HIV-infected
pregnant women on a protease-inhibitor (PI) triple antiretroviral regimen were
twice as likely to have a preterm delivery compared to those on a triple
nucleoside reverse transcriptase inhibitor (NRTI) regimen, Kathleen M. Powis
and colleagues reported in a secondary analysis from a randomised clinical
trial (the MmaBana study) in Botswana published in the August 15 edition of the
Journal of Infectious Diseases.
But in an accompanying editorial Athena P. Kourtis and Mary Glenn Fowler caution
that further research is needed before making recommendations about ART during pregnancy as a consequence of the risk of pre-term delivery attached to any regimen.
Antiretroviral
therapy in HIV-infected women during pregnancy and breastfeeding for their own
health and for the prevention of HIV transmission to their infants is
recognised as a highly effective public health strategy.
The
parent
study from which this analysis is taken demonstrated that both a PI-based
regimen and NRTI-based regimen started late in pregnancy (26-34 weeks into the
pregnancy) were highly efficacious in reducing maternal viral load at delivery
and transmission rates to the infant.
However,
the link between a PI-based regimen and the risks of preterm delivery (before
37 weeks of pregnancy) continues to be controversial. Some observational
studies have suggested a link, while others have not.
These
studies have been primarily in resource-rich settings. In resource-poor
settings any increase in preterm delivery can have an adverse effect on infant
survival. Identifying risk factors for preterm delivery and determining the
contributing role of PI-based regimens is essential for the development of guidelines.
The
authors looked at risk factors for preterm delivery in a cohort of HIV-infected
pregnant women with CD4 cell counts under 200 cells/mm3 randomised
to get either PI-based regimen (lopinavir/ritonavir/zidovudine/lamivudine) or
NRTI-based regimen (abacavir/zidovudine/lamivudine) at 26-34 weeks of pregnancy
in a clinical trial to prevent mother-to-child transmission (MmaBana).
They
also looked at maternal weight gain in late pregnancy and infant disease and
death rates up to six months of age. Poor weight gain is known to be a risk
factor for preterm delivery. PI-based regimens are known to cause
gastrointestinal problems and adverse metabolic effects. Maternal change in
body mass index (BMI) one month after the start of ART was compared according
to treatment arm and delivery (preterm compared to term).
Among
women (267) in the PI arm preterm delivery rates were higher than among the 263
women in the NRTI arm, 21.4% compared to 11.8%, p=.003. The PI-based regimen
was the most significant risk factor, (OR: 2.03, 95% CI: 1.26-3.27, p=0.004).
While
median change in body weight in those in the PI arm was lower than in the NRTI
arm one month after starting ART, there was no significant association with
preterm delivery.
Serious
infant illness, defined as hospitalisation and death up to six months of age,
did not differ by maternal regimen. Kourtis and Fowler suggest that this is
probably because most preterm deliveries would have been near term, adding that
this would have been useful data to include.
While
acknowledging the importance of this first randomised controlled trial to show
a difference between ART and the risk of preterm delivery, Kourtis and Fowler
caution that the issue is not simple. The study, they add, has the potential to
raise more questions than answers.
They
note, as do the authors, that the MmaBana study was not powered to answer the
question of preterm delivery. As such the sample size may not be adequate. In Botswana the
preterm delivery rate in the general population is 20%. As a consequence, Kourtis
and Fowler note that to validate an increase in the risk of preterm delivery to
the degree seen in the PI arm would require a much larger sample size.
Kourtis
and Fowler also highlight the unexplained finding of the considerable lower
rate of preterm delivery in the NRTI arm.
Noting
the high number of twin deliveries in the NRTI arm compared to the PI arm,
Kourtis and Fowler state that while the differences cannot be linked to the
type of ART regimen “this serves as a reminder that chance differences can be
present even in randomly allocated groups.”
Kourtis
and Fowler question whether late start of ART could be linked to preterm
delivery: approximately one third of those who delivered preterm had had ART
for less than thirty days. The highest rate of preterm delivery was seen in
those who started ART later regardless of treatment arm.
They
suggest that data from the same setting comprising women with similar baseline
CD4 cell counts but who had been on a simplified prophylactic regimen, for
example, zidovudine and/or single-dose nevirapine, would be helpful for
comparison.
They
further question the timing of enrolment that limits the ability to look at
very preterm deliveries (less than 32 weeks of pregnancy), which are associated
with more severe infant outcomes.
Kourtis
and Fowler note that several randomised studies have suggested there may be a
link between PI use and preterm delivery. However, they cite the Kesho Bora
study as the only other study that “sheds light on the issue.” Over 800 women
in Burkina Faso, Kenya and South Africa with CD4 cell counts
between 200 and 500 cells/mm3 were randomised to a PI triple ART
regimen orzidovudine and single dose nevirapine. ARVs were started between 28
and 36 weeks of pregnancy, except for single-dose nevirapine. No difference was
seen in the preterm delivery rates.
Kourtis
and Fowler stress the relevance and rigour of the findings in a field where
more information is needed.
PI-based
ART regimens are a critical component of PMTCT and treatment programmes with
proven benefits for maternal and child health.
Kourtis
and Fowler conclude further studies and careful consideration of the questions
raised are needed before recommendations can be made regarding ARVs for PMTCT
and the risk of preterm delivery.
References
Powis KM et al. Increased risk of preterm delivery among HIV-infected women
randomised to protease versus nucleoside reverse transcriptase inhibitor-based
HAART during pregnancy. JID 204: 506-14, doi: 10.1093/infdis/jir307, 2011.
Kourtis
AP and Fowler MG, Editorial commentary, Antiretroviral
use during pregnancy and risk of preterm delivery: more questions than answers.
JID 204: 493-4, doi: 10.1093/infdis/jir318, 2011.