Treatment with a ritonavir-boosted protease inhibitor during pregnancy increases risk of preterm delivery

Antiretroviral therapy during pregnancy is associated with an increased risk of premature delivery, French researchers report in Clinical Infectious Diseases. The large study showed that treatment with a ritonavir-boosted protease inhibitor was especially associated with prematurity.

“Our findings suggest a relationship between cARV [combination antiretroviral] use and preterm delivery,” comment the authors. “Our most important finding was a significant association between prematurity and ritonavir-boosted PI [protease inhibitor] therapy.”

The authors of an editorial which accompanies the study suggest that it “advances our understanding of the relationship between ART [antiretroviral therapy] in pregnancy and preterm delivery by addressing some of the limitations of earlier studies”.

The risk of mother-to-child transmission of HIV can be reduced to less than 1% by the use of antiretroviral therapy during pregnancy. This treatment can cause side-effects and there are therefore concerns about its implications for both maternal and infant health.

Nevertheless, the risks of therapy are outweighed by its benefits. Despite this, European research has consistently shown a relationship between antiretroviral treatment during pregnancy and an increased risk of prematurity. It is important to note that most US research has failed to find this association.

French investigators wanted to establish a clearer understanding of this issue. They therefore studied all singleton pregnancies (a pregnancy with one baby) in HIV-positive women in France between 1990 and 2009. A sub-analysis focused on women who started antiretroviral treatment based on a protease inhibitor during pregnancy between 2005 and 2009.

Factors other than HIV therapy that can increase the risk of prematurity were controlled for in the investigators’ analysis.

A total of 13,271 pregnancies were included in the study; the results showed that the overall prematurity rate increased significantly between 1990 and 2009.

Between 1990 and 1993, when no treatment was used to reduce the risk of vertical transmission, the prematurity rate was 9.2%. This increased to 9.6% between 1994 and 1996, when AZT monotherapy was the standard of care during pregnancy. A further increase to 12.4% was observed between 1997 and 1999, a time when dual nucleoside reverse transcriptase inhibitor (NRTI) treatment was the standard of care. In the era of modern triple-drug therapy (2005 to 2009), the prematurity rate was 14%. These increases were highly significant (p < 0.01).

After controlling for other factors that can increase the risk of prematurity, the use of combination antiretroviral therapy during pregnancy was significantly associated with preterm delivery (adjusted hazard ratio [aHR] = 1.69; 95% CI, 1.38-2.07).

The risk of premature delivery was higher for women who were already taking HIV therapy when they became pregnant, compared to those who started therapy during pregnancy (aHR = 1.31; 95% CI, 1.11-1.55).

Analysis was then restricted to the 1253 women who started therapy based on a protease inhibitor between 2005 and 2009. Most of these women (85%) were treated with a ritonavir-boosted protease inhibitor. The most frequently used drug of this type was lopinavir/ritonavir (Kaletra, 81%), and the most commonly prescribed non-boosted protease inhibitor was nelfinavir (prior to its withdrawal: 92%).

The overall rate of prematurity was 13.6%. It was higher for the women treated with a boosted protease inhibitor compared to those taking a non-boosted protease inhibitor (14.4 vs 9.1%, p = 0.053). The rate of severe prematurity was approximately 3% for both treatment groups.

Initial analysis showed a strong association between treatment with a ritonavir-boosted protease inhibitor and an increased risk of premature delivery (aHR = 2.03; 95% CI, 1.06-3.89, p = 0.03). However, this association weakened when hepatitis C co-infection, viral load and time of treatment initiation were excluded (aHR = 1.76; 95% CI, 0.97-3.19, p = 0.06).

Type of premature delivery differed according to the use of boosted and non-boosted protease inhibitors.

The risk of a spontaneous preterm delivery did not differ between the two types of protease inhibitor.

However, women taking a ritonavir booster were more likely to have an induced premature delivery.

Moreover, women treated with this class of drug were also significantly more likely to experience a complication during pregnancy requiring hospitalisation (p = 0.003).

“Ritonavir is associated with complex metabolic changes and could interfere with the adrenal systems of both the mother and fetus,” suggest the authors. “Because these adrenal systems are involved in the spontaneous onset of labour, ritonavir-boosted protease inhibitors may influence its timing.”

They also offer an explanation for the increased risk of induced preterm delivery associated with ritonavir: “Patients treated with ritonavir had more maternal metabolic and vascular complications, leading to an increase in induced premature births.”

The authors conclude, “Our findings suggest a plausible explanation or the association between cARV therapy and prematurity that merits further investigation. Because boosted protease inhibitor therapies are standard of care during pregnancy, this may have important clinical implications."

Sibiude J et al. Premature delivery in HIV-infected women starting protease inhibitor therapy during pregnancy: role of the ritonavir booster? Clin Infect Dis, 54: 1348-59, 2012 (click here for the free abstract).

Thorne C et al. A new piece in the puzzle of antiretroviral therapy in pregnancy and preterm delivery risk. Clin Infect Dis, 54: 1361-63, 2012.