Norvir (ritonavir)–boosted protease inhibitor therapy has been linked to preterm deliveries in a French perinatal cohort, according to results published online ahead of print by the journal Clinical Infectious Diseases (CID). The findings jibe with other European studies finding an association between antiretroviral (ARV) treatment and premature births, but they conflict with several studies performed in the United States.

The benefit of providing ARV therapy to HIV-positive women is unquestionable. It has helped decrease mother-to-child transmission of HIV to 1 percent in industrialized countries. Yet there is ongoing concern about ARV-related toxicities during pregnancy, including preterm delivery.

There has been a strong relationship between ARV therapy and preterm delivery in at least five European cohort analyses, explained Jeanne Sibiude, MD, of the French Institut National de la Santé et de la Recherche Médicale (INSERM) and her colleagues in prefacing their CID paper. In the United States, a similar relationship was documented in one study, though the INSERM team noted that most American evaluations have not found a connection between ARV treatment and preterm deliveries.

“The objectives of our study were, first, to study trends in prematurity between periods with different types of standard care and, second, to evaluate factors and attempt to identify potential mechanisms associated with preterm birth among patients starting [protease inhibitor]–based ARV therapy during pregnancy,” Sibiude and her colleagues wrote. “We also distinguished spontaneous from induced preterm births and identified the pregnancy complications that led to these outcomes.”

The researchers studied trends in prematurity (defined as infants born before 37 weeks) among 13,271 singleton pregnancies—in which women living with HIV are carrying just one fetus—in the Agence Nationale de Recherche sur le SIDA (ANRS) French Perinatal Cohort from 1990 through 2009. Also highlighted by the authors was an in-depth analysis of 1,253 pregnancies involving HIV-positive women who used a protease inhibitor–based regimen.

Across the board, the rate of preterm deliveries increased during four eras of perinatal ARV treatment captured by the ANRS data period. From 1990 to 1993, when ARV treatment was unlikely to be prescribed during pregnancy, 9.2 percent of pregnancies ended in preterm births. From 1994 to 1996, when Retrovir (zidovudine) monotherapy was standard during pregnancy, the preterm birth rate was 9.6 percent. With the use of dual-nucleoside reverse transcriptase inhibitor therapy during pregnancy from 1997 to 1999, the preterm delivery rate was 12.4 percent. With triple-ARV therapy, which became standard-of-care for pregnant women living with HIV in 2005, the preterm birth rate was 14.3 percent.

The upward trend in preterm deliveries, from 1990 to 2009, was statistically significant.  
After adjusting the data for disparities between the eras—factors like the women’s ages at delivery, history of intravenous drug use, geographic origin and CD4 cell counts—the risk of preterm births was 69 percent higher from 2005 to 2009, compared with the Retrovir-monotherapy era (1994 to 1996).

Sibiude and her colleagues also noted that the risk of prematurity was higher among women already undergoing ARV therapy at the time of conception, compared with women whose treatment began during pregnancy, regardless of ARV therapy type.

From 2005 to 2009, the risk of prematurity among pregnant women receiving a Norvir-boosted protease inhibitor regimen—most were using Kaletra (ritonavir plus lopinavir)—was roughly twice that of women receiving an unboosted protease inhibitor regimen. The premature birth rate was 14.4 percent among women receiving a Norvir-boosted protease inhibitor regimen, compared with 9.1 percent among women receiving an unboosted protease inhibitor regimen.

The difference hinged mainly on preterm deliveries associated with obstetrical complications ultimately requiring induced labor; rates of spontaneous preterm deliveries were not significantly higher among women receiving a Norvir-boosted protease inhibitor regimen versus unboosted protease inhibitor-based therapy.

“We found that boosted PI was more strongly associated with induced than with spontaneous premature birth,” Sibiude and her colleagues reported. “Pregnancy complications, including preeclampsia, gestational diabetes and liver toxicity, were associated with induced prematurity and were also significantly more frequent in the boosted than nonboosted PI group.”

Why the confirmed increased risk of preterm births in the European cohort but not most U.S. studies? “The differences may be attributable simply to chance or to variability in the numbers of patients studied,” the researchers suggested, “but there may be real differences between countries and between periods with respect to the populations studied, confounding risk factors and drug regimens used.”

Sibiude and her colleagues concluded: “We found a higher rate of prematurity associated with boosted PI, compared with nonboosted ARV, which was independent of other risk factors.”

The researchers added that women receiving Norvir had more maternal metabolic and vascular complications, leading to induced premature births. “Although a causal relationship cannot be confirmed,” they noted, “our findings suggest a plausible explanation for the association between [ARV] therapy and prematurity that merits further investigation. Because boosted PI therapies are standard care during pregnancy, this may have important clinical implications.”