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Combination ledipasvir-sofosbuvir for the treatment of chronic hepatitis C virus infection: a review and clinical perspective.

ABSTRACT: Chronic hepatitis C treatment has continued to evolve, and interferon-free, oral treatment with direct-acting antiviral agents is the current standard of care. Recently, a new treatment, which is a combination of two direct-acting antiviral agents, ledipasvir 90 mg (anti-NS5A) and sofosbuvir 400 mg (anti-NS5B), has been approved in the US and the European Union for the treatment of chronic hepatitis C viral infection. In Phase III trials among chronic hepatitis C virus genotype 1 monoinfected (treatment-naïve, treatment-experienced, and with advanced liver disease or posttransplant) patients and HIV-hepatitis C virus coinfected patients, the ledipasvir-sofosbuvir fixed-dose combination is associated with a higher rate of sustained virologic response at 12 weeks after therapy has ceased. According to preliminary data, the ledipasvir-sofosbuvir combination also may be effective against hepatitis C genotype 4 virus infection. The ledipasvir-sofosbuvir combination taken orally is generally well-tolerated. Moreover, the combination treatment may suppress the effect of predictive factors of chronic hepatitis C that have historically been known to be associated with treatment failure. Thus, the fixed-dose single-tablet combination of ledipasvir-sofosbuvir offers a new era for the effective treatment of a variety of patients suffering from chronic hepatitis C virus infection.

SUBMITTER: Nkuize M

PROVIDER: S-EPMC4902143 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Combination ledipasvir-sofosbuvir for the treatment of chronic hepatitis C virus infection: a review and clinical perspective.

Nkuize Marcel M Sersté Thomas T Buset Michel M Mulkay Jean-Pierre JP

Therapeutics and clinical risk management 20160603

Chronic hepatitis C treatment has continued to evolve, and interferon-free, oral treatment with direct-acting antiviral agents is the current standard of care. Recently, a new treatment, which is a combination of two direct-acting antiviral agents, ledipasvir 90 mg (anti-NS5A) and sofosbuvir 400 mg (anti-NS5B), has been approved in the US and the European Union for the treatment of chronic hepatitis C viral infection. In Phase III trials among chronic hepatitis C virus genotype 1 monoinfected (t ...[more]

PMID: 27350749

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Project description:BACKGROUND & AIMS:The combination of ledipasvir and sofosbuvir has been approved for treatment of genotype 1 hepatitis C virus (HCV) infection, including an 8-week regimen for treatment-naïve patients without cirrhosis and a baseline level of HCV RNA <6 million IU/mL. We analyzed data from a multicenter, prospective, observational study to determine real-world sustained virologic responses 12 weeks after treatment (SVR12) with regimens containing ledipasvir and sofosbuvir and identify factors associated with treatment failure. METHODS:We collected data from 2099 participants in the HCV-TARGET study with complete virologic data (per-protocol population). We analyzed data from 1788 patients receiving ledipasvir-sofosbuvir (282 for 8 weeks, 910 for 12 weeks, 510 for 24 weeks, and 86 for a different duration) and 311 receiving ledipasvir-sofosbuvir plus ribavirin (212 for 12 weeks and 81 for 24 weeks, 18 for other duration) to estimate SVR12 (with 95% confidence interval [CI]), and logistic regression methods to identify factors that predicted an SVR12. RESULTS:The overall study population was 25% black, 66% with HCV genotype 1A infection, 41% with cirrhosis, 50% treatment-experienced, and 30% receiving proton pump inhibitors at start of treatment. In the per-protocol population, SVR12s were achieved by 96% of patients receiving ledipasvir-sofosbuvir for 8 weeks (95% CI, 93%-98%), 97% receiving the drugs for 12 weeks (95% CI, 96%-98%), and 95% receiving the drugs for 24 weeks (95% CI, 93%-97%). Among patients also receiving ribavirin, SVR12 was achieved by 97% of the patients receiving the drugs for 12 weeks (95% CI, 94%-99%) and 95% receiving the drugs for 24 weeks (95% CI, 88%-99%). Of the 586 patients who qualified for 8 weeks of treatment, only 255 (44%) received the drugs for 8 weeks. The rate of SVR12 among those who qualified for and received 8 weeks of therapy was similar in those who qualified for 8 weeks but received 12 weeks therapy (96%; 95% CI, 92%-99% vs 98%; 95% CI, 95%-99%). Factors that predicted SVR12 were higher albumin (?3.5 g/dL), lower total bilirubin (?1.2 g/dL), absence of cirrhosis, and absence of proton pump inhibitor use. CONCLUSIONS:Regimens containing ledipasvir and sofosbuvir are highly effective for a broad spectrum of patients with HCV genotype 1 infection treated in different clinical practice settings. Expanded use of 8-week treatment regimens for eligible patients is supported by these real-world results. Modification of proton pump inhibitor use may increase rates of SVR. ClinicalTrials.gov no. NCT01474811.

Project description:BackgroundHepatitis 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.MethodsThis 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.FindingsFrom 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]).InterpretationLedipasvir-sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women.FundingNational 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.

Dataset Information

Combination ledipasvir-sofosbuvir for the treatment of chronic hepatitis C virus infection: a review and clinical perspective.

Publications

Combination ledipasvir-sofosbuvir for the treatment of chronic hepatitis C virus infection: a review and clinical perspective.

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