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BHIVA statement on safety signal in infants born to mothers conceiving on dolutegravir

Tuesday 27 August 2019

In May 2018, the BHIVA HIV in Pregnancy Guidelines Committee released a statement advising on dolutegravir (DTG) use at the time of conception and in pregnancy [1], based on a preliminary unscheduled analysis of an ongoing birth surveillance study in Botswana. At the time, the study reported an increased risk of neural tube defects (NTDs); there were four cases of infants with NTD among 426 women who conceived a pregnancy while taking DTG-based antiretroviral therapy (ART) regimens. The reported rate was approximately 0.9% compared to a 0.1% rate of NTDs among infants born to women taking non-DTG-based regimens at the time of conception.

Further analysis of prospective surveillance data on 1683 women from the Tsepamo study in Botswana was presented at the 10th IAS Conference on HIV Science in Mexico City [2] and published [3] on 22 July. These women were on DTG-based ART regimens at the time of conception and five neural tube defects were reported (0.3%). This compares to a rate of NTDs of 0.1% in women who conceived on non-DTG-containing ART, and 0.04% in those taking efavirenz-containing regimens at the time of conception. The greater number of conceptions on DTG in this analysis provides a more precise estimate with narrower confidence intervals (95% CI 0.06–067) than the initial data, and shows a smaller difference in incidence of NTDs between exposure to DTG at conception and exposure to other ART.

Two other studies reported NTD rates in infants exposed to DTG at conception [4]. An NTD surveillance study, also conducted in Botswana, reported an NTD rate of 0.66% in 152 DTG-exposed pregnancies and a retrospective analysis from Brazil reported no NTDs among infants born to 382 women who conceived on DTG [5]; the overall rate of NTDs in Brazil is <0.06%. Furthermore, the most recent update from the Antiretroviral Pregnancy Registry (APR) showed that among 248 DTG exposures at conception there was one NTD giving a prevalence of 0.40% [6]. However, this estimate is based on a single NTD among a relatively small number of exposures.

The writing group recognises that incidence of NTDs varies between countries and not all countries have introduced folic acid fortification.

The World Health Organization has updated recommendations for first-line treatment regimens to include DTG, in combination with a nucleoside reverse transcriptase inhibitor backbone, as preferred first-line treatment for people living with HIV, including women of child-bearing potential. This decision was taken in the context of the potential risks of negative aspects of other ART choices [7].

The writing group agrees that all women living with HIV should be given all available information and supported to make informed choices regarding ART, at all stages of their reproductive life.

In light of these further prospective surveillance data, the writing group offers the following advice:

  • All women wishing to conceive should be given appropriate preconception advice and commenced on a high dose of folic acid (5 mg daily) regardless of their combination (c)ART regimen;

  • Women should be informed of all available information regarding ART and conception, and be supported to make an informed choice.


Summary

1. For a woman on DTG wishing to conceive

a. Women should be fully informed that the prevalence of NTDs is higher following DTG exposure at conception than with other types of ART at conception (equating to 3 per 1000 births vs 1 per 1000 births).

b. The best safety data for pregnancy are for efavirenz or atazanavir/ritonavir (ATV/r) as per the BHIVA guidelines on the management of HIV in pregnancy and postpartum 2018 [8].

c. A woman choosing to continue DTG while planning to conceive will be supported in this decision and advised to commence or continue folic acid 5 mg daily until closure of the neural tube.

2. For a woman on DTG not planning children but of child-bearing age

a. As per BHIVA standards of care [9], people living with HIV should have access to accurate information about the full range of contraceptive and pregnancy choices.

b. While on DTG, the same considerations for contraceptive choice should be made as for other ART with additional information provided on the potential additional risk of NTD.

3. For a woman on DTG who becomes or is pregnant

a. We acknowledge that the neural tube has closed within 6 weeks of conception. If DTG is the best ART choice for the woman, the NTD risk of 0.3% should be discussed and if a woman accepts this risk then DTG can be continued in pregnancy.

b. A woman who presents in pregnancy more than 6 weeks after conception should continue her current regimen unless there are other reasons to consider switching.

c. If the woman chooses to switch, use a regimen on which there are more safety data in pregnancy, such as efavirenz or ATV/r as per the BHIVA guidelines on the management of HIV in pregnancy and postpartum 2018 [8].

d. Detailed anomaly scans should be performed as per national pregnancy guidelines with no additional scans required.

4. For a woman who is pregnant and not yet on cART

a. The recommendations of Section 6.3 of the BHIVA guidelines on the management of HIV in pregnancy and postpartum 2018 remain applicable (see [8]).

For safety data on antiretroviral agents in pregnancy please refer to the APR (www.apregistry.com) or seek advice from an expert colleague.

This report highlights the need to continue to prospectively report pregnancies to the National Surveillance of HIV in Pregnancy and Childhood (www.ucl.ac.uk/nshpc) and the APR.


For further information: please contact Jo Josh on +44 (0) 7787 530922 or jo@commsbiz.com


References

1. British HIV Association. BHIVA statement on Potential Safety Signal in Infants Born to Women Conceiving on Dolutegravir (on behalf of the BHIVA HIV in Pregnancy Guidelines Committee). May 2018. Available at: https://www.bhiva.org/BHIVA-statement-on-Dolutegravir (accessed August 2019).

2. Raesima MM, Forhan S, Thomas V et al. Addressing the safety signal with dolutegravir use at conception: Additional surveillance data from Botswana. 2019. 10th IAS Conference on HIV Science. Mexico City, Mexico. Abstract MOAX0106LB.

3. Zash R, Holmes L, Diseko M et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med 2019; DOI: 10.1056/NEJMoa1905230 [Epub ahead of print].

4. International AIDS Society. Dolutegravir safety: New evidence and updated guidance on antiretroviral treatment for women. Available at: https://www.youtube.com/watch?v=cYCebg2_NFw (accessed August 2019).

5. Pereira G, Kim A, Jalil E et al. No occurrences of neural tube defects among 382 women on dolutegravir at pregnancy conception in Brazil. 2019. 10th IAS Conference on HIV Science. Mexico City, Mexico. Abstract MOAX0104LB.

6. Mofensen M, Vannappagari V, Scheuerle AE et al. Periconceptional antiretroviral exposure and central nervous system (CNS) and neural tube birth defects – data from Antiretroviral Pregnancy Registry (APR). 2019. 10th IAS Conference on HIV Science. Mexico City, Mexico. Abstract TUAB0101.

7. World Health Organization. WHO recommends dolutegravir as preferred HIV treatment option in all populations. Available at: https://www.who.int/news-room/detail/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations (accessed August 2019).

8. British HIV Association. BHIVA guidelines on the management of HIV in pregnancy and postpartum 2018. Available at: https://www.bhiva.org/pregnancy-guidelines (accessed August 2019).

9. British HIV Association. Standards of care for people living with HIV 2018. Available at: https://www.bhiva.org/file/KrfaFqLZRlBhg/BHIVA-Standards-of-Care-2018.pdf (accessed August 2019).