Over the past decade, data have suggested that antiretroviral therapy (ART) may be associated with an increased risk for adverse pregnancy outcomes, namely, preterm birth (PTB). But a combination of methodologic challenges, demographic gaps, and spotty clinical data has left the question unresolved, especially for pregnant women with HIV who reside in developed countries.
"Given that a lot of the emerging data has come out of resource-limited settings where patient and clinical characteristics are different from developed world settings like the United States, we felt that this was an important question to address," Kartik Venkatesh, MD, PhD, a high-risk obstetrician and perinatal epidemiologist at the Ohio State Wexner Medical Center, told Medscape Medical News.
In a prospective cohort study of US women with or at risk for HIV, Venkatesh and his colleagues found that ART exposure (including highly active antiretroviral therapy [HAART]) was associated with as much as an 80% decline in the likelihood of PTB (defined as birth <34 weeks). The study was published in the upcoming special April issue of HIV Medicine, devoted to women and HIV.
24 Years of Data Analyzed
Venkatesh and his team analyzed self-reported birth data of women with singleton live-born pregnancies enrolled in the ongoing, multicenter, prospective observational Women's Interagency HIV Study (WIHS) from October 1, 1995, to March 31, 2019.
"We first looked at women with HIV vs without HIV, [who were] matched on many clinical and sociodemographic characteristics and at similarly high risk of some of these obstetrical outcomes like PTB," explained Venkatesh. "We then looked at the relative impact of antiretroviral therapy amongst women living with HIV compared to no antiretroviral therapy."
ART regimens were classified as none, monotherapy, dual therapy, or HAART. (HAART was defined as more than three antiretrovirals, including at least one protease inhibitor [PI], nonnucleoside reverse transcriptase inhibitor, integrase inhibitor, or entry inhibitor.) In this cohort, for 63.5% of women receiving ART, therapy was initiated before pregnancy (mean duration of HAART, 6 years), and most were virally suppressed.
Among the 4944 women assessed in the WIHS trial, 74% (3,646) had HIV. In total, 383 women had 488 singleton deliveries, including 218 women with HIV (272 deliveries) and 165 without HIV (216 deliveries). Sociodemographics in both cohorts were well matched. For most participants, the mean age was 40–41 years at delivery, most were non-Hispanic Black persons, and the mean pregnancy body mass index was ≥29 kg/m2. Of the women with HIV, 33% had chronic hypertension; of those without HIV, 42.1% had chronic hypertension; 4.7% and 5.0%, respectively, had pregestational diabetes.
The findings showed that PTB risk <34 weeks was similar between women with (10%) and without HIV (8%) (adjusted risk ratio [aRR], 1.30; 95% CI, 0.74 – 2.31). Among deliveries to women with HIV who were receiving ART, PTB risk <34 weeks was lower with HAART (7%) compared with not receiving ART (26%) (aRR, 0.19), as well as with monotherapy or dual therapy (3% vs no ART) (aRR, 0.12). Notably, 67% of deliveries to women receiving HAART included a PI-containing regimen, but these women were not significantly more likely to have a PTB <34 weeks in comparison with women taking non-PI HAART regimens (aRR, 2.61; 95% CI, 0.65 – 10.59). Results were similar for secondary outcomes (PTB <28 weeks, <37 weeks).
Filling In the Gaps Toward the Safest Regimen
"This study spans 25 years, so it covers a lot of the history of HIV in pregnancy and is reassuring around using ART in pregnancy," Shahin Lockman, MD, told Medscape Medical News. Lockman is an associate professor of infectious diseases at Brigham and Women's Hospital and a co-PI of the Botswana Clinical Trials Unit at the Botswana Harvard AIDS Institute Partnership. She was not involved in the study. "One of the worst things for a mother and for pregnancy outcomes, for the fetus and baby's health and development, is uncontrolled maternal HIV,'' she said.
Lockman also noted potential confounders that drive poor birth outcomes in Southern African women compared with US women, making comparisons between this and other observational studies difficult. Still, she said that the question is not whether women should be receiving treatment but whether or not there are differences between antiretroviral regimens.
"One of the areas that we did not go deeper into was the subtype of antiretroviral therapy, given the relatively small study numbers [did not] allow us to do a robust analysis," Venkatesh said.
Rather, he emphasized that the findings might lend more weight to speculation that immunologic characteristics associated with HIV status and immunotherapy — such as low CD4 cell counts prior to delivery, or duration of HIV infection — may be important drivers of adverse birth outcomes among women with HIV taking ART.
And at least in this cohort, many of these characteristics were similar between the treatment groups.
Both researchers agree that the findings — while reassuring — highlight the importance of collecting robust obstetric and safety data as part of prospective databases of individuals living with HIV, not only in resource-limited settings but also among the domestic US population.
"We've learned a lot over the last 10 years," Lockman said. "Some regimens (like lopinavir/ritonavir or nevirapine) are associated with significantly worse birth outcomes, whereas efavirenz doesn't seem to be, or less so, and dolutegravir seems to be associated with even better outcomes. So, I think that where we are moving is to regimens that are the safest."
Moving forward, Venkatesh explained, not only should researchers focus on exploring which antiretrovirals are safest in this context but also if the use of preexposure prophylaxis during conception periods affects birth outcomes.
Venkatesh and Lockman report no relevant financial relationships.
HIV Med. 2022 Apr;23:406-416. Full text
Liz Scherer is an independent journalist specializing in infectious and emerging diseases, cannabinoid therapeutics, neurology, oncology, and women's health. @LizScherer
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Image 1: The Ohio State University Wexner Medical Center
Image 2: Dr Shahin Lockman
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Cite this: Liz Scherer. ART Associated With Less Risk of Preterm Birth in Large US Study - Medscape - Mar 18, 2022.