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Tsepamo: Potential uptick of neural-tube defects with dolutegravir-based ART

Pearl Toh
22 Aug 2019

Children born to women receiving dolutegravir-based antiretroviral therapy (ART) for HIV since conception have an uptick of neural-tube defects compared with those whose mothers took non-dolutegravir ART at conception, additional follow-up data from the Tsepamo surveillance study show.

Since preliminary data from the Tsepamo study in May 2018 have signalled a potential association between dolutegravir exposure at conception and neural-tube defects, regulatory agencies have advised that the use of dolutegravir be limited among women planning pregnancy. The current study presented at IAS 2019 includes additional data from follow-up of new births since May 2018, with expansion of study sites from eight to 18 hospitals in Botswana. [N Engl J Med 2019;doi:10.1056/NEJMoa1905230]

Among 119,033 deliveries examined during the study period of August 2014 to March 2019, there were 98 cases of neural-tube defects (0.08 percent) reported.

The defects were more prevalent among offspring whose mothers were on dolutegravir- vs non-dolutegravir-based ART at conception (0.30 percent vs 0.10 percent), corresponding to a difference of 0.20 percentage points between groups (95 percent confidence interval [CI], 0.01–0.59).

“Since our initial 2018 report, the estimated prevalence has diminished in magnitude to approximately 3 per 1,000 births but remains greater than for all other types of antiretroviral exposure at conception [at 1 per 1,000],” said the researchers.

Of the five neural-tube defects detected in deliveries by mothers who were receiving dolutegravir-based ART at conception, two were myelomeningoceles, while the remaining cases comprised one anencephaly, one encephalocele, and one iniencephaly.

Furthermore, major external structural defects were also more prevalent among offspring of women treated with dolutegravir-based ART at conception than those whose mothers were on non-dolutegravir ART at conception (0.95 percent vs 0.68 percent, difference, 0.27 percentage points, 95 percent CI, −0.13 to 0.87).

The prevalence of neural-tube defects was 0.04 percent with exposure to efavirenz at conception, 0.03 percent with initiation of dolutegravir-based ART during pregnancy, and 0.08 percent in HIV-negative mothers.

What do these all mean? 

“The potential association between dolutegravir and neural-tube defects was unexpected,” said the researchers, given that no such signals were detected in preclinical studies of the drug.

“What do these new findings mean for the ongoing global rollout of HIV treatment? First, we should not panic and demote dolutegravir from the preferred to an alternative regimen or preclude its use among women of reproductive age,” wrote Drs Diane Havlir and Meg Doherty from the University of California, San Francisco in San Francisco, California, US and the WHO in Geneva, Switzerland, respectively in an editorial. [N Engl J Med 2019;doi:10.1056/NEJMe1909363]  

“Dolutegravir and other integrase inhibitors represent a substantial advance to our treatment arsenal, outperforming other agents in nearly all studies in terms of the rapidity of viral suppression, side-effect profile, and resilience to HIV resistance,” they stressed.

Women with HIV should be given a choice on their preferred therapy with a discussion on the risk and benefit involved, pointed out Havlir and Doherty, who noted that a previous modelling study indicates that the benefits of dolutegravir among women in terms of lives saved and reduction in HIV transmissions outweigh the risk. [Ann Intern Med 2019;170: 614-625]

“Second, we need more data,” they stated. “Is dolutegravir or dolutegravir plus TAF* the true culprit?”

As folate deficiency is an established risk factor for neural-tube defects and folate-fortified grains are not mandated in Botswana, the researchers said more data on dolutegravir are warranted from other regions.

“Our findings highlight the need to address global disparities in access to effective contraception and preconception folate repletion, which would benefit the health of all women,” they stated. The study also underlines the need to reinforce postmarketing surveillance of new HIV therapies for rare outcomes.

 

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