Episode #15 – Fresh stART: ARTing for Two

June 28, 2021

Summary

Dr. Rebecca Zash shares her advice on approaching a new diagnosis of HIV during pregnancy.

Credits

Host(s): Sara Dong

Guest: Rebecca Zash

Writing/Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guest

Rebecca Zash, MD

Dr. Rebecca Zash is an attending physician in the Division of Infectious Diseases at Beth Israel Deaconess Medical Center, an Assistant Professor at Harvard Medical School, and a research associate at the Harvard TH Chan School of Public Health and the Botswana Harvard AIDS Institute Partnership. After medical school at the University of North Carolina, Chapel Hill, Rebecca completed internal medicine residency and infectious diseases fellowship at Beth Israel Deaconess Medical Center. As part of her ID fellowship, Rebecca moved with her family to Botswana to pursue research on the safety of antiretroviral medications during pregnancy, and she has continued to focus her research efforts on understanding the mechanisms of adverse birth outcomes among HIV-infected women on ART. In addition to research and patient care, she also serves as the associate director for global health programs in the Internal Medicine residency at BIDMC.

Culture

Rebecca loves the season for grilling and eating outside!

Consult Notes

Consult Q

New diagnosis of HIV in pregnancy

One-liner

25 yo pregnant female who presents in her first trimester at 9 weeks gestation and was diagnosed with new HIV infection found on prenatal screening

Key Points

Jump to:

We started the episode with Rebecca’s thoughts on approaching the clinic visit about a new diagnosis of HIV during pregnancy. A summary and some notes based on the discussion:

Recognize and acknowledge that there is a huge level of anxiety and stress with the pregnancy, regardless of whether it was a planned pregnancy or not. When you bring HIV into this discussion, it can be even more overwhelming. Pregnancy though can be an opportune time to engage someone in their health as they are often motivated to stay healthy for themselves and the baby.
Rebecca likes to bring the focus to the main point: “we’re here to help keep you and your baby healthy”
The initial evaluation of a pregnant patient with HIV should include and emphasize:
- - Assessment of HIV disease status
  - Planning for ART (or continuing/modifying if applicable in a patient with known HIV on therapy). All pregnant women with HIV should initiate ART as early in pregnancy as possible, regardless of HIV VL or CD4 count. Discuss benefits/risks of ART related to:
    - - Maternal health and preventing risk of disease progression
      - Prevention of perinatal transmission of HIV
      - Benefits of ART to achieve and maintain viral suppression, which reduces risk of sexual transmission to partners who do not have HIV
      - Potential adverse effects of ART for women, fetus/infants, and potential interactions
  - Need for strict adherence to avoid resistance, optimize health outcomes, minimize risk of perinatal HIV transmission
- Discuss topics such as breastfeeding and future family planning early on to better understand your patient’s goals

Rebecca also discussed general principles to keep in mind when selecting an ART regimen for a pregnant patient.

Primary goal: your pregnant patient is placed on an ART regimen that she can tolerate and that will get her viral load suppressed as quickly as possible
In addition, you want to discuss medication use in pregnancy. Rebecca explained that she avoids the language of “safe” or “not safe” in pregnancy and prefers to discuss that this is a risk-benefit analysis. There is not really enough research to ever really know the full scope.

So what are the preferred regimens for initial antiretrovirals to use in a pregnant patient?

Check out the guidelines links and infographics as well!
Preferred dual NRTI backbone includes:
- - Abacavir/Lamivudine (ABC/3TC) or
  - Tenofovir with Emtricitabine or Lamivudine (TDF/FTC or TDF/3TC)
Then you combine with either:
- - Ritonavir-boosted protease inhibitor (Atazanavir/ritonavir or Darunavir/ritonavir; ATV/r or DRV/r) or
  - INSTI (dolutegravir or raltegravir; DTG or RAL)
A few notes on alternative options:
- - TAF/FTC is currently listed as an alternative dual-NRTI backbone
  - Zidovudine/3TC is not recommended for initial therapy in nonpregnant adults and has the negatives of BID dosing and potential for toxicity.
Again, the goal is to construct a regimen that is easy to tolerate. For the vast majority of patients, Rebecca prefers dolutegravir!
- - Here is the study that Rebecca mentioned: Lockman S, Brummel SS, Ziemba L, et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2021;397(10281):1276-1292. doi:10.1016/S0140-6736(21)00314-7
  - The study randomized newly started pregnant patients (14-28 wks) to DTG/TAF/FTC, DTG/TDF/FTC, or Efavirenz/TDF/FTC. The dolutegravir regimens had superior virologic efficacy, and the DTG/TAF/FTC group had the lowest frequency of composite adverse pregnancy outcomes.
  - The only bummer is that there is not a one pill once a day option for this regimen
  - Could still choose ABC, but this requires HLA testing and you’ll want to start your patient on therapy asap!

In most circumstances, a woman with HIV on a fully suppressive combination should be continued on her current regimen (as discontinuing therapy could cause a viral rebound that increases risk of HIV transmission to the fetus). We discussed what ART drug(s) you would not recommend in pregnancy or that might warrant a switch

You can check out DHHS Guidelines Table 5 here for details by ART regimen component
Rebecca emphasized concern with cobicistat containing regimens
- - Use of atazanavir/cobicistat, darunavir/cobicistat, or elvitegravir/cobicistat regimens during pregnancy is associated with lower plasma drug exposures due to physiologic changes associated with pregnancy
    - - In PK studies from the 2nd/3rd trimesters, cobicistat lowers level of darunavir and possibly elvitegravir due to changes in volume of distribution, and these lower drug exposures pose increased risk of virologic failure (although we don’t have much clinical evidence here)
  - If a patient becomes pregnant and is fully suppressed on cobicistat-containing regimen, would think about risk/benefits of switch. In some scenarios, patients may be at high risk with switching regimen (e.g. someone who would have difficulty with adherence if no longer on one pill once a day regimen who would have high risk of 3rd trimester viremia). If reasonable though, could switch from cobi regimen
A quick note: there is no data on two drug regimens in pregnancy

Rebecca gave an overview on the questions surrounding dolutegravir in pregnancy or women trying to conceive and possible neural tube defects. Here is a quick overview and links to the key papers:

A quick reminder that neural tube defects (NTDs) are a failure of the neural tube to close, which happens in the first 6 weeks of pregnancy

Preliminary data from an observational surveillance study of birth outcomes in a cohort of pregnant women with HIV in Botswana was released in 2018
- - The original observational study demonstrated similar adverse birth outcomes among pregnant women who initiated DTG-based and efavirenz-based ART: Zash R, Jacobson DL, Diseko M, et al. Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study. Lancet Glob Health. 2018;6(7):e804-e810. doi:10.1016/S2214-109X(18)30218-3
  - However later in 2018, investigators detected a higher-than-expected number of NTDs among infants born to women who started treatment with DTG before conception (4 cases in 426 women or 0.94% had NTD in study, whereas reported incidence of NTD was expected at 1/1000). Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med. 2018;379(10):979-981. doi:10.1056/NEJMc1807653
In 2018, the US FDA issued safety alert that warned of potential serious neural tube defects in infants born to mothers who received DOL at time of becoming pregnant and early in first trimester
Unfortunately there were not a lot of other sources of data, but investigators continued to collect information. Subsequently these data from Botswana were updated in 2019 and reported a lower rate of neural tube defects than initially reported, albeit slightly higher than baseline rate of neural tube defects in the population and slightly higher than in pregnant women who received efavirenz. Prevalence was 2/2000, so with more data, risk seemed much lower.
- - Zash R, Holmes L, Diseko M, et al. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med. 2019;381(9):827-840. doi:10.1056/NEJMoa1905230
More recently, a multicenter open-label RCT enrolled ~600 pregnant women with HIV to receive 1 of 3 different ART regimens at 14 and 28 wks gestation: DTG + TAF/FTC, DTG + TDF/FTC, Efavirenz + TDF/FTC
- - Lockman S, Brummel SS, Ziemba L, et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2021;397(10281):1276-1292. doi:10.1016/S0140-6736(21)00314-7
  - The DTG containing regimens, especially when combined with TAF/FTC, had more rapid rates of virologic suppression and best safety profile
So the current guidelines were updated to say:
- - Dolutegravir is a preferred drug for pregnant women with HIV, regardless of trimester and for women trying to conceive. In most causes, DTG should be continued when become pregnant
  - It is still recommended to discuss the risk/benefit balance in the face of limited data
All pregnant women and those who might conceive should take at least 400 mcg of folic acid daily (of note, food in Botswana / studies mentioned was not routinely fortified with folate)

How often should viral load be monitored in pregnancy? Plasma HIV RNA levels in pregnant women with HIV should be monitored at:

Initial antenatal visit
2-4 weeks after initiating or changing ART
Monthly until RNA levels are undetectable
At least every 3 months once stable

We ended the episode with a discussion around breastfeeding.

Check out the direct link to the DHHS guidelines here: Recommendations for the Use of ARV Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the US

A few other links:

The DHHS guidelines do not recommend breastfeeding for women with HIV living in the US. The reasoning for this recommendation from DHHS is outlined at the link above and below — it includes:

- - Maternal ART reduces but does not completely eliminate the risk of HIV transmission via breast milk
  - Safe and affordable infant feeding alternatives are readily accessible in the US
  - The postpartum period can be a challenging time to remain fully adherent to ART
  - There is a paucity of safety data on most modern ARV regimens during breastfeeding
This differs from other countries where cost limits access to formula and where inadequate quantities of safe water or formula have been associated with high rates of infant mortality

It’s not totally clear if U=U applies to breastfeeding. Studies have shown maternal ART during pregnancy and infant ARV prophylaxis during breastfeeding can reduce but not entirely eliminate risk of breast milk associated HIV transmission. As Rebecca mentioned, we have some older data with older drugs, mostly outside of the US, which reported cases of HIV transmission with breastfeeding when mom had a suppressed viral load. There were also cases of virus found in the breastmilk of a suppressed patient. In the DTG/efavirenz/PI era though, there has not been documented transmission in virologically suppressed women via breastfeeding. We also know that breastfeeding is recommended in most high incidence HIV countries in Africa and Southeast Asia, and despite many people breastfeeding and taking DTG, there have not been transmissions.

- There are a variety of relevant studies looking at this, which have been summarized by the DHHS and WHO previously (and I’ll have some further links below)
- Unfortunately breastmilk transmission is still theoretically possible and hard to prove it doesn’t happen

As we discussed in the show, women may have various reasons to desire breastfeeding as they may face environmental, social, familial, or personal pressures or stigmas. Focusing exclusively on risk of perinatal transmission fails to acknowledge those pressures and the advantages that might be lost with breastfeeding. Women who have questions about breastfeeding or who desire to breastfeed should receive patient-centered, evidence-based counseling on infant feeding options.

The DHHS guidelines now include some guidance on discussing and supporting risk-reduction measures to minimize risk of HIV transmission to infants in women who choose to breastfeed (all can be accessed at the link above). There should also be close communication between patient and the ID/OB-GYN/pediatric teams.
Rather than providing links to the various specific studies, I have tried to create a list of a few papers that often summarize the available evidence and talk more in detail about the ethics and conversations surrounding this topic:

Other miscellaneous mentions and notes:

HIV testing is standard of care for all sexually active women and is a routine component of preconception care
Partners or all pregnant women should be referred for HIV testing when their status is unknown
Discuss family planning / reproductive desires /contraception with all women on an ongoing basis throughout the course of their HIV care!
Maternal ARV use may be associated with increase in preterm delivery and increased risk of low birth weight / small for gestational age, but given clear benefits for ART for women’s health and prevention of perinatal transmission, HIV treatment should not be withheld.
Like textbook references?
- Mandell, Principles and Practice of ID, 8th Ed., 9th Ed.
- Long, Principles and Practice of Pediatric ID, 5th Ed.
- Comprehensive Review of Infectious Diseases
- AAP Red Book

Episode Art & Infographics

Goal

Listeners will be able to apply guideline and evidence-based recommendations to provide HIV care to a newly infected pregnant patient

Learning Objectives

After listening to this episode, listeners will be able to:

Summarize the goals of the initial evaluation for new HIV diagnosis in pregnancy
List the recommended antiretroviral regimens for pregnant individuals
Describe the current DHHS guideline recommendations regarding breastfeeding.

Disclosures

Our guest (Rebecca Zash) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Zash, R., Dong, S. “#15: ARTing for Two”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/6fc7c006-2ff5-4c07-a15b-e988a3f301ee

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