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

Safety of Direct-acting Antivirals During Pregnancy

In the absence of conclusive evidence from DAA exposure during human pregnancy, assessments of DAA safety are based on data derived from animal reproduction toxicology studies. Table 2 summarises the results of these pre-clinical studies on embryofoetal toxicity, teratogenicity, placenta transfer and breast milk. The literature search strategy can be found in Appendix S1. Although the majority of the adverse effects of drugs are related to direct foetal exposure because of placental transfer, drugs may also affect the developing foetus indirectly by disturbing placental function.[89] However, the species-specific placental physiology, as well as immunological and endocrinological differences hamper the translation of placental drug effects from animal studies.[90] A large registry of infants intrauterine-exposed to DAAs is needed to assess long-term effects in humans. Such an approach has been undertaken for HIV, the Antiretroviral Pregnancy Registry, and has been proven to be successful in monitoring effects of intrauterine exposure to antiretrovirals.[91] Adding HCV to an existing pregnancy registry may be an option worth considering.

Sofosbuvir/Daclatasvir

The only data available on sofosbuvir/daclatasvir in human pregnancy include one study on accidental sofosbuvir/daclatasvir exposure around the time of conception (n = 7). No adverse birth outcomes were reported but one infant tested HCV positive at 18 months with low viral load, which is not unexpected as all women discontinued therapy early, before week 9 of gestation.[53]

Sofosbuvir administration showed no adverse effects in pre-clinical reproduction toxicology studies using rabbits at exposure levels comparable to 10-fold the recommended human dose (RHD). As sofosbuvir could not be detected in rodent plasma probably due to high esterase activity, assessment of reproductive toxicity tests in rats are based on exposure to the major (inactive) metabolite GS-331007. At GS-331007 exposure levels following a 10-fold RHD, no effect on intrauterine development or any malformations were seen in rats.[92,93] As sofosbuvir was detectable in human plasma, data from rodent studies regarding sofosbuvir exposure should be interpreted with caution. For daclatasvir, embryofoetal toxicity (external and/or visceral malformations) in rabbits and rats was reported by the EMA. However, exposure in rats and rabbits was 4.6 and 16-fold RHD respectively.[94] Remarkably, the Food and Drug Administration (FDA) reported no concerns for embryofoetal toxicity in rats when exposed to 6x RHD and in rabbits when exposed to 22-fold RHD.[95]

In the general patient population, this DAA combination has a favourable safety profile. The most frequently reported adverse reactions were fatigue, headache and nausea.[71,74] A special warning for the use of sofosbuvir (in combination with either daclatasvir or ledipasvir) and amiodarone was based on observed bradycardia in several patients.[96]

Sofosbuvir/Ledipasvir

Data on sofosbuvir/ledipasvir use during pregnancy are limited to two conference abstracts: one study performed in India included pregnant women living with HCV who requested treatment because of anxiety about vertical transmission (n = 15), and DAAs were started during the second and early third trimester;[54] and the other, previously mentioned, is a phase I trial of sofosbuvir/ledipasvir started during the second trimester of pregnancy (n = 8) from the USA.[52] Both studies reported no safety concerns; there were are no cases of vertical transmission to date in the USA study, but the number is yet to be reported for the Indian study. Considering the small number of women in the two studies, a lack of vertical transmission would not be unusual even in the absence of treatment.

The decision to study sofosbuvir/ledipasvir in a clinical setting is supported by a favourable embryofoetal safety profile based on pre-clinical studies. As stated earlier in this review, sofosbuvir use seems safe for the developing offspring in rats and rabbits. At exposure levels of 3.4-fold RHD, minor effects of ledipasvir on fertility of female rats were reported. However, this was not seen at 2-fold RHD and effects were likely related to non-adverse maternal toxicity.[97] The FDA reported that there are no clear adverse effects on foetal development in rats and rabbits at 4-fold and 2.3-fold RHD respectively. However, a lower body weight of the offspring in rats at an exposure level of 4-fold RHD is reported by the EMA and at slightly higher exposure levels (4.6-fold RHD), an increased incidence of skeletal variations was observed.[57,98] In the absence of other toxicity findings, this effect on the offspring may be related to non-adverse maternal toxicity.

In terms of adverse events, fatigue and headache were reported in adult patients treated with ledipasvir/sofosbuvir.[57]

Sofosbuvir/Velpatasvir (±Voxilaprevir)

The EMA reports a possible teratogenic effect (visceral malformations) due to velpatasvir exposure of 0.7-fold RHD in pregnant rabbits; however, according to the FDA label, this is written as being of "no significant effect". Mice and rat studies found no embryofoetal adverse effects at 23-fold RHD and 4-fold RHD respectively. There was no evidence of placental transfer of velpatasvir as it could not be detected in litter after a single dose of 30 mg/kg on gestation day 13 or 18. Maternal voxilaprevir administration did not result in adverse embryofoetal effects in rats (141-fold RHD) and rabbits (4-fold RHD). No data on placental transfer of voxilaprevir in animals have been reported.[99–102]

The most common adverse effects seen in clinical studies were headache, fatigue and nausea. When combined with voxilaprevir, diarrhoea and nausea were also reported as common adverse events.[58,75]

Grazoprevir/Elbasvir

Grazoprevir and elbasvir reproduction studies have failed to reveal any adverse effects in rats (10-fold RHD) and rabbits (18-fold RHD).[103,104]

In patients with HCV, reported adverse reactions were fatigue and headache with a special warning for plasma liver enzyme (ALT) elevations. The rate of late ALT elevations during treatment was directly related to plasma exposure to grazoprevir and generally occurred from approximately 8 weeks after start of treatment. These late ALT elevations were typically asymptomatic and resolved with ongoing therapy with grazoprevir/elbasvir or after completion of therapy.[105]

Glecaprevir/Pibrentasvir

Registration files state that either glecaprevir administration in rats (63-fold RHD) or pibrentasvir administration in mice (100-fold RHD) did not result in reproductive toxic effects. However, this conclusion was considered questionable because maternal toxicity with some embryofoetal toxicity precluded the ability to evaluate glecaprevir in rabbits at human clinical exposures.[106,107]

In clinical studies, the most commonly reported adverse reactions were fatigue and headache. Occasionally, elevations of total bilirubin levels have been reported in patients using glecaprevir/pibrentasvir. The effect is more pronounced with higher glecaprevir plasma levels and is likely due to glecaprevir-mediated inhibition of bilirubin transport and metabolism.[108] Although maternal bilirubin elevations are asymptomatic and transient, the effects on the foetus may be questionable as unconjugated bilirubin can cross the placental barrier.[109] Therefore, it may be hypothesised that high maternal bilirubin levels may increase the risk of neonatal jaundice.

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