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Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study
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CROI 2019: A PHASE ONE STUDY OF LEDIPASVIR/SOFOSBUVIR
IN PREGNANT WOMEN WITH HEPATITIS C VIRUS
"Although this study had a small sample size, the implications of our findings for progressing towards the goal of HCV eradication are substantial.....Pregnancy is an ideal time for both HCV screening28 and treatment because of increased engagement in the health-care system and enhanced maternal investment in neonatal health outcomes. Both the US Centers for Disease Control and Prevention (on April 10, 2020)29 and the US Preventive Services Task Force (on March 2, 2020)30
recommended universal HCV screening in pregnancy, so that all pregnant women can know their HCV status. Women who are found to have HCV can be linked to HCV treatment and their infants can be appropriately screened. Our study shows that HCV screening and treatment during pregnancy are possible and provides a fundamental step towards the development of a safe and effective clinical pathway for treating HCV during pregnancy.
Antiviral drugs are used in pregnancy for two primary reasons: to prevent perinatal infection and to treat maternal infection. For women with chronic infection in whom cure is impossible or challenging, such as women with HIV or hepatitis B virus infections, the use of antiviral medications in pregnancy is focused on prevention of perinatal infection. However, cure is highly likely with HCV direct-acting antiviral drugs. Therefore, in this study, we chose to evaluate the a complete therapeutic course because of the substantial maternal health benefits provided through prevention of cirrhosis and hepatocellular carcinoma in the mother, while simultaneously preventing perinatal HCV transmission. Although the risk of perinatal HCV transmission is low (4-8%), several studies describe that perinatal HCV transmission is often not tested for, resulting in missing cases of paediatric HCV infection.23, 24
Even though direct-acting antiviral drug regimens are now being developed for children as young as 3 years, many children will continue to go undiagnosed. It remains unclear what effect active HCV infection might have on development.25, 26
Antenatal HCV treatment could eradicate maternal HCV infection and prevent the sequalae of HCV infection not only in the current pregnancy, but also in future pregnancies."
"None of the infants had detectable HCV RNA at birth by cord blood sampling. During the 12-month follow-up, none of the infants had a detectable HCV RNA test.....Importantly, there was a 100% cure rate among the participants in the study, with a greater than 4 log decline in viral load within 10-21 days after treatment initiation. The 100% cure rate was achieved, despite one participant missing 15 doses of ledipasvir-sofosbuvir around weeks 9 and 10 of treatment because of an opioid use relapse. Among nine maternal participants and nine infant participants, there were no clinically significant safety concerns identified with regards to maternal health, pregnancy outcomes, and infant health, including neurodevelopment, that could be contributed to ledipasvir-sofosbuvir......The timing of perinatal HCV transmission is uncertain, but it is thought that at least a third of HCV transmissions occur antenatally before the onset of labour. 21
Thus, initiation of treatment in the second trimester could plausibly reduce the risk of antenatal transmission and could prevent all intrapartum HCV transmission. Although it is prudent to limit medication use during pregnancy, the use of ledipasvir-sofosbuvir during pregnancy is one situation in which maternal benefits of the medication use are likely to outweigh the unknown risk of fetal exposure. Ledipasvir-sofosbuvir was well tolerated and there were no substantial safety concerns identified in this study. These findings of safety are similar to those recently reported by El-Sayed and colleagues. 22
In El-Sayed and colleagues' study, of seven women with first trimester daclatasvir-sofosbuvir exposure, all had full-term deliveries of infants without congenital anomalies. Six of the women discontinued daclatasvir-sofosbuvir at week 4 and one discontinued at week 8. Only the woman who discontinued at week 8 had a sustained virological response. Notably, one perinatal HCV transmission occurred in a woman who did not have a sustained virological response. 22"
Research in context
Evidence before this study
Hepatitis C virus (HCV) infection is one of the most consequential impacts of the opioid epidemic among injection drug users. As a result, the prevalence of HCV has escalated among a growing population of pregnant women with opioid use disorder. Despite perinatal HCV transmission rates ranging from 4% to 8%, there are no interventions proven to reduce the risk of perinatal HCV transmission. The past decade has brought a revolution in treatment options for HCV, with several US Food and Drug Administration approved direct-acting antiviral drug combinations, which result in a 96-99% cure rate after only 8-12 weeks of therapy, are orally administered, and well tolerated. These new treatments offer an opportunity to treat maternal HCV infection while the woman is engaged in prenatal care and act to prevent perinatal transmission of HCV. However, as of April 13, 2020, to the best of our knowledge, there are no published studies on the safety or efficacy of direct-acting antiviral drugs for the treatment of HCV during pregnancy. We searched the MEDLINE and PubMed databases from Jan 1, 1996, to April 13, 2020, for clinical trials published in English, using the search terms "hepatitis C virus" and "pregnancy".
Added value of this study
To the best of our knowledge, this is the first clinical trial of HCV treatment during pregnancy with the direct-acting antiviral combination ledipasvir-sofosbuvir. We enrolled nine pregnant women with HCV who completed a 12-week course of ledipasvir-sofosbuvir starting at 23 weeks of gestation. At 12 weeks post-treatment, all the participants were cured of HCV without any clinically significant pharmacokinetic changes with ledipasvir or sofosbuvir administered during pregnancy. All infants were HCV negative and no maternal or neonatal safety concerns were identified.
Implications of all the available evidence
These data suggest that administration of ledipasvir-sofosbuvir starting at 23 weeks of gestation is safe and effective for HCV cure. However, a larger effectiveness study is warranted before this strategy can be recommended and incorporated into routine clinical practice. Further, in this study, 34% of pregnant women screened were ineligible for participation because they had genotype 2 or 3 infection; therefore, evaluation of a pangenotypic regimen should be considered.
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Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study
Sept 2020 Lancet Microbe - Catherine A Chappell, Kimberly K Scarsi, Brian J Kirby, Vithika Suri, Anuj Gaggar, Debra L Bogen, Ingrid S Macio, Leslie A Meyn, Katherine E Bunge, Elizabeth E Krans, Sharon L Hillier
Summary
Background
Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women.
Pregnant women with HCV do not receive treatment during pregnancy because there is an absence of data regarding the safety and efficacy of highly effective direct-acting antivirals in pregnancy. Pregnant women are usually excluded from participating in clinical trials of new drugs. Prospective evaluations of medications for use in pregnancy often lag by years after approval or are not done at all.
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A fundamental first step towards the development of a clinical pathway for treating HCV during pregnancy is to establish safe and therapeutic drug exposures during pregnancy.
Methods
This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants. A reference group of women who had participated in pharmacokinetic studies of ledipasvir-sofosbuvir during phase 2 and 3 trials was used. Participants were enrolled at Magee-Womens Hospital (Pittsburgh, PA, USA) between 23 and 24 weeks' gestation and had a 12-week course of oral ledipasvir-sofosbuvir (daily 90 mg ledipasvir plus 400 mg sofosbuvir). Three 12-h intensive pharmacokinetic visits were done at 25-26, 29-30, and 33-34 weeks' gestation and individual pharmacokinetics were summarised by geometric mean across the three visits. The primary outcome, analysed in all participants without suspected dosing errors, was the ledipasvir-sofosbuvir area under the concentration-time curve of the dosing interval (AUCtau) during pregnancy compared with the reference group by geometric mean ratio. This study is registered with ClinicalTrials.gov, NCT02683005.
Findings
From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Eight (89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the pregnant women versus the non-pregnant reference group (geometric mean ratio of AUCtau ledipasvir 89·3% [90% CI 68·7-116·1]; sofosbuvir 91·1% [78·0-106·3]).
Interpretation
Ledipasvir-sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women.
Funding
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health/Office of Research on Women's Health, and Gilead Sciences.
Ledipasvir-sofosbuvir is a candidate for treatment of HCV during pregnancy because preclinical data showed no safety concerns when ledipasvir and sofosbuvir were administered to pregnant rats and rabbits at higher doses than those used to treat HCV in humans.
On the basis of drug interaction studies, ledipasvir bioavailability in humans is estimated to be less than 30%.
Ledipasvir requires an acidic environment for absorption, is 99·8% protein bound, 30% is hepatically metabolised by unknown oxidative pathways, and it is primarily eliminated via biliary excretion, resulting in a plasma half-life of 47 h.
Sofosbuvir is a phosphoramidate prodrug and is hydrolysed intracellularly by human catepsin A or carboxylesterase 1 and nucleotide-binding protein 1 to the pharmacologically active intracellular GS-331007 triphosphate, which is dephosphorylated to the primary circulating metabolite GS-331007. The bioavailability of sofosbuvir is more than 80% and a high-fat meal increases sofosbuvir exposure by 67-91%. Sofosbuvir is 61-65% plasma protein bound, 14% is hepatically metabolised by phosphorylation, and 80% is renally excreted. As a prodrug, the sofosbuvir half-life is 0·4 h, and the half-life of GS-331007 is 27 h.
Given the substantial physiological changes in pregnancy that influence the pharmacokinetics of many medications,
the primary objective of this study was to compare the pharmacokinetic parameters of ledipasvir-sofosbuvir administered to pregnant women with HCV infection to those of a historical reference group of non-pregnant women with HCV infection. The secondary objectives were to define the safety of, and virological response to, ledipasvir-sofosbuvir treatment during pregnancy.
Results
From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Among screened women, 20 (69%) were excluded because of genotype 2 or 3 infection (ten [34%]), ongoing illicit drug use (four [14%]), declining study participation (three [10%]), intention to deliver off-site (two [7%]), and concern about possible cirrhosis because their aspartate aminotransferase to platelet ratio was more than 1 (one [3%]). All nine infants completed the study and all nine infants completed the 6-month HCV RNA assessment. All participants completed the 12-week course of study drug before delivery and completed the three pharmacokinetic visits. However, one participant was excluded from the pharmacokinetic analysis because of non-adherence with the dosing schedule, as evidenced by high sofosbuvir concentrations (179 and 196 ng/mL) at the pre-dose timepoint in two of the three visits (appendix p 57). Because of the short half-life of sofosbuvir, the presence of high sofosbuvir concentrations pre-dose suggested that the participant ingested sofosbuvir immediately before the scheduled visit.
All enrolled participants were white, with a median age of 31 years (range 25-38), and the majority (eight [89%]) were Medicaid insured. Although many participants had multiple risk factors for HCV infection, including having tattoos, condomless anal sex, and intravenous drug use, eight (89%) participants attributed their HCV infection to previous intravenous drug use, and one (11%) had HCV infection due to perinatal HCV transmission (table 1). The historical reference group comprised 43 women with a median age of 52 years (range 21-69), median bodyweight of 70 kg (47-136), 39 (91%) were white, three (7%) were Asian, and one (2%) was black. No further details on race or ethnicity were available in the original database.
The ledipasvir, sofosbuvir, and GS-331007 pharmacokinetic parameters by gestational age are shown in table 2 and figure 1. Table 3shows the overall pharmacokinetic parameters during pregnancy compared with the reference group. There were no clinically significant changes noted in any of the pharmacokinetic parameters for sofosbuvir or ledipasvir between pregnancy and the reference group (geometric mean ratios showed a maximum reduction of 16·5% for ledipasvir). However, GS-331007 exposure was 38% lower in pregnant women than in non-pregnant women (table 3). A post-hoc power analysis showed that eight women in the test group and 43 women in the reference group provided more than 80% power to detect a decrease in sofosbuvir or ledipasvir AUCtau of more than 30%.
Protein binding was similar across all three gestational age timepoints (figure 2). The mean proportion of sofosbuvir that was unbound during pregnancy was 21·7% (SD 3·6) compared with 17·6% (2·5) in the reference group. The mean proportion of ledipasvir that was unbound during pregnancy was 0·005% (0·001) compared with 0·014% (0·043) in the reference group (figure 2).
The HCV viral load at enrolment ranged from 1·0 × 105 to 73·5 × 105 copies per mL, with only one participant having a viral load greater than 6 × 105 copies per mL (figure 3). Upon initiation of ledipasvir-sofosbuvir, the viral load declined, and all participants had an undetectable viral load by the third pharmacokinetic visit between 33 and 35 weeks of gestation. One (11%) participant had a detectable HCV viral load at delivery; however, she also had the highest viral load at enrolment and had an opioid use relapse during the course of her treatment that resulted in approximately 15 missed doses of medication between weeks 9 and 11 of treatment. All nine (100%) participants had an undetectable viral load 12 weeks after completion of treatment, meeting the definition of HCV cure.
Five (56%) participants had an adverse event related to ledipasvir-sofosbuvir, four (44%) were grade 1 (three [33%] nausea or vomiting and one [11%] diarrhoea) and one (11%) was grade 2 (fatigue); none of these adverse events resulted in discontinuation of treatment. Eight (89%) infants delivered at term (37 weeks of gestation or more) and nine (100%) had normal birthweights more than 2500 g. The preterm infant delivered at 36 weeks and 6 days because of severe gestational hypertension. None of the infants had detectable HCV RNA at birth by cord blood sampling. Three infants were admitted to the neonatal intensive care unit for treatment for neonatal opioid withdrawal syndrome (two [22%]) and a brachial plexus injury (one [11%]) resulting from a shoulder dystocia at the time of delivery (table 4). During the 12-month follow-up, none of the infants had a detectable HCV RNA test. 60 infant adverse events were recorded during the 12-month follow-up, none of which were related to ledipasvir-sofosbuvir exposure. Of the 60 infant adverse events, 40 (67%) were grade 1, 15 (25%) were grade 2, four were grade 3 (7%), and one (<2%) was grade 4. The grade 3 and 4 adverse events included two (22%) of nine infants who required admission to hospital for treatment of neonatal opioid withdrawal syndrome, one (11%) infant who required admission to hospital for a viral illness at 7 months of age, and one (11%) infant who required admission to the neonatal intensive care unit for respiratory distress (grade 3) after a shoulder dystocia (grade 4). The infant growth parameters (bodyweight, length, head circumference) were all within the normal range and trajectory throughout the 12-month follow-up period. Two (22%) infants were referred for early intervention during the follow-up because of concerns regarding motor development; however, all nine infants had a normal neurodevelopmental assessment at the last contact. All of the infants were assessed for congenital abnormalities at birth and at each follow-up visit and none were identified. All of the maternal safety laboratory evaluations, which included a complete blood count, liver function tests, and creatinine, were normal during treatment as well as the post-treatment assessment.
Discussion
In this phase 1 study of antenatal HCV treatment with ledipasvir-sofosbuvir, no clinically significant pharmacokinetic differences in total ledipasvir or total sofosbuvir were identified in pregnant women compared with in the non-pregnant reference group, nor were differences in drug concentrations identified by gestational age. Although there was a 38% reduction in exposure to the renally eliminated sofosbuvir metabolite GS-331007 in pregnant women compared with non-pregnant women, probably due to increased glomerular filtration rate during pregnancy,
20 this result is not considered to be clinically significant because GS-331007 is an inactive metabolite and does not contribute to efficacy. Compared with the reference group, we observed numerically higher unbound sofosbuvir, which is not expected to be clinically relevant, and unexpectedly lower unbound ledipasvir in pregnant women. Importantly, there was a 100% cure rate among the participants in the study, with a greater than 4 log decline in viral load within 10-21 days after treatment initiation. The 100% cure rate was achieved, despite one participant missing 15 doses of ledipasvir-sofosbuvir around weeks 9 and 10 of treatment because of an opioid use relapse. Among nine maternal participants and nine infant participants, there were no clinically significant safety concerns identified with regards to maternal health, pregnancy outcomes, and infant health, including neurodevelopment, that could be contributed to ledipasvir-sofosbuvir.
The timing of perinatal HCV transmission is uncertain, but it is thought that at least a third of HCV transmissions occur antenatally before the onset of labour. 21
Thus, initiation of treatment in the second trimester could plausibly reduce the risk of antenatal transmission and could prevent all intrapartum HCV transmission. Although it is prudent to limit medication use during pregnancy, the use of ledipasvir-sofosbuvir during pregnancy is one situation in which maternal benefits of the medication use are likely to outweigh the unknown risk of fetal exposure. Ledipasvir-sofosbuvir was well tolerated and there were no substantial safety concerns identified in this study. These findings of safety are similar to those recently reported by El-Sayed and colleagues. 22
In El-Sayed and colleagues' study, of seven women with first trimester daclatasvir-sofosbuvir exposure, all had full-term deliveries of infants without congenital anomalies. Six of the women discontinued daclatasvir-sofosbuvir at week 4 and one discontinued at week 8. Only the woman who discontinued at week 8 had a sustained virological response. Notably, one perinatal HCV transmission occurred in a woman who did not have a sustained virological response. 22
Antiviral drugs are used in pregnancy for two primary reasons: to prevent perinatal infection and to treat maternal infection. For women with chronic infection in whom cure is impossible or challenging, such as women with HIV or hepatitis B virus infections, the use of antiviral medications in pregnancy is focused on prevention of perinatal infection. However, cure is highly likely with HCV direct-acting antiviral drugs. Therefore, in this study, we chose to evaluate the a complete therapeutic course because of the substantial maternal health benefits provided through prevention of cirrhosis and hepatocellular carcinoma in the mother, while simultaneously preventing perinatal HCV transmission. Although the risk of perinatal HCV transmission is low (4-8%), several studies describe that perinatal HCV transmission is often not tested for, resulting in missing cases of paediatric HCV infection.23, 24
Even though direct-acting antiviral drug regimens are now being developed for children as young as 3 years, many children will continue to go undiagnosed. It remains unclear what effect active HCV infection might have on development.25, 26
Antenatal HCV treatment could eradicate maternal HCV infection and prevent the sequalae of HCV infection not only in the current pregnancy, but also in future pregnancies.
This phase 1 evaluation of the pharmacokinetics and safety of ledipasvir-sofosbuvir for 12 weeks during pregnancy substantially expands our knowledge of HCV treatment during pregnancy and suggests that the pharmacokinetics of ledipasvir-sofosbuvir are similar in pregnant and non-pregnant women. However, there are limitations and challenges to this study that warrant attention. The small sample size precluded our ability to detect infrequent maternal or neonatal adverse events associated with ledipasvir and sofosbuvir exposure or a small reduction in the efficacy of ledipasvir-sofosbuvir when administered during pregnancy. Future studies should carefully choose an appropriate control group because there are coexisting factors, including poverty, substance use, and opioid exposure, that could have an effect on safety outcomes.27
The small sample size was directly related to the strict eligibility criteria for this study. First, the most substantial barrier to study recruitment and enrolment was the inability to confirm that women had chronic HCV infection (with a positive HCV test at least 6 months before enrolment) because many women were newly diagnosed during prenatal care screening. Second, there was an unexpectedly high prevalence of HCV genotypes 2 and 3, which accounted for ten (34%) of 29 women who were excluded after screening. Finally, the majority of women with HCV have a history of injection drug use and have psychological and social comorbidities, including housing instability, lack of childcare and transportation, and ongoing illicit drug use that precluded their participation in this time-intensive study. These strict eligibility criteria might limit the generalisability of our findings to the entire population of pregnant women with HCV infection.
Although this study had a small sample size, the implications of our findings for progressing towards the goal of HCV eradication are substantial. The results of this study suggest that no dose adjustment is needed for administration of ledipasvir-sofosbuvir during pregnancy to achieve therapeutic concentrations; therefore, larger studies evaluating the safety and efficacy of ledipasvir-sofosbuvir in pregnancy should move forward. Because ledipasvir-sofosbuvir is only approved for HCV genotypes 1, 4, 5, and 6, the pharmacokinetic evaluation of a pangenotypic regimen should concurrently be considered. Pregnancy is an ideal time for both HCV screening28 and treatment because of increased engagement in the health-care system and enhanced maternal investment in neonatal health outcomes. Both the US Centers for Disease Control and Prevention (on April 10, 2020)29 and the US Preventive Services Task Force (on March 2, 2020)30
recommended universal HCV screening in pregnancy, so that all pregnant women can know their HCV status. Women who are found to have HCV can be linked to HCV treatment and their infants can be appropriately screened. Our study shows that HCV screening and treatment during pregnancy are possible and provides a fundamental step towards the development of a safe and effective clinical pathway for treating HCV during pregnancy.
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