Debate Over Dolutegravir in Early Pregnancy: A Top HIV Clinical Development of 2018

In 2018, the same year we learned that a two-drug initial HIV treatment regimen featuring dolutegravir (Tivicay, DTG) was viable for many of our patients, we also got a much-less-welcome dolutegravir (Tivicay, DTG)-related surprise. Early in the year, a research team conducting the Tsepamo study, a large observational study of pregnant women in Botswana, found an association between early maternal DTG exposure and defects of the neural tube of infants.

The many details of this story are important:

  • First, Tsepamo is funded by the U.S. National Institutes of Health, led by a team from the Harvard AIDS Partnership in Botswana, and is designed to look specifically for associations among HIV status, antiretroviral exposure during pregnancy, and infant neural tube defects.
  • Second, in this amazing project, trained midwives at eight different hospitals physically examined infants born to women with and without HIV for signs of neural tube defects.
  • Third, neural tube defects due to drug exposure appeared to occur during the first 28 days or so from conception.
  • Fourth, in May 2016, Botswana shifted from efavirenz (Sustiva, Stocrin, EFV)/emtricitabine (Emtriva, FTC)/tenofovir disoproxil fumarate (Viread, TDF) to emtricitabine/TDF (Truvada) plus DTG as first-line antiretroviral therapy.
  • Fifth, folic acid supplementation during pregnancy is not standard in Botswana.
  • Last, the research team was asked by the World Health Organization to look at the accumulated data to determine whether a risk of neural tube defects in infants born to mothers exposed to EFV could be detected.

This initial, unplanned analysis of 88,755 examined live births did not show a link between EFV and neural tube issues. However, comparatively, there was a higher prevalence of neural tube defects in infants whose mothers were taking DTG at the time of conception.

Of the 86 infants with neural tube defects identified, four were born to the 426 mothers taking DTG at conception -- a rate of 0.94%. In comparison, neural tube defects were rarer in the 11,300 infants whose mothers were exposed at conception to any non-DTG antiretroviral (0.12%), the 66,057 infants whose mothers were HIV negative (0.09%), and even the 2,812 infants whose mothers were exposed to DTG later in pregnancy (0.0%).

In a subsequent update that increased to 596 the number of women exposed to DTG at conception, no additional cases of infant neural tube defects were identified, dropping the prevalence rate in this group to 0.67%. The next analysis will be conducted in March 2019.

The Bottom Line

The suggestion that an antiretroviral taken by a mother can harm her infant is gravely concerning under any circumstance. Recall that it was birth defects due to a medication that helped usher in the current rigorous U.S. drug approval system. In the case of DTG, the possibility that it could increase the risk of neural tube defects threatens to undercut a promising approach to HIV therapy that is EFV- and protease inhibitor-free.

DTG is much better tolerated than these older regimens, and recent results from the DolPHIN-1 trial show that this very integrase inhibitor produced more rapid declines in the viral load of pregnant women, with larger proportions having undetectable levels of viremia at the critical time of birth than women taking EFV. It is important to underscore that the Tsepamo study did not find an association between neural tube defects and maternal exposure to DTG later in pregnancy.

After the study findings were announced, women of the AfroCAB, an advocacy network of representatives across Africa, issued a communiqué urging caution and a resistance to conclusion jumping. They called for a measured and shared approach to decision-making that includes women and point out that the issue of DTG and birth defects touches many women, not only those who are or are planning to become pregnant. Importantly, better access to affordable contraception is a centerpiece of the recommendations from this group.

Perinatal guidelines have been updated to reflect the data, which remain preliminary. Generally, these recommendations are consistent and logical. But, as the AfroCAB advocates stress, decisions regarding the use of DTG in women who are or could become pregnant must be made not through the consensus of guideline committees but by a woman and her health care provider.

Top 10 Clinical Developments of 2018
0. Introduction
1. GEMINI and the Rise of Two-Drug HIV Therapy
2. Debate Over Dolutegravir in Early Pregnancy
3. Integrase Inhibitors and Weight Gain
4. PrEP and the Decline in New HIV Diagnoses
5. On-Demand Prevention in France
6. Bictegravir Has Finally Arrived
7. Abacavir, Platelets, and a Cardiovascular Verdict
8. African-American Men and HIV Treatment Outcomes
9. The Long-Acting Bandwagon
10. Designing HIV-Resistant People

David Alain Wohl, M.D., is a professor of medicine in the Division of Infectious Diseases at the University of North Carolina (UNC). He is site leader of the UNC AIDS Clinical Trials Unit at Chapel Hill, director of the North Carolina AIDS Education and Training Center (AETC), and co-director of HIV services for the North Carolina state prison system. In 2014, he became co-director of the UNC-Duke Clinical RM Ebola Response Consortium.