Optimizing responses to drug safety signals in pregnancy: the example of dolutegravir and neural tube defects

Abstract

Introduction The unexpected identification of a neural tube defect (NTD) safety signal with preconception dolutegravir (DTG) exposure in the Botswana Tsepamo birth outcomes study brought into sharp focus the need for reliable data on use of new antiretrovirals in pregnancy, improved pharmacovigilance systems to evaluate safety of new drugs being introduced into populations including women of reproductive potential, and balanced risk‐benefit messaging when a safety signal is identified. Discussion The Tsepamo study NTD safety signal and accompanying regulatory responses led to uncertainty about the most appropriate approach to DTG use among women of reproductive potential, affecting global DTG roll‐out plans, and limiting DTG use in adolescent girls and women. It also revealed a tension between a public health approach to antiretroviral treatment (ART) and individual choice, and highlighted difficulties interpreting and messaging an unexpected safety signal with uncertainty about risk. This difficulty was compounded by the lack of high‐quality data on pregnancy outcomes from women receiving ART outside the Tsepamo surveillance sites and countries other than Botswana, resulting in a prolonged period of uncertainty while data on additional exposures are evaluated to refute or confirm the initial safety signal. We discuss principles for evaluating and introducing new drugs in the general population that would ensure collection of appropriate data to inform drug safety in adolescent girls and women of reproductive potential and minimize confusion about drug use in this population when a safety signal is identified. Conclusions The response to a signal suggesting a possible safety risk for a drug used in pregnancy or among women who may become pregnant needs to be rapid and comprehensive. It requires the existence of appropriately designed surveillance systems with broad population coverage; data analyses that examine risk‐benefit trade‐offs in a variety of contexts; guidance to transform this risk‐benefit balance into effective and agreed‐upon policy; involvement of the affected community and other key stakeholders; and a communication plan for all levels of knowledge and complexity. Implementation of this proposed framework for responding to safety signals is needed to ensure that any drug used in pregnancy can be rapidly and appropriately evaluated should a serious safety alert arise.

Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels

“…The potential link between DTG and higher rates of NTDs has created uncertainty among care providers, led to a reduction in use of DTG among women of reproductive age in some countries, and rekindled calls for greater vigilance and more antiretroviral safety studies in pregnancy [ [48] , [49] , [50] ]. Our findings, are in agreement with the Botswana results, and provide support for DTG usage in pregnancy being associated with a small increase in NTDs.…”

Ethical issues in therapeutic use and research in pregnant and breastfeeding women

“…As further Botswanan women who had conceived on dolutegravir reached delivery, the signal for embryotoxicity diminished, and by July 2019, dolutegravir-based regimens were adopted by the WHO as preferred first-line antiretroviral therapy, including for women of childbearing potential. Many lessons can be learned from this unfolding of events, particularly with relation to communication and the complexity of risk-benefit considerations as recently discussed by Mofenson and colleagues 62 . Pertinent to our current paper are the considerations that the affected community and other key stakeholders be involved throughout, and that information be provided to engage all levels of knowledge.…”

Pregnancies among women living with HIV using contraceptives and antiretroviral therapy in western Kenya: a retrospective, cohort study

“…In light of the possible association between dolutegravir and birth defects, many national HIV treatment programs initially defaulted to recommending efavirenz-containing ART as the best option for women of reproductive potential [ 6 ]. However, our prior work, a retrospective analysis of electronic medical record (EMR) data from one program in western Kenya, has demonstrated reduced effectiveness of contraceptive implants when concurrently used with efavirenz-containing ART [ 7 ].…”