Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial

Mizokami, Masashi; Yokosuka, Osamu; Takehara, Tetsuo; Sakamoto, Naoya; Korenaga, Masaaki; Mochizuki, Hitoshi; Nakane, Kunio; Enomoto, Hirayuki; Ikeda, Fusao; Yanase, Mikio; Toyoda, Hidenori; Genda, Takuya; Umemura, Takeji; Yatsuhashi, Hiroshi; Ide, Tatsuya; Toda, Nobuo; Nirei, Kazushige; Ueno, Yoshiyuki; Nishigaki, Yoichi; Betular, Juan; Gao, Bing; Ishizaki, Akinobu; Omote, Masa; Mo, Hongmei; Garrison, K.D.; Pang, Phillip S.; Knox, Steven J.; Symonds, William T.; McHutchison, John G.; Izumi, Namiki; Omata, Masao

doi:10.1016/s1473-3099(15)70099-x

Cited by 344 publications

(393 citation statements)

References 11 publications

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“…However, this combination therapy takes 24 weeks to complete, which is twice as long as standard DAA combination therapy for patients with HCV/1b (SOF/LDV or OBV/PTV/r). In addition, combination therapy of DCV/ ASV causes liver dysfunction, headache, and pyrexia (Kumada et al 2014) at rates more frequent than combination therapy of SOF/LDV (Mizokami et al 2015) or OBV/ PTV/r . Furthermore, combination therapy of DCV/ASV was not normally used for patients with RAVs associated with resistance to NS5A inhibitors, such as Y93 or L31 mutations; combination therapy of SOF/LDV or OBV/PTV/r was found to be more efficient for these patients than DCV/ASV.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy with Ombitasvir/Paritaprevir/Ritonavir for Dialysis Patients Infected with Hepatitis C Virus: A Prospective Multi-Institutional Study

Sato

Hosonuma

Yamazaki

et al. 2017

Tohoku J. Exp. Med.

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Hepatitis C virus (HCV) infection is common in dialysis patients worldwide and nosocomial HCV spread within dialysis facilities continues to develop. Combination therapy with daclatasvir and asunaprevir (DCV/ ASV) that has proven efficacy for dialysis patients infected with genotype 1b HCV (HCV/1b) has several concerns in Japan. The recently available combination therapy with ombitasvir, paritaprevir, and ritonavir (OBV/PTV/r) is not contraindicated in patients with chronic renal failure and has more safety profile and shorter treatment period than that with DCV/ASV. We evaluated the effects of combination therapy with OBV/PTV/r in four dialysis patients infected with HCV/1b, who were eligible for our study. On-treatment assessments included standard laboratory testing, serum HCV RNA and symptom-directed physical examinations. Three patients had a sustained virological response at 12 weeks after treatment, but one remaining patient had viral breakthrough. Notably, the patient with viral breakthrough had been coinfected with HCV/1b and HCV/2b; namely, HCV/2b with resistance-associated variations was not eradicated by the combination therapy. Among the three patients responsive to the combination therapy, one patient complained of appetite loss and itching, while in another patient the therapy was discontinued due to itching, exacerbation of wamble, and a falling tendency probably due to interaction with valsartan. These AEs were ameliorated or disappeared after the completion of the therapy. The significance of our study is persuasive virological evaluation associated to the combination therapy and reasonable interpretation of AEs. In conclusion, combination therapy with OBV/PTV/r may have promise as an efficacious therapy, but caution regarding AEs should be practiced.

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Section: Discussionmentioning

confidence: 99%

Combination Therapy with Ombitasvir/Paritaprevir/Ritonavir for Dialysis Patients Infected with Hepatitis C Virus: A Prospective Multi-Institutional Study

Sato

Hosonuma

Yamazaki

et al. 2017

Tohoku J. Exp. Med.

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“…Additionally, as the treatment for chronic HCV infection has changed dramatically in recent years, the historical trends in treatment tolerability and threshold of withdrawal from treatment are also important. [2][3][4] Future studies with a larger sample size are needed to provide this information.…”

Section: Discussionmentioning

confidence: 99%

“…1) In recent years, the development of direct-acting antiviral agents has resulted in an improvement in the sustained virologic response rate, a common treatment outcome based on viral RNA levels, to more than 90% in phase II and III trials. [2][3][4] While this approach is very useful for the treatment of HCV infection, it is extremely expensive at present. 5) Therefore, the well-established approach of combining pegylated interferon (PEG-IFN) and ribavirin to treat chronic HCV infection is still used in particular situations.…”

mentioning

confidence: 99%

Comparison of the Safety Profiles of Pegylated Interferon α-2a and α-2b Administered in Combination with Ribavirin for Chronic Hepatitis C Infection: A Real-World Retrospective Cohort Study

Ide

Sato

Imai

et al. 2016

Biological & Pharmaceutical Bulletin

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This study compares the safety profiles of pegylated interferon (PEG-IFN) α-2a and α-2b administered in combination with ribavirin, based on the variable of time to withdrawal from treatment due to adverse events. We conducted a real-world retrospective cohort study using the Japanese interferon database. Based on eligibility criteria, individuals with chronic hepatitis C virus (HCV) infection were identified in the database covering the period December 2009 to August 2015. The primary outcome measure was defined as difference in time to withdrawal from treatment due to adverse events between patients receiving PEG-IFN α-2a combined with ribavirin and those receiving PEG-IFN α-2b combined with ribavirin. The difference was analyzed using the multivariate Cox proportional hazards regression model. A frailty model was also applied to consider regional (prefectural) variation. After eligibility evaluation, 11058 individuals were included in the analysis. 3774 were treated with PEG-IFN α-2a, and 6764 with PEG-IFN α-2b, with 11.84 and 12.30% respectively withdrawing from treatment due to adverse events. The Cox model showed no significant difference between the two groups (hazard ratio (HR), 95%CI; 0.918, 0.817 to 1.031; p 0.1475). The results were consistent even when regional variation and other confounding variables were adjusted in the frailty model. In conclusion, there may be no difference in time to withdrawal from treatment due to adverse events between PEG-IFN α-2a and PEG-IFN α-2b combined with ribavirin. Applying the method used here to future studies using novel treatment regimens may also provide important information for the treatment of chronic HCV infection in clinical practice.

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“…*Cause of death was related to cardiac arrest from gastrointestinal infection. (35) RBV use increased the number of AEs reported, treatment-related AEs, and AEs leading to study drug modification/interruption for subjects 65 years of age (Table 3). The addition of RBV increased the number of elderly subjects who experienced at least one AE from 75% to 85%.…”

Section: Safetymentioning

confidence: 99%

Safety and efficacy of ledipasvir/sofosbuvir for the treatment of genotype 1 hepatitis C in subjects aged 65 years or older

et al. 2016

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Elderly subjects have been historically underrepresented in clinical trials involving antiviral hepatitis C therapies. The aim of this analysis was to retrospectively evaluate the safety and efficacy of ledipasvir/sofosbuvir (LDV/SOF) by age groups of <65 years versus 65 years among subjects enrolled in phase 3 trials. Four open-label phase 3 clinical trials evaluated the safety and efficacy of LDV/SOF with or without ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C virus. Sustained virological response at 12 weeks, treatment-emergent adverse events (AEs), and graded laboratory abnormalities were analyzed according to age group. Of the 2293 subjects enrolled in four phase 3 trials, 264 (12%) were 65 years of age, of whom 24 were aged 75 years. Sustained virological response at 12 weeks was achieved by 97% (1965/ 2029) of subjects aged <65 years and 98% (258/264) of subjects aged 65 years. The most common AEs in both LDV/ SOF groups that occurred in 10% of subjects were headache and fatigue. The rate of study discontinuation due to AEs was similar in the two age cohorts. The use of RBV in 1042 (45%) subjects increased the number of AEs, treatmentrelated AEs, and AEs leading to study drug modification/interruption, particularly among elderly subjects. Conclusions: LDV/SOF with or without RBV was highly effective for treatment of genotype 1 chronic hepatitis C virusin subjects aged 65 and older. Addition of RBV did not increase sustained virological response at 12 weeks rates but led to higher rates of AEs, especially in elderly subjects. (HEPATOLOGY 2016;63:1112-1119 C hronic hepatitis C viral (HCV) infection is an important cause of morbidity and mortality in infected individuals worldwide.(1) The World Health Organization estimates that the worldwide prevalence of HCV infection is 2.2%, representing 123 million people.(2) Globally, HCV accounts for 27% of liver cirrhosis and 25% of hepatocellular carcinoma cases.(3) Although the rate of HCV is decreasing overall due to attrition from mortality, (4,5) the rate of HCV-related cirrhosis is anticipated to increase by Abbreviations: AE, adverse event; CI, confidence interval; eGFR, estimated glomerular filtration rate; HCV, hepatitis C virus; LDV/SOF, ledipasvir/sofosbuvir; RAV, resistance-associated variant; RBV, ribavirin; SVR12, sustained virological response at 12 weeks

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Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial

Cited by 344 publications

References 11 publications

Combination Therapy with Ombitasvir/Paritaprevir/Ritonavir for Dialysis Patients Infected with Hepatitis C Virus: A Prospective Multi-Institutional Study

Combination Therapy with Ombitasvir/Paritaprevir/Ritonavir for Dialysis Patients Infected with Hepatitis C Virus: A Prospective Multi-Institutional Study

Comparison of the Safety Profiles of Pegylated Interferon α-2a and α-2b Administered in Combination with Ribavirin for Chronic Hepatitis C Infection: A Real-World Retrospective Cohort Study

Safety and efficacy of ledipasvir/sofosbuvir for the treatment of genotype 1 hepatitis C in subjects aged 65 years or older

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