Perspective

Tsepamo: 3 in 1,000 infants exposed to dolutegravir have neural tube defects

Photo of Rebecca Zash
Rebecca Zash

According to results from the ongoing Tsepamo study in Botswana, infants born to women who took the integrase inhibitor dolutegravir for HIV infection from conception remained at an elevated risk for neural tube defects, with three in 1,000 born with these conditions. However, the findings, which were presented at the International AIDS Society Conference in Mexico City and published in The New England Journal of Medicine, showed that the risk is significantly lower than previously estimated.

Following these results, WHO strengthened its recommendation for dolutegravir as a first-line treatment for HIV for all populations, including pregnant women and those of childbearing potential.

Early signal of safety issues

In May 2018, the FDA issued a safety alert about dolutegravir after preliminary findings from the Tsepamo study suggested that women who received the drug at the time of becoming pregnant or early in the first trimester were at a higher risk for having an infant with neural tube birth defects impacting the brain, spine and spinal cord. Rebecca Zash, MD, an assistant professor of medicine at Beth Israel Deaconess Medical Center and a research fellow in the department of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, and colleagues continued their surveillance for these birth defects across Botswana.

The researchers identified 119,477 deliveries occurring between August 2014 and March 2019. Of these births and stillbirths, 98 (0.08%; 95% CI, 0.07%-0.1%) had neural tube defects.

Among the 1,683 mothers in the study who were taking dolutegravir from conception, five of their infants had neural tube defects (0.3%; 95% CI, 0.13%-0.69%) — lower than the 0.94% prevalence initially reported back in 2018. These defects included myelomeningoceles (n = 2), anencephaly, encephalocele and iniencephaly (n = 1 each).

In comparison, 15 infants born to 14,792 mothers taking any other ART regimen from conception had neural tube defects (0.1%; 95% CI, 0.06%-0.17%). Three infants born to mothers on efavirenz from conception had neural tube defects (0.03%; 95% CI, 0.01%-0.11%). The prevalence of neural tube defects was also lower among infants born to women who began taking dolutegravir during pregnancy (n = 1 of 3,840; 0.03%; 95% CI, 0%-0.15%), and among infants born to women who did not have HIV infection (n = 70 of 89,372; 0.08%; 95% CI, 0.06%-0.10%).

Overall, children were 0.2 percentage points (95% CI, 0.01% to 0.59%) more likely to have neural tube defects when their mothers were taking dolutegravir compared with any other ART regimen from conception.

Implications of the findings

Zash and colleagues said the findings linking dolutegravir to birth defects in children were “unexpected.” A possible explanation could be folate deficiency associated with the compound.

“Folate deficiency is a well-known risk factor for neural-tube defects, and folate antagonism by dolutegravir has been investigated as a potential mechanism to explain our clinical data,” they wrote.

Additional surveillance is planned, they added.

Although dolutegravir was linked to a higher risk for neural tube defects among newborns in the Tsepamo study, findings published in Annals of Internal Medicine suggested the drug may prevent many more deaths and HIV transmissions among women than efavirenz. Researchers said the findings support a “context-specific discussion about the tradeoffs between the risks for harm and the benefits” of both treatment options.

Zash described Tsepamo as “the gold-standard study for evaluating the risk for neural tube defects and exposure to dolutegravir at conception.”

“The small risk for neural tube defects that Tsepamo found is just one piece of information regarding the use of dolutegravir in pregnancy, and it has to be weighed against the large projected benefits of dolutegravir,” she said. “Determining the best ART treatment for women of reproductive age potential is really a risk-benefit analysis, and Tsepamo has been able to quantify this particular risk.”

Zash added that there are “good data” to suggest that recommending dolutegravir to women who are already pregnant is both safe and effective.

“Given the benefits, dolutegravir should definitely be recommended for women who start ART during pregnancy,” she said. “For women who are starting ART before they get pregnant, I personally think that it is reasonable for physicians to recommend dolutegravir given the small absolute increased prevalence that we found in Tsepamo weighed against the benefits of dolutegravir, taking into account the patient’s history, preferences and values.”

In response to the Tsepamo study findings and other available evidence, WHO reaffirmed its recommendation for dolutegravir as a first-line drug.

Meg Doherty, MD, MPH, PhD, coordinator of treatment and care in the Department of HIV/AIDS at WHO, said in a press briefing that the decision was made based on the overall decreasing prevalence of neural tube defects, most of which occurred in countries that do not have folate fortification. In addition, Doherty said the recommendation is important in the context of drug resistance to nevirapine or efavirenz before starting therapy, with 12 of 18 countries reporting resistance to treatment at more than 10%.

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“It is much more urgent at this point to start to reinforce the use of new regimens, including dolutegravir,” she said.

Dolutegravir was approved in the United States in 2013. It is available under the brand name Tivicay (ViiV Healthcare) and as part of fixed-dose combinations under the brand names Juluca (dolutegravir/rilpivirine, ViiV Healthcare) and Triumeq (abacavir/dolutegravir/lamivudine; ViiV Healthcare). – by Katherine Bortz

References:

Dugdale CM, et al. Ann Intern Med. 2019;doi:10.7326/M18-3358.

FDA. FDA Drug Safety Communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). https://www.fda.gov/drugs/drugsafety/ucm608112.htm. Accessed July 19, 2019.

UNAIDS. Botswana. https://www.unaids.org/en/regionscountries/countries/botswana. Accessed July 20, 2019.

Zash R, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1905230.

Zash R, et al. N Engl J Med. 2018;doi:10.1056/NEJMc1807653.

Disclosures: Zash reports no relevant financial disclosures.

Photo of Rebecca Zash
Rebecca Zash

According to results from the ongoing Tsepamo study in Botswana, infants born to women who took the integrase inhibitor dolutegravir for HIV infection from conception remained at an elevated risk for neural tube defects, with three in 1,000 born with these conditions. However, the findings, which were presented at the International AIDS Society Conference in Mexico City and published in The New England Journal of Medicine, showed that the risk is significantly lower than previously estimated.

Following these results, WHO strengthened its recommendation for dolutegravir as a first-line treatment for HIV for all populations, including pregnant women and those of childbearing potential.

Early signal of safety issues

In May 2018, the FDA issued a safety alert about dolutegravir after preliminary findings from the Tsepamo study suggested that women who received the drug at the time of becoming pregnant or early in the first trimester were at a higher risk for having an infant with neural tube birth defects impacting the brain, spine and spinal cord. Rebecca Zash, MD, an assistant professor of medicine at Beth Israel Deaconess Medical Center and a research fellow in the department of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, and colleagues continued their surveillance for these birth defects across Botswana.

The researchers identified 119,477 deliveries occurring between August 2014 and March 2019. Of these births and stillbirths, 98 (0.08%; 95% CI, 0.07%-0.1%) had neural tube defects.

Among the 1,683 mothers in the study who were taking dolutegravir from conception, five of their infants had neural tube defects (0.3%; 95% CI, 0.13%-0.69%) — lower than the 0.94% prevalence initially reported back in 2018. These defects included myelomeningoceles (n = 2), anencephaly, encephalocele and iniencephaly (n = 1 each).

In comparison, 15 infants born to 14,792 mothers taking any other ART regimen from conception had neural tube defects (0.1%; 95% CI, 0.06%-0.17%). Three infants born to mothers on efavirenz from conception had neural tube defects (0.03%; 95% CI, 0.01%-0.11%). The prevalence of neural tube defects was also lower among infants born to women who began taking dolutegravir during pregnancy (n = 1 of 3,840; 0.03%; 95% CI, 0%-0.15%), and among infants born to women who did not have HIV infection (n = 70 of 89,372; 0.08%; 95% CI, 0.06%-0.10%).

Overall, children were 0.2 percentage points (95% CI, 0.01% to 0.59%) more likely to have neural tube defects when their mothers were taking dolutegravir compared with any other ART regimen from conception.

PAGE BREAK

Implications of the findings

Zash and colleagues said the findings linking dolutegravir to birth defects in children were “unexpected.” A possible explanation could be folate deficiency associated with the compound.

“Folate deficiency is a well-known risk factor for neural-tube defects, and folate antagonism by dolutegravir has been investigated as a potential mechanism to explain our clinical data,” they wrote.

Additional surveillance is planned, they added.

Although dolutegravir was linked to a higher risk for neural tube defects among newborns in the Tsepamo study, findings published in Annals of Internal Medicine suggested the drug may prevent many more deaths and HIV transmissions among women than efavirenz. Researchers said the findings support a “context-specific discussion about the tradeoffs between the risks for harm and the benefits” of both treatment options.

Zash described Tsepamo as “the gold-standard study for evaluating the risk for neural tube defects and exposure to dolutegravir at conception.”

“The small risk for neural tube defects that Tsepamo found is just one piece of information regarding the use of dolutegravir in pregnancy, and it has to be weighed against the large projected benefits of dolutegravir,” she said. “Determining the best ART treatment for women of reproductive age potential is really a risk-benefit analysis, and Tsepamo has been able to quantify this particular risk.”

Zash added that there are “good data” to suggest that recommending dolutegravir to women who are already pregnant is both safe and effective.

“Given the benefits, dolutegravir should definitely be recommended for women who start ART during pregnancy,” she said. “For women who are starting ART before they get pregnant, I personally think that it is reasonable for physicians to recommend dolutegravir given the small absolute increased prevalence that we found in Tsepamo weighed against the benefits of dolutegravir, taking into account the patient’s history, preferences and values.”

In response to the Tsepamo study findings and other available evidence, WHO reaffirmed its recommendation for dolutegravir as a first-line drug.

Meg Doherty, MD, MPH, PhD, coordinator of treatment and care in the Department of HIV/AIDS at WHO, said in a press briefing that the decision was made based on the overall decreasing prevalence of neural tube defects, most of which occurred in countries that do not have folate fortification. In addition, Doherty said the recommendation is important in the context of drug resistance to nevirapine or efavirenz before starting therapy, with 12 of 18 countries reporting resistance to treatment at more than 10%.

PAGE BREAK

“It is much more urgent at this point to start to reinforce the use of new regimens, including dolutegravir,” she said.

Dolutegravir was approved in the United States in 2013. It is available under the brand name Tivicay (ViiV Healthcare) and as part of fixed-dose combinations under the brand names Juluca (dolutegravir/rilpivirine, ViiV Healthcare) and Triumeq (abacavir/dolutegravir/lamivudine; ViiV Healthcare). – by Katherine Bortz

References:

Dugdale CM, et al. Ann Intern Med. 2019;doi:10.7326/M18-3358.

FDA. FDA Drug Safety Communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). https://www.fda.gov/drugs/drugsafety/ucm608112.htm. Accessed July 19, 2019.

UNAIDS. Botswana. https://www.unaids.org/en/regionscountries/countries/botswana. Accessed July 20, 2019.

Zash R, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1905230.

Zash R, et al. N Engl J Med. 2018;doi:10.1056/NEJMc1807653.

Disclosures: Zash reports no relevant financial disclosures.

    Perspective
    Monica Gandhi

    Monica Gandhi

    Before May 2018, we were all set. WHO, based on the evidence for greater potency, tolerability and a higher genetic barrier to resistance, was just about to announce that dolutegravir-based regimens should supplant efavirenz-based regimens as first-line therapy worldwide. However, that month brought a surprising, confusing and unexplained finding reported by Zash and colleagues from the Tsepamo cohort in Botswana. They found that the use of dolutegravir during conception or the first trimester by pregnant women may result in an increased risk of neural tube defects in their babies.

    The change in the guidelines proceeded as planned, but with a large asterisk sign indicating that women of childbearing age should be warned about this potential signal of the use of dolutegravir and neural tube defects and likely be treated with efavirenz-based regimens instead. 

    The first report from the Tsepamo cohort, published in The New England Journal of Medicine in August 2018, indicated a rate of 0.9% of neural tube defects associated with the use of dolutegravir among mothers during conception or the first trimester. That rate dropped to 0.67% by the time the authors presented additional data from the Tsepamo cohort at AIDS 2018. In the most recent NEJM study, presented at IAS, the rate has now dropped to 0.3% a very small but significant increase over the baseline 0.1% rate of neural tube defects in the general population and among women in this observational cohort study not on dolutegravir.

    What do these findings indicate? First and foremost, we should not throw out the baby with the bathwater. Dolutegravir is a highly potent medication, reduces viral loads (like all integrase inhibitors) rapidly, is generally well-tolerated and, importantly, has a high genetic barrier to resistance. Dolutegravir is superior to efavirenz and should replace efavirenz as the anchor drug in first-line ART regimens for most individuals worldwide. The rate of a potential signal between the use of this drug during conception and the first trimester and neural tube defects has dropped significantly over a year with more data. The signal may disappear altogether with time.

    For now, however, the rate of neural tube defects with dolutegravir (0.3%) in the Tsepamo cohort is increased over the baseline prevalence (0.1%) and should be viewed with measured caution. Informing women of this potential risk — as indicated in the WHO guidelines — should continue until we can further unravel this signal. But this new analysis, along with other data from other cohorts of women of childbearing age from Brazil and other countries, should give us some comfort. Dolutegravir is a good drug. Use it with caution, and let women decide. We need potent and well-tolerated medications for individuals living with HIV worldwide as we attempt to combat the epidemic and institute universal treatment for all.

    • Monica Gandhi, MD, MPH
    • Professor of medicine
      University of California, San Francisco
      Medical director
      “Ward 86” HIV Clinic, Zuckerberg San Francisco General Hospital

    Disclosures: Gandhi reports no relevant financial disclosures.

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