response to WHO: Dolutegravir is best drug in pregnancy

ray martin emailed me back as below, raising the unfortunately common issue of PEP (post-exposure prophylaxis) for needlesticks and the recommendation to use raltegravir (and INSTI which may actually be more likely to have an effect on folate) as opposed to dolutegravir in "persons who are pregnant or are of childbearing potential", per UpToDate

raises suggestion that women of childbearing potential might be advised to try to avoid pregnancy during the time taking PEP...  and, if possibly very early pregnancy, checking pregnancy test and discussing pros/cons of INSTI-based regimen

geoff

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From: Ray Martin
Sent: Monday, August 12, 2019 8:29 AM
To: Geoff A. Modest, M.D. <GModest@uphams.org>
Subject: Re: WHO: Dolutegravir is best drug in pregnancy

Hi Geoff,

Thanks for this.  Working in employee health I write Rx's for PEP following high-risk needle sticks and have been prescribing raltegravir for pregnant women instead of dolutegravir.  UpToDate still recommends not to use dolutegravir if a pregnancy is first trimester, probably reflecting that the authors of UTD haven't had the opportunity to review the relevant data and update the article.

Ray

On Mon, Aug 12, 2019 at 8:11 AM Geoff A. Modest, M.D. <GModest@uphams.org> wrote:

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The World Health Organization (WHO) is now recommending dolutegravir (DTG) as the preferred first- and second-line drug for all patients with HIV, including women who are pregnant or of child-bearing age, seehttps://www.who.int/news-room/detail/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations

There was initial concern about a potential link between DTG and neural tube defects (see http://gmodestmedblogs.blogspot.com/2019/01/hiv-treatment-in-pregnant-women.html ), since 4 cases were found in Botswana out of 426 women who became pregnant while on DTG, above the expected background level. Many countries advised women to avoid DTG and instead to use efavirenz (EFV)-based treatments. The change in WHO recommendations reflect the results of new studies, but include in their modeling DTG’s ease of use, low level of adverse effects, high genetic barrier to resistance, and increased effectiveness, especially in light of increasing resistance to EFV (in 2019, 12 of 18 countries surveyed by the WHO reported pre-treatment drug resistance levels exceeding the recommended threshhold of 10%) 

The Botswana follow-up study was recently published (see hiv doluteg pregnancy nejm2019 in dropbox, or DOI: 10.1056/NEJMoa1905230). 

Details: 

--Botswana was the first African country to shift from EFV- to DTG-based treatment for HIV 

--comparing women on the different HIV meds: no significant difference in measured confounders of obesity, diabetes, or exposure to antiepileptic drugs or trimthophrim-sulfamethoxazole 

--median time from HIV diagnosis to conception: 97 weeks in the DTG group, more in other groups; CD4=566 with only 4% <200  

--folate: prescribed preconception in 0.1%; during pregnancy 69% [unclear what time in the pregnancy the folate was prescribed] 

--the current study increased the birth-outcome surveillance from 8 to 18 sites in 2018 

Results: 

--119,033 deliveries were analyzed from August 2014 through March 2019: 98 neural-tube defects were identified (0.08% of deliveries) with 72 having live births (0.06%) 

--DTG-taking mothers (1683 deliveries): 5 neural tube defects [0.30% (0.13-0.69%)] 

    --2 myelomeningocele 

    --1 anencephaly 

    --1 encephalocele 

    --1 iniencephaly 

--1 neural tube defect in a woman who started DTG during pregnancy, at 8 weeks gestation 

--non-DTG regimens (14,792 deliveries): 15 neural tube defects [0.10% (0.06-0.17)] 

    --in those on EFV: 3 defects in 7959 deliveries [0.04% (0.01-0.11)] in mothers taking EFV at conception

--HIV-uninfected women: 70 neural tube defects in 89,372 deliveries (0.08%) 

--major external structural defects: 0.95% in women on DTG, 0.68% in those on non-DTG regimens, 0.59% in non-HIV infected women. Not statistically significant 

--overall difference in women on DTG at conception vs other meds = 0.22 percentage points 

 Commentary: 

--neural tube defects occur by the end of the 6th week of pregnancy (ie, the 1 neural tube defect in the woman who started DTG at 8 weeks was unlikely related to the DTG)

--this study found 1 additional case in women on DTG, 1 in 1257 (0.08%) additional women after the initial 4 in 426 women (ie, a much lower level than in the original report), though still  higher than in those women on non-DTG based regimens or those without HIV infection

--relationship with folate deficiency, which has known association with neural tube defects:  

    --preconception folate supplementation is an existing WHO recommendation, and is the standard of care in industrialized nations 

        --Botswaba does not mandate folate-fortified grain

    --no increase in non-neural tube defects in those on DTG (actually fewer than with EFV, with the exception of stillbirths), though none of the differences were substantial (ie, DTG seems to be associated with a specific increase in neural tube defects)

    --in vitro studies have found partial antagonism between DTG and folate at high concentrations, as well as some supportive animal studies of this relationship

    --only 0.1% of women (ie 1 person) was on preconceptual folate in this observational study; and neural tube defects occur by the 6th week of pregnancy

--that being said, studies have found that folate antagonism only happens at very high levels of DTG and other INSTIs, raising the question of its clinical revelance (see https://www.ncbi.nlm.nih.gov/pubmed/31167838 ).  [though one might imagine that there could be some variability in response in humans, and folate deficiency could  be a real effect in some women who happen to have been on DTG for a long time and also have very low folate levels anyway at the time of conception (possibly from eating very low folate foods)] 

--this was an observational study, with very low prevalence in neural tube defects (very small numbers of them in this study), potentially leading to large changes in relative risk but small differences in absolute risk [eg, there were apparently only 1/2 the number to defects in those on EFV than those not infected with HIV at all!!]. and, as with all observational studies, lots of potential unaccounted-for confounders (eg, though Botswana did accept DTG-based regimens, why were some women on DTG instead of EFV? was it random?? or was there some aspect of the woman's condition or pregnancy that led the clinicians to choose DTG??)

So, 

it does seem to be a problem denying women of child-bearing age (50% of those worldwide with HIV infection) from the best group of anti-HIV meds, unless there is pretty clear evidence of a major problem. The above data do suggest that there may well be an increase in neural tube defects, though less than in the initial report, leading to the overall WHO analysis recommending DTG regimens as the preferred ones in light of increasing EFV resistance.  It seems quite possible that the neural tube problem may revolve around effective folate deficiency made worse by the potential DTG antagonism of folate, perhaps further exacerbated by the low level of preconceptual folate use (0.1%) and the very early-gestation development of neural tube defects (likely before many women seek pregnancy care in the first place), in a population without clear guidelines to have folate supplementation anyway.  But, even though the folate link seems to be quite possible, it is a bit of a leap of faith to jump to DTG as the preferred agent without clear evidence that folate is the problem, and that any increase in neural tube defects could be eliminated with regular folate supplementation.  

DTG is a really great drug, especially in those countries with high prevalence of EFV-resistance. it is unfortunate that the WHO recommendations do not stress/reinforce the importance of folate supplementation in these recommendations. In high income countries, it does make sense (to me) to perform HIV resistance testing prior to starting meds in women of childbearing age and not use INSTI-based meds such ast DTG if pregnancy is possible and the EFV-based meds work well and are well-tolerated (after a discussion of pros and cons with the women). After all, EFV-based regimens were the huge game-changers in HIV disease and huge numbers of people did very well with them

Seems like it would be reasonable to make sure there is adequate folate supplementation in women of childbearing age who are now recommended to get dolutegravir

One potential easy option (should be tested) is coformulation of DTG with folate…. 

geoff

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