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

Abstract and Introduction

Abstract

Background: With the global efforts to eradicate hepatitis C virus (HCV), treatment during pregnancy is becoming a priority for research as this, and maternal cure should reduce vertical transmission. However, as information on the efficacy and safety of direct-acting antivirals (DAAs) in pregnancy is generally lacking, treatment of HCV infection during pregnancy is not currently recommended.

Aim: To provide an overview of current knowledge regarding maternal exposure, placental handling and safety of DAAs during pregnancy and lactation

Methods: A literature search was performed focusing on the effect of pregnancy on maternal exposure to DAAs, the placental handling of DAAs, the safety of DAAs for mother and child during pregnancy and the safety of DAAs during lactation.

Results: Exposure to all DAAs studied is likely to be altered during pregnancy, mostly related to pregnancy-induced effects on drug absorption and metabolism. Although animal studies show that most DAAs are reported to cross the placenta and transfer into breast milk, most DAA combinations show a favourable safety profile. Because of the rapid viral decline after treatment initiation, and to avoid the critical period of organogenesis, treatment may be started at the end of the second trimester or early third trimester.

Conclusions: Treatment of HCV infection during pregnancy is realistic, as DAAs are highly effective and treatment duration is relatively short. There is an urgent need to study DAAs during pregnancy and lactation to contribute to the goal of HCV elimination.

Introduction

In 2015, there were an estimated 71 million persons chronically infected with hepatitis C virus (HCV), resulting in 1.34 million deaths that year.[1] With the global efforts of the World Health Organization to eradicate HCV by 2030, it is important to identify individuals at risk and provide treatment as soon as possible after diagnosis.[2] While the majority of infections among adults in many settings are linked to injection drug use, the most important source of paediatric HCV infection is vertical transmission of the virus, responsible for approximately 60% of paediatric HCV cases globally.[3,4] Among pregnant women, estimates of HCV prevalence have ranged from 0.1% to 8% from different countries and settings.[5–8]

Vertical Transmission of HCV. A large meta-analysis performed by Benova et al reported a 5.8% risk of vertical transmission of HCV, resulting in 1700 HCV-infected newborns in the USA yearly.[9,10] In addition to high maternal HCV viral load, the review states that maternal HIV co-infection increased the risk of vertical transmission of HCV to around 10%.[9,11,12] However, the majority of the co-infected pregnant women included were not taking antiretroviral therapy, and a recent study suggested that those on antiretroviral therapy have a similar risk of transmitting HCV to those with HCV mono-infection.[13] The prevalence of HCV and HIV co-infection among pregnant women varies across settings. One study in Rwanda reported that 3.9% of pregnant women with HCV were co-infected with HIV.[14] In a Western/Central European cohort of pregnant women living with HIV, 12% were co-infected with HCV.[14,15] In addition to high maternal HCV viral load and having HIV, membrane rupture for more than 6 hours before delivery and internal foetal monitoring (uterine or foetal scalp) have been reported to contribute to an increased risk of vertical HCV transmission.[16] Currently, most studies suggest that the risk of transmission may be reduced by elective caesarean section, particularly in the case of HCV/HIV co-infection.[17–19] Based on timing of positive HCV RNA test results in the newborn, timing of transmission is thought to occur during intrauterine, peripartum and postpartum periods.[20] Transmission may be most frequent during the peripartum period (estimated 40%-50%) when there is blood-blood contact during delivery. In this case, the child will be born HCV-RNA negative, but detectable RNA levels are expected after the first 3 days of life. It is estimated that intrauterine transmission accounts for approximately 30% of the cases, based on HCV-RNA positivity at or shortly after delivery.[21] The exact mechanisms by which intrauterine transmission occurs are not well understood, but may include trophoblast-mediated endocytosis of HCV and/or transcytosis of viral particles.[22] Postpartum transmission via breastfeeding is rare, as the proportion of children acquiring HCV is similar among those who were breastfed compared to those who were not.[17]

Testing and Consequences of HCV in the Newborn. Although vertical transmission seems to be the most important source of paediatric HCV infection, a retrospective cohort study showed that many children of women with chronic HCV are not screened and therefore many paediatric HCV cases will be missed.[23] A critical reason for the low proportion of exposed infants who are screened is related to the delay in diagnosis, as HCV antibody testing can only be performed at or after 18 months of age, and the chance of loss to follow-up in the intervening period is high.[24] Testing for HCV-RNA positivity in the newborn is generally not routinely performed, but should be recommended in infants born to HCV-RNA positive mothers.[25] The majority (80%) of children acquiring HCV through vertical transmission do not clear the infection spontaneously, resulting in chronic paediatric HCV infection.[26] Although liver injury from chronic HCV infection generally progresses slowly early in life, serious liver damage can occur during childhood and beyond.[27–29] One centre reported five children (out of 91 included patients, mean age: 9 years) with an accelerated course of HCV and early development of decompensated liver disease requiring liver transplantation, two of whom subsequently died.[30] In addition to concerns about the physical health of the child with HCV, there may be high levels of distress in the family.[31] Treatment regimens based on direct-acting antivirals (DAAs) for children with chronic HCV ≥ 12 years of age or ≥ 35 kilograms were approved by the FDA in April 2017.[32] Phase I and II trials of several DAA combinations for children aged 3–12 years are currently ongoing [ClinicalTrials.gov: NCT03067129, NCT03080415, NCT03487848, NCT03022981]. Unfortunately, there will be no treatment available prior to the age of 3 in the near future as this is not requested by the European Medicines Agency (EMA). Therefore, treatment of children with vertically acquired HCV may be complicated as loss to follow-up in healthcare later in life is likely to be high, as is the case in some settings for HIV.[33,34]

Effect of HCV on Pregnancy Outcome. In addition to the risk of vertical HCV transmission, maternal HCV infection may increase the risk of adverse pregnancy outcomes. Recently, a protocol has been published for a study which will undertake an extensive systematic review of pregnancy outcomes in women with HCV; results are expected soon.[35] Only a small proportion of available studies have sufficient power to adjust for potential confounding variables such as tobacco, alcohol and drug use. These studies report an association between maternal HCV infection and the risk of gestational diabetes and intrahepatic cholestasis of pregnancy.[36,37] In addition, an increased risk of preterm birth was reported and children born to women living with HCV were more likely to have a lower birth weight and to be small for gestational age.[38–41]

Considerations for HCV Treatment During Pregnancy. Diagnosis and treatment of HCV in pregnant women is becoming a priority area of research as this has potential, not only to cure the mother, but also to prevent vertical transmission.[42,43] Until recently, ribavirin was a cornerstone of HCV therapy. As this drug is known to be teratogenic and embryotoxic in all animal species studied, its use—and consequently all classical forms of HCV therapy—during pregnancy has been contra-indicated.[44] However, new, potentially much safer combinations of DAAs drugs are now available that are ribavirin free. The relative short duration of treatment (8–12 weeks) and the rapid viral load decline following treatment initiation makes treatment and cure of women with chronic HCV late in pregnancy realistic.[24,45] Testing and treatment during pregnancy seems a unique opportunity, as loss to follow-up of mother and child postpartum is high in many low and middle income country settings, and pregnant women are engaged in healthcare during this period, being highly motivated to take actions to ensure their own health and the health of their unborn child.[23,46,47] In 2018, the American Association for the Study of Liver Disease (AASLD)/Infectious Diseases Society of America (IDSA) guidelines recommended universal HCV screening in pregnancy which was already suggested by other countries such as France and Pakistan a few years earlier.[24,48,49] It is, however, not being implemented widely thus far as other guidelines, such as from the Centers for Disease Control and Prevention and the Society for Maternal-Foetal Medicine, have not yet adopted the recommendation. It is estimated that such a screening strategy, followed by treatment after pregnancy, would be cost-effective for maternal treatment and would identify around 300 newborns with vertical HCV in the USA annually.[50] However, pregnant women may experience psychological stress as treatment start has to be postponed to the postpartum period. A recent survey showed that among women with (a history of) HCV, 60% were willing to undergo HCV therapy during pregnancy given the fact that it would reduce the risk of vertical transmission, and despite the lack of safety data.[51]

Despite recent interest and major advancements in available treatment options, data on DAAs in this population are limited to three abstracts on either intentional or accidental exposure during pregnancy in a small number of women.[52–54] There are a number of important aspects to consider prior to implementation of DAA therapy during pregnancy, which we review here. These are: (a) The effect of pregnancy on maternal exposure to DAAs; (b) The placental handling of DAAs; (c) Safety of DAAs for mother and child during pregnancy; (d) Safety of DAAs during the lactation period. Implementation and costs of antenatal HCV screening are also important but will not be considered here. We identify research gaps on the potential use of DAAs in pregnant and breastfeeding women living with HCV.

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