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 utero 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.
Saleska JL et al. Use of antiretroviral therapy during pregnancy and adverse birth outcomes among women living with HIV-1 in low- and middle-income countries: a systematic review. J Acquir Immune Defic Syndr 79 (1): 1-9, 2018.