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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.

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.

SUBMITTER: Freriksen JJM

PROVIDER: S-EPMC6773363 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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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.

Freriksen Jolien J M JJM van Seyen Minou M Judd Ali A Gibb Diana M DM Collins Intira J IJ Greupink Rick R Russel Frans G M FGM Drenth Joost P H JPH Colbers Angela A Burger David M DM

Alimentary pharmacology & therapeutics 20190825 7

<h4>Background</h4>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.<h4>Aim</h4>To provide an overview of current knowledge regarding maternal exposure, placental han ...[more]

PMID: 31448450

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Project description:Background & aimsDevelopment of resistance results from mutations in the viral genome, and the presence of selective drug pressure leads to the emergence of a resistant virus population. The aim of this study was to analyze the impact of genetic variability on the genetic barrier to drug resistance to DAAs.MethodsThe genetic barrier was quantified based on the number and type of nucleotide mutations required to impart resistance, considering full-length HCV NS3, NS5A and NS5B regions segregated by genotype into subtypes 1a, 1b, 2a, 2b and 3a. This study analyzeds 789 NS3 sequences, 708 sequences and 536 NS5B sequences deposited in the European Hepatitis C Virus Database, in the following resistance-associated positions: NS3: F43/I/L/S/V, Q80K/R, R155K/G, A156G/S/T and D168A/C/E/G/H/N/T/V/Y; NS5A: L/M28A/T/V, Q30E/H/R, L31F/I/M/V, H58D or P58S and Y93C/F/H/N/S; NS5B: S282P/R/T, C316H/N/Y, S368T, Y448C/H, S556G/R, D559R.ResultsVariants that require only one transversion in NS3 were found in 4 positions and include F43S, R80K, R155K/G and A156T. The genetic barrier to resistance shows subtypic differences at position 155 of the NS3 gene where a single transition is necessary in subtype 1a. In the NS5A gene, 5 positions where only one nucleotide change can confer resistance were found, such as L31M which requires one transversion in all subtypes, except in 0.28% of 1b sequences; and R30H, generated by a single transition, which was found in 10.25% of the sequences of genotype 1b. Other subtypic differences were observed at position 58, where resistance is less likely in genotype 1a because a transversion is required to create the variant 58S. For the NS5B inhibitors, the genetic barrier at positions conferring resistance was nearly identical in subtypes 1a and 1b, and single transitions or transversions were necessary in 5 positions to generate a drug-resistant variant of HCV. The positions C316Y and S556D required only one transition in all genotypes, Y448H and S556 G/N/R positions required only one transition for up to 98.8% of the sequences analyzed. A single variant in position 448 in genotype 1a is less likely to become the resistance variant 448H because it requires two transversions. Also, in the position 559D a transversion and a transition were necessary to generate the resistance mutant D559H.ConclusionResults revealed that in 14 out of 16 positions, conversion to a drug-resistant variant of HCV required only one single nucleotide substitutions threatening direct acting antivirals from all three classes.

Project description:Many women drink during pregnancy and lactation despite recommendations to abstain. In animals, alcohol exposure during pregnancy and lactation influences lung and immune development, plausibly increasing risk of asthma and lower respiratory tract infections (LRTIs). Studies in humans are few.In the Norwegian Mother and Child Cohort Study, we examined maternal alcohol intake during pregnancy and lactation in relation to risk of current asthma at 36 months (49,138 children), recurrent LRTIs by 36 months (39,791 children), and current asthma at 7 years (13,253 children). Mothers reported frequency and amount of alcohol intake each trimester and the first 3 months following delivery. We calculated adjusted relative risk (aRR), comparing children of drinkers to nondrinkers, using Generalized Linear Models.A total of 31.8% of mothers consumed alcohol during first trimester, 9.7% during second trimester, and 15.6% during third trimester. Infrequent and low-dose prenatal alcohol exposure showed a modest statistically significant inverse association with current asthma at 36 months (aRRs ~ 0.85). No association was seen with the highest alcohol intakes during the first trimester when alcohol consumption was most common. RRs of maternal alcohol intake during pregnancy with recurrent LRTIs were ~1, with sporadic differences in risk for some metrics of intake, but without any consistent pattern. For current asthma at 7 years, similar inverse associations were seen as with current asthma at 36 months but were not statistically significant. Among children breastfed throughout the first 3 months of life, maternal alcohol intake during this time was not significantly associated with any of the 3 outcomes.The low levels of alcohol exposure during pregnancy or lactation observed in this cohort were not associated with increased risk of asthma or recurrent LRTIs. The slight inverse associations of infrequent or low-dose prenatal alcohol exposure with asthma may not be causal.

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Dataset Information

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.

Publications

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.

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