Exposure to protease inhibitor (PI)-based regimens and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may
each be linked to low birth weight and pre-term births in infants of mothers
living with HIV in lower-income countries, but the choice of nucleoside reverse transcriptase
inhibitor (NRTI) backbone also appears to influence this risk, according to
a systematic review of studies published in the Journal of Acquired Immune
Deficiency Syndromes

Safety of antiretroviral drug regimens used during pregnancy
received renewed attention at the recent 22nd International AIDS
Conference (AIDS 2018)
in Amsterdam, where results of an observational study in Botswana
showed a higher risk of neural tube defects in infants of women who took the
integrase inhibitor dolutegravir around the time of conception.

That finding has led some African countries to step back from
prescribing dolutegravir
to women with childbearing potential until more is
known, but experts have warned that older regimens employing lopinavir/ritonavir (PIs) or efavirenz (an NNRTI) may also carry risks of adverse birth outcomes.

Several adverse birth outcomes have been linked to
antiretroviral drug exposure at the time of conception or during the first
trimester of pregnancy. Low birth weight for gestational age has been linked in
some studies to antiretroviral drugs. Neural tube defects have been reported at
a higher frequency in infants exposed to antiretroviral drugs at conception.
There is also some evidence that exposure to PIs is associated
with pre-term birth.

Pre-term birth and low birth weight are risk factors for
infant mortality and morbidity and for poorer physical and cognitive
development. Pre-term birth is a major risk factor for low birth weight.

Infants born to women living with HIV are more likely to be
born prematurely (a pre-term birth) than other infants. The reasons for this
are uncertain; studies conducted in Europe have shown an association between in
antiretroviral therapy (ART) exposure and prematurity, whereas studies of women in North America
and Latin America have not identified the same association.

Whereas mother-to-child transmission of HIV has declined
dramatically since the use of three-drug antiretroviral regimens during
pregnancy became standard practice, the prevalence of low birth weight in
infants born to women living with HIV has not declined to the same extent.

The conflicting findings regarding factors associated with
pre-term birth or low birth weight make it difficult to know how to reduce the
risk. There is a lack of systematic reviews of studies from lower- and middle-income
countries that use currently recommended regimens. To clarify the risk,
researchers from Ohio State University carried out a systematic review of
studies published in the past five years.

The review excluded studies in which a majority of participants
started ART in the last trimester of pregnancy or during delivery,
as ART initiated at this time is unlikely to have an impact
on pre-term delivery or intrauterine growth. The review included both randomised
and observational studies.

The study authors identified 13 high-quality studies which
reported on low birth weight or pre-term birth in infants of women who took
antiretroviral drugs during pregnancy, and in which the results were reported
according to the regimens used in the study. The studies comprised comparisons of either NNRTI-based or PI-based regimens with either NRTI monotherapy or three-drug regimens containing only NRTIs, comparisons of NNRTI- or PI-based regimens, and comparisons of NNRTI-based regimens. No studies of integrase inhibitor-based regimens were identified for inclusion.

Synthesis of the study results led the authors to conclude
that there was mixed evidence regarding the harms and benefits of most regimens
in relation to low birth weight or pre-term birth.

A PI-based regimen combining lopinavir/ritonavir with
zidovudine/lamivudine increased the risk of pre-term birth compared to
zidovudine monotherapy or NRTI-based three-drug treatment containing abacavir.
However, there was no difference in the risk of pre-term birth when a PI-based
regimen was compared to an efavirenz-based regimen.

Efavirenz-based regimens were not associated with pre-term
birth or were protective against pre-term birth.

Both PI-based and non-PI-based regimens increased the risk
of low birth weight compared to zidovudine monotherapy in at least one study
reviewed but study findings did not show one drug or one NRTI backbone to be
consistently associated with low birth weight.

The authors of the systematic review note that the harmful
or protective effects of PI-based or NNRTI-based regimens varied according to
the NRTIs used. Whereas one study found
that a PI-based regimen carried an increased risk of pre-term
birth when used with zidovudine/lamivudine, an efavirenz-based regimen that
included tenofovir and emtricitabine protected against low birth weight in one study.

The authors of the systematic review say that simultaneously
reducing mother-to-child transmission and reducing the prevalence of low birth
weight and pre-term birth is challenging. For example, in the PROMISE study,
the regimen that was associated with the lowest rate of HIV transmission was
associated with the highest prevalence of low birth weight (lopinavir/ritonavir
plus zidovudine/lamivudine).

The authors concede that the great diversity in study
populations, access to antenatal care and specific antiretroviral drugs made it
a challenge to compare specific antiretroviral regimens. Nevertheless, they say
that their analysis shows that there does seem to be a harmful association
between some antiretroviral regimens and pre-term birth and low birth weight,
and reducing the risk of adverse birth outcomes among children born to women
living with HIV should be prioritised alongside the minimisation of
mother-to-child HIV transmission.