Dolutegravir preconception signal: time is up for shoddy surveillance
Polly Clayden, HIV i-Base
The news in May 2018 of a potential risk of neural tube defects in infants born to women taking dolutegravir (DTG) at the time of conception sent shockwaves through the HIV community.
But, despite massive global investment, aggressive transition plans – as well as calls for years for more systematic recording of outcomes when women receive ART in pregnancy– few prospective birth registrieshave been established in other settings that can refute or confirm this finding.
Meanwhile, women of child-bearing age, whether they intend to become pregnant or not, are being told that they must stick with (or go back to) efavirenz (EFV) – a drug that, before this news, was in the process of being replaced with DTG.
The Botswana data
On 18 May 2018, the World Health Organisation (WHO) issued a statement after a potential safety signal with DTG was identified relating to neural tube defects in infants who had been exposed to this antiretroviral at the time of conception. 
The safety signal was found at a preliminary, unscheduled analysis of an ongoing observational study in Botswana. The Tsepamo study is a birth surveillance programme, started after the introduction Option B+ (lifelong ART for all pregnant women) in Botswana. When it was designed, there was still some uncertainty about EFV and birth defects.
Tsepamo compares birth outcomes with exposure from conception and/or during pregnancy to the most common ART regimens used in the country since 2014. Surveillance is conducted at eight maternity wards in government hospitals, representing about 45% of all births. Data are extracted from all consecutive births at 24 weeks or more gestational age, using obstetric records. Livebirth and stillbirth outcomes in HIV positive are also compared to those in HIV negative women.
Botswana is an ideal setting to do this analysis. There is high HIV prevalence (about 22%), high uptake of ART in pregnancy (about 90%) and the majority of women (over 95%) deliver in a healthcare facility. Due to changes in national guidelines there has been a variety of regimens to compare since the study began. Botswana began using DTG as preferred first-line in May 2016.
The study had previously reported reassuring data (similar to that with EFV) with DTG started during pregnancy. [2, 3] The most recent figures, published in Lancet Global Health online 4 June 2018, includes 1729 pregnant women who started DTG-based ART and 4593 EFV-based ART in pregnancy.  The risk for any adverse birth outcome among women on DTG versus EFV was similar: 33·2% vs 35·0%; aRR 0·95 (95% CI 0·88 to 1·03). As was the risk of any severe birth outcome: 10·7% vs 11·3% (95% CI 0·94 0·81 to 1·11).
But adverse pregnancy outcomes among HIV positive women continue to be elevated compared with HIV negative women, despite ART. When these data were released the Tsepamo investigators emphasised that the findings were reassuring but not the whole story. And that birth outcomes with DTG exposure from conception still needed to be evaluated.
The preconception analysis revealed four cases of neural tube defects (spina bifida, anencephaly, encephalocele/iniencephaly) out of 426 births to 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.
WHO’s May statement was followed by several others, including from US President’s Emergency Plan for AIDS Relief (PEPFAR), US Food and Drug Administration (FDA), European Medicines Agency (EMA), US Department of Health and Human Services (DHHS), as well as a Dear doctor letter from ViiV Healthcare [5–9].The recommendations suggest varying degrees of caution.
The WHO statement advises that pregnant women who are already taking DTG should not stop ART and should speak with their health provider for additional guidance. For women of childbearing age starting ART, including pregnant women, it says, treatment should be based on drugs for which adequate efficacy and safety data are available; an EFV-based regimen is a safe and effective first‐line regimen. DTG might be considered in cases where consistent contraception can be assured (if other first‐line ART cannot be used in women of childbearing age).
PEPFAR encourages countries to continue with their transition to tenofovir disoproxil fumarate, lamivudine, and DTG (TLD), but states that transition times might be altered to allow for the use of EFV-based regimens for certain women. Until further data are available, it recommends that women with HIV who wish to become pregnant should take EFV-based regimens. Any mention of contraception for women who do not wish to become pregnant is notable by its absence.
The EMA advises avoiding DTG for women who are trying to become pregnant and contraceptive use for those who are not. But they add that if pregnancy is confirmed in the first trimester while a woman is taking DTG, switch to an alternative treatment unless there is no suitable alternative. This last recommendation seems a little overcautious, unless the pregnancy is recognised extremely early, given that the risk window for neural tube defects is 0–28 days. Both the Southern African Clinicians Society and the British HIV Association (BHIVA) have also taken this approach. [10, 11]
Many low- and middle-income countries have already begun to transition (or are in the process of transitioning) to DTG-based regimens and are reviewing their policies based on this new information. It appears that several countries are taking a conservative approach and giving all women of reproductive age EFV-based first-line irrespective of their circumstances. The Kenyan Ministry of Health has pretty much banned DTG for women aged 15–49. 
WHO is working with many stakeholders worldwide to follow pregnant women with preconception DTG exposure to ensure more information is available to inform countries’ recommendations. 
Data from clinical trials
New antiretrovirals are usually introduced with major gaps in information on their safety in pregnancy. [14,15] In low- and middle-income countries women of child-bearing age make up nearly half (44%) of the population who are on ART, or need to be so, and might become pregnant. 
Typically, pregnant women are excluded from registration and strategic trials of new drugs and even data from non-pregnant women are scant when approval is sought or a drug is recently approved. See Table 1 for numbers of women in DTG registrational and post marketing studies.
Table 1: Number of women in ViiV dolutegravir studies
|Study||Design||Results||Women DTG arm (n)|
DTG + ABC/3TC vs
833 ART naive participants
|DTG arm superior (driven by lower rate of discontinuation)||67|
2NRTI + DTG vs
2NRTI + RAL
822 ART naive participants
2NRTI + DTG vs
2NRTI + DRV/r
484 ART naive participants
OB + DTG vs OB + RAL
719 treatment experienced participants
2NRTI/DTG vs current ART
551 suppressed participants, switch
|SWORD 1+2||Phase 3
RPV + DTG vs current ART
1024 suppressed participants, switch
|DTG + RPV non-inferior||120|
ATV/r + TDF/FTC
495 treatment naive women
2NRTI + DTG vs2NRTI + LPV/r
627 experienced participants
Week 24 data and large subsets from weeks 36 and 48
2NRTI + DTG twice daily vs2NRTI + EFV with RIF-based co-treatment
|DTG 50 mg twice daily with RIF safe + effective at 24 weeks||36|
Key: ABC, abacavir; ART, antiretroviral treatment; ARV, antiretroviral; ATV/r, atazanavir/ritonavir; DTG, dolutegravir; DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; NRTI, nucleos/tide reverse transcriptase inhibitor; OB, optimised background; RAL, raltegravir; RIF, rifampicin; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; VL, viral load; 3TC, lamivudine
There are data from a few women who became pregnant in DTG phase 3 trials and post marketing but these are not in sufficient numbers to pick up a rare adverse event such as a neural tube defect, nor have a comparator. [17–19]
Preclinical safety data did not show developmental toxic effects or teratogenicity – although these categories are no longer used, DTG is FDA category B. [20, 21]
In their excellent soon-to-be-published tour de force, HIV treatment in pregnancy, Bailey et al raise the important question of whether more regulatory push is needed to make sure that pharmaceutical companies expedite appropriate studies to generate pregnancy data (similar to that for paediatrics) 
Beyond regulatory trials, strategy trials of new drugs should also follow up women who become pregnant within the study remaining on the study drug unless there is a good reason not to. 
Other registries and studies
Currently there is a flurry of activity to try and determine whether the safety signal from Botswana was a chance finding.
There are about 600 more pregnant women who started DTG before conception in Tsepamo who are being followed, and data should be available within the next 9–12 months.
As far as other “early adopter” countries are concerned, similar programmes to Tsepamo are in place in Uganda and Malawi.  But the transition to DTG is only just beginning so neither country will have much to report yet.
Brazil has been using DTG in its national programme since early 2017, and has an excellent reporting system, but it is unlikely that the numbers of exposures will be substantial. 
Data from high-income countries are frequently collected and there has been longer term DTG use – although far fewer women with HIV.
This includes reports to the Antiretroviral Pregnancy Registry (APR).  APR is an international (although largely US), voluntary, prospective registry that monitors prenatal antiretroviral exposures to detect potential increases in the risk of birth defects. The APR produces twice-yearly reports.
Antiretroviral exposure is classified by earliest trimester, which means starting ART any time in the first three months. Due to the narrow exposure window of interest for neural tube defects, the current interim report through to 31 January 2018 (published June 2018) included supplementary information on preconception DTG exposure. Only a small number of exposures (121) have been reported to date among which there were no neural tube defects. 
The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) is a network of cohort and surveillance studies conducting epidemiologic research on pregnant women and children with HIV and children exposed to HIV during pregnancy.
Data for 81 infants presented in 2017 reported defects in four infants – these are from any pregnancy exposures (55 mothers ART preconception) and not neural tube defects. [27, 28] EPPICC is currently analysing preconception exposures to date across participating European countries.
Most European countries have their own surveillance, some like the UK and Ireland NSHPC (National Study of HIV in Pregnancy and Childhood) and theSwiss MoCHiV (Mother and Child HIV Cohort Study) contribute to EPPICC. Others like the French Perinatal Cohort do not.
Most impenetrable are adverse event reporting systems. Accessing FAERS (AERS) data (data within the FDA’s drug Adverse Event Reporting System) requires the investigative skills of a sleuth (plus US $420 for a drug safety analysis)  Obviously, there is no denominator from spontaneous reporting but it is also tricky to work out whether or not events have been reported more than once under different descriptions.
So, despite much global commitment to hunting down neural tube risk data – where registries have not yet been established, numbers are too few or data are impossible to interpret – this might be easier said than done.
It is hard to imagine how in 2018 we could be in this situation where women with HIV are being so woefully underserved.
It was not that long ago that analyses were underway to try and work out whether the risk of neural tube defects, seen in preclinical primate studies with EFV, was similar for humans. 
A series of systematic reviews found no evidence of an increased risk of overall or neural tube defects associated with preconception/first trimester exposure to EFV. [31–33] But the authors rated the overall evidence base to be of low quality and each review concluded with a call for well-designed and supported surveillance systems to look at safety of antiretrovirals in pregnancy:
“It is also critical that as efavirenz use increases among women in these countries that support is given to establish adequate pharmacovigilance systems to better define the risk” (2010).
“Prospective surveillance systems particularly in developing countries are needed to improve data reporting and inform the assessment of risk of rare defects” (2011).
“Surveillance planning efforts have recently been established in several countries and such efforts need to be sustained and supported…The data generated from these efforts to improve data collection and reporting will inform future guidelines on the safety of efavirenz and other antiretrovirals in pregnancy” (2014).
Since the EFV signal was first documented, other commentaries with recommendations to set up good surveillance systems are too numerous to mention.
WHO also produced a technical brief – Surveillance of antiretroviral drug toxicity during pregnancy and breastfeeding in October 2013. 
This provides an overview of approaches for assessing the safety of antiretrovirals in pregnancy and breastfeeding. It was intended for national HIV programme managers and implementing partners, such as NGOs and academic institutions, that are responsible for implementing systems to monitor the safety of antiretroviral drugs (our italics).
It includes information on the development and maintenance of: 1. a prospective pregnancy exposure registry; 2. a birth defect surveillance programme; and 3. a prospective monitoring of cohorts of mother–infant pairs, during the breastfeeding period at sentinel sites. In other words, an instruction manual, for setting up such systems.
So, what needs to be done?
- Surveillance systems need to be established in countries where DTG and, in the future, other new HIV drugs will be introduced – including long-acting ones that will need extra consideration in pregnancy. This is somewhat after the event for DTG in many places. But HIV is not going to go away for a while, women of childbearing age will likely continue to make up almost half the epidemic, and DTG will not be the last new HIV drug.
Donors, particularly those supporting aggressive transition, need to ensure that accompanying surveillance programmes are also set up and supported. Those in any doubt about how to approach this need look no further than Botswana’s excellent example – which could be adapted to different settings. And a quick internet search will find WHO’s “how to” document.
- Include more pregnant women in research. PHASES (Pregnancy and HIV/AIDS: Seeking Equitable Study), is a project to develop recommendations for advancing research to address the evidence gaps in pregnant women.  The aim is a rigorous evidence base for safer and faster access to new HIV medicines.
- Regulators need be more demanding.  Studies that are mandatory to get full drug approval tend to get done. The potential safety preconception safety signal with DTG highlights the need for large pharmacovigilance studies.
- Contraception, contraception, contraception. This review has mainly looked at the sorry state of surveillance in pregnancy. But because of this, it is likely that many women who could benefit from DTG might be denied it. If approximately one million pregnant women a year receive ART but over 15 million are of child bearing age and on or in need of ART,  a vast number of women remain who do not plan: to have more children, children at that particular time, or children at all.
The unmet need for effective family planning in many low-income countries is massive and this can be particularly so among HIV positive women.  Whether the DTG preconception safety signal is confirmed or turns out to have happened by chance, improving these services would offer huge benefits.
Unfortunately, the global gag rule (more politely known as the Mexico City policy), that blocks US funding, including from PEPFAR, for organisations that use their own non-US funding to for abortion-related activities  – and is dramatically expanding under the current administration – is not going to be helpful with improving contraceptive services. Creative solutions will be needed and other more progressive donors need to step up.
While we wait for further information, more nuanced discussions on provision of DTG to women – rather than a blanket ban for those aged 15–49 – are critical. These discussions need to include women with HIV and their communities, to remember the reasons why DTG was chosen as an optimal antiretroviral in the first place (including improved resistance and side effects profiles), and take broader risk/benefits into consideration.
- WHO statement on DTG. 18 May 2018.
- Zash R et al. Dolutegravir/tenofovir/emtricitabine (DTG/TDF/FTC) started in pregnancy is as safe as efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in Botswana. IAS 2017. 23–26 July 2017. Paris. Oral abstract MOAX0202LB.
- Clayden P. Preliminary results on dolutegravir use in pregnancy are reassuring. HTB. 10 August 2017.
- Zash, R et al. Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study. Lancet Glob Health. Published online 4 June 2018.
- PEPFAR statement on potential safety issue affecting women living with HIV using dolutegravir at the time of conception.
- 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.
- EMA press release. New study suggests risk of birth defects in babies born to women on HIV medicine dolutegravir. 18 May 2018.
- US DHHS. Recommendations regarding the use of dolutegravir in adults and adolescents with HIV who are pregnant or of child-bearing potential. 30 May 2018.
- 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).
- Statement from the Southern African HIV Clinicians Society. 19 May 2018.
- BHIVA statement on potential safety signal in infants born to women conceiving on dolutegravir. 22 May 2018.
- Nkala N. Kenya bans use of HIV drug dolutegravir by pregnant and breastfeeding women. Outbreak News Today. 5 July 2018.
- WHO. Q&A on DTG use in women of childbearing age.23 May 2018
- Zash M et al. Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges. Expert Opin Drug Saf.2016 Nov;15(11):1501-https://www.tandfonline.com/doi/full/10.1080/14740338.2016.1226281
- Slogrove AL et al. Toward a universal antiretroviral regimen: special considerations of pregnancy and breast feeding.Curr Opin HIV AIDS.2017 Jul;12(4):359-368.
- Bailey H et al. HIV treatment in pregnancy. The Lancet HIV. 2018. Forthcoming.
- Hill A et al. Safety and pharmacokinetics of dolutegravir in HIV-positive pregnant women: a systematic review. J Virus Erad. 2018 Apr; 4(2): 66–71.
- World Health Organization Transition to new antiretrovirals in HIV programmes; 2017. http://apps.who.int/iris/bitstream/handle/10665/255888/WHO-HIV-2017.20-eng.pdf (PDF)
- Vitoria M et al. When could new antiretrovirals be recommended for national treatment programmes in low-income and middle-income countries: results of a WHO think tank. Curr Opin HIV AIDS 2017; 12: 414– 422. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459586/toxic
- ViiV Healthcare. Full prescribing information: dolutegravir; 2013.
- Kandel CE et al. A review of the pharmacology, efficacy, and safety in the treatment of HIV. Drug Des Devel Ther 2015; 9: 3547– 3555. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500604
- Clayden P. What to do when a woman becomes pregnant. November 2017.
- Mofensen L. In utero ART exposure and the need for pharmacovigilance. Lancet Glob Health. Published online 4 June 2018.
- Clayden P. Brazil to start using dolutegravir first-line in its national programme. HTB. 1 October 2016.
- The Antiretroviral Pregnancy Registry
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry Interim Report for 1 January 1989 through 31 January 2018. Wilmington, NC: Registry Coordinating Center; 2017.
- Thorne C et al. Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir. IAS 2017. 23–26 July 2017. Paris. Poster abstract MOPEC0609.
- Thorne C et al. Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir. 9th International Workshop on HIV Pediatrics 2017. 21–22 July 2017. Paris. Oral abstract 10.
- De Santis M et al. Periconceptional exposure to efavirenz and neural tube defects. Arch Intern Med. 11 February 2002.
- Ford et al. Safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. AIDS. 19 June 2010.
- Ford et al. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 28 November 2011.
- Ford et al. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS March 2014.
- WHO. Surveillance of antiretroviral drug toxicity during pregnancy and breastfeeding. October 2013.
- 35. Krubiner CB et al.AdvancingHIVresearch with pregnant women: navigating challenges and opportunities. AIDS. 24 September 2016.
- Jhangri GS et al. Unmet need for effective family planning in HIV-infected individuals: results from a survey in rural Uganda. J Fam Plann Reprod Health Care 2012;38:23-9.
- Trump D. Presidential Memorandum Regarding the Mexico City Policy. The White House. 23 January 2017.