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

Discussion

There are multiple reasons to either consider or defer DAA treatment during pregnancy as reviewed extensively by others.[7,114,115] Although the AASLD/IDSA guidelines recommend universal screening of pregnant women,[24] no DAA regimen is currently approved for treatment during pregnancy because of insufficient human safety and efficacy data and treatment is therefore delayed until after delivery. The high chance of loss to follow-up of both mother and her HCV-exposed child in many settings, together with loss of healthcare insurance after pregnancy may complicate adequate maternal and paediatric treatment, highlighting the pregnancy period as a unique window of opportunity to both cure the mother and prevent vertical transmission of HCV.[46,116]

Standard dosing regimens of currently used DAAs may be suboptimal for the pregnant patient population as pregnancy-induced pharmacokinetic changes may influence maternal drug exposure, hence efficacy of the drugs. The expected increased elimination of DAAs, both because of a potentially increased biliary excretion as well as induction of metabolising enzymes, may potentially lead to subtherapeutic levels. This pregnancy-induced effect is expected to be less pronounced for sofosbuvir/ledipasvir and glecaprevir/pibrentasvir compared to other DAA combinations. Instead of adjusting the dose—which is rarely done in clinical practice—a DAA combination less prone to pregnancy-induced effects could be chosen, if available.

Apart from data on maternal exposure to DAAs, early data on placental handling and subsequent foetal exposure are important to study possible placental toxicity of DAAs as well as the potential of DAAs to provide foetal pre-exposure prophylaxis. Several ex vivo and in vitro models may provide insight into pharmacokinetics, including placental transfer of drugs.[87,117] The ex vivo placental perfusion model, using human term placentas yet unexposed to drugs, can be helpful in studying the initial phase of placental DAA handling and may provide an estimation of foetal exposure. Subsequently, pregnancy-PBPK modelling can be used as a tool to assess foetal plasma levels upon maternal administration of different dosing regimens.[118] In the view of potential pre-exposure prophylaxis, foetal exposure to DAAs may, next to maternal viral load reduction, contribute to the reduced risk of vertical transmission. In contrast to HIV, research has yet not focused on the use of DAAs for pre-exposure prophylaxis in the general population. Future research is needed to clarify the role of foetal exposure in reducing the chance of vertical transmission.

Most DAAs are reported to cross the placental barrier in either rats and/or rabbits when administered early during pregnancy. In clinical practice, it is more likely that treatment will be started late in pregnancy to avoid the critical period of foetal organogenesis. Therefore, data from animal reproductive toxicity studies are difficult to extrapolate to the human clinical situation as there is a difference in timing of treatment and because of the large interspecies variability in placental anatomy, both affecting the extent of placental passage. Based on animal studies, it is likely that postpartum exposure to DAAs may occur via breastfeeding. Nowadays, breastfeeding is not contra-indicated in women with chronic HCV. However, this advice may change if breastfeeding women are treated with DAAs in the future, given that fact that all DAAs are detected in milk of rats, with grazoprevir levels in milk being 400% of maternal levels.

In order to decide on the timing of treatment, it is not only important to assess the most critical window of possible teratogenic effects of drug exposure (generally the earlier phase of pregnancy), but also to consider the timing of vertical transmission of HCV. As peripartum blood-blood contact may be the most important source of vertical transmission, maternal HCV RNA should be undetectable during delivery. Ideally, treatment would be completed before delivery. In that case, taking into account that women living with HCV may deliver preterm,[40] the optimal time period to start DAA treatment may be at the end of the second trimester (at around week 23/24 of gestation) or early third trimester (at around 27/28 weeks of gestation), in case of a 12- or 8 week treatment period respectively, and may have to be extended until after delivery to complete treatment. For late presenters (>28 weeks of gestation), treatment may still be effective as DAAs cause a rapid viral decline, resulting in undetectable HCV RNA in just 2–4 weeks.[119]

The choice for a specific DAA combination should be based on safety data from animal reproductive studies and safety and efficacy data from the nonpregnant patient population. Further research on safety, PK and efficacy in pregnant women is warranted prior to implementation of treatment in this population. Research on the potential effect of maternal DAA use on the state of foetal-directed immune tolerance is of particular importance in this population as DAAs are thought to improve the proliferative potential of HCV-specific T cell response again which may decrease immune tolerance.[120] Furthermore, foetal exposure should be assessed, eg by measuring umbilical cord blood concentrations, when women continue treatment until after delivery. This information is needed to assess the potential of DAAs for pre-exposure prophylaxis. Furthermore, an international registry is needed to provide a safety net to detect adverse effects after intrauterine or postpartum DAA exposure.

Next to safety and efficacy data, various other factors have to be taken into account to decide which HCV treatment regimen should be preferred. Firstly, genotype specificity of DAAs plays an important role as the phase I study on sofosbuvir/ledipasvir in pregnancy had to exclude a third of the pregnant women for participation because of genotype 2 or 3 infection.[52] As genotyping is costly, not feasible in all settings and delays treatment start, future research may focus particularly on the use of the pan-genotypic DAA combinations glecaprevir/pibrentasvir and sofosbuvir/velpatasvir (with or without voxilaprevir) during pregnancy. Furthermore, the use of co-medication may determine the DAA regimen of first choice. In the case of HCV/HIV co-infection, EFV should not be used in combination with any DAA and when boosted PIs are part of cART, only sofosbuvir/ledipasvir or sofosbuvir/velpatasvir should be used concomitantly. If women use proton pump inhibitors (PPIs) during pregnancy, neither sofosbuvir/ledipasvir nor sofosbuvir/velpatasvir should be prescribed. In case of concomitant use of strong CYP3A4 inducers, eg rifampicin, sofosbuvir/ledipasvir should be advised. Lastly, local drug availability and costs may determine which drug will be prescribed, despite the fact that this DAA regimen may not be the regimen of first choice based on animal safety data, genotype specificity or potential for DDIs. An important example that needs to be taken into consideration is the widespread use of sofosbuvir/daclatasvir in Egypt, which is one of the countries with the highest HCV prevalence worldwide.[121] Women becoming pregnant using daclatasvir are advised to stop their treatment because of the lack of knowledge regarding safety and efficacy,[53] despite not knowing whether cessation of treatment during pregnancy, likely resulting in HCV disease relapse, may be less advantageous than continuing treatment. Given the paucity of data and the potential exposure to daclatasvir during conception or early pregnancy, research is needed on daclatasvir efficacy in human pregnancy and global pregnancy registry databases are warranted to assess its safety.

Ideally, a pan-genotypic, safe and effective DAA combination would be available to all pregnant women living with HCV, diagnosed by a (cost-effective) universal screening programme. However, cost-effectiveness of specific DAA combinations, local drug availability and preferences of pregnant women themselves and their treating physicians play a dominant role and these factors have to be taken into consideration.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....