University of Oxford researchers assessed evidence from 34 studies involving over 57,000 pregnant women with HIV and found that protease inhibitor-based antiretroviral therapies significantly increased the risk of babies being small or very small for their gestational age. Still, there were no other adverse pregnancy outcomes than treatments without protease inhibitors.
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Globally, more than 37 million people lived with HIV in 2020, including 19 million women of childbearing age (UNAIDS). Each year, around 1.3 million of these women become pregnant, most of whom live in sub-Saharan Africa, where maternal and child mortality rates remain high.
Antiretroviral therapy is recommended for all pregnant women living with HIV. This plays a crucial role in improving maternal health and reducing the transmission of HIV from mother to child. However, there has been a critical lack of evidence on whether antiretroviral therapies increase the risk of adverse pregnancy outcomes such as preterm birth, low birth weight, stillbirth, and babies being small for their gestational age.*
In particular, there has been concern about a type of antiretroviral drug called protease inhibitors (including atazanavir, lopinavir, and darunavir). Current guidelines recommend that protease inhibitor-based therapies be used in pregnancy only if ‘first-line’ treatments (such as integrase and reverse-transcriptase based treatments) are either unsuitable or unavailable. These guidelines also often advise against using a specific protease inhibitor, lopinavir/ritonavir (LPV/r), citing an increased risk of preterm birth. However, these recommendations are based on limited evidence and can restrict treatment options for pregnant women with HIV.
Researchers from the National Perinatal Epidemiology Unit (NPEU) at Oxford Population Health have conducted the most extensive review of the evidence on pregnancy outcomes for various antiretroviral therapies to address this knowledge gap. This included a comparison of protease inhibitors vs non-protease inhibitor-based antiretroviral treatments and comparing different types of protease inhibitors in relation to the risk of 11 specific pregnancy outcomes for women living with HIV.** The analysis included 34 studies conducted between 1980 and 2020, involving over 57,000 pregnant women living with HIV in 22 countries.
The study found that protease inhibitors were associated with an increased risk of babies being small or very small for their gestational age, compared with non-protease inhibitor antiretroviral therapies (24% and 40% higher risk, respectively). However, protease inhibitors were not associated with an increased risk of pre-term birth or any other adverse pregnancy outcome. No significant differences in pregnancy outcomes were found between the three protease inhibitor therapies, lopinavir, atazanavir, and darunavir.
Dr Joris Hemelaar (NPEU), the senior author of the study, said: ‘Antiretroviral therapy in pregnancy has clear benefits for maternal health and prevention of HIV transmission to the child, but our study has shown for the first time that protease inhibitors are associated with babies being small or very small for their gestational age. However, there was no increased risk of preterm birth or other adverse pregnancy outcomes. This means protease inhibitors remain an essential option for pregnant women living with HIV if other treatments are unsuitable, for example, due to drug resistance or unavailable. The evidence presented here indicates that the commonly used protease inhibitors atazanavir, lopinavir, and darunavir are comparable with regard to perinatal outcomes, which should inform international treatment guidelines.
‘As the global number of pregnant women living with HIV receiving antiretroviral therapy increases, women should be assisted in making an informed decision about the use of antiretroviral therapy in pregnancy, taking account of all available evidence. Their choice of therapy should consider all relevant factors besides safety and pregnancy outcome data, including the extent to which the virus can be suppressed, adverse drug effects, adherence to drug prescriptions, antiretroviral drug resistance, drug interactions, and drug cost and availability.’
With over 70% of the studies assessed in high-income countries, Dr Hemelaar added that there is an urgent need for more research on pregnancy outcomes from different antiretroviral treatments in low- to middle-income countries, where the burden of HIV is highest.
Professor Yvonne Gilleece, a spokesperson for the British HIV Association (BHIVA) and immediate past chair of the BHIVA guidelines on the management of HIV in pregnancy and the postpartum period, said: ‘Pregnancy is a unique life situation in which we must consider the safety of both the birthing parent and the baby. Due to the ongoing under-representation of all women in clinical trials, particularly pregnant women, we do not have enough evidence to base all our management decisions. This systematic review includes large numbers of pregnant women living with HIV and can therefore improve an informed discussion regarding the safety of using protease inhibitors during pregnancy.’
Source: University of Oxford