The way forward for use of dolutegravir in women of childbearing age

Organisation: Position: Deadline Date: Location:

The safety of the HIV treatment drug, dolutegravir (DTG), during pregnancy has been one of the most urgent questions in global health for the past year, with new studies and updated WHO guidelines presented at the 10th IAS Conference on HIV Science.

At the 22nd International AIDS Conference (AIDS 2018) last year, data from the Tsepamo study in Botswana suggested that the use of DTG in early pregnancy may be linked to neural tube defects (NTDs), serious birth defects of the brain and spine.

As a result, some countries have paused their plans to make DTG-based regimens their preferred first-line therapy and the World Health Organisation (WHO) issued a note of caution about the use of DTG by women of childbearing age as part of its interim guidelines recommending DTG as the preferred first- and second-line antiretroviral therapy for people living with HIV.

At the 10th IAS Conference on HIV Science (IAS 2019), additional research from Botswana has found that the risk of NTDs is less than was signalled last year. To help clinicians and health ministries act on these findings, WHO issued updated recommendations on antiretroviral therapy and DTG use.

To inform these recommendations, a number of community and scientific forums were held to discuss the issue directly with women of reproductive age who have the least access to obtaining DTG.

“Community engagement, including input from women living with HIV, has played a key role in updating these recommendations and will be critical to rolling them out,” Jacque Wambui, African Community Advisory Board (AFROCAB) member, Kenya, said.

“Ultimately, what is most important is offering women the choice to make informed decisions,” Anton Pozniak, International AIDS Society president and IAS 2019 international scientific chair, said.

WHO updated these recommendations based on new evidence.

Botswana’s Tsepamo study analysed more than 119,000 deliveries from August 2014 to April 2019, including nearly 1,700 among women who were taking DTG-based therapy around conception. With more data, the researchers have found the risk in the prevalence of NTDs among women taking DTG is less than originally signalled. Specifically, NTDs occurred in three per 1,000 deliveries among women on DTG from conception – compared with one per 1,000 deliveries among women taking other ARV regimens.

Abstract: Neural tube defects by antiretroviral and HIV exposure in the Tsepamo Study, Botswana
Session: IAS 2019 Co-Chairs’ choice (Monday, 22 July, 14:30 – 16:00; Sala A)
(Abstract not yet available online)

A second analysis from Botswana analysed health facilities that were not included in the Tsepamo study. Examining data from 22 facilities from October 2018 to March 2019, researchers confirmed one case of NTDs in pregnancies of 152 mothers who had been taking DTG-based therapy at conception. By comparison, two cases of NTDs occurred among pregnancies of more than 2,300 HIV-negative mothers.

Abstract: Addressing the preconception safety signal with dolutegravir: additional data from Botswana
Session: IAS 2019 Co-Chairs’ choice (Monday, 22 July, 14:30 – 16:00; Sala A)
(Abstract not yet available online)

A surveillance-based analysis from Brazil included 1,468 women who became pregnant while taking antiretroviral therapy – 382 of whom were taking DTG at conception. In this case, no cases of NTDs were seen. This evidence backs up the overall conclusion that even if DTG-based therapy is associated with an elevated risk of NTDs, the risk remains quite low.

Abstract: No occurrences of neural tube defects among 382 women on Dolutegravir at pregnancy conception in Brazil
Session: IAS 2019 Co-Chairs’ choice (Monday, 22 July, 14:30 – 16:00; Sala A)
(Abstract not yet available online)

To help put these findings in context and to provide urgently needed guidance, WHO issued updated recommendations on antiretroviral treatment. These guidelines reconfirm the recommendation to use DTG-containing regimens as the preferred option for first-line and second-line antiretroviral treatment (ART) across all populations.

The guidelines development group also emphasized the need for ongoing monitoring of the risk of NTDs and the importance of supporting women’s autonomy in decision making and informed choice.

“There is still a risk that we and countries need to monitor closely, but at this point, dolutegravir should be accessible for women of childbearing age due to the overwhelming benefits it offers,” Meg Doherty, coordinator of treatment and care in the department of HIV/Hepatitis and STIs at WHO, said. “What treatment options to pursue is a decision that a woman should make in consultation with her healthcare provider.”

Ambassador Deborah L Birx, US global Aids coordinator and US Special Representative for Global Health Diplomacy, commented that the Presidents Emergency Plan for AIDS Relief (PEPFAR) was committed to supporting countries in their continued transition to DTG. “DTG offers many benefits, including that it is better tolerated by the patient, leads to improved outcomes, such as faster viral suppression, and often costs less,” she said. “It is clear that transitioning to DTG will accelerate our progress toward controlling the HIV epidemic.”

Earlier this month, Pozniak, Doherty and Wambui alongside several other coauthors, released a commentary which provided additional context before the new data shared at IAS 2019 became available.

Commentary 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.

Authors
Lynne M Mofenson, Anton L Pozniak, Jacque Wambui, Elliot Raizes, Andrea Ciaranello, Polly Clayden, Peter Ehrenkranz, Ade Fakoya, Andrew Hill, Saye Khoo, Imelda Mahaka, Surbhi Modi, Cynthia Moore, Andrew Phillips, George Siberry, Kenly Sikwese, Claire Thorne, Heather D Watts, Meg Doherty, Nathan P Ford

IAS 2019 material
Journal of the International Aids Society (JIAS) commentary


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