Integrase Inhibitors and Gestational Weight Gain: Should Women Worry?

Liz Scherer

September 12, 2022

In recent years, increased use of integrase strand transferase inhibitor (INSTI) antiviral treatment (ART) has raised concerns about weight gain and adverse outcomes in patients with HIV. This is especially true regarding possible excessive gestational weight gain, which in women without HIV has been associated with maternal gestational diabetes, hypertensive and liver conditions, as well as related risks for preterm birth, fetal macrosomia, and higher weight after birth. 

Unfortunately, few studies in pregnant women with HIV have moved out of the controlled environment into real-world settings, potentially limiting current knowledge about the impact of gestational weight gain — as well as strategies to both prevent it and the associated adverse outcomes.

That is what a team of infectious disease specialists at the Hospital Federal dos Servidores do Estado in Rio de Janeiro, Brazil recently sought to answer among a cohort of INSTI-experienced and INSTI-naive women with BMIs less than 25 kg/m2 (underweight/normal weight) and higher than 25 kg/m2.

Surprising Findings

The investigators determined that rates of excessive weight gain were significantly higher in INSTI-naive women with BMI less than 25 who experienced rates as high as 31.6% compared with approximately 12% of women who conceived while on INSTIs, regardless of BMI values at baseline (P = .004). 

However, rates of unfavorable pregnancy outcomes (eg, small for gestational age, preterm birth, stillbirth, death) appeared to be low overall and similar among all the study groups.

Dr Trevon Fuller

"We had some discussions when we were working on this and thought that the weight gain might have adverse effects," Trevon Fuller, PhD, lead author and a postdoctoral student at the Hospital Federal dos Servidores do Estado, told Medscape Medical News

"But it looked like the weight gain might actually be good, to the extent that we didn't see any harm to the mom or the baby of those underweight or normal weight women who were naive to INSTIs," he explained.

Fuller and his team enrolled 198 pregnant women living with HIV who sought care at the Hospital Federal dos Servidores do Estado — a national reference center for USAID's Prevention of Mother to Child Transmission strategic program — between October 2014 and October 2021.

Participants were divided into two primary cohorts: BMI less than 25 at enrollment (n = 74) or BMI of 25 or higher (n = 124), and then further divided by timing of INSTI-based combined ART: 

  • INSTI-naive: women using INSTI-based ART (raltegravir [Isentress] 400 mg twice per day or dolutegravir [Tivicay] 50 mg/day plus 2 non-nucleoside reverse transcriptase inhibitors — lamivudine plus tenofovir disoproxil fumarate or lamivudine plus zidovudine) for 4 weeks between baseline and near delivery.

  • INSTI-experienced: women who became pregnant while using INSTIs for at least 6 months before conception. 

Among underweight/normal weight participants, 77% (n = 57) were INSTI-naive and 23% (n = 17) INSTI-experienced, and among overweight/obese participants, 81.5% (n = 101) were INSTI-naive, and 18.5% (n = 23) were experienced.

Maternal age, which did not differ significantly by BMI or treatment experience, was a median of 28 years, and most participants were non-White. All participants were virally suppressed near delivery.

Study findings, which were published online September 5 in HIV Medicine, highlighted that median weight near delivery in participants who were overweight/obese at baseline was similar regardless whether they were treatment-experienced (90 kg [198 lb]) or treatment-naive (82.3 kg [181 lb]), P = .026.

However, participants who were underweight/normal weight who were INSTI-naive had significantly higher rates of gestational weight gain (31.5%, 18/57) compared with those of underweight/normal weight who were INSTI-experienced (11.8%, 2/17), P = .004. Notably, this gain was significant in all categories of change (ie, low < 0.18 kg/week, normal 0.18–0.59 kg/week), and high > 0.59 kg/week).

"One of the things that we took away was that this weight gain is primarily happening with women who are starting INSTIs," said Fuller. 

"The data suggest that [it] might be temporary in the sense that there's not going to be continuous weight gain but that it will probably approach some type of horizontal asymptote," he added.

Although obstetric and neonatal outcomes were secondary measures, the investigators did not observe any significantly different outcomes when comparing the groups, and there were no stillbirths, neonatal deaths, or macrosomia.

Preterm delivery rates in underweight/normal weight participants who were INSTI-experienced (11.8%, 2/17) and INSTI-naive (5.3%, 3/57) were similar to overweight/obese participants who were INSTI-experienced (13%, 3/23) and INSTI-naive (6.9%, 7/101).

The same was true for low birthweight.

Dr Sigal Yawetz

Still, the study appears to raise more questions than it answers, Sigal Yawetz, MD, an infectious disease specialist at Brigham and Women's Hospital in Boston, Massachusetts, told Medscape — a factor that she said is common also in some of the more recent randomized controlled studies, such as IMPAACT PROMISE.

Yawetz, who was not involved in the study, also noted, "The groups were small, so comparisons within the groups are difficult, and so many people were excluded that it's hard to know if there were adverse outcomes related to this…It's very confounded."

The World Health Organization estimates that there are roughly 1.3 million pregnant women with HIV, 81% of whom are on antiretroviral therapy. Although the literature continues to evolve, data suggest that in general, Black women are at greater risk for gestational weight gain.

"We have to remember that women who gain excess weight in pregnancy are still going to be with this weight following pregnancy as well," Yawetz said. "So, it might impact their pregnancy, but also their health after delivery and for subsequent pregnancies, which we don't have data for yet."

Fuller agrees that more data are needed and mentioned that the team plans to study this further, ideally with larger sample sizes.

Yet, despite the lingering questions, there is a silver lining, one that Yawetz was emphatic about.

"I really welcome people doing studies on this because we really need the data. By far, integrase inhibitors are the first-line regimen all over the world for pregnant women and if you look at the gestalt or full picture, this is the best regimen to give pregnant women," she said.

Fuller and Yawetz report no relevant financial relationships. The study was independently supported.

HIV Med. Published online September 5, 2022. Abstract

Liz Scherer is an independent journalist specializing in infectious and emerging diseases, cannabinoid therapeutics, neurology, oncology, and women's health.

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