“If we don’t include women in trials, we are not protecting women” – dolutegravir in pregnant women living with HIV

Update on neural tube defects
Image: Rebecca Zash presenting Tsepamo study results at the AIDS 2018 conference in Amsterdam. Photo by Liz HIghleyman.

Exposure to dolutegravir around conception or in early pregnancy is associated with a slight, but non-significant difference in the increased risk of neural tube defects compared to other antiretrovirals, participants at the 23rd International AIDS Conference (AIDS 2020: Virtual) heard this week.

Dr Rebecca Zash of the Beth Israel Deaconess Medical Center, Boston, presented updated data from the Tsepamo study, an ongoing birth outcomes surveillance programme in Botswana. The prevalence of neural tube defects among infants born to women on dolutegravir at the time of conception appears to be stabilising at approximately 2 in 1000 deliveries (0.2%) compared to other antiretrovirals at 1 in 1000 (0.1%).

The conference also heard the results of a meta-analysis of five recent randomised clinical trials in sub-Saharan Africa in which pregnant women took a dolutegravir-based or efavirenz-based regimen. The safety profiles were similar, but there was greater viral suppression in women taking dolutegravir.

Neural tube defects

Neural tube defects are severe birth defects of the brain, spine or spinal cord. They happen within the first weeks of conception, often before a woman knows she is pregnant. Causes are multiple and include a lack of folic acid as well some medications.

Glossary

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

meta-analysis

When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

middle income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. There are around 50 lower-middle income countries (mostly in Africa and Asia) and around 60 upper-middle income countries (in Africa, Eastern Europe, Asia, Latin America and the Caribbean).

mother-to-child transmission (MTCT)

Transmission of HIV from a mother to her unborn child in the womb or during birth, or to infants via breast milk. Also known as vertical transmission.

In May 2018, the Tsepamo study unexpectedly identified an association between dolutegravir use at conception and neural tube defects. Findings from other studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in March 2019 were inconclusive, highlighting the overall lack of safety data on antiretrovirals in pregnancy and, in particular, early pregnancy.

Pregnant women are excluded from most clinical drug trials, due to concerns about potential harm to the foetus. However, without a solid evidence-base on drugs used in pregnancy, pregnant women may be at risk of harmful interventions, inadequate treatment and/or failed prevention of maternal disease.

An estimated 15 million people in low- and middle-income countries could be on dolutegravir in the next few years. Close to half of this population will be women of reproductive age.

Additional data from Tsepamo, collected through March 2019, presented at the 10th International AIDS Society Conference on HIV Science (IAS 2019) and in the New England Journal of Medicine, showed a prevalence of neural tube defects of 0.3% when dolutegravir had been taken at conception. This was reassuringly lower than the figure previously given (0.9%), but still significantly higher than that for other risk groups (approximately 0.1%).

Consequently the World Health Organization recommended that dolutegravir should be available to all women, with the added caution that there was still a risk and close monitoring was essential.

Updated data

This week, Zash reported data up to April 2020: an additional 39,200 births have been recorded, bringing the total to 158,244 deliveries.

There are 28 additional neural tube defects, including two associated with exposure to dolutegravir at conception and one associated with exposure to dolutegravir in pregnancy.

Among women taking dolutegravir at conception, the prevalence of neural tube defects has decreased from 0.3% to 0.19% (7 neural tube defects out of 3591 deliveries).

Prevalence in other exposure groups has not changed substantially.

Among women taking other antiretrovirals at conception, the prevalence is 0.11% (21 out of 19,361 deliveries).  Among women exposed to efavirenz at conception, the prevalence is 0.07% (8 out of 10,958 deliveries).

Among women who started dolutegravir during pregnancy, the prevalence is 0.04% (2 out of 4581 deliveries).

Among HIV-negative women, there were 87 neural tube defects out of 119,630 deliveries, a prevalence of 0.07%.

The difference in prevalence between women taking dolutegravir at conception and all other exposure groups has also decreased. It is now 0.09%, but this is not statistically significant (95% CI: -0.03%-0.30%), down from 0.20% (95% CI:0.01-0.59).

“These prevalence difference estimates now suggest about one excess neural tube defect per 1000 births exposed to dolutegravir at conception,” Zash concluded. “These findings allow for the broader use of dolutegravir in women.”  

It's now "time to lay to rest" concerns about neural tube defects in infants born to women taking dolutegravir, "given the incredible benefits of dolutegravir," Dr Monica Gandhi added at a press conference.

“Women are not a niche population; to maintain gender equity requires pregnancy safety data,” Zash commented. “If we don’t include women in trials, we are not protecting women.”

Meta-analysis: dolutegravir and efavirenz in pregnancy

Dr Sumbul Fatima Asif of Imperial College London and colleagues undertook a meta-analysis to pull together data from newer randomised controlled trials studying pregnant women, to compare the safety and efficacy of dolutegravir and two drugs from the NRTI class with the previous standard of care, efavirenz and two NRTIs.

Dolutegravir with two NRTIs is now recommended as a first-line option (tenofovir, lamivudine or emtricitabine + dolutegravir). It is well tolerated with a rapid reduction in viral load. However, there is a paucity of safety and efficacy data on dolutegravir use in pregnancy.

A total of 1074 pregnant women took part in the five trials that were selected: DOLPHIN-1, DOLPHIN-2, IMPAACT 2010, ADVANCE and NAMSAL. The studies were conducted in South Africa, Uganda, Brazil, Botswana, India, Tanzania, Thailand, USA, Zimbabwe and Cameroon.

NAMSAL and ADVANCE enrolled women at conception. IMPAACT 2010 enrolled women in both the second and third trimesters, and the DOLPHIN studies in the third trimester.                                                                                          

Results

Viral suppression and pre-term births were the only outcomes with a significant difference between women on dolutegravir- and efavirenz-based regimens, respectively.

Viral suppression rates were close to three times higher among women on dolutegravir compared to efavirenz, odds ratio (OR) 2.90, (95% CI: 1.54-5.46), p=0.001.

Unexpectedly, all five cases of mother-to-child transmission of HIV were in the dolutegravir arms of the studies. Two were in IMPAACT 2010 and three in DOLPHIN-2. Nonetheless, no significant difference was found between dolutegravir- and efavirenz-based regimens in terms of mother-to-child transmission, 1% and 0%, respectively, p=0.17.

There were marginal differences between the treatment safety of dolutegravir and efavirenz.

  • Pre-term births: 8% and 12% in dolutegravir and efavirenz arms, respectively (p=0.04).
  • Stillbirths: 4% and 2% respectively (p=0.06).
  • Neonatal deaths: 2% and 3% respectively (p=0.68).
  • Severe adverse event in mother or infant: 22% and 23% respectively (p=0.06).

The ADVANCE and IMPAACT 2010 both had two dolutegravir-based arms, one with tenofovir disoproxil fumarate (TDF) and one with tenofovir alafenamide (TAF). Overall there were no significant differences between these arms. However, weight increased in all three arms of the ADVANCE trial, with the greatest gain in the TAF/emtricitabine/dolutegravir arm.

Dr Asif concluded that while the safety profiles are similar, these findings only relate to the short-term effects of the medications. Most women, she stressed, are likely to become pregnant after being on antiretroviral treatment for years.

These findings, she added, should be confirmed with studies on the long-term safety profile of dolutegravir due to its association with weight gain, noticeably higher in black females, and related risk of obesity-associated adverse birth outcomes.

References

Zash R et al. Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana. 23rd International AIDS Conference, abstract OAXLB0102, 2020.

Asif SF et al. Faster virological suppression with dolutegravir versus efavirenz in pregnancy does not lower the risk of HIV mother-to-child transmission: a meta-analysis of 5 clinical trials in 1074 pregnant women. 23rd International AIDS Conference, abstract OABLB0105, 2020.