Review Article

Direct-acting Antivirals for the Treatment of HCV During Pregnancy and Lactation

Implications for Maternal Dosing, Foetal Exposure, and Safety for Mother and Child

Jolien J. M. Freriksen; Minou van Seyen; Ali Judd; Diana M. Gibb; Intira J. Collins; Rick Greupink; Frans G. M. Russel; Joost P. H. Drenth; Angela Colbers; David M. Burger

Disclosures

Aliment Pharmacol Ther. 2019;50(7):738-750. 

In This Article

Effect of Pregnancy on Maternal Exposure to Direct-acting Antivirals

Pregnancy-associated anatomical and physiological changes may influence drug pharmacokinetics (PK), in some cases leading to the need for dose adjustments.[55] To date, only one abstract is available on sofosbuvir/daclatasvir in pregnancy and two abstracts on sofosbuvir/ledipasvir.[52–54] Although all women included in these three studies had a rapid HCV RNA response to therapy, no results from PK analysis are reported (yet). Because of absence of available clinical PK data to date, the effect of pregnancy-induced alterations on drug disposition may be predicted based on their PK properties. For each DAA, we discuss the impact of pregnancy on maternal DAA exposure by considering the potential effect on drug absorption, distribution, metabolism and excretion, as well as potential drug-drug interactions (DDIs) with combination antiretroviral therapy (cART) for treatment of HIV. The literature search strategy can be found in Appendix S1. The expected pregnancy-induced changes in maternal DAA exposure are described below and summarised in Table 1.

Absorption

Pregnancy-induced alterations of gastrointestinal function, such as delayed-gastric emptying, prolonged gastrointestinal transit time and reduced gastric acidity, can either increase or decrease drug absorption.[55,56] Ledipasvir and velpatasvir show pH-dependent absorption, with a decreased solubility at a higher pH. Reduced gastric acidity during pregnancy may therefore result in lower exposure.[57,58] During pregnancy, women often suffer from nausea and heartburn for which antacids and/or proton pump inhibitors (PPIs) may be prescribed.[59] It has been shown that velpatasvir and ledipasvir exposure in healthy volunteers treated with PPIs such as omeprazole, is reduced up to 40%.[60,61] Therefore, co-administration of PPIs with velpatasvir or ledipasvir during pregnancy should be avoided if possible.[57,58]

Distribution

Apart from physiological changes (eg body volume and tissue perfusion), physicochemical factors (eg drug lipophilicity and molecular weight) determine drug distribution. For example, the increase in body fat during pregnancy is likely to increase the volume of distribution of highly lipophilic drugs, such as DAAs, which in turn may result in lower peak plasma levels, prolonged half-life and lower amplitude of plasma concentrations at steady state. However, little information is available to estimate the contribution of the increased fat mass to the decrease in plasma levels often observed during pregnancy.[55,62] All DAAs, except sofosbuvir, show a high degree of plasma protein binding.[63] Particularly for these highly protein bound drugs, an increase in the unbound fraction may be expected due to decreased plasma levels of the main drug-binding plasma proteins albumin and α1-acid glycoprotein during pregnancy. For most drugs, the total concentration decreases during pregnancy while the unbound concentrations are unaffected. Therefore, it is crucial to measure the unbound plasma concentration in pregnancy, next to total plasma concentrations, to reliably identify the effect of pregnancy on the pharmacologically active unbound concentration. This should be taken into account in future studies on DAA pharmacokinetics in pregnancy.[64]

Metabolism

Pregnancy-induced changes in the activity of drug-metabolising enzymes including cytochrome P450 (CYP) and the uridine diphosphate glucuronosyltransferase (UGT) family have been observed. While the mechanism of the observed changes has not been identified, accumulated data suggest that the changes are regulated by rising concentrations of hormones.[55] Increased CYP3A4 capacity in liver and/or intestine is expected to have the most profound impact on DAA pharmacokinetics compared to other metabolising enzymes.[65] Tracy et al reported that CYP3A activity increased by 35%-38% during pregnancy[66] and, except for sofosbuvir/ledipasvir, exposure to all DAA combinations may be affected to some extent by induction of CYP3A-mediated metabolism. The use of potent CYP3A inducers in combination with DAAs that are metabolised by CYP3A4 is currently contra-indicated, as this may reduce DAA efficacy, possibly resulting in virological failure.[65] The moderate pregnancy-induced increase in CYP3A4 activity may have less profound effects compared to the effects of concomitant use of strong CYP3A inducers on DAA exposure, but dose adjustments of DAAs during pregnancy may have to be considered. For some DAA combinations, only exposure to a single component may be affected by pregnancy-induced changes. For example, exposure to velpatasvir and voxilaprevir, but not to sofosbuvir, is influenced by CYP3A activity. However, a dose adjustment of individual components is complicated since all DAA combination treatments are available as fixed-dose combinations, except for sofosbuvir and daclatasvir, which are available as separate formulations. Data from phase IV trials suggest that sustained virological response is not related to plasma concentrations of glecaprevir in nonpregnant patients on high-dose proton pump inhibitors (PPIs), implying that the levels were well above the therapeutic threshold. A slight decrease in glecaprevir exposure, caused by moderate CYP3A4 induction due to pregnancy, is therefore expected to be of less clinical relevance.[67,68] Regarding daclatasvir, the recommended daclatasvir dose of 60 mg QD is increased to 90 mg QD when co-administered with moderate inducers of CYP3A4A, as reductions in exposure of 25% have been observed frequently for CYP3A4 substrates.[62] A moderate increase in CYP3A activity due to pregnancy may also require an increase in daclatasvir dose. However, the clinical relevance of increased CYP3A4 metabolism for daclatasvir in pregnancy is unknown as its oral clearance is significantly lower in women than in men, resulting in higher exposure in women.[69]

Excretion

Elimination of DAAs (except for sofosbuvir) occurs mainly via biliary excretion as parent drug. Pregnancy may alter the expression of drug transporters in metabolising and eliminating organs, but there is little quantitative information on the influence of pregnancy on transporter activity in the basolateral and canalicular membrane of hepatocytes, and the resulting effect on DAA excretion. Due to this lack of knowledge, no pregnancy physiologically-based pharmacokinetic (PBPK) models have been published which simulate the role of biliary drug excretion.[70] Sofosbuvir is mainly renally eliminated as its pharmacologically inactive metabolite GS-331007 (78%) and to a lesser extent as unchanged sofosbuvir (3.5%). Because pregnancy leads to an increase in renal blood flow and glomerular filtration rate, renal clearance of sofosbuvir may be increased during pregnancy. It is, however, unclear whether this could influence plasma levels to the point of requiring dose adjustment.[55,71]

Drug-drug Interactions (DDIs) in Case of Maternal Viral Co-infection

For the treatment of maternal hepatitis B co-infection, tenofovir disoproxil fumarate (TDF) is preferred.[72] As TDF may also be part of combination antiretroviral therapy (cART) for treatment of HIV, literature on DDIs between cART and DAAs can be consulted.[65] DDIs between HCV and cART are an important consideration in the treatment of (pregnant) HCV/HIV co-infected women,[14,15] and are well described in the literature.[65,73] However pregnancy-induced alterations could also influence either HCV and/or HIV drug exposure as a third factor, making the translation of DDIs from the nonpregnant patient population to pregnant women complicated. Here we do not elaborate on drug combinations that are already contra-indicated in the nonpregnant population, but focus on specific DDIs that may be of concern due to the possible effects of pregnancy on drug exposure. A first example is efavirenz, commonly used as part of cART, but known to decrease daclatasvir exposure via induction of CYP3A4, with an area under the plasma concentration-time curve (AUC) geometric mean ratio (GMR) with 90% CI of 0.68 (0.60, 0.78).[74] The recommended daclatasvir dose is therefore increased (90 mg instead of 60 mg once daily) in patients using efavirenz. In pregnant women, an increase of daclatasvir dose may also be warranted as pregnancy also affects CYP3A4 activity, resulting in lower daclatasvir plasma levels compared to nonpregnant patients. In addition, use of efavirenz with ledipasvir results in a reduction of ledipasvir exposure (AUC GMR [90% CI] of 0.66 [0.59, 0.75]); the pregnancy-related increase in gastric pH is likely to also decrease ledipasvir exposure.[57] Lastly, concomitant use of darunavir/ritonavir with sofosbuvir/velpatasvir/voxilaprevir results in higher voxilaprevir due to inhibition of organic-anion-transporting polypeptide (OATP)-1B1, P-glycoprotein (P-gp) and CYP3A, with an AUC GMR (90% CI) of 2.43 (2.15, 2.75), but is considered to be not clinically relevant in the nonpregnant population.[75] During pregnancy twice daily darunavir, instead of once daily, is recommended and therefore concomitant use of darunavir/ritonavir and sofosbuvir/velpatasvir/voxilaprevir should be contra-indicated.

According to the guidelines, dolutegravir has low potential for DDIs and may therefore seem of particular interest for use in women living with HCV and HIV.[65] However, a recent report highlighted an increased incidence of neural tube defects associated with dolutegravir use around the time of conception. Further safety data are awaited to confirm or refute this finding and in the meantime dolutegravir use around the time of conception should be avoided,[76] although if used after the first trimester, there is no increased risk of neural tube defects. As the choice for HCV as well as cART is mainly dependent on local drug availability, which is limited in low-income countries, it might not be possible to prescribe the combination of preference. Based on available data regarding possible DDIs between DAAs and cART, and taking potential effects of pregnancy on their pharmacokinetics into consideration, the choice of combination treatment should be made by local physicians.

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