four were smoking prior to conception, three were using psychoactive substances and seven were using concomitant medication.
Farrow T et al. Cumulative safety review of elvitegravir and bictegravir use during pregnancy and risk of neural tube defects. International Congress on Drug Therapy in HIV Infection (HIV Glasgow), Glasgow, 2018, abstract P030.
Kowalska J et al. Exposure to dolutegravir in pregnant HIV-positive women in Central and Eastern Europe and neighbouring countries: data from the ECEE Network Group. International Congress on Drug Therapy in HIV Infection (HIV Glasgow), Glasgow, 2018, abstract P004.
Money D et al. An analysis of congenital anomalies in pregnant women living with HIV in Canada: no signal for neural tube defects in women exposed to dolutegravir. International Congress on Drug Therapy in HIV Infection (HIV Glasgow), Glasgow, 2018, abstract P001.
Weissmann D et al. Use of integrase inhibitors in HIV-positive pregnant women: data from the Frankfurt HIV Cohort. International Congress on Drug Therapy in HIV Infection (HIV Glasgow), Glasgow, 2018, abstract P002.