Dolutegravir has many advantages for people living with HIV. It is an integrase strand transfer inhibitor that offers very good tolerability, a rapid decrease of viral load and a high barrier to drug resistance [1,2]. Over the past few years, through the efforts of multiple stakeholders and government leadership, antiretroviral regimens containing dolutegravir have become accessible in even the lowest-income settings. Plans to transition most people living with HIV to dolutegravir-containing regimens promise a more efficacious, safe and durable regimen for individuals, as well as acceleration towards the goal of achieving epidemic control through viral suppression in communities.
However, data from the Tsepamo birth defect surveillance study in Botswana suggests that periconceptional use of dolutegravir may be associated with a small (under 1%) but significantly increased risk of neural tube defects in infants compared with the risk for infants of women receiving non-dolutegravir regimens or HIV-negative women [3,4,5]. In response, HIV treatment guidelines groups have made recommendations on the potential safety risks of periconceptional dolutegravir exposure until further data is available.
The World Health Organization (WHO) released a statement  advising countries and ministries to follow existing 2016 WHO Consolidated ARV Guidelines and consider that:
- Pregnant women already taking dolutegravir should not to stop their antiretroviral therapy and should seek additional guidance from their health providers.
- Antiretroviral therapy for women of childbearing age, including pregnant women, should be based on drugs for which adequate efficacy and safety data are available.
- If other first‐line antiretrovirals cannot be used in women of childbearing age, look at use of dolutegravir if consistent contraception can be assured.
- Programmes should continue strengthening pharmacovigilance, including monitoring of birth outcomes.
An update of this guidance, based on further data, should be available in mid-2019.
The International AIDS Society convened a high-level forum of experts to discuss considerations raised by the study and in relation to dolutegravir, including:
- Data quality, data interpretation and appropriate messaging of the risks and benefits of administering antiretroviral therapy to women of childbearing age living with HIV
- Engagement of communities
- The complexities of delivering a clear and straightforward message to stakeholders, including governments, ministries of health, regulatory agencies and the women themselves.
The aim of the forum was to deliver a set of considerations in order to optimize access to dolutegravir-containing regimens even if uncertainties remain regarding the specific risk of neural tube defects. Additionally, the forum included an academic exercise where the dolutegravir safety signal was used as an example of how to respond if a similar situation were to occur in future; the outputs and process of this exercise could be applied to other drugs used in pregnancy and inform regulators’ pharmacovigilance plans. Consequently, the forum’s work should be considered synergetic with other efforts, notably that of the World Health Organization Advisory Committee on the Safety of Medical Products, guideline processes and other regulatory agencies.
Over two forum meetings (in September and in November 2018) and a community engagement meeting in Johannesburg, the experts identified several issues around the dolutegravir safety signal, including insufficient multi-stakeholder engagement in particular with communities, difficulties in delivering a message with insufficient clarity, and difficulties in the collection of robust data.
The forum developed a frequently asked questions document , an academic paper (in press), a summary of the outcomes for communities, meeting reports and other documents that can be used as resources to address the aspects of safety signal detection. These documents are for wide dissemination and will be useful for healthcare service users, communities, healthcare providers, ministries of health and international non-governmental organizations.
Please keep visiting this website for updates over the next six months: the forum is now working in smaller groups, addressing the identified issues around responses to the safety signal.
- Orrell C, Kintu K, Coombs JA, et al. DolPHIN-1: Randomised controlled trial of dolutegravir (DTG)- versus efavirenz (EFV)-based therapy in mothers initiating antiretroviral treatment in late pregnancy. International AIDS Conference, Amsterdam, July 2018, Abstract THAB0307LB. http://programme.aids2018.org/Abstract/Abstract/13144
- Brenner BG, Wainberg MA. Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance. Virus Res. 2017;239:10-9.
- WHO Statement on DTG – Geneva 18 May 2018: http://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdf?ua=1
- Zash R. Surveillance for Neural Tube Defects following Antiretroviral Exposure from Conception, the Tsepamo study (Botswana). International AIDS Conference, Amsterdam July 2018 Abstract TUSY15. http://programme.aids2018.org/Programme/Session/1589
- Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med. 2018;379:979-81.
- Forum on the risks of periconceptional dolutegravir exposure. FAQs: Dolutegravir and women of childbearing potential: Interim considerations; 2018. Available at: http://www.iasociety.org/Portals/0/Files/DTG_FAQ.pdf.