Potential safety signal for dolutegravir from the time of conception

Polly Clayden, HIV i-Base

On 18 May 2018, the World Health Organisation (WHO) issued a statement following the identification of a potential safety issue with dolutegravir (DTG) related to neural tube defects in infants born to women who were taking DTG at the time of conception.

The safety issue was found at a preliminary unscheduled analysis of the ongoing observational study in Botswana that previously reported reassuring data on DTG started during pregnancy. The analysis revealed four cases of neural tube defects (spina bifida, anencephaly, encephalocele/iniencephaly) out of 426 women who became pregnant while taking DTG.

This rate of approximately 0.9% compares with a 0.1% risk of neural tube defects in infants born to women taking other ARVs at the time of conception.

The originator company ViiV Healthcare will release a Dear Doctor letter next week and BHIVA plan to issue recommendations for women in the UK. (Note: the BHIVA statement [6] and Dear Doctor letter [7] are now both online).

i-Base will provide further commentary next week on plans to monitor women who have conceived on DTG and are currently pregnant (particularly in Botswana and Brazil) and for better follow up of pregnancies exposed to DTG and other new antiretrovirals.

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The WHO statement was swiftly followed by others from PEPFAR, FDA, EMA and the Southern African HIV Clinicians Society (SAHCS). [2, 3, 4, 5]

Until there are more data to guide them, the recommendations suggest varying degrees of caution. The WHO statement (in full below) advises: 

• Pregnant women who are taking DTG should not stop their ARV therapy and should speak with their health provider for additional guidance. 
• Antiretroviral (ARV) therapy for women of childbearing age, including pregnant women should be based on drugs for which adequate efficacy and safety data are available; an efavirenz–based regimen is a safe and effective first‐line regimen. 
• If other first‐line ARVs cannot be used in women of childbearing age, DTG may be considered in cases where consistent contraception can be assured. 
• Programmes should continue strengthening pharmacovigilance including monitoring of birth outcomes. 
• PEPFAR encourages countries to continue with their transition to tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD), but states that transition times might be altered to allow for the use of efavirenz-based regimens for certain women. Until further data are available, they recommend that women with HIV who wish to become pregnant should take efavirenz-based regimens.

How this might work in real-life, where a large proportion of people using ART are women of child-bearing potential, a large proportion of pregnancies are unplanned, access to contraception can be inadequate, and fertility rates can be rather high (approaching 6 in Uganda, Zambia and Malawi), remains to be seen. 

References

1. WHO statement on DTG. 18 May 2018.
   http://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdf (PDF)
2. PEPFAR statement on potential safety issue affecting women living with HIV using dolutegravir at the time of conception.
   https://www.pepfar.gov/press/releases/282221.htm
3. EMA press release. New study suggests risk of birth defects in babies born to women on HIV medicine dolutegravir. 18 May 2018.
   http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2018/05/news_detail_002956.jsp&mid=WC0b01ac058004d5c1
4. US FDA. FDA Drug Safety Communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). 18 May 2018.
   https://www.fda.gov/Drugs/DrugSafety/ucm608112.htm
5. Statement from the Southern African HIV Clinicians Society. 19 May 2018.
   http://sahivsoc.org/Files/Dtg%20in%20Pregnancy%20Statement_1905.pdf (PDF)
6. BHIVA statement on potential safety signal in infants born to women conceiving on dolutegravir. (22 May 2018).
   https://i-base.info/htb/34205
7. GSK Dear Doctor letter. Tivicay (dolutegravir), Triumeq (dolutegravir, abacavir, lamivudine), Juluca (dolutegravir, rilpivirine): neural tube defects reported in infants born to women exposed to dolutegravir at the time of conception. Ref: IE/DLG/0001/18. (22 May 2018).
   http://www.hpra.ie/docs/default-source/default-document-library/important-safety-information—tivicay-(dolutegravir)-triumeq-(dolutegravir-abacavir-lamivudine)-juluca-(dolutegravir-rilpivirine).pdf?sfvrsn=0

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WHO statement on DTG (18 May 2018)

Potential safety issue affecting women living with HIV using dolutegravir at the time of conception

The investigator of an independent NIH‐funded study has identified a potential safety issue with the HIV antiretroviral medicine dolutegravir (DTG), and reported it to the World Health Organization (WHO) and ViiV Healthcare. The potential safety issue is related to neural tube defects in infants born to women who were taking DTG at the time of conception.

The issue has been identified from a preliminary unscheduled analysis of an ongoing observational study in Botswana, which has found 4 cases of neural tube defects out of 426 women who became pregnant while taking DTG. This rate of approximately 0.9% compares to a 0.1% risk of neural tube defects in infants born to women taking other antiretroviral medicines at the time of conception.

Information on neural tube defects

The neural tube is the foundation of the spinal cord, brain and the bone and tissues that surround it. Neural tube defects occur when the neural tube fails to completely form; this formation takes place between 0 and 28 days after conception. Neural tube defects may be related to folate deficiency, other medications or family history.

WHO recommends that women take daily supplements of folic acid before conception and during pregnancy to help prevent neural tube defects.

Details on preliminary findings concerning the potential safety issue

Preliminary data from the aforementioned study in Botswana so far seem to suggest that the potential safety issue arises from a woman’s exposure to DTG at the time of conception, rather than during pregnancy. From the same study, there is currently no evidence of any infant born with a neural tube defect to a woman who started DTG during her pregnancy.

Surveillance is ongoing for additional pregnant women in Botswana who were exposed to DTG at time of conception. Their deliveries will be monitored closely over the next 9 months (May 2018 – February 2019), and results are expected to be known soon thereafter. These data will provide more information about the safety of DTG for women of childbearing age.

According to manufacturer ViiV Healthcare, DTG was tested in a complete package of reproductive toxicology studies, including embryofetal development studies in rats and rabbits, where dosing occurred during the sensitive window for neural tube defects in these species. There was no evidence of adverse developmental outcomes in these studies.

WHO response

WHO recognizes that dolutegravir (DTG) has established efficacy, tolerability and a high genetic barrier to resistance.

Current WHO Guidelines released in 2016 cautioned that there were insufficient data for using DTG during pregnancy or breastfeeding and recommended efavirenz (EFV) in combination with tenofovir (TDF) + lamivudine (3TC) or emtricitabine (FTC) as the preferred option in pregnancy.

WHO convened an expert guideline development group meeting on 16‐18 May 2018 to review all available data on the efficacy and safety data of dolutegravir, including the Botswana data, and will release updated guidance on the role of DTG in first‐ and second‐ line HIV treatment in the coming months.

In the interim, WHO advises that countries and ministries follow the existing 2016 WHO Consolidated ARV Guidelines, and consider the following:

•   Pregnant women who are taking DTG should not stop their ARV therapy and should speak with their health provider for additional guidance.
•   Antiretroviral (ARV) therapy for women of childbearing age, including pregnant women should be based on drugs for which adequate efficacy and safety data are available; an efavirenz–based regimen is a safe and effective first‐line regimen.
•   If other first‐line ARVs cannot be used in women of childbearing age, DTG may be considered in cases where consistent contraception can be assured.
•   Programmes should continue strengthening pharmacovigilance including monitoring of birth outcomes.

For further information contact: pvsupport@who.int

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