After much hand-wringing, the World Health Organization (WHO) has issued new, reassuring guidance that dolutegravir (Tivicay, DTG) is recommended as a first- and second-line antiretroviral treatment across all populations.
This updated guidance, released at the 10th International AIDS Society (IAS) Conference on HIV Science in Mexico City, is based on new data from Botswana and Brazil that found the risk of neural tube defects is much lower than was reported in the 2018 Tsepamo study.
Now, with dolutegravir firmly re-established as a preferred HIV regimen, public health experts are preparing for the hard work of polishing dolutegravir's damaged reputation among providers who are likely to prescribe it.
Experts gathered in Mexico City reflected on the unfortunate reality that many women have been denied dolutegravir since the Tsepamo study results were published in May 2018.
"Nine million women have had zero access to this drug for the past 15 months," said Ambassador Deborah Birx, M.D., coordinator of the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), speaking at an IAS press conference.
Birx and other researchers applauded the swift action of the National Institutes of Health, Centers for Disease Control and Prevention, local public health ministries, and many other organizations that collaborated on robust surveillance studies designed to quickly resolve pressing questions about dolutegravir's safety profile.
However, community activist Jacque Wambui of the National Empowerment Network of People Living with HIV/AIDS in Kenya criticized the public health response, noting since the initial scare, it's been difficult for women of childbearing age to access the drug.
"We made decisions for women," said Birx, "and we made decisions that limited their choice."
New Data From Botswana and Brazil
In 2018, initial results from the Tsepamo study indicated a high prevalence rate of neural tube defects, at about 0.94% -- or almost one in every 100 infants born to mothers taking dolutegravir -- prompting the WHO and the Food and Drug Administration to issue warnings about the drug.
Following the initial data, researchers on the Tsepamo study in Botswana decided to expand the study to see if this would hold up in a larger group of women. Overall, they analyzed more than 100,000 deliveries from August 2014 and March 2019.
Of the 1,683 women who were taking dolutegravir from conception, five infants were born with neural tube defects -- a prevalence rate of 0.3%. This is much lower than the rate reported in the initial Tsepamo results.
Speaking at the IAS press conference, Rebecca Zash, M.D., of the Harvard T.H. Chan School of Public Health in the United States, cautioned that this is still about 0.26% higher than the rate that would be expected for women taking efavirenz.
"While there may be a risk of neural tube defects for dolutegravir, this risk is small and needs to be weighed against all the benefits," she said.
Meanwhile, the Botswana Ministry of Health analyzed data from 22 health facilities that were not included in the Tsepamo study. The country had already implemented dolutegravir as a preferred regimen two years prior, so public health experts were keen to learn more about the possible risks, explained Mmakgomo Mimi Raesima, M.D., of the Botswana Ministry of Health and Wellness, speaking at the IAS press conference.
Of 3,076 recorded pregnancies, 742 women were HIV positive, and 152 of those women were taking dolutegravir. Across the cohort, six cases of suspected neural tube defects were detected, but only three were included in the final analysis after a clinician blinded to the dolutegravir status reviewed and excluded three of the cases.
Ultimately, one of the cases occurred among the 152 women who had taken dolutegravir, for a prevalence rate of 0.66%. That's compared to two cases among the cohort of 2,328 HIV-negative mothers, for a prevalence of 0.09%.
Raesima acknowledged that 0.66% is still high -- but not as high as the 2018 Tsepamo results.
"What is important to note is that our data suggests that neural tube defect risk with [dolutegravir] exposure at conception remains less than 1%," she said. "The next thing we have to be thinking about is: What does it mean?"
In Brazil, researchers may have an answer. Brazil has a comprehensive program of government-funded prenatal care that includes folic acid supplements, which are thought to be protective against fetal neurological defects.
In the wake of the 2018 Tsepamo study, Brazilian health authorities launched their own investigation but found no recorded cases of neural tube defects among 382 women taking dolutegravir at conception.
The analysis, presented by Fernanda Fernandes Fonseca, M.D., of the Ministry of Health in Brazil, included 1,468 pregnant women taking antiretroviral therapy, including dolutegravir and efavarinz. Because there were no cases of neural tube defects reported, there was no difference between the two groups.
The Brazil study implies that even if there is an elevated risk with dolutegravir-based therapy, that risk remains low -- especially when women are given folate supplements.
WHO Offers Clarifying Guidance, Next Steps
In a weighted analysis of all the available evidence, the WHO concluded that the overall global estimate for the prevalence of neural tube defects among infants exposed to dolutegravir is 0.36% -- much lower than the 0.94% prevalence reported back in the 2018 Tsepamo study.
Meanwhile, the WHO noted that the majority of cases seen so far are in countries where folate supplementation is not universal and emphasized the importance of folate supplements during pregnancy for all women, but particularly for HIV-positive women on antiretroviral therapy.
"[The] goal of this rapid update was to help [ministries] of health as they were grappling with what was a very difficult year," said Meg Doherty, M.D., Ph.D., M.P.H., with the WHO in Switzerland, speaking at the IAS press conference. "There was a decision to make dolutegravir reconfirmed in first line [and] move it from a conditional recommendation to a preferred recommendation."
Doherty said that part of the reason for the strong recommendation is that dolutegravir -- despite these fetal development safety data -- is seen as the best defense against the global threat of NNRTI resistance.
According to a new WHO report, she said, a dozen countries are now reporting resistance levels of over 10%. Now, Doherty said, it's "much more urgent to reinforce the use of these new regimens, including dolutegravir."
Broadly, this entire safety scare speaks to the importance of including women and communities in the decision-making process.
"Women wanted options and wanted the opportunity to have that conversation with clinicians," Doherty said.
"Whatever happened should never happen again," echoed Wambui, noting that after the initial Tsepamo study was published, "there are those who are not even told" about the potential risks and benefits of dolutegravir treatment.
"Let the woman know what the risks are, what the benefits are -- and let the woman decide for herself," she said.