HIV Protease Inhibitors in Pregnancy

Abstract

The impact of antiretroviral therapy (ART) on the natural history of HIV-1 infection has resulted in dramatic reductions in disease-associated morbidity and mortality. Additionally, the epidemiology of HIV-1 infection worldwide is changing, as women now represent a substantial proportion of infected adults. As more highly effective and tolerable antiretroviral regimens become available, and as the prevention of mother-to-child transmission becomes an attainable goal in the management of HIV-infected individuals, more and more HIV-positive women are choosing to become pregnant and have children. Consequently, it is important to consider the efficacy and safety of antiretroviral agents in pregnancy. Protease inhibitors are a common class of medication used in the treatment of HIV-1 infection and are increasingly being used in pregnancy. However, several studies have raised concerns regarding pharmacokinetic alterations in pregnancy, particularly in the third trimester, which results in suboptimal drug concentrations and a theoretically higher risk of virologic failure and perinatal transmission. Drug level reductions have been observed with each individual protease inhibitor and dose adjustments in pregnancy are suggested for certain agents. Furthermore, studies have also raised concerns regarding the safety of protease inhibitors in pregnancy, particularly as they may increase the risk of pre-term birth and metabolic disturbances. Overall, protease inhibitors are safe and effective for the treatment of HIV-infected pregnant women. Specifically, ritonavir-boosted lopinavir- and atazanavir-based regimens are preferred in pregnancy, while ritonavir-boosted darunavir- and saquinavir-based therapies are reasonable alternatives. This paper reviews the use of protease inhibitors in pregnancy, focusing on pharmacokinetic and safety considerations, and outlines the recommendations for use of this class of medication in the HIV-1-infected pregnant woman.

Adverse effects of antiretroviral therapy in pregnant women infected with HIV in Brazil from 2000 to 2015: a cohort study

“…It is known that protease inhibitors can cause lipid metabolic changes, metabolic syndrome, lipodystrophy, changes in the carbohydrate metabolism and increased cardiovascular risk in every HIV infected patient [ 47 – 49 ]. Some studies had demonstrated that during pregnancy women in use of PI also presented higher rates of dyslipidemia, metabolic syndrome, lipodystrophy, diabetes and pre-eclampsia [ 50 – 52 ], as some of our data also demonstrated.…”

HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction

“…Of the 3 different classes of drugs tested—NRTIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs), and PIs—only PIs resulted in reduced progesterone levels (Figure 1 A ). RTV, known for its significant impact on CYP enzymes [ 20 ], had the strongest inhibitory effect on progesterone levels. ATV and LPV also decreased progesterone levels, while darunavir (DRV) was the only PI tested that did not significantly affect progesterone release.…”

“…Progesterone is synthesized from maternal cholesterol, and its synthesis, metabolism, and clearance depend on a variety of enzymes, many belonging to the cytochrome (CYP) family. PIs, especially ritonavir (RTV), affect the expression and activity of CYP enzymes [ 20 ], and it has been speculated that this is a mechanism through which PIs could alter sex steroid hormone levels [ 21 , 22 ]. Elevated 17-hydroxyprogesterone and dehydroepiandrosterone-sulfate levels suggestive of adrenal dysfunction have been reported in neonates exposed perinatally and postnatally to RTV-boosted lopinavir [ 23 ].…”

Risk factors for pre‐term birth in a Canadian cohort of HIV‐positive women: role of ritonavir boosting?

“…Previous studies on PTB have generally considered PIs as a single group for comparison against no treatment, non-nucleoside reverse transcriptase inhibitor (NNRTI) or nucleoside reverse transcriptase inhibitor (NRTI) based regimens, not distinguishing whether they were used with or without ritonavir (RTV) boosting [20]. However, RTV, used individually or as a boosting agent, has its own unique side-effect profile.…”