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Tuberculosis Prevention Therapy in HIV+ Pregnant Women versus Waiting until After Delivery: A Delicate Risk-Benefit Conversation
Study findings suggest that waiting until after delivery to start preventive therapy is associated with fewer adverse events
October 3, 2019—In a study published by The New England Journal of Medicine today, Dr. Amita Gupta and colleagues found evidence to suggest that administering isoniazid preventive therapy (IPT) to prevent tuberculosis among HIV+ pregnant women who are taking antiretroviral therapy (ART) offered no benefits over beginning IPT at 12 weeks after delivery. Moreover, IPT during pregnancy is associated with higher adverse composite pregnancy events, including higher rates of low birth weight, preterm birth, stillbirth, and congenital anomalies. The World Health Organization’s guidelines for preventing TB in HIV+ pregnant women currently recommend isoniazid preventive therapy.
A multicenter, double-blind, placebo-controlled, non-inferiority trial was conducted that randomly assigned 956 HIV+ pregnant women to receive the current standard of care of a 28-week course of IPT, which was initiated either during pregnancy (immediate) or 12 weeks postpartum (deferred). Mother-infant pairs were then followed for 4 years. This trial was conducted in countries with high burden of both HIV and TB: South Africa, Zimbabwe, Uganda, Botswana, Tanzania, Thailand, India, and Haiti.
Researchers found that 23.6% of women who received IPT during pregnancy experienced adverse pregnancy outcomes, versus 17% for those who received IPT at 12 weeks postpartum—a statistically significant difference. There were no significant differences in adverse outcomes among the live-born infants followed in the study.
Although isoniazid has been around since the 1950s, this is the first randomized trial to study isoniazid preventive therapy in pregnant women, and the first trial to compare safety in initiating IPT during pregnancy with deferring administration until postpartum. WHO’s clinical care guidelines are based on data from non-pregnant populations. Pregnant women have been excluded from clinical trials; thus the safety, efficacy, and optimal timing of IPT for pregnant women receiving antitretroviral therapy for HIV are unknown.
Lead author and Johns Hopkins Professor of Medicine and Public Health Amita Gupta, MD, MHS, is scientific protocol chair and a PI for the study. “We have long known that pregnancy introduces a variety of physiological changes, but it’s only recently that we’ve begun to look at how those changes affect disease immunity and the body’s capacity to absorb, distribute, and metabolize drugs that are routinely administered to pregnant women,” Gupta says. “Pregnant women are routinely prescribed medications based on care standards for the non-pregnant population. But because they have been excluded from clinical trials, there is an alarming lack of data on whether these medications are safe and effective in pregnant women. This study highlights the costs associated with treating patients in the absence of reliable data.”
The findings of this study suggest the need to reevaluate current recommendations for tuberculosis prevention among pregnant women. Tuberculosis is the number one cause of severe illness and death among HIV-infected populations in low and middle income, high-TB incidence settings including India and Sub-Saharan Africa. HIV+ pregnant women in these settings are more gravely affected.
Authors on the study are Amita Gupta, MD, MHS; Grace Montepiedra, PhD; Lisa Aaron, MS; Gerhard Theron, MD; Katie McCarthy, MPH; Sarah Bradford, MPH; Tsungai Chipato, MBChB, FRCOG, MCE; Tichaona Vhembo, MBChB, MPH; Lynda Stranix-Chibanda, MBChB, MMED; Carolyne Onyango-Makumbi, MBChB, MS; Gaerolwe R. Masheto, MD; Avy Violari, MD; Blandina T. Mmbaga, MD, MMED, PhD; Linda Aurpibul, MD, MPH; Ramesh Bhosale, MD; Vidya Mave, MD, MPH; Vanessa Rouzier, MD; Anneke Hesseling, MD, PhD; Katherine Shin, PharmD; Bonnie Zimmer, BS; Diane Costello, BS; Timothy R. Sterling, MD; Nahida Chakhtoura, MD, MsGH; Patrick Jean Philippe, MD; Adriana Weinberg, MD for the IMPAACT P1078, TB APPRISE (TB Ante vs. Postpartum Prevention with INH in HIV Seropositive Mothers and Their Exposed Infants) Study Team.
The study was supported by the National Institutes of Health, National Institute of Allergy and Infectious Disease, under grant numbers U01AI069465, UM1AI069465, and UM1AI068632.