[pronut-hiv] Is protease inhibitor use during pregnancy linked to premature delivery?

["ProNut-HIV" <pronut-hiv@healthnet.org>]

Aidsmap 

An observational study from the University of Miami has found that the
use of protease inhibitor-based antiretroviral therapy during pregnancy
is associated with an increased risk of premature delivery. The
study's findings were published in the 1st May edition of The
Journal of Infectious Diseases. 

The use of antiretroviral therapy during pregnancy has dramatically
improved the health of women and reduced the levels of mother-to-child
transmission of HIV. However, the safety and efficacy of most anti-HIV
drugs have not been formally tested in randomised clinical trials. 

In the absence of randomised trials, a number of observational studies
have examined the effects of anti-HIV treatment on the outcomes of
pregnancy, with diverging conclusions. For example, a large European
cohort of 2300 women found that exposure to antiretroviral therapy
containing a protease inhibitor more than doubled the risk of preterm
delivery. In contrast, a recent study of 2120 women from the United
States found no link between combination antiretroviral therapy and
either preterm delivery or low birth weight. 

To gain a better understanding of the effect of antiretroviral therapy
during pregnancy, investigators from Miami carried out an analysis of
their data on outcomes in 1337 HIV-positive women. Although some of
these women were included in the American study above, the investigators
wished to restrict their analysis to one site, in order to ensure that
all women included were treated according to the same protocols and
standards of care. 

The study, which ran from 1990 to 2002, included 999 women who received
anti-HIV therapy. Of these, 492 received one anti-HIV drug, 373 received
combination therapy without a protease inhibitor and 134 received
protease inhibitor-based combination therapy. An additional 338 women
did not receive therapy. 

The investigators found that use of a combination including a protease
inhibitor led to an elevated risk of delivery before 37 weeks'
gestation, compared to combination therapy without a protease inhibitor
(odds ratio: 1.8; p = 0.03). This was determined after correction for a
range of risk factors, including drug and alcohol use, smoking and
previous preterm delivery. 

Preterm delivery was also associated with a history of previous preterm
delivery (p < 0.001) and antiretroviral treatment for less than three
weeks (p < 0.001), although this may be a marker of late presentation
rather than a direct effect of shorter drug treatment. 

In contrast, there were no significant differences in birth weight or
rates of stillbirth between treatment groups. 

The authors claim that their results show that there is a risk to
protease inhibitor use during pregnancy. "Although it is reassuring
that there does not appear to be an increased risk of adverse pregnancy
outcome associated with monotherapy or combination therapy without a
protease inhibitor, we believe that protease inhibitors should be used
with caution," they write. 

"The results of the present study suggest that a decision to initiate
combination therapy with a protease inhibitor during pregnancy should be
made with caution and emphasise the importance of counselling patients
about the risks of prematurity before the initiation of therapy," they
add. 

However, in an accompanying editorial commentary, Ruth Tuomala and
Sigal Yawetz of Brigham and Women's Hospital, Boston, argue that the
divergent conclusions of the Miami study and other similar studies could
be due to their observational design. 

The two doctors point out that the mothers prescribed protease
inhibitors during the Miami study took these drugs because they had low
CD4 cell counts or because they had experienced failure of a previous
protease inhibitor-sparing regimen. The large European study, which had
similar conclusions to the results from Miami, had similar criteria for
protease inhibitor use. 

Tuomala and Yawetz argue that the health of the mothers could be more
directly linked to premature delivery than the drugs themselves. "It
is likely that the finding of an effect on preterm delivery of
combination antiretroviral therapy that includes protease inhibitors is
unavoidably and inextricably confounded by indication for therapy of
maternal disease," they write. 

The doctors make a strong case for future studies being randomised and
controlled, in order to provide clearer information on the effects of
protease inhibitors on the outcomes of pregnancy. 

In addition, they suggest that these be limited to mothers who do not
need treatment themselves, in order to determine the effects of
treatment on the outcomes of pregnancy independently of the mothers'
state of health. Although these studies may be difficult to carry out
because of ethical considerations, they would help to clear up some of
the confusion around the risks of HIV treatment during pregnancy. 

"The true association between protease inhibitor use and adverse
pregnancy outcome is unlikely to be determined by further analysis of
observational data," they write. "It is time to facilitate
large-scale, randomised, controlled clinical trials aimed at carefully
defining the risks associated with combination antiretroviral therapy
regimens used during pregnancy by women receiving antiretroviral therapy
for foetal protection and whose HIV disease would not otherwise require
therapy." 

References 

Cotter AM et al. Is antiretroviral therapy during pregnancy associated
with an increased risk of preterm delivery, low birth weight, or
stillbirth? J Infect Dis 193: 1195-1201, 2006. 

Tuomala RE et al. Protease inhibitor use during pregnancy: is there an
obstetrical risk?. J Infect Dis 193: 1191-1194, 2006.