Contradicting 2018 interim findings that dolutegravir use in pregnancy increased the risk of the rare birth defects, a Botswana follow-up study found no significant difference in the rate of neural tube defects among infants based on whether their mothers were taking a regimen that contained dolutegravir at conception.
A 2018 report had suggested that HIV-positive women’s use of the drug at conception increased the risk of the rare birth defects. POZ reports that the multiyear study known as Tsepamo, which previously suggested that HIV-positive women’s use of the antiretroviral dolutegravir around the time of conception was tied to a higher risk of neural tube defects among their babies, has finally concluded that this interim finding amounted to a false alarm.
With greater follow-up time, the study of new mothers in Botswana found no significant difference in the rate of neural tube defects among infants based on whether their mothers were taking a regimen that contained dolutegravir at conception.
A neural tube defect, including spina bifida and anencephaly, occurs when an infant experiences incomplete development of the brain or spinal cord. Such defects typically arise during the first several weeks of gestation.
The interim finding that dolutegravir was associated with these birth defects, reported in 2018, led the World Health Organisation (WHO) to delay its recommendation of the highly potent integrase inhibitor for pregnant women and those of childbearing potential. In July 2019, after further data showed that the risk was low, the WHO went ahead and recommended the antiretroviral (ARV) as a preferred first-line treatment option for all populations with HIV, including such women.
Dr Rebecca Zash, of Beth Israel Deaconess Medical Centre in Boston, presented updated findings from the Tsepamo study on Tuesday at the International AIDS Conference, held virtually this year due to the COVID-19 pandemic.
During a teleconference with reporters Dr Monica Gandhi, of the University of California – San Francisco, said the updated Tsepamo findings “completely lay to rest” concerns about the safety of dolutegravir with regard to neural tube defects and “should give us even more comfort to recommend dolutegravir” to women who are pregnant or may become pregnant.
The Tsepamo study, launched in Botswana in August 2014, was originally designed to evaluate the risk of neural tube defects related to HIV-positive women’s exposure to efavirenz.
Efavirenz is sold under the brand name Sustiva and is included in Atripla (efavirenz/tenofovir disoproxil fumarate/emtricitabine). The ARV is no longer widely used in the US due to its neuropsychiatric side effects but is included at different doses in Mylan’s cut-price single-tablet regimens Symfi (efavirenz 600 milligram/lamivudine/tenofovir disoproxil fumarate) and Symfi Lo (efavirenz 400 mg/lamivudine/tenofovir disoproxil fumarate), which were approved in 2018.
After dolutegravir was rolled out in Botswana in mid-2016, the study adjusted to include the new ARV in its comparative analyses.
Dolutegravir is sold as an individual tablet under the brand name Tivicay and is included in the single-tablet regimens Dovato (dolutegravir/lamivudine), Juluca (dolutegravir/rilpivirine) and Triumeq (dolutegravir/abacavir/lamivudine).
In Tsepamo, trained midwives alert the study’s research assistants if they find an abnormality after examining a new-born. A medical geneticist then reviews photos of the abnormality. Between August 2014 and July 2018, the study included eight sites that between them cared for about 45% of all women giving birth in Botswana. By September 2018, the study expanded to include 18 sites, covering about 72% of all births in the sub-Saharan African nation. Since September 2019, the study has maintained surveillance at 16 sites, covering about 70% of all births.
In April 2018, the WHO asked Tsepamo’s investigators to share any preliminary data from the study as the global agency prepared for an upcoming committee meeting pertaining women’s use of dolutegravir around the time of conception.
Zash and her colleagues reported at the International AIDS Conference in Amsterdam in July 2018 that there were four cases of neural tube defects among babies born to 426 women in Tsepamo who had taken dolutegravir at conception, for a rate of 0.94%. By comparison, the neural tube defect rate among women with HIV who took any other ARVs at conception was 0.12% (14 such defects among babies born to 11,300 women). The rate was 0.05% (3 of 5,787) among women with HIV who took efavirenz at conception, zero percent (0 of 2,812) among women who started dolutegravir during pregnancy and 0.09% (61 of 66,057) among HIV-negative women.
Because the sample size of women who had taken dolutegravir at conception remained relatively small at the time of the interim analysis, the study authors could not determine with great confidence whether the apparent increased risk of neural tube defects associated with the integrase inhibitor had been driven by chance.
The investigators would need longer follow-up time to allow for any statistical noise to settle – and, the report says, settle it did, in favour of the safety of dolutegravir use at conception. Subsequent results from the study through March 2019, which Zash presented in August 2019 at the 10th International AIDS Society Conference on HIV Science in Mexico City, indicated that, in fact, the risk of neural tube defects among babies born to women who took dolutegravir was much lower than seen in the 2018 analysis.
Between May 2018 and March 2019, the study had seen only one additional case of a neural tube defect among infants born to the women who took dolutegravir at conception, an overall group that had grown fourfold since the first analysis.
At that time, the neural tube defect rate fell to 0.3% (5 of 1,683) among women exposed to dolutegravir at conception. The rate was 0.10% (15 of 14,792) among women exposed to any other ARV at conception, 0.04% (3 of 7,959) among women exposed to efavirenz at conception, 0.03% (1 of 3,840) among women exposed to dolutegravir during pregnancy and 0.08% (70 of 89,372) among HIV-negative women.
The report says Zash has now reported results from the study running through 30 April, 2020. Since the 2019 report, there have been only two additional cases of neural tube defects—among babies born to 1,908 women exposed to dolutegravir at conception.
So now, the neural tube defect rate is just 0.19% (7 of 3,591) among women exposed to dolutegravir at conception. Otherwise, the rate is 0.11% (21 of 19,361) among women exposed to any other ARV at conception, 0.07% (8 of 10,958) among women exposed to efavirenz at conception, 0.04% (2 of 4,581) among women exposed to dolutegravir starting during pregnancy and 0.07% (87 of 119,630) among HIV-negative women.
Zash and her colleagues concluded that with additional follow-up time since the 2018 report, the neural tube defect rate among babies born to women exposed to dolutegravir during conception was levelling off at about 2 per 1,000 births. They concluded that there was no statistically significant difference in this rate compared with the rate seen among women taking non-dolutegravir ARV regimens around the time of conception.
Abstract
Background: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)–infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies.
Methods: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals.
Results: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, −0.13 to 0.87).
Conclusions: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.)
Authors
Rebecca Zash, Lewis Holmes, Modiegi Diseko, Denise L Jacobson, Sean Brummel, Gloria Mayondi, Arielle Isaacson, Sonya Davey, Judith Mabuta, Mompati Mmalane, Tendani Gaolathe, M Essex, Shahin Lockman, Joseph Makhema, Roger L Shapiro
AIDS 2020 Virtual, the International AIDS Society conference (abstract OAXLB0102)
[link url="https://www.poz.com/article/dolutegravir-use-conception-tied-neural-tube-defects"]POZ material[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMc1807653"]NEJM correspondence[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa1905230"]10th International AIDS Society Conference on HIV Science abstract (NEJM 2)[/link]
[link url="http://www.natap.org/2020/IAC/IAC_112.htm"]IAC 2020 study results[/link]