Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy: Mechanisms, Clinical Implications and Knowledge Gaps

Abstract

Prevention of mother-to-child transmission of HIV and optimal maternal treatment are the most important goals of antiretroviral therapy in pregnant women with HIV. These goals may be at risk due to possible reduced exposure during pregnancy caused by physiological changes. Limited information is available on the impact of these physiological changes. This is especially true for HIV-integrase inhibitors, a relatively new class of drugs, recommended first-line agents and hence used by a large proportion of HIV-infected patients. Therefore, the objective of this review is to provide a detailed overview of the pharmacokinetics of HIV-integrase inhibitors in pregnancy. Second, this review defines potential causes for the change in pharmacokinetics of HIV-integrase inhibitors during pregnancy. Despite increased clearance, for raltegravir 400 mg twice daily and dolutegravir 50 mg once daily, exposure during pregnancy seems adequate; however, for elvitegravir, the proposed minimal effective concentration is not reached during pregnancy. Lower exposure to these drugs may be caused by increased hormone levels and, subsequently, enhanced drug metabolism during pregnancy. The pharmacokinetics of bictegravir and cabotegravir, which are under development, have not yet been evaluated in pregnant women. New studies need to prospectively assess whether adequate exposure is reached in pregnant women using these new HIV-integrase inhibitors. To further optimize antiretroviral treatment in pregnant women, studies need to unravel the underlying mechanisms behind the changes in the pharmacokinetics of HIV-integrase inhibitors during pregnancy. More knowledge on altered pharmacokinetics during pregnancy and the underlying mechanisms contribute to the development of effective and safe antiretroviral therapy for HIV-infected pregnant women.

Inhibition of HTLV-1 Infection by HIV-1 First- and Second-Generation Integrase Strand Transfer Inhibitors

“…Moreover, more clinical trials are needed to investigate the efficacy of using anti-retrovirals (combining RT and INSTI inhibitors with or without IFN-alpha or valproic acid) in reducing PVL thereby reducing chances of transmission between partners, but also in cases of organ donor transplantation, and possibly preventing the evolution of asymptomatic carrier to HTLV-1 associated disease. Treating pregnant women with INSTIs might warrant some caution; given the reduced exposure of elvitegravir during pregnancy it increases the risk of virological failure and mother-to-child transmission (Momper et al, 2018; van der Galien et al, 2019). The WHO issued a drug safety alert for dolutegravir 5 following the observation that children born to HIV-1 positive mothers treated with dolutegravir at the time of conception were more likely to have neural tube defects (Zash et al, 2018).…”

Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically‐Based Pharmacokinetic Modeling

“…For some antiretroviral drugs, for instance raltegravir and elvitegravir, a reduction in maternal exposure is reported due to pregnancy-induced changes that affect either the absorption, distribution, metabolism, or excretion of the drug. 10,11 Subtherapeutic maternal antiretroviral exposure may result in virologic breakthrough leading to MTCT and/ or resistance. 12 Because of the long period between US Food and Drug Administration (FDA) approval and the first published results on PK in pregnancy (median 6 years), prescription of antiretrovirals during pregnancy is often off-label, without sufficient information on the dose-exposure relationship in this specific population.…”

Brief Report: Surveillance of Congenital Anomalies After Exposure to Raltegravir or Elvitegravir During Pregnancy in the United Kingdom and Ireland, 2008–2018

“…For EVG/c, there is very limited clinical experience in pregnancy; although embryo-foetal toxicity was not shown in preclinical animal models, caution is needed in extrapolating to humans. However, there are concerns regarding its pharmacokinetic profile of increased clearance and subsequent risk for virological rebound, particularly regarding pregnancy use 12,21,22 . The DTG and NTD safety signal has raised awareness of the large number of peri-conception exposures (at least 2000) needed to rule out an increased risk of NTD, due to it being a rare outcome 25 .…”