Source: Healio Interview
Disclosures: Gandhi reports no relevant financial disclosures.
October 01, 2019
7 min read
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What to consider when treating pregnant women with HIV

Source: Healio Interview
Disclosures: Gandhi reports no relevant financial disclosures.
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Monica Gandhi, MD, MPH
Monica Gandhi, MD, MPH

An estimated 6,000 to 7,000 women with HIV give birth each year in the United States, according to the American Pregnancy Association. Although there have been significant advances in treatment since the start of the HIV/AIDS epidemic, pregnant women have about half as many treatment options as other adults with HIV, Monica Gandhi, MD, MPH, professor of medicine and medical director of the Ward 86 HIV clinic at the University of California, San Francisco, reported at CROI 2019. This is partly due to concerns with the safety and virologic efficacy of some antiretrovirals, but also because there are not enough data on many “good drugs” in this patient population.

“When there is less data, it becomes more about expert opinion,” Gandhi said during her presentation.

Healio spoke with Gandhi to learn more about current recommendations and best practices for antiretroviral (ARV) use in pregnant women with HIV in the United States.

Dolutegravir

A big topic of conversation in this area is the use of dolutegravir. According to WHO, dolutegravir is more effective, more convenient and associated with fewer adverse events than other currently available ARVs. It also has a high genetic barrier to drug resistance, which is increasing globally. In a recent survey conducted by WHO this year, 12 out of 18 countries reported pretreatment drug resistance levels that exceeded the recommended threshold of 10%.

However, in May 2018, the FDA issued a safety alert warning about a potential risk for neural tube birth defects when dolutegravir is taken at the time of becoming pregnant or early in the first trimester. These initial data from the Tsepamo Study showed that 0.94% of infants (4 of 426 babies) who were exposed to dolutegravir had neural tube birth defects vs. 0.1% of infants (14 of 11,173) who were exposed to other ARVs during early pregnancy.

Despite these findings, WHO recommended dolutegravir-based regimens as the preferred treatment for all patients with HIV, but the recommendation was conditional in pregnant women. In the United States, the Department of Health and Human Services (HHS) guideline panel for the treatment of pregnant women with HIV— a working group of the Office of AIDS Research Advisory Council (OARAC) — updated its own guidance to recommend dolutegravir in pregnant women during the second and third trimester, but not to pregnant women during the first trimester or nonpregnant women trying to conceive.

Since then, more recent data from the Tsepamo Study presented in July 2019 revealed that the rate of neural tube birth defects was lower than previously estimated — 0.3% among infants born to mothers who were taking dolutegravir from conception. Following these results, WHO strengthened its recommendation for dolutegravir as a first-line treatment for all HIV populations, including pregnant women in the first trimester and women of childbearing age.

“The U.S. has not yet followed suit,” Gandhi said in an interview. “The rate of neural tube birth defects is not down to the same level as the general population. Moreover, there are more treatment options in the United States. Therefore, the HHS panel is still evaluating the question.”

Nahida Chakhtoura, MD, MsGH, panel chair and executive secretary of the OARAC working group, told Healio/Infectious Disease News that the panel is currently working on updating its recommendations. She said new guidance is expected to be released in November or early December 2019.

In light of these recent updates, Gandhi said many experts in the field question the link between dolutegravir and birth defects and whether this signal is just a “statistical fluke.” Still, over the past year, researchers have investigated possible explanations for an association. Since folate deficiency can also cause neural tube birth defects, recent in vitro studies explored the possibility that dolutegravir — and potentially other integrase strand transfer inhibitors (INSTIs) — may inhibit folate transport across the placenta, according to Gandhi. So far, the data are conflicting, she said.

“Whether dolutegravir and other integrase inhibitors inhibit folate or not, we need to work harder to provide basic prenatal care provision, which includes folate for women of child-bearing age and women who are pregnant,” Gandhi said. “Since folate is so cheap, I think we are going to see a movement toward implementing programs that provide folate supplementation in Africa. That’s one good thing that will come out of this.”

Switching regimens

If a woman is receiving dolutegravir and becomes pregnant, current U.S. guidelines recommend that physicians and patients consider the following:

  • neural tube birth defects may have already developed and the additional risk for neural tube birth defects may be small, depending on gestational age;
  • there is a “background risk” for neural tube birth defects, regardless of treatment regimen or HIV status, ranging from 0.05% to 0.01% among women without HIV and those with HIV who are receiving a non-dolutegravir regimen; and
  • switching regimens often leads to viral rebound, which could increase the risk for perinatal HIV transmission.

“The idea of switching out dolutegravir is usually not recommended,” Gandhi said. “It’s more like, don’t start dolutegravir in women who are trying to conceive to begin with.”

The guidelines, however, do recommend that physicians consider switching treatment for pregnant women receiving bictegravir, doravirine and ibalizumab because there are not enough data on these drugs during pregnancy. Physicians should also consider switching cobicistat-containing regimens, including atazanavir/cobicistat, darunavir/cobicistat and elvitegravir/cobicistat, to another HIV treatment regimen. Recent pharmacokinetic (PK) data from the IMPAACT p1026 trial are “very convincing that cobicistat regimens are a concern during pregnancy due to lower drug levels,” Gandhi said. The trial assessed the safety and efficacy of once daily elvitegravir and cobicistat in 30 women during pregnancy and postpartum. Gandhi reported at CROI that elvitegravir levels were 24% lower in the second trimester and 44% lower in the third trimester vs. the postpartum period. Cobicistat exposure levels dropped even further — 44% lower during the second trimester and 59% lower during the third trimester vs. postpartum. Data also showed that 19 out of 25 patients with evaluable data were not virally suppressed when they gave birth, likely because of the lower drug levels, according to Gandhi.

As a result, U.S. guidelines state that if a pregnant woman remains on a cobicistat-containing regimen, “absorption should be optimized, and viral load should be monitored frequently.

Sex differences in PK enhanced during pregnancy

Many ARVs demonstrate reduced drug exposure during the second and third trimesters of pregnancy, although to a lesser extent than cobicistat, according to Gandhi.

“Even prior to pregnancy, there are sex difference in pharmacokinetics for ARVs, and for drugs in general,” she said during the presentation.

Women, she explained, have lower gastric acid and delayed gastric emptying, which result in slower drug absorption. Additionally, women generally weigh less, have more proportional fat, varying plasma levels throughout the menstrual cycle, less organ flow, increased progesterone and smaller organs, all of which contribute to disparate drug levels in women compared to men.

“PK sex differences are complicated already,” Gandhi said. “Pregnancy changes these PK parameters even further.”

Specifically, pregnancy is associated with slower gastrointestinal motility, reduced gastric acid secretions, expanded intravascular volume, decreased albumin, and increased body fat, progesterone and blood flow.

“All of these put together, in general, lead to lower drug levels in pregnancy, especially in the third trimester, than you would see in the nonpregnant state,” Gandhi said.

Practical considerations

When prescribing treatment for a pregnant woman with HIV, the first thing that physicians should consider is patient preference, according to Gandhi. A BMJ study published in 2017 investigated the values and treatment preferences of women who were pregnant, postpartum or considering pregnancy. The study revealed several themes, including distress about adverse events, desire to reduce vertical transmission, desire for the child to be healthy, desire for oneself to be healthy and pill burden.

“None of the studies weighed the relative importance of these outcomes directly, but pill burden/medication complexity appears to be a lower priority for most women compared with other factors,” the researchers wrote.

Other important considerations for physicians prescribing treatment is to be aware that switching can be disruptive; to think about gastrointestinal concerns, such as nausea and vomiting and potential drug-drug interactions between ARVs and heartburn medication; drug-drug interactions in general; to always prescribe tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to patients, including pregnant women, with hepatitis B; and to be mindful of which single-pill combinations are appropriate, according to Gandhi. Of the eight single-pill combinations currently available for HIV, only three can be used during pregnancy, she said. Dolutegravir/abacavir/lamivudine (dolutegravir/abacavir/3TC; Triumeq; ViiV Healthcare) is preferred after the first trimester. Meanwhile, rilpivirine/TDF/FTC (Complera; Gilead Sciences) and FTC/TDF/efavirenz (Atripla; Gilead Sciences) are available as alternative options.

Recommended vs. not recommended ARVs

HHS guidelines further outline which specific ARVs are recommended during pregnancy. Preferred ARVs at this time, according to Gandhi, include:

  • abacavir/3TC;
  • TDF/FTC;
  • raltegravir;
  • dolutegravir after the first trimester;
  • atazanavir/ritonavir; and
  • darunavir/ritonavir.

The guidelines also list alternative ARVs, defined by HHS as “acceptable” treatments with generally favorable — yet limited — safety data that may be associated with concerns regarding PK, dosing, tolerability, formulation, administration or drug-drug interactions. These include:

  • zidovudine;
  • efavirenz;
  • rilpivirine; and
  • lopinavir/ritonavir.

ARVs that are not recommended during pregnancy are:

  • elvitegravir/cobicistat/tenofovir alafenamide/FTC (elvitegravir/cobicistat/TAF/FTC);
  • elvitegravir/cobicistat/TDF/FTC;
  • atazanavir/cobicistat;
  • darunavir/cobicistat;
  • darunavir/cobicistat/TAF/FTC;
  • ·nevirapine;
  • etravirine;
  • maraviroc;
  • T20; and
  • dolutegravir/rilpivirine.

Finally, ARVs that do not have enough data for use in pregnant women include:

  • TAF;
  • bictegravir;
  • doravirine;
  • bictegravir/TAF/FTC;
  • doravirine/TDF/3TC;
  • rilpivirine/TAF/FTC;
  • ibalizumab;
  • fostemsavir; and
  • cabotegravir.

Although questions remain about the performance and safety of many ARVs in pregnancy, Gandhi stressed that there are still plenty of good options.

“For the last 25 years, we knew that women could have babies safely,” she said. “For any woman who desires pregnancy, there should be no limitations on her desires for pregnancy and children because it’s absolutely doable to reduce the risk for transmission from mother to baby down to zero. Women should not be concerned about transmission and should determine their child-bearing desires completely independent of HIV status.” 

References:

American Pregnancy Association. HIV/ AIDS During Pregnancy. https://americanpregnancy.org/pregnancy-complications/hiv-aids-during-pregnancy/. Accessed Sept. 18, 2019.

Gandhi M. Abstract 60. Presented at: CROI; March 4-7, 2019; Seattle.

WHO. WHO recommends dolutegravir as preferred HIV treatment option in all populations. https://www.who.int/news-room/detail/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations. Accessed Sept. 24, 2019.

FDA. FDA Drug Safety Communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). https://www.fda.gov/drugs/drugsafety/ucm608112.htm. Accessed July 19, 2019.

USCF. Possible Safety Issue with Dolutegravir during Pregnancy: Reports of Neural Tube Defects. http://hivinsite.ucsf.edu/insite?page=hmq-2018-05-22. Accessed Sept. 24, 2019.

Kouanfack C, et al. New Engl J Med. 2019;doi:10.1056/NEJMoa1904340.

NIH. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. https://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed Sept. 24, 2019.

Zash R, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1905230.

Momper JD, et al. AIDS. 2018;doi:10.1097/QAD.0000000000001992.

Lytvyn L, et al. BMJ. 2017;doi:10.1136/bmjopen-2017-019023.

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