Analysis of Subgroup Differences in the ION-3 Trial of Ledipasvir-Sofosbuvir in Chronic Hepatitis C Infection.
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SUBMITTER: Kowdley KV
PROVIDER: S-EPMC4567098 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Treatment of hepatitis C virus (HCV) infection with ledipasvir/sofosbuvir promises tremendous benefits, but high cost may impede implementation of this regimen. Subgroups with excellent response to 8 weeks of treatment might respond to a shorter course. In ION-3, 423 previously untreated HCV genotype 1-infected patients without cirrhosis had outcome data after receiving ledipasvir/sofosbuvir for 8 weeks. After reanalyzing published ION-3 data, we found that sustained virologic response (SVR) rates varied significantly by gender (P = .002) and rs12979860 genotype (P trend = .03), exceeding 98% in women and rs12979860-CC individuals. The very high SVR rates in these subgroups suggest that these factors might be considered in selecting patients to receive 8 weeks of ledipasvir/sofosbuvir and support shorter trials of this regimen in selected patients.
| S-EPMC4324232 | biostudies-literature
Project description: Not available
| S-EPMC4567096 | biostudies-literature
Project description: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.
| S-EPMC4902143 | biostudies-literature
Project description:The interferon (IFN)-free regimens for chronic hepatitis C (CHC) have high efficacy and superior health-related quality of life (HRQOL) in European/North American patients. The impact of these regimens on HRQOL of the Japanese CHC patients is not known.The Short Form-36 was administered before, during, and after treatment to CHC patients with genotype 1 treated with ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV) for 12 weeks and genotype 2 treated with SOF + RBV for 12 weeks in clinical trials. The HRQOL data were analyzed with reference to treatment regimens and clinical factors.A total of 494 CHC patients were included (19% cirrhotic, 69% genotype 1, 52% treatment-naive; 153 received SOF + RBV, 170 received LDV/SOF + RBV, 171 received LDV/SOF). The sustained virologic response-12 rates for these regimens were 97%, 98%, and 100%, respectively. CHC patients treated with LDV/SOF, SOF + RBV, or LDV/SOF + RBV regimens had similar HRQOL scores at baseline. During treatment, more adverse events were experienced by those treated with RBV-containing regimens (46% vs 22%, P < 0.0001). The decrements in HRQOL were also significant in RBV groups: up to -3.8 points (treatment week-4), -5.2 (treatment week-12), and -3.2 (posttreatment week-12) (all P < 0.001). In contrast, RBV-free regimen (LDV/SOF) was associated with an improvement in HRQOL up to +4.1 points throughout the treatment (P < 0.01). In multivariate analysis, the use of RBV was independently associated with lower HRQOL during and after treatment (beta up to -6.4 points, P = 0.0001).Japanese CHC patients treated with RBV-containing regimens show mild HRQOL impairment. In contrast, patients treated with LDV/SOF not only showed high efficacy but also improvement of HRQOL.
| S-EPMC5370780 | biostudies-literature
Project description:Prevalence of chronic hepatitis C (CH-C) infection in patients of Asian ancestry ranges between 1% and 20%. Interferon (IFN)- and ribavirin (RBV)-containing regimens for CH-C have a negative impact on patient-reported outcomes (PROs) during treatment. The aim of this study was to assess the impact of IFN-free RBV-free sofosbuvir (SOF)-based regimens on PROs in CH-C patients of Asian ancestry. In this observational retrospective study, the PRO data from 12 multicenter multinational phase 3 clinical trials (2012-2015, conducted in Europe, North America, Australia, and New Zealand) of SOF-based regimens with and without IFN, ledipasvir (LDV), and/or RBV were used. At baseline, during treatment, and post-treatment, patients completed 4 validated PRO questionnaires (SF-36, CLDQ-HCV, FACIT-F, and WPAI:SHP). The resulting PROs in Asian patients were compared across the treatment regimens. Of 4485 of the trials' participants, 106 patients were of Asian ancestry (55.7% male, 69.8% treatment-naïve, 17.0% cirrhotic). In comparison with other patients, the Asian CH-C cohort was younger, had lower BMI, and lower rates of pre-treatment psychiatric comorbidities (anxiety, depression, sleep disorders) (all P < .05). At baseline, Asian patients also had lower SF-36 physical functioning scores (on average, by -5.6% on a normalized 0-100% PRO scale, P = .001). During treatment, Asian CH-C patients experienced a decline in their PRO scores while receiving IFN and/or RBV-containing regimens (up to -19.6%, P < .001). In contrast, patients receiving LDV/SOF experienced no PRO decrement and improvement of some PRO scores during treatment (+9.0% in general health of SF-36, P = .03). After achieving SVR-12, some of the PRO scores in Asian patients improved regardless of the regimen (up to +9.3%, P < .001). In multivariate analysis of Asian patients, the use of LDV/SOF was independently associated with higher PRO scores during and soon after the end of treatment (betas +15.0% to +29.3%, all P < .05). Other predictors of PRO impairment included depression, type 2 diabetes mellitus, and cirrhosis. The use of IFN- and RBV-free LDV/SOF regimens leads to PRO improvement in Asian patients with CH-C during treatment. Achieving SVR-12 results in improvement of PRO scores.
| S-EPMC4782840 | biostudies-literature
Project description:Background and aims:Treatment of hepatitis C virus (HCV) infection has significantly changed during the last few years. The combination of ledipasvir and sofosbuvir has been shown to treat high proportions of patients with HCV genotype 1 with remarkable tolerability. The aim of the work was to assess the efficacy and safety of sofosbuvir plus ledipasvir in treating treatment-naïve Egyptian patients with genotype 4 HCV infection. Patients and methods:In this open-label randomized study, 200 treatment-naive patients who were HCV antibody positive and HCV RNA positive by polymerase chain reaction, aged >18 years, were enrolled. The patients were classified into two groups: group I included 100 patients who received single therapy with sofosbuvir plus ledipasvir for 12 weeks and group II included 100 patients who received sofosbuvir plus oral weight-based ribavirin for 24 weeks. The primary end point was a sustained virological response at 12 weeks (SVR12) after the end of treatment, determined by quantitative polymerase chain reaction for HCV RNA. Results:Group I patients showed statistically significant (p<0.05) higher SVR12 compared with group II patients (99% vs. 80%). There was no statistical difference (p>0.05%) between the studied groups regarding the frequencies of the side effects (26% vs. 29%). The most common adverse effects were headache, fatigue, myalgia, and cough. Conclusion:Sofosbuvir and ledipasvir treatment for 12 weeks was well tolerated by patients with HCV genotype 4 and resulted in 99% SVR for all patients who received 12 weeks of the study drugs. ClinicalTrials.gov Identifier: NCT02992457.
| S-EPMC5840188 | biostudies-literature
Project description:For children under 12 years of age who have chronic hepatitis C virus (HCV) infection, there are currently no approved treatments with direct-acting antiviral agents. We therefore evaluated the safety and efficacy of ledipasvir-sofosbuvir in HCV-infected children aged 3 to <6 years. In an open-label study, patients 3 to <6 years old chronically infected with HCV genotype 1 (n = 33) or 4 (n = 1) received weight-based doses of combined ledipasvir-sofosbuvir as granules (33.75 mg/150 mg for weights <17 kg or 45 mg/200 mg for weights ?17 kg) for 12 weeks. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12). For the first 14 patients, intensive pharmacokinetic sampling was done on day 10 of treatment. All patients had been infected through perinatal transmission and were treatment naïve. No patients had known cirrhosis. Ten patients (29%) weighed <17 kg. SVR12 was achieved in 97% of patients (33 of 34); the patient who did not achieve SVR12 was 3 years old and discontinued treatment after 5 days because of an adverse event "abnormal drug taste." The most common adverse events were vomiting (24% of patients), cough (21%), and pyrexia (21%). No patients experienced a serious adverse event. Intensive pharmacokinetic analysis of 13 patients for whom data were evaluable confirmed that the doses selected were appropriate. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 3 to <6 years old with chronic HCV infection.
| S-EPMC7028138 | biostudies-literature
Project description: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. 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.
| S-EPMC7491553 | biostudies-literature
Project description:Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon-based treatment than patients of other races. In the phase 3 ION program, the single-tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open-label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment-naïve and treatment-experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment-emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non-black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non-CC, and had a lower serum alanine aminotransferase at baseline than non-black patients. Overall, 95% of black and 97% of non-black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non-black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin-containing arms of the studies. No differences were observed in overall safety by race.A once-daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non-black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events.
| S-EPMC4738375 | biostudies-other
Project description:Postmarketing cases of hepatitis B virus (HBV) reactivation during hepatitis C treatment have been reported. We analyzed serum samples from patients in a clinical trial of ledipasvir-sofosbuvir in Taiwan and Korea. Of the 173 patients enrolled, 103 (60%) had been previously infected with HBV. None showed evidence of HBV reactivation.
| S-EPMC6276897 | biostudies-literature