Although a woman’s use of the HIV drug dolutegravir at conception may increase the risk of often-fatal neural tube defects in her child, a new study suggests that the risk may be offset by the drug’s ability to decrease deaths among women and prevent HIV transmission to their children and sexual partners. The report, led by researchers at Massachusetts General Hospital (MGH), is being published online in the Annals of Internal Medicine.

“Dolutegravir is one of the most effective drugs that we have to treat HIV and could be a ‘game-changer’ in sub-Saharan Africa,” says Caitlin Dugdale, MD, of the MGH Division of Infectious Diseases and the Medical Practice Evaluation Center, who led the study. “However, as countries consider replacing current first-line treatment with now less expensive dolutegravir-based treatment, it is important to evaluate the risks and benefits of using it globally for millions of women who could become pregnant.”

Dolutegravir has been available in the US since 2013 and is part of recommended first-line HIV treatment in resource-rich countries. It has fewer side effects and lower rates of treatment failure than efavirenz, the current first-line treatment in most low- and middle-income countries. While dolutegravir was previously unaffordable in these countries, recent negotiations led to development of a generic version that costs only $75 per person per year. Many developing countries most affected by the HIV epidemic had planned to roll out dolutegravir in 2018 but delayed these plans after a birth surveillance study in Botswana released preliminary data suggesting that dolutegravir may pose harm to unborn children by increasing the risk of neural tube defects.

Dugdale says, “We are waiting on more data to know if the preliminary results of the Botswana study were a statistical fluke or a finding of real concern; but while we wait, policymakers still have to make decisions about what treatment to recommend for women with HIV who could become pregnant.”

To look at the potential effects of different HIV treatment options for women from a public health perspective, the researchers used a well-established mathematical model of HIV along with epidemiologic data from South Africa and treatment efficacy data from clinical trials. With this model, they projected clinical outcomes over five years for approximately 3.1 million women of child-bearing age with HIV in South Africa and their children. They compared a policy of using dolutegravir-based treatment for all women to the current policy of first-line efavirenz-based treatment for all women with HIV. The model projected the number of anticipated deaths from any cause among women and children, HIV transmissions to men and children, and dolutegravir-related neural tube defects over five years in South Africa.

The researchers found that use of efavirenz-based first-line treatment would lead to 4,400 fewer deaths among children compared with dolutegravir-based treatment, largely due to the reduced risk of birth defects. However, dolutegravir-based treatment was projected to lead to more than 13,000 fewer deaths among women, nearly 60,000 fewer HIV transmissions to male partners, and over 7,000 fewer HIV infections in children. Overall, the study found that there were fewer deaths with dolutegravir-based treatment than with efavirenz-based treatment.

Study co-author Linda-Gail Bekker, MD, PhD, of the University of Cape Town and the past president of the International AIDS Society says, “The results of this modeling study show us that the issue is not so simple as saying we should take dolutegravir off the table because a woman might become pregnant. Instead these results highlight the importance of making sure that women are given all of the information about the benefits as well as the risks of dolutegravir so that they can make an informed decision about the best choice of treatment.”

Rochelle Walensky, MD, MPH, of the MGH Division of Infectious Diseases and the Medical Practice Evaluation Center, senior author of the study adds, “The findings of our analysis suggest that, when looking at the ‘bigger picture’ effects of dolutegravir-based treatment beyond the risk of birth defects, dolutegravir offers many benefits for women, their partners and their children over currently recommended first-treatment.”

Dugdale is an instructor in Medicine, and Walensky is a professor of Medicine at Harvard Medical School, while Bekker is a professor of Medicine at the University of Cape Town. Additional co-authors of the Annals of Internal Medicine report are Andrea Ciaranello, MD, MPH, Madeline Stern, Kenneth Freedberg, MD, MSc, MGH; Landon Myer, MBChB, PhD, and Robin Wood, MMed, DSc (Med), University of Cape Town; Paul Sax, MD, Brigham & Women’s Hospital; and Elaine Abrams, MD, Columbia University.

This research was funded by the National Institute of Allergy and Infectious Disease grants T32 AI007433, R37 AI058736, R01 AI042006 and R37 AI093269; Eunice Kennedy Shriver National Institute of Child Health and Human Development grant R01 HD079214, and the Steve and Deborah Gorlin MGH Research Scholars Award. This study was also funded in part by the NIH-funded Harvard University Center for AIDS Research.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America’s Best Hospitals."