ledipasvir and Liver-Cirrhosis

The addition of ribavirin (RBV) to the combination treatment of Ledipasvir (LDV) and Sofosbuvir (SOF) remains controversial in the treatment of hepatitis C virus (HCV) infection. We performed a meta-analysis to assess the efficacy and safety of the LDV-SOF with and without RBV in treating HCV genotype 1 patients.. The electronical databases of PubMed Medline, EMBASE database, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov website with registered trials were searched. Eligible studies were randomized controlled trials (RCTs) and prospective cohort studies that assessed the efficacy and safety of LDV-SOF with or without RBV in patients with HCV genotype 1 (GT 1). Two reviewers independently screened studies, extracted data and assessed methodology quality. Review Manager 5.3 software was used to analyze the data.. Seven studies involving 2,626 patients with HCV GT 1 - some of whom had cirrhosis - were included in this meta-analysis. The addition of RBV to LDV- SOF regimen neither significantly improved sustained viral response at 12 weeks (SVR12) after the last dose of treatment (RR=1.00, 95%CI 0.99-1.01, p=0.99) nor decreased virologic breakthrough (RR=1.01, 95%CI 0.14-7.19, p=0.99) and relapse (RR=1.36, 95% CI 0.81-2.29, p=0.24). There was no significant difference in the incidence of discontinuation (RR=0.61, 95%CI 0.25-1.53, p=0.30) between LDV- SOF therapy and LDV- SOF plus RBV. LDV- SOF plus RBV therapy had significantly higher rate of the overall adverse events (RR=0.88, 95%CI=0.84- 0.92, p<0.00001). LDV - SOF therapy had higher incidence of serious adverse events (RR=1.60, 95%CI=1.00-2.56, p=0.05) than LDV-SOF plus RBV.. This meta-analysis suggests that LDV-SOF based therapy is a safe and effective treatment for patients with GT 1 HCV. The addition of RBV to LDV-SOF may increase toxicity without achieving improved efficacy. However, due to the relatively small sample sizes and moderate risk of bias of included studies, large-scale and high-quality clinical research is still needed to confirm the results.

Topics: Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Prospective Studies; Ribavirin; Sofosbuvir; Treatment Outcome

With the arrival of all-oral directly acting antiviral (DAA) therapy with high cure rates, the promise of hepatitis C virus (HCV) eradication is within closer reach. The availability of generic DAAs has improved access to countries with constrained resources. However, therapy is only one component of the HCV care continuum, which is the framework for HCV management from identifying patients to cure. The large number of undiagnosed HCV cases is the biggest concern, and strategies to address this are needed, as risk factor screening is suboptimal, detecting <20% of known cases. Improvements in HCV confirmation through either reflex HCV RNA screening or ideally a sensitive point of care test are needed. HCV notification (e.g., Australia) may improve diagnosis (proportion of HCV diagnosed is 75%) and may lead to benefits by increasing linkage to care, therapy and cure. Evaluations for cirrhosis using non-invasive markers are best done with a biological panel, but they are only moderately accurate. In resource-constrained settings, only generic HCV medications are available, and a combination of sofosbuvir, ribavirin, ledipasvir or daclatasvir provides sufficient efficacy for all genotypes, but this is likely to be replaced with pangenetypic regimens such as sofosbuvir/velpatasvir and glecaprevir/pibrentaasvir. In conclusion, HCV management in resource-constrained settings is challenging on multiple fronts because of the lack of infrastructure, facilities, trained manpower and equipment. However, it is still possible to make a significant impact towards HCV eradication through a concerted effort by individuals and national organisations with domain expertise in this area.

Topics: Aminoisobutyric Acids; Antiviral Agents; Australia; Benzimidazoles; Carbamates; Continuity of Patient Care; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Drugs, Generic; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Proline; Pyrrolidines; Quinoxalines; Ribavirin; Risk Factors; Sofosbuvir; Sulfonamides; Valine

This review summarizes published data on sofosbuvir-based regimens for patients infected with HCV GT1 with a focus on evaluating the optimal and possible durations of treatment.. PubMed and conference abstract books published between 2011-2015 were searched.. HCV treatment has decreased from 24 week regimens to studies done as short as 4 weeks. History of prior treatment or cirrhosis have consistently shown lower SVR12 rates with shorter duration therapies. Low cure rates have been seen in patients within 4 week trials, however, select patients with low fibrosis scores, low HCV VL and HCV GT-1b have moderate cure rates.. Most patients will require 12-24 weeks of therapy. Further studies are needed to elucidate the predictors of treatment response to short duration therapies and optimal combination of DAAs.

Topics: Antiviral Agents; Benzimidazoles; Disease Management; Drug Administration Schedule; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Ribavirin; RNA, Viral; Sofosbuvir; Time Factors; Treatment Outcome; Viral Load

Hepatitis C virus (HCV)-related cirrhosis is the leading cause for liver transplantation (LT) in developed countries. One of the most troubling complications following LT in patients with HCV is that of recurrence. Unfortunately, this occurs in nearly all patients with HCV. Patients suffering recurrence are known to have faster times to fibrosis and consequently higher rates of graft failure. In general, patients whom undergo transplantation for HCV cirrhosis have higher mortalities comparatively. It is for this reason that HCV in post-transplant patients must be strictly monitored for and treated. Until recently, treatment with standard therapy or pegylated interferon and ribavirin was only marginally effective and the use in this population was off-label. With the advent of direct acting antivirals (DAA), hopes for improved sustained virologic response (SVR) exists. This review will attempt to provide an update regarding recent data for HCV treatment in post-transplant patients, and by doing so, hopefully shed light on a previously dim and dreaded illness.

Topics: Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Fluorenes; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Transplantation; Oligopeptides; Polyethylene Glycols; Proline; Pyrrolidines; Recombinant Proteins; Recurrence; Ribavirin; Risk Factors; Simeprevir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uridine Monophosphate; Valine; Viral Load

To review the pharmacology, efficacy, and safety of ledipasvir-sofosbuvir for the treatment of chronic hepatitis C virus (HCV).. A literature search through clinicaltrials.gov, EMBASE, and PubMed was conducted (January 1966 to October 2014) using the terms ledipasvir, sofosbuvir, GS-5885, and GS-7977. References from retrieved articles and abstracts presented at recent meetings were reviewed for any additional material. The prescribing information was also reviewed.. Phase 1, 2, and 3 human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of ledipasvir and sofosbuvir for HCV were identified.. Ledipasvir-sofosbuvir, a fixed-dose combination (FDC) tablet inhibiting nonstructural (NS) 5A and 5B proteins, without peginterferon and ribavirin is indicated for adult patients with genotype 1 HCV infection who are treatment naïve or experienced, with or without cirrhosis. Pivotal trials (n = 1952) have demonstrated that once-daily administration of ledipasvir-sofosbuvir for 12 or 24 weeks is effective at achieving sustained virological response (SVR) rates (94%-99%) in treatment-naïve patients (12 weeks), treatment-experienced patients without cirrhosis (12 weeks), and treatment-experienced patients with cirrhosis (24 weeks). Treatment-naïve patients without cirrhosis and baseline viral levels of less than 6 million IU/mL may be considered for 8 weeks of treatment. The most common adverse drug events (ADEs) associated with ledipasvir-sofosbuvir include headache, fatigue, insomnia, nausea, and diarrhea.. Ledipasvir-sofosbuvir is the first interferon- and ribavirin-free FDC agent that has SVR rates much greater than 94%, with minimal ADEs, for the treatment of chronic HCV genotype 1 in naïve and treatment-experienced patients.

Topics: Adult; Animals; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Fluorenes; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Liver Cirrhosis; Nausea; Ribavirin; Sofosbuvir; Uridine Monophosphate

The recent October 2014 approval of the fixed dose combination (FDC) of the NS5B polymerase inhibitor sofosbuvir (SOF) and the NS5A inhibitor ledipasvir (LDV) for the treatment of treatment-naive and -experienced HCV genotype 1a/1b (HCV-1) has marked a new era of IFN and ribavirin free treatment for chronic hepatitis C. SOF/LDV combination is approved for 12 weeks in treatment-naive patients with and without cirrhosis. For treatment-experienced patients, it is approved for 12 weeks in patients without cirrhosis but for 24 weeks in patients with cirrhosis. A shorter 8-week course of treatment can be considered for treatment-naive patients who have pretreatment HCV RNA of < 6 million IU/ml and do not have cirrhosis.. The purpose of this synopsis is to review the pharmacotherapy and results of pivotal clinical trials for SOF/LDV as the current standard-of-care for HCV-1 patients. We also briefly discuss emerging data with SOF/LDV for certain special populations. Preliminary data is also emerging for HCV genotypes non-1, but their discussion is beyond the scope of this synopsis. The review was done based on data from Phase I, II and III published studies as well as data presented at major national and international meetings.. The FDC of LDV (90 mg) and SOF (400 mg) has a sustained virologic response of approximately 96% when given as a once-a-day pill for 3 months to both treatment-naive and -experienced HCV-1 patients with the exception of prior null responders with cirrhosis. The latter group of patients also achieves high sustained virologic response of 95% but with therapy for 24 weeks. In addition, emerging data suggest that this FDC regimen may be effective in the treatment of HCV-1 co-infected patients with HIV, HCV-1 and -4, patients with cirrhosis and hepatic decompensation and those with post-liver transplant HCV recurrence.

Topics: Antiviral Agents; Benzimidazoles; Clinical Trials as Topic; Drug Combinations; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Meta-Analysis as Topic; Recurrence; Sofosbuvir; Uridine Monophosphate; Viral Nonstructural Proteins

Topics: 2-Naphthylamine; Administration, Oral; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Combinations; Fluorenes; Genotype; Germany; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Liver Cirrhosis; Proline; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine

The prevalence of anti-hepatitis C virus antibody in Punjab, India is 3.6%, with 728,000 people estimated to have viremic chronic hepatitis C (CHC). The Mukh-Mantri Punjab Hepatitis C Relief Fund, launched on 18th June 2016, provides no-cost generic direct-acting antivirals (DAAs) with sofosbuvir + ledipasvir ± ribavirin or sofosbuvir + daclatasvir ± ribavirin with the goal of eliminating CHC from Punjab. We assessed the safety and efficacy of decentralized treatment of CHC in a public health care setting.. Primary care providers from 3 university and 22 district hospitals were trained to provide algorithm-based DAA treatment and supervised by telehealth clinics conducted fortnightly. The diagnosis of cirrhosis was based on clinical and radiological evidence, including aspartate aminotransferase-to-platelet ratio index (APRI ≥2.0) and FIB-4 score (>3.25), or on liver stiffness measurement ≥12.5 kPa on Fibroscan®.. We enrolled 48,088 individuals with CHC (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhosis; 69.9% genotype [GT] 3) between 18th June 2016 to 31st July 2018. While 36,250 (75.4%) patients completed treatment, 5,497 (11.4%) had treatment interruptions and 6,341 (13.2%) patients are currently ongoing treatment. Sustained virological response at 12 weeks after treatment completion (SVR12) was achieved in 91.6% of patients per protocol, 67.6% in intention-to-treat (ITT) analysis, where all interruptions were treated as failures, and 91.2% in a modified ITT analysis where all patients with successful SVR12 in the interruptions arm were included as cured. SVR12 rates in patients with and without cirrhosis and GT3 versus non-GT3 were comparable. The SVR12 rate was 84.4% in patients who had treatment interruptions.. Decentralized care of patients with CHC using generic all-oral DAA regimens is safe and effective regardless of genotype or presence of cirrhosis. ClinicalTrials.gov number: NCT01110447.. We assessed the safety and efficacy of public health care using no-cost all-oral generic direct-acting antiviral drugs against hepatitis C in the state of Punjab, India. The goal is elimination of chronic hepatitis C (CHC) by 2030 and involves primary care providers at 25 sites in the state. We enrolled 48,088 individuals (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhotic; 69.9% genotype 3) between 18th June 2016 to 31st July 2018. Cure was achieved in 91.6% of patients, demonstrating that decentralized care of CHC with generic all-oral regimens is safe and effective.

Topics: Adult; Antiviral Agents; Benzimidazoles; Clinical Protocols; Delivery of Health Care; Disease Eradication; Drug Therapy, Combination; Female; Fluorenes; Hepatitis C, Chronic; Humans; India; Liver Cirrhosis; Male; Public Health; Ribavirin; Sofosbuvir; Sustained Virologic Response; Telemedicine

Almost 30 years ago, about 30% of Japanese hemophiliacs became infected with HIV-1 and hepatitis C virus (HCV) after receiving contaminated blood products. While several studies have reported the high efficacy and safety of direct acting antivirals (DAA) in HIV-1 co-infected patients, such data are limited in hemophiliacs.. We conducted a single-center, open-label study involving 27 Japanese patients (median age; 45 years) with inherited bleeding disorders who were co-infected with HCV/HIV-1. Patients with HCV genotype 1 (GT1) and GT4 received ledipasvir (90 mg) plus sofosbuvir (400 mg), those with HCV GT2 received sofosbuvir plus weight-based ribavirin, and those with HCV GT3 received daclatasvir (60 mg) plus sofosbuvir. Treatment was continued for 12 weeks in all patients. The primary endpoints were rate of sustained virologic response at 12 weeks after end of therapy (SVR12) and occurrence of adverse events during DAA therapy.. Eighteen (67%) patients had had received interferon-based therapy, and 11 (41%) had compensated cirrhosis. HCV genotypes were GT1a 4 (15%), GT1b 16 (59%), GT1 undetermined 2 (7%), GT2a 1 (4%), GT3a 3 (11%) and GT4a 1 (4%). All patients were on combination antiretroviral therapy (cART) and had undetectable HIV-1 viral load (<20 copies/μL) at baseline. All patients achieved SVR12. Serious adverse events were observed in 3 patients: arteritis of the leg, which resolved after completion of DAA therapy, asymptomatic QT prolongation and gastrointestinal hemorrhage. cART failure was noted in one patient due to emergence of raltegravir resistance during ledipasvir/sofosbuvir treatment. Although α-fetoprotein, Mac-2 binding protein glycosylation isomer (M2BPGi), and Fibro Scan (FS) scores decreased in most patients during DAA therapy, M2BPGi (>2.0 cutoff index) and FS scores (>15.0 kPa) were still high in 6 patients at week 36.. DAA therapy is effective in all patients. However, adverse events and efficacy of cART should be monitored closely.

Topics: Adult; Antiviral Agents; Benzimidazoles; Carbamates; Coinfection; Drug Therapy, Combination; Female; Fluorenes; Hemophilia A; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Imidazoles; Interferons; Liver Cirrhosis; Male; Middle Aged; Pyrrolidines; RNA, Viral; Sofosbuvir; Valine; Viral Load

Interferon- and ribavirin (RBV)-free regimens can improve patient-reported outcomes (PROs) during treatment.. To compare PROs during treatment with ledipasvir and sofosbuvir (LDV/SOF) to placebo and to LDV/SOF + RBV.. Treatment-experienced CH-C genotype 1 patients with compensated cirrhosis (N = 154) were randomized to receive 24 weeks of LDV/SOF or 12 weeks of placebo followed by 12 weeks of LDV/SOF + RBV (the SIRIUS clinical trial). While blinded to their HCV RNA level and study treatment, patients completed PRO questionnaires (SF-36, FACIT-F, CLDQ-HCV, WPAI:SHP) at baseline, during and post-treatment.. Baseline PRO scores were similar between the two study arms. Patients receiving LDV/SOF showed improvement in a number of PROs (predominantly related to mental health) starting as early as 4 weeks after treatment initiation; no PRO decrement from baseline were noted, and no PRO scores were inferior to placebo (all P > 0.05). In the second 12 weeks, patients who were receiving LDV/SOF continued to improve PROs (up to +9.2% from a 100% maximum possible score, P < 0.05), while patients receiving LDV/SOF + RBV had less gains or no improvement in their PRO scores. However, regardless of the regimen, patients who successfully cleared the virus (N = 149) had significant improvement in all aspects of PROs (up to +12.2% by post-treatment week 12, up to +16.9% by week 24).. Treatment-experienced cirrhotic patients experience a notable improvement of their PROs during treatment with LDV/SOF. Furthermore, achieving SVR-12 is associated with significant PRO improvement, which further improves at post-treatment week 24 in this difficult to treat group of patients with chronic hepatitis C.

Topics: Aged; Antiviral Agents; Benzimidazoles; Drug Monitoring; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Patient Outcome Assessment; Ribavirin; RNA, Viral; Sofosbuvir

Treatment of genotype 1 hepatitis C virus (HCV) infection with combination directly acting antivirals (DAA) for 8-24 weeks is associated with high rates of sustained virologic response (SVR). We previously demonstrated that adding a third DAA to ledipasvir and sofosbuvir (LDV/SOF) can result in high SVR rates in patients without cirrhosis. In this study, we investigated whether a similar regimen would yield equivalent rates of cure in patients with advanced liver fibrosis.. Fifty patients were enrolled at the Clinical Research Center of the National Institutes of Health and associated healthcare centers. Enrollment and follow-up data from April 2014 to June 2015 are reported here. Eligible participants were aged ≥18 years, had chronic HCV genotype 1 infection (serum HCV RNA ≥2000 IU/mL), and stage 3-4 liver fibrosis. HCV RNA was measured using a reverse-transcription polymerase chain reaction assay.. Of patients treated with LDV, SOF, and the NS3/4A protease inhibitor GS-9451 for 6 weeks, 76% (38 of 50; 95% confidence interval, 60%-85%) had SVR achieved 12 weeks after the end of treatment. There was no statistically significant difference in treatment efficacy between treatment-naive patients (72%, 18 of 25) and those with treatment experience (80%; 20 of 25) (P = .51). Overall, 11 patients (22%) experienced virologic relapse, and 1 (2%) was lost to follow-up at 4 weeks after treatment. No serious adverse events, discontinuations, or deaths were associated with this regimen.. Adding a third DAA to LDV/SOF may result in a moderate SVR rate, lower than that observed in patients without cirrhosis. Significant liver fibrosis remains an impediment to achieving SVR with short-duration DAA therapy.. CT01805882.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Cohort Studies; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Quinolines; Sofosbuvir; Treatment Outcome; Young Adult

Data about the response of hepatitis C virus (HCV) genotype 5 to approved and experimental treatment regimens are scarce. We assessed the efficacy and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HCV genotype 5.. We did this open-label, multicentre, single-arm, phase 2 trial at five hospitals in France. Eligible patients were at least 18 years old and had chronic infection with HCV genotype 5, with plasma HCV RNA of at least 10,000 IU/mL. We used BLAST analyses of NS5B partial sequences to establish the genotype and subtype at screening. Patients were given a fixed-dose combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir orally once per day for 12 weeks. The primary endpoint was the proportion of patients with a sustained viral response, defined as HCV RNA concentration less than 15 IU/mL at 12 weeks after the end of treatment (SVR12). We analysed efficacy and safety in all patients who received at least one dose of ledipasvir-sofosbuvir. This trial is registered with EudraCT, number 2013-003978-27, and with ClinicalTrials.gov, number NCT02081079.. From March 7 to June 10, 2014, we recruited 41 patients, including 21 who were treatment naive and 20 who were treatment experienced. All patients were of white ethnic origins. All 41 patients who started treatment completed the full 12 weeks of treatment and had undetectable HCV RNA at their final treatment visit. In the overall study population, 39 (95%, 95% CI 83-99) of 41 patients achieved SVR12. SVR12 was achieved by 20 (95%, 76-100) of the 21 patients who were treatment naive and 19 (95%, 75-100) of the 20 patients who were treatment experienced. Eight (89%) of nine patients with cirrhosis achieved SVR12, whereas 31 (97%) of the 32 patients without cirrhosis achieved SVR12. The two patients who did not reach SVR12 both had IL28B TT genotype and had viral relapse within 4 weeks of the end of treatment. The most common adverse events were asthenia (16 [39%] patients), headache (11 [27%] patients), and fatigue (four [10%] patients). One patient had a serious adverse event, worsening depression, which we judged to be unrelated to study treatment.. The oral regimen of ledipasvir-sofosbuvir is an effective and well-tolerated treatment for patients with HCV genotype 5 infection who are treatment naive or treatment experienced.. Gilead Sciences.

Topics: Administration, Oral; Aged; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; France; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; RNA, Viral; Sofosbuvir; Treatment Outcome; Viral Load

Ledipasvir/sofosbuvir ± ribavirin administered for 12 weeks to patients with genotype-1 HCV infection and compensated cirrhosis is effective and well-tolerated. The Phase II TRILOGY-1 and TRILOGY-2 studies investigated whether ledipasvir/sofosbuvir plus the non-nucleotide NS5B inhibitor GS-9669 or the NS3/4A protease inhibitor vedroprevir could reduce treatment duration and/or eliminate the need for ribavirin in genotype-1 HCV-infected patients with compensated cirrhosis.. In TRILOGY-1, 100 cirrhotic patients were randomized (1:1:1) to 8 weeks of ledipasvir/sofosbuvir plus ribavirin, ledipasvir/sofosbuvir plus GS-9669 250 mg or ledipasvir/sofosbuvir plus GS-9669 500 mg. In TRILOGY-2, 46 previously treated cirrhotic patients were randomized (1:1) to 8 weeks of ledipasvir/sofosbuvir plus vedroprevir ± ribavirin. The primary end points were the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12) and safety.. In both studies, most patients were male (each 65%) and white (92-96%), infected with HCV genotype-1a (62-70%) and had IL28B non-CC genotypes (82-87%). In total, 37-39% of patients were Hispanic or Latino. SVR12 rates were similar across treatment arms in TRILOGY-1 (82-91%) and TRILOGY-2 (88-95%); no patient had on-treatment virological failure. Two serious adverse events (acute myocardial infarction and cardiomyopathy) were reported in two patients participating in TRILOGY-1, both of whom had pre-existing cardiac conditions. Laboratory abnormalities were infrequent.. All ledipasvir/sofosbuvir-based regimens were well-tolerated. To shorten therapy and eliminate ribavirin, use of a more potent third agent or a third agent with a different mechanism of action may be required.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Sofosbuvir

The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR.. Patients enrolled in TACR from 2017-2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12).. 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P < 0.001) was the most important factor associated with treatment failure. Incidence of adverse events was 15.8%, with fatigue being the most common.. LDV/SOF is effective and well tolerated in routine clinical practice in Taiwan. Cure rates were high across patient populations.

Topics: Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Registries; Ribavirin; Sofosbuvir; Taiwan; Uridine Monophosphate

: Background: There are limited data available on the influence of direct-acting antivirals used to treat chronic hepatitis C (CHC) on growth in children. In this study, we aimed to analyze the growth parameters in children treated with ledipasvir/sofosbuvir (LDV/SOF). Methods: We included 38 patients (16 girls and 22 boys) aged 10−17 years treated with LDV/SOF for CHC (33 infected with genotype 1 and 5 with genotype 4; 36 were treated for 12 weeks, and 2 for 24 weeks according to the current guidelines). Patient weight and height were measured at baseline, after 4 weeks of treatment, at the end of the treatment (EOT), and 12 weeks and one year after the EOT. Body mass index (BMI), BMI z and height-for-age (HA) z scores were calculated according to the WHO Child Growth Standards and Growth reference data using the WHO anthropometric calculator AnthroPlus v. 1.0.4. In addition, correlations between BMI z scores and liver fibrosis (liver stiffness measurement, LSM), the aspartate transaminase (AST)-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4) and liver steatosis (controlled attenuation parameter, CAP) were analyzed. Results: At baseline, 5/38 (13%) patients were obese (BMI z score >2 SD), 4/38 (11%) were overweight, and 29 (76%) were normal. A significant increase was observed in mean weight, height and BMI both 12 weeks and one year after the treatment compared to the baseline, whereas no differences were observed for BMI z scores and HA z scores. Baseline BMI z scores correlated with alanine aminotransferase levels (r = 0.33, 95% CI 0.01−0.58, p = 0.04), LSM (r = 0.40, 95% CI 0.09−0.65, p = 0.01), the APRI (r = 0.33, 95% CI 0.02−0.59, p = 0.03), and the CAP (r = 0.40, 95% CI 0.08−0.64, p = 0.01). No similar correlations were reported at 12 weeks posttreatment. Conclusions: Treatment with LDV/SOF in children with CHC (genotypes 1 and 4) did not negatively influence the patients’ growth. However, higher baseline BMI z scores correlated with more advanced liver fibrosis and steatosis in children with CHC.

Topics: Adolescent; Antiviral Agents; Benzimidazoles; Child; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Sofosbuvir; Treatment Outcome

To evaluate the efficacy and safety of ledipasvir/sofosbuvir (LDV/SOF) therapy in hepatitis C virus (HCV)-infected Korean patients in a real clinical setting.. A total of 273 patients who received LDV/SOF therapy between May 2016 and February 2021 were consecutively enrolled and analyzed. A per-protocol analysis was performed to evaluate the virologic response.. Seventy-five percent were infected with genotype 1, and 25% were infected with genotype 2. A hundred eightyone (66.3%) patients had chronic hepatitis, 74 (27.1%) had compensated cirrhosis, eight (2.9%) had decompensated cirrhosis, and 10 (3.7%) had undergone liver transplantation. Undetectable HCV RNA at week 4 was achieved in 90.2% (231/256) of patients, 99.2% (250/252) achieved the end of treatment response, and 98.1% (202/206) achieved sustained virologic response at 12 weeks post-treatment (SVR12). According to liver function, the SVR12 rates were 99.3% (135/136) in chronic hepatitis, 96.4% (53/55) in compensated cirrhosis, and 100% (6/6) in decompensated cirrhosis. The SVR12 rates according to the genotype were 98.2% (167/170) for genotype 1 and 97.2% (35/36) for genotype 2. An 8-week LDV/SOF treatment in treatment-naïve chronic hepatitis patients with HCV RNA < 6,000,000 IU/mL at baseline resulted in 100% (23/23) SVR12 rates. Overall, LDV/SOF was tolerated well, with a 0.7% (2/273) discontinuation rate due to adverse events that were unrelated to LDV/SOF.. LDV/SOF is effective and safe for treating HCV-infected Korean patients with high SVR12 rates.

Topics: Antiviral Agents; Cohort Studies; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Republic of Korea; RNA; Sofosbuvir; Treatment Outcome

Hepatitis C virus (HCV)-related decompensated cirrhosis is a severe life-threatening illness. The safety of direct-acting antivirals (DAAs) has opened a gate of hope for that subgroup of patients who were previously contraindicated for interferon therapy.. We aimed at the investigation of the safety and efficacy of different DAAs regimens in the treatment of HCV-related decompensated cirrhosis patients, to determine sustained virological response (SVR)12 rates and to analyze the factors associated with response.. A retrospective, single-center study including HCV-related decompensated cirrhosis patients who received DAAs. Demographic, laboratory and clinical data were analyzed. The SVR12 rate was the primary outcome measure. Secondary outcomes included the predictors of response, changes in the baseline model for end-stage liver disease and child-turcotte-pugh (CTP) scores, and fibroindices (APRI and fibrosis-4 index) at 12 weeks after treatment.. In total, 145 eligible patients (141 with CTP class B and 4 with class C) were enrolled in this study. SVR12 was achieved by 88.06% (118/134) of efficacy population on different DAAs regimens, Treatment was discontinued in 11 patients because of severe side effects without any deaths. Younger age showed a significant positive association with SVR12.. DAAs can be used for the treatment of HCV-related decompensated liver disease, with acceptable SVR12 rates and safety profiles.

Topics: Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; End Stage Liver Disease; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Pyrrolidines; Retrospective Studies; Severity of Illness Index; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Valine

To assess the degree of liver stiffness using transient elastography in Egyptian children infected with hepatitis C virus (HCV) at baseline and 1 year after achievement of sustained virologic response (SVR) with direct acting antivirals.. This prospective study included children infected with HCV who received treatment with sofosbuvir/ledipasvir and achieved SVR. At baseline and 1 year after achievement of SVR, the extent of hepatic fibrosis was assessed by transient elastography using FibroScan to measure liver stiffness, in addition to noninvasive markers including aspartate aminotransferase/platelet ratio index (APRI) and fibrosis-4 (FIB-4) index.. The study included 23 cases that had variable degrees of fibrosis at baseline; their ages ranged between 10 and 18 years. At baseline, 13 patients had F1; 3 patients had F1-F2; 1 patient had F2; 3 patients had F3; 2 had F3-F4; and 2 patients with F4. One year after achievement of SVR, there was a statistically significant improvement in liver stiffness, APRI, and FIB-4 index (P = .03, <.001, .02, respectively). In 13 patients (56.5%), the liver stiffness improved; in 7 patients, it was stationary; and the remaining 3 patients showed mild increase in liver stiffness that was, however, associated with improvement in APRI and FIB-4 index. Comorbid conditions and previous treatment with interferon were not associated with increased liver stiffness 1 year after SVR.. Egyptian children infected with HCV genotype 4 achieved significant regression in liver stiffness after treatment with direct acting antivirals.

Topics: Adolescent; Antiviral Agents; Aspartate Aminotransferases; Benzimidazoles; Child; Elasticity Imaging Techniques; Female; Fluorenes; Genotype; Hepatitis C; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Prospective Studies; Sofosbuvir

Hepatitis C virus (HCV) can be eliminated by direct-acting antivirals in patients with decompensated liver cirrhosis. Although viral clearance in decompensated liver cirrhosis leads to improvement of the liver function and quality of life, changes in the skeletal muscle mass after sustained virologic response (SVR) in patients with decompensated liver cirrhosis have not been reported. We present the first report of skeletal muscle mass improvement with the achievement of SVR for HCV in a 76-year-old woman with decompensated liver cirrhosis. After achieving SVR through ledipasvir/sofosbuvir treatment, the patient showed an improvement in her liver function and an increase in her skeletal muscle mass.

Topics: Aged; Antiviral Agents; Benzimidazoles; Female; Fluorenes; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Muscle, Skeletal; Quality of Life; Sofosbuvir; Treatment Outcome

Chronic Hepatitis C (CHC) is a common progressive healthcare challenge that leads to liver cirrhosis, liver failure, and hepatocellular carcinoma. The optimum therapy was a combination of pegylated interferon and ribavirin, which was associated with moderate response and severe side effects. Sofosbuvir revolutionized CHC treatment, especially in combination with other antiviral agents.. The aim of this study was to compare and evaluate the safety and efficacy of sofosbuvir/ daclatasvir versus sofosbuvir/ledipasvir for the treatment of non-cirrhotic naïve patients with chronic Hepatitis C Virus (HCV) genotype 4 infection for 12 weeks.. One hundred CHC genotype 4 patients (70 females, 30 males) were recruited from the hepatology clinic at the Beni-Suef general hospital. Patients were randomly allocated into two groups that received a 12 weeks treatment of either sofosbuvir 400 mg/daclatasvir 60 mg or sofosbuvir 400 mg/ledipasvir 90 mg. The sustained virological response 12 weeks post-treatment (SVR12) (HCV RNA < Lower Limit of Quantification (LLOQ)) was determined to evaluate efficacy. The clinical laboratory tests and any reported adverse effects starting from the administration of the first dose till 30 days after the last dose were assessed to evaluate safety. The main outcome measure was the assessment of the safety, efficacy and compliance of sofosbuvir/ daclatasvir versus sofosbuvir/ledipasvir for the treatment of non-cirrhotic naïve CHC genotype 4 patients for 12 weeks.. SVR12 was achieved by 98% and 96% of patients receiving sofosbuvir plus ledipasvir and sofosbuvir plus daclatasvir, respectively. The most common adverse events reported were headache, and fatigue. No patients discontinued treatment due to adverse events.. The findings from this study suggest that the 12 weeks treatment regimens of sofosbuvir plus daclatasvir and sofosbuvir plus ledipasvir were both efficacious and well-tolerated in patients with HCV genotype 4 infection. Impact on Practice: In this paper, we report on the most recent approaches in the treatment of Hepatitis C genotype 4 patients in Egypt. This is significant because this article focuses on comparing the efficacy and tolerability of the most commonly used antiviral drugs in Egypt.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Egypt; Female; Fluorenes; Genotype; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Pyrrolidines; Random Allocation; Sofosbuvir; Treatment Outcome; Valine

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.

Topics: Animals; Antiviral Agents; Benzimidazoles; Carbamates; Cost-Benefit Analysis; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Imidazoles; Liver Cirrhosis; Models, Animal; Pyrrolidines; Ribavirin; Sofosbuvir; Swine; Valine

Direct acting antiviral (DAA) hepatitis C (HCV) medications are funded in New Zealand since 2016 for some and since 2019 for all genotypes. The purpose of this study was to review New Zealand-wide data of the use of generic HCV DAA medications imported through Tasmanian FixHepC Buyer's Club and the associated side effect profiles.. This is a retrospective data audit on the use of generic DAAs to treat HCV; outcomes from consecutive hepatitis C patients (naïve and pre-treated) treated with generic DAAs (sofosbuvir/ledipasvir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, ribavirin) collected from all known sites that used Buyer's club medications in eight New Zealand district health board regions were summarised. Demographic, disease characteristics, FibroScan and blood markers' (platelets, ALT, GGT, AFP) data were collected.. Study sample was 81.8% New Zealand European, 64.8% male of median 56.0 (IQR: 48.0-60.0) years old. Three participants (4.5%) were HIV positive. 74.7% of the participants had signs of fibrosis (F1-F4); 40.5% had cirrhosis/scaring (F4). 61.7% of the patients were naïve to treatment. 42.0%, 40.1% and 12.0% received sofosbuvir/ledipasvir, sofosbuvir/daclatasvir, sofosbuvir/velpatasvir, respectively; 32.1% also received ribavirin. 80.2% of patients received treatment for 12 weeks. 95.1% (154/162) of the sample achieved sustained virological response at 12 weeks post-treatment, 2.5% relapsed, 1.2% were lost to follow-up. The main minor side effects included fatigue, headache, difficulty sleeping, experienced by 21.7%, 7.0%, 7.0%, respectively. An average total cost for medication and monitoring was 2,027 to 2,659 NZD (12 weeks), and 3,054 to 4,260 NZD (24 weeks) per patient.. Generic DAAs to treat hepatitis C are safe, efficient and a cheaper than branded medications option.

Topics: Aged; Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Drugs, Generic; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; HIV Seropositivity; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; New Zealand; Pyrrolidines; Retrospective Studies; Sofosbuvir; Sustained Virologic Response; Valine; Viral Load

To assess the efficacy and safety of sofosbuvir based generic Direct Acting Antivirals (DAAs) in treatment of Hepatitis C virus (HCV) in adolescents with thalassemia major (TM).. In this prospective single-arm study, 18 TM adolescents with Chronic Hepatitis C received sofosbuvir based generic DAAs. Patients with genotype 1 and genotype 3 received ledipasvir and daclatasvir respectively. Two cirrhotic patients with genotype 3 also received ribavirin.. The mean age of patients was 15.1 y, of which 12 had genotype 1, 5 had genotype 3 and 1 had an undetermined genotype. Six patients had cirrhosis and 1 was treatment experienced. Sixteen of 18 patients (89%; 95% confidence interval 74 to 100%) achieved sustained virological response at 3 mo post completion of treatment with DAAs. There was a significant reduction in alanine aminotransferase levels (p < 0.001), HCV RNA load (p < 0.001) and ferritin levels (p < 0.026) at 3 mo post completion of treatment. There were no major adverse events associated with the use of DAAs.. Generic DAAs are effective and safe in TM adolescents with HCV.

Topics: Adolescent; Antiviral Agents; Benzimidazoles; beta-Thalassemia; Carbamates; Child; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Prospective Studies; Pyrrolidines; Ribavirin; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Valine; Viral Load

The efficacy of ledipasvir/sofosbuvir (LDV/SOF) have been demonstrated in randomized controlled trials, however,there is an unmet need for real-world effectiveness data. It is important to gather data regarding potential predictors of treatment failure with (LDV/SOF). Predictors of sustained virologic response (SVR) to all-oral HCV regimens can inform nuanced treatment decisions. The objectives of this study were to evaluate the effectiveness of LDV/SOF, SVR12 as main endpoint and SVR24 as second endpoint, and identify predictors of treatment failure.. Retrospective and observational study carried out from April 2015 to January 2016. Inclusion criteria: patients with HCV infection treated with LDV/SOF for 12 weeks during study period. The patients that were treated during 24 weeks were excluded as well as those treated with peg-interferon. Binary logistic regression was used to predict what variable was associated with treatment failure.. A total of 122 patients were analyzed achieving SVR12 91.80% (112/122) of them. The patients with HCV genotype (GT) 1a or GT1b or GT4 achieved SVR12. Only one pre-treated non-cirrhotic HCV GT1 patients relapsed to treatment. The lowest SVR12 were obtained for GT3, 43.75%, (7/16). Everybody that got SVR12 achieved SVR24. None of the variables analyzed significantly influenced the SVR12, except GT (p=0.001). Almost all the relapses occurred in GT3.. LDV/SOF combination has been very effective to treat GT1 and GT4 infected patients, however, has constituted a suboptimal therapeutic option for those patients infected with GT3, regardless of the rest of the variables analyzed.

Topics: Antiviral Agents; Benzimidazoles; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Liver Cirrhosis; Male; Middle Aged; Recurrence; Regression Analysis; Retrospective Studies; Sofosbuvir; Sustained Virologic Response; Treatment Failure

The effectiveness of a 12-week course of sofosbuvir-ledipasvir in treatment-experienced HCV genotype 1b-infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post-treatment week 12 (SVR12) of sofosbuvir-ledipasvir in combination with ribavirin for 12 weeks, and sofosbuvir-ledipasvir alone for 24 weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12 weeks with Ribavirin and 260 with sofosbuvir-ledipasvir alone for 24 weeks) consecutive HCV genotype 1b-infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24 weeks, respectively (P = .002). The baseline characteristics of patients treated for 12 weeks were significantly different from those treated for 24 weeks as regards their younger age (P = .002), prevalence of Child-Pugh class A (P = .002), lower MELD scores (P = .001) and smaller number of nonresponders (P = .04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analyses (P = .007 and P = .008, respectively). The SVR rate was unaffected by age, gender, BMI, Child-Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir-ledipasvir plus ribavirin administered for 12 weeks was less effective than sofosbuvir-ledipasvir alone given for 24 weeks. At odds with European guidelines, the recommended 12-week treatment with sofosbuvir-ledipasvir alone might be suboptimal for this setting of patients.

Topics: Aged; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepatitis C; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Prospective Studies; Ribavirin; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET).. We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow-up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per-protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available.. The per-protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16-5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46-6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59-7.00) were associated with SVR12.. In an analysis of safety and effectiveness data from the HCV-TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment-experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Longitudinal Studies; Male; Middle Aged; North America; Prospective Studies; Ribavirin; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Young Adult

We aimed to describe the real-world efficacy and safety of combination therapy with ledipasvir and sofosbuvir (LDV/SOF) for chronic hepatitis C virus (HCV) genotype 1 (GT1) infection.. This retrospective analysis of a prospective, nationwide, multicenter registry included GT1-infected patients treated with LDV/SOF for 12 weeks. We assessed the rate of sustained virological response at 12 weeks post-treatment (SVR12), incidence of adverse events, and serum markers of hepatocellular carcinoma (HCC).. Among the 1461 patients included (mean age, 69 years; 29.5% aged > 75 years; cirrhosis, 23.8%; history of treatment for HCC, 10.9%), the overall SVR12 rate was 98.4% (1438/1461). Factors associated with treatment failure were cirrhosis (odds ratio, 4.19; p = 0.014) and resistance-associated substitutions (RASs) in NS5A at baseline (odds ratio, 7.78; p = 0.0004). The SVR12 rate in patients with cirrhosis and NS5A RASs was 93.0% compared to 100% in patients without cirrhosis or NS5A RASs. In patients with SVR, the levels of alpha-fetoprotein (AFP), AFP-L3, and Mac-2 binding protein glycosylation isomer (M2BPGi) decreased from baseline to end of treatment (from 13.4 ± 37.6 to 6.0 ± 10.6 ng/mL, p < 0.0001; from 2.2 ± 4.9 to 1.5 ± 6.3%, p < 0.005; and from 3.6 ± 3.7 to 2.0 ± 3.5 cut-off index, p < 0.0001; respectively). Adverse events were rare and not associated with age. No decrease in estimated glomerular filtration rate was observed in patients with baseline chronic kidney disease stage 3.. LDV/SOF therapy is highly effective and safe in elderly Japanese patients with HCV GT1, even in the presence of cirrhosis or NS5A RASs. Patients with SVR may have a lower risk of HCC.

Topics: Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Japan; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Red Cross; Retrospective Studies; Risk; Sofosbuvir; Sustained Virologic Response; Treatment Failure; Viral Nonstructural Proteins; Young Adult

There is scant data on use of sofosbuvir containing directly acting antiviral (DAA) regimens in chronic kidney disease (CKD) patients. Recently generic versions of DAAs have become available in low-income countries including India. The aim of this study was to study the efficacy and safety of generic sofosbuvir in combination with generic ribavirin, ledipasvir or daclatasvir in HCV-infected patients with CKD including patients with advanced CKD (CKD stage 4 or 5 with an estimated glomerular filtration rate (GFR) <30 mL/min or those on dialysis).. Seventy-one CKD patients (76% male, 84.5% on maintenance haemodialysis, 23.9% cirrhosis) with HCV infection were included in the study. Full-dose sofosbuvir was used in combination with ribavirin (n = 26, for 24 weeks, 69.2% genotype 1, 30.8% genotype 3), ledipasvir (n = 26, for 12 weeks, all genotype 1) and daclatasvir (n = 19, for 12 weeks, all genotype 3).. Sustained virological response (SVR) (HCV RNA <12 IU/mL) at 12 weeks after stopping treatment was seen in 100% of the patients in all the 3 groups. At 24-week follow-up after end of therapy, 1 patient in sofosbuvir plus ledipasvir group relapsed. At 48-week follow-up after end of therapy, 1 more patient in sofosbuvir plus ribavirin group relapsed.. Full-dose sofosbuvir-based DAA therapy using generics is highly effective for individuals with HCV infection and CKD including advanced CKD (CKD stage 4 or 5 with an e-GFR <30 mL/min or those on dialysis).

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Drugs, Generic; Female; Fluorenes; Genotype; Glomerular Filtration Rate; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; India; Liver Cirrhosis; Male; Middle Aged; Pyrrolidines; Renal Dialysis; Renal Insufficiency, Chronic; Ribavirin; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Valine; Viral Load; Young Adult

Topics: Antiviral Agents; Benzimidazoles; Fluorenes; Genotype; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Retreatment; Ribavirin; Simeprevir; Sofosbuvir

There is a paucity of information on chronic hepatitis C (CHC) patients treated with direct antiviral agents (DAAs) in Asia. We invited Asia-Pacific physicians to collate databases of patients enrolled for CHC treatment, recording baseline clinical, virologic and biochemical characteristics, sustained virologic response at week 12 (SVR12) and virologic failure. SVR12 outcome was based on intention to treat (ITT). Multivariate analysis was used to assess independent risk factors for SVR12 using SPSS version 20. A total of 2171 patients from India (n = 977), Myanmar (n = 552), Pakistan (n = 406), Thailand (n = 139), Singapore (n = 72) and Malaysia (n = 25) were collected. At baseline, mean age was 49 years, 50.2% were males, and 41.8% had cirrhosis. Overall, SVR12 was 89.5% and by genotype (GT) based on ITT and treatment completion, respectively, was 91% and 92% for GT1, 100% and 100% for GT2, 91% and 97% for GT3, 64% and 95% for GT4, 87% and 87% for GT6 and 79% and 91% for GT untested. Patients with cirrhosis had SVR12 of 85% vs 93% for noncirrhosis (P < 0.001) (RR 2.1, 95% CI 1.4-3.1, P = 0.0002). Patients with GT1 and GT3 treated with sofosbuvir/ribavirin (SR) had 88% and 89% SVR12, respectively, but those GT6 treated with sofosbuvir/ledipasvir (SL) had only 77.6% SVR12. Multivariate analysis showed absence of cirrhosis was associated with higher SVR12 (OR 2.0, 95% CI 1.3-3.1, P = 0.002). In conclusion, patients with GT1 and GT3 with/without cirrhosis had surprisingly high efficacy using SR, suggesting that Asians may respond better to some DAAs. However, poor GT6 response to SL suggests this regimen is suboptimal for this genotype.

Topics: Adult; Antiviral Agents; Asia; Benzimidazoles; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Ribavirin; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

Topics: Adult; Antiviral Agents; Benzimidazoles; Benzoates; beta-Thalassemia; Cryoglobulinemia; Deferasirox; Deferoxamine; Elasticity Imaging Techniques; Female; Ferritins; Fluorenes; Hepatitis C, Chronic; Humans; Iron Chelating Agents; Iron Overload; Liver Cirrhosis; Male; Quality of Life; Sofosbuvir; Triazoles; Viral Load

Ledipasvir and sofosbuvir is a well-tolerated regimen with high sustained virological response (SVR) rates in pre-liver transplant patients infected with chronic hepatitis C virus (HCV), but data in liver transplant recipients outside of clinical trials is limited.. To address this knowledge gap and assess SVR rates without the use of ribavirin in liver transplant recipients METHODS: This is a retrospective study examining the treatment of 75 post-liver transplant recipients with ledipasvir and sofosbuvir without ribavirin. Differences between SVR cohorts and predictors of SVR were analysed in an intention-to-treat (ITT) fashion.. A total of 408 genotype 1, HCV patients were treated with ledipasvir/sofosbuvir from October 2014 to August 2015 at our centre. Seventy-three patients were post-liver transplant and were treated with a median of 2.9 years from transplant. Ledipasvir/sofosbuvir achieved an SVR12 of 95.9%. African Americans made up 28.8% of the cohort. Sixty-three per cent of patients were treated previously, including 13.7% of patients previously treated with direct-acting antivirals. Only 2.7% had recurrent allograft cirrhosis, and the majority (90.4%) was on calcineurin inhibitor based immunosuppressive therapy. Approximately 82% of patients had chronic kidney disease (CKD) stage 2 or 3. In univariate logistic regression, only detectable week 8 viral load was predictive of failure to achieve SVR.. Our data confirm excellent SVR outcomes and favourable safety and tolerability profiles with ledipasvir/sofosbuvir without ribavirin in post-liver transplant recipients infected with HCV, despite treatment guidelines to use ribavirin.

Topics: Aged; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Liver Transplantation; Logistic Models; Male; Middle Aged; Retrospective Studies; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Viral Load

We assessed the impact of direct-acting antiviral (DAA) therapy on liver fibrosis regression measured by transient elastography (TE) in patients with chronic hepatitis C virus (HCV) infection.. A prospective cohort study was carried out in HCV monoinfected patients with advanced liver fibrosis or cirrhosis receiving interferon (IFN)-containing or IFN-free DAA therapy. Liver stiffness (LS) score more than 14.5 kPa indicated LS-defined cirrhosis. The primary outcome was improvement in liver stiffness measurement (LSM) at week 24 after treatment measured as (a) decrease in the median LS compared with baseline and (b) at least a 20% decrease in LSM compared with baseline. A multivariate logistic regression model was utilized to identify the factors associated with at least a 20% improvement in LSM.. Of a total of 304 patients, 172 (56.6%) had LS-defined cirrhosis before treatment. LSM decreased from the baseline median value of 16.9 (interquartile range: 11.8-27.7) kPa to a post-treatment week 24 score of 11.9 (interquartile range: 8.2-20.9) kPa (P<0.0001). Of a total of 304 patients, 198 (65.1%) achieved at least a 20% reduction in LS. In multivariate logistic regression analysis, sustained virological response (SVR) was associated significantly with this reduction (P<0.0001). The addition of IFN to the treatment regimen had no impact on the decrease in LSM. Despite decreasing baseline LSM, more than half of the LS-defined cirrhotic patients remained cirrhotic at week 24 after treatment.. In patients with advanced fibrosis, pretreatment LS significantly reduced during DAA therapy. SVR was the only independent factor associated with the regression in LSM. However, irrespective of achieving SVR, liver damage still persisted in a substantial proportion of patients. Thus, early treatment of HCV-infected patients can significantly prevent residual liver damage.

Topics: Adult; Antiviral Agents; Benzimidazoles; Disease Eradication; Drug Therapy, Combination; Elasticity Imaging Techniques; Female; Fluorenes; Genotype; Georgia (Republic); Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Ribavirin; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

Little real-world cohort data has been reported for Asians who have received interferon-free regimens with sofosbuvir (SOF) for chronic hepatitis C virus (HCV) infection. We evaluated the effectiveness and safety in clinical practice of ledipasvir (LDV) plus SOF for Japanese patients infected with HCV genotype 1.. This large, multicenter, real-world cohort study consisted of 772 patients treatment-naive or -experienced, with or without compensated cirrhosis, who were treated with LDV (90 mg)/SOF (400 mg) for a fixed 12-week duration. Direct sequence analysis of the NS5A genes (L31 and Y93) was performed at baseline.. Almost all (99.6%) were infected with HCV genotype 1b. The overall sustained virological response 12 weeks after the end of treatment (SVR12) rate was 98.8% (763/772). Multivariable logistic regression analysis extracted male (odds ratio [OR] 6.62, p = 0.024), cirrhosis (OR 20.1, p = 0.0054), and baseline NS5A resistance-associated variants (RAVs) (OR 29.3, p = 0.0018) as independently associated with treatment failure. Notably, the SVR12 rate for cirrhosis patients with baseline NS5A RAVs (87.5%, 49/56) was statistically lower than for the other groups. This tendency was found except for patients with prior daclatasvir/asunaprevir failure. All patients with treatment failure had NS5A Y93H at relapse, whether or not they had NS5A RAVs at baseline. Serious adverse effects were very rare, and discontinuation was required for only five (0.6%) patients.. LDV/SOF for HCV genotype 1b was exceptionally effective, however, NS5A RAVs undermined the virological effect for cirrhosis patients. Moreover, LDV/SOF was shown to be safe, irrespective of age or fibrosis status.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Cohort Studies; Drug Resistance, Viral; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Risk Factors; Sex Factors; Sofosbuvir; Sustained Virologic Response; Treatment Failure; Viral Nonstructural Proteins; Young Adult

Infections with the hepatitis C virus (HCV) are a global public health problem. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. Newly introduced direct acting antivirals, especially interferon-free regimens, have improved rates of sustained viral response above 90% in most patient groups and allow treating patients who were ineligible for treatment in the past. These new regimens have replaced former treatment and are recommended by current guidelines. However, there is an ongoing discussion on high pharmaceutical prices. Our aim was to assess the long-term cost-effectiveness of treating hepatitis C genotype 1 patients with sofosbuvir/ledipasvir (SOF/LDV) treatment in Germany.. We used a Markov cohort model to simulate disease progression and assess cost-effectiveness. The model calculates lifetime costs and outcomes (quality-adjusted life years, QALYs) of SOF/LDV and other strategies. Patients were stratified by treatment status (treatment-naive and treatment-experienced) and absence/presence of cirrhosis. Different treatment strategies were compared to prior standard of care. Sensitivity analyses were performed to evaluate model robustness.. Base-case analyses results show that in treatment-naive non-cirrhotic patients treatment with SOF/LDV dominates the prior standard of care (is more effective and less costly). In cirrhotic patients an incremental cost-effectiveness ratio (ICER) of 3,383 €/QALY was estimated. In treatment-experienced patients ICERs were 26,426 €/QALY and 1,397 €/QALY for treatment-naive and treatment-experienced patients, respectively. Robustness of results was confirmed in sensitivity analyses.. Our analysis shows that treatment with SOF/LDV is cost-effective compared to prior standard of care in all patient groups considering international costs per QALY thresholds.

Topics: Adult; Antiviral Agents; Benzimidazoles; Cost-Benefit Analysis; Fluorenes; Genotype; Germany; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Liver Transplantation; Markov Chains; Middle Aged; Models, Theoretical; Public Health; Quality of Life; Quality-Adjusted Life Years; Sensitivity and Specificity; Sofosbuvir

Novel treatments for hepatitis C virus (HCV) infection are highly efficacious but costly. Thus, many insurers cover therapy only in advanced fibrosis stages. The added health benefits and costs of early treatment are unknown.. To assess the cost-effectiveness of (1) treating all patients with HCV vs only those with advanced fibrosis and (2) treating each stage of fibrosis.. This study used a decision-analytic model for the treatment of HCV genotype 1. The model used a lifetime horizon and societal perspective and was representative of all US patients with HCV genotype 1 who had not received previous treatment. Comparisons in the model included antiviral treatment of all fibrosis stages (METAVIR [Meta-analysis of Histological Data in Virial Hepatitis] stages F0 [no fibrosis] to F4 [cirrhosis]) vs treatment of stages F3 (numerous septa without cirrhosis) and F4 only and by specific fibrosis stage. Data were collected from March 1 to September 1, 2014, and analyzed from September 1, 2014, to June 30, 2015.. Six HCV therapy options (particularly combined sofosbuvir and ledipasvir therapy) or no treatment.. Cost and health outcomes were measured using total medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), calculated as the difference in costs between strategies divided by the difference in QALYs.. We simulated 1000 individuals, but present the results normalized to a single HCV-infected person. In the base-case analysis, among patients receiving 8 or 12 weeks of sofosbuvir-ledipasvir treatment, treating all fibrosis stages compared with treating stages F3 and F4 adds 0.73 QALYs and $28,899, for an ICER of $39,475 per QALY gained. Treating at stage F2 (portal fibrosis with rare septa) costs $19,833 per QALY gained vs waiting until stage F3; treating at stage F1 (portal fibrosis without septa), $81,165 per QALY gained compared with waiting until stage F2; and treating at stage F0, $187,065 per QALY gained compared with waiting until stage F1. Results for other regimens show a similar pattern. At base-case drug prices, treating 50% of all eligible US patients with HCV genotype 1 would cost $53 billion. In sensitivity analyses, the ICER for treating all stages vs treating stages F3 and F4 was most sensitive to cohort age, drug costs, utility values in stages F1 and F2, and percentage of patients eligible for 8-week therapy. Except for patients aged 70 years, the ICER remains less than $100,000 per QALY gained. A 46% reduction in cost of sofosbuvir-ledipasvir therapy decreases the ICER for treating at all fibrosis stages by 48%.. In this simulated model, treating HCV infection at early stages of fibrosis appeared to improve health outcomes and to be cost-effective but incurred substantial aggregate costs. The findings may have implications for health care coverage policies and clinical decision making.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Cost-Benefit Analysis; Decision Support Techniques; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Middle Aged; Quality-Adjusted Life Years; Severity of Illness Index; Sofosbuvir; Treatment Outcome; United States; Viral Load; Young Adult

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, treatment-related AEs, and AEs leading to study drug modification/interruption, particularly among elderly subjects.. 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.

Topics: Age Factors; Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Clinical Trials, Phase III as Topic; Cohort Studies; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorenes; Follow-Up Studies; Genotype; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Patient Safety; Randomized Controlled Trials as Topic; Retrospective Studies; Ribavirin; Risk Assessment; Sex Factors; Sofosbuvir; Treatment Outcome

Currently the only Food and Drug Administration-approved treatment for children with chronic hepatitis C virus is pegylated interferon with ribavirin, which is associated with significant adverse effects and low sustained virologic response rates. In this report, we discuss the use of ledipasvir/sofosbuvir to treat an adolescent with cirrhosis secondary to chronic hepatitis C virus.

Topics: Adolescent; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Sofosbuvir; Viral Load

Topics: Adult; Antiviral Agents; Benzimidazoles; Carbamates; Coinfection; Directly Observed Therapy; Drug Therapy, Combination; Female; Fluorenes; Hepatitis C, Chronic; HIV Infections; Humans; Imidazoles; Liver Cirrhosis; Male; Medication Adherence; Middle Aged; Opiate Substitution Treatment; Opioid-Related Disorders; Pyrrolidines; Severity of Illness Index; Sofosbuvir; Substance Abuse Treatment Centers; Valine

New treatments for chronic hepatitis C virus (HCV) are highly effective in patients coinfected with human immunodeficiency virus (HIV). This study estimated the cost-effectiveness of treatments for genotype 1 (GT1) HCV in HIV-coinfected patients.. A Markov model based on HCV natural history was used. The base-case analysis included both treatment-naïve and -experienced patients. Alternatives were ombitasvir/paritaprevir/ritonavir, dasabuvir with or without ribavirin (3D ± R) for 12 or 24 weeks, sofosbuvir plus peginterferon and R (SOF + PR) for 12 weeks, SOF + R for 24 weeks, and no treatment (NT). A subgroup analysis restricted to treatment-naïve, non-cirrhotic patients compared 3D ± R for 12 weeks to SOF plus ledipasvir (LDV) for 12 weeks and NT. Transition probabilities, utilities, and costs were obtained from the published literature. Outcomes were measured over a lifetime horizon and included rates of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death, total costs, life-years, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER).. In the base-case, SOF + R was dominated by both SOF + PR and 3D ± R. Compared to SOF + PR, 3D ± R had an ICER of $45,581. The lifetime rates of liver morbidity and mortality were lower among those treated with 3D ± R compared to SOF + PR, SOF + R, or NT. In the subgroup analysis, 3D ± R was cost-effective compared to NT at a threshold of $50,000 per QALY (ICER $27,496). SOF/LDV had an ICER of $104,489 per QALY gained compared to 3D ± R.. In the GT1 HCV population coinfected with HIV, 3D ± R was cost-effective compared to NT, SOF + R, and SOF + PR. In the treatment-naïve sub-population, 3D ± R was cost-effective compared to NT and SOF/LDV.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Cyclopropanes; Disease Progression; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Interferon-alpha; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Markov Chains; Middle Aged; Polyethylene Glycols; Proline; Quality-Adjusted Life Years; Recombinant Proteins; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; United States; Uracil; Valine

Herein we report a previously undescribed case of treatment-emergent non-structural protein 5A (NS5A) resistance mutations, Q30H and Y93C, leading to a failure of 24-week course of sofosbuvir/ledipasvir+ribavirin therapy for the treatment of hepatitis C virus (HCV) genotype 1a in interferon-experienced, human immunodeficiency virus type 1 (HIV-1) co-infected patient with cirrhosis.

Topics: Antiviral Agents; Benzimidazoles; Drug Resistance, Viral; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Liver Cirrhosis; Male; Middle Aged; Mutation, Missense; Ribavirin; Sofosbuvir; Treatment Failure; Viral Nonstructural Proteins

Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal for those with ongoing viraemia and is associated with higher rates of allograft failure and death. However, the optimal timing of HCV treatment for patients awaiting transplant remains unclear.. To evaluate the comparative cost-effectiveness of treating HCV pre-LT vs. post-LT (pre-emptive or after HCV recurrence).. A Markov state-transition model was created to simulate the progression of a cohort of HCV-genotype 1 or 4 cirrhotic patients from the time of transplant listing until death. We then used this model to study the cost-effectiveness of ledipasvir-sofosbuvir (LDV/SOF) with ribavirin for 12 weeks, administered for three separate treatment strategies: (i) pre-LT; (ii) post-LT preemptively prior to HCV recurrence; or (iii) post-LT after HCV recurrence.. In the base-case analysis using a median model for end-stage liver disease (MELD) score <25 at the time of transplant, we found that pre-LT treatment of HCV led to more QALYs for fewer dollars compared to other strategies. Analysis limited to living donor LT recipients revealed that pre-LT treatment was also the most cost-effective strategy. When the analysis was repeated for MELD ≥25, decompensated disease (Child-Pugh class B or C), and hepatocellular carcinoma cases, preemptive post-LT strategy was more cost-effective.. Treatment of HCV prior to liver transplantation appears to be the most cost-effective strategy for patients with a MELD score <25. For patients with a MELD ≥25 or decompensated cirrhosis, preemptive post-liver transplantation treatment before HCV recurrence is the most cost-effective strategy.

Topics: Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Disease Progression; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Neoplasm Recurrence, Local; Quality-Adjusted Life Years; Ribavirin; Sofosbuvir; United States

To gather data on the antiviral efficacy and safety of second generation direct acting antiviral (DAA) treatment with respect to sustained virological response (SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this setting.. Two hundred and sixty patients treated with SOF combination partners PR (n = 51), R (n = 10), SMV (n = 30), DCV (n = 81), LDV (n = 73), or 3D (n = 15). 144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were post-liver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3.. Two hundred and forty/256 (93.7%) patients achieved SVR12 (mITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/nL, 88% post-liver transplantation, 95% for GT1a, 93% for GT1b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10 (P < 0.0001), liver cirrhosis (P = 0.005) at baseline. In Interferon-free treatment GT3 had significantly lower SVR rates than GT1 (P = 0.016). Side effects were mild.. Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into "real-world". Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/nL and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.

Topics: Adult; Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Hypertension, Portal; Imidazoles; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Pyrrolidines; Retrospective Studies; Ribavirin; Simeprevir; Sofosbuvir; Treatment Outcome; Valine

New interferon-free anti-HCV regimens are highly efficacious with a favorable safety profile. We assessed health-related quality of life (HRQL) and work productivity in patients with different stages of hepatic fibrosis treated with sofosbuvir+ledipasvir.. Four questionnaires [Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), Short Form-36 (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity Index:Specific Health Problem (WPAI:SHP)] were administered at baseline, during, and after treatment with sofosbuvir+ledipasvir+ribavirin or sofosbuvir+ledipasvir (ION-1,2,3 clinical trials). Metavir fibrosis stage was determined from pre-treatment liver biopsies.. There were 1005 patients included (stage F0: n=94; F1: n=311; F2: n=301; F3: n=197; F4: n=102). At baseline, patients with more advanced fibrosis had more HRQL impairments, predominantly related to physical functioning (stage 0 vs. stage 4 by up to 0.126 on a normalized 0-1 scale p<0.0001). During and post-treatment, HRQL remained lower in patients with advanced fibrosis. After achieving sustained virologic response, significant improvements from baseline in most HRQL domains were observed regardless of fibrosis stage (by 0.024-0.103 on a 0-1 scale; all p>0.05 across fibrosis stages). In multivariate analysis, advanced fibrosis was independently associated with impairment of HRQL and work productivity (beta up to -0.056 in comparison with none-to-mild fibrosis, p<0.05). However, improvement of HRQL and work productivity after viral clearance was not related to the stage of fibrosis (all p>0.05).. Although advanced hepatic fibrosis is associated with HRQL and work productivity impairment, viral eradication with sofosbuvir+ledipasvir leads to HRQL improvement regardless of fibrosis stage. HCV patients with early fibrosis experience similar improvement of patient reported outcomes as those with advanced fibrosis.

Topics: Antiviral Agents; Benzimidazoles; DNA, Viral; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Quality of Life; Sofosbuvir; Surveys and Questionnaires