ledipasvir and Hepatitis-C

Hepatitis C virus (HCV) infection is an independent risk factor associated with adverse outcomes in patients with end-stage renal disease (ESRD). Due to the wide variety of direct-acting antiviral regimens (DAAs) and the factor of renal insufficiency, careless selection of anti-hepatitis C treatment can lead to treatment failure and safety problems. The integrated evidence for optimized therapies for these patients is lacking. This study would conduct comparisons of different DAAs and facilitate clinical decision-making.. We conducted a systematic literature search in multiple databases (PubMed, Ovid, Embase, Cochrane Library, and Web of Science) up to 7 August 2023. Study data that contained patient characteristics, study design, treatment regimens, intention-to-treat sustained virologic response (SVR), and adverse event (AE) data per regimen were extracted into a structured electronic database and analyzed. The network meta-analysis of the estimation was performed by the Bayesian Markov Chain Monte Carlo methods.. Our search identified 5,278 articles; removing the studies with duplicates and ineligible criteria, a total of 62 studies (comprising 4,554 patients) were included. Overall, the analyses contained more than 2,489 male individuals, at least 202 patients with cirrhosis, and no less than 2,377 patients under hemodialysis. Network meta-analyses of the DAAs found that receiving ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (R) plus dasabuvir (DSV), glecaprevir (G)/pibrentasvir (P), and sofosbuvir (SOF)/ledipasvir (LDV) ranked as the top three efficacy factors for the HCV-infected ESRD patients. Stratified by genotype, the G/P would prioritize genotype 1 and 2 patients with 98.9%-100% SVR, the SOF/DCV regimen had the greatest SVR rates (98.7%; 95% CI, 93.0%-100.0%) in genotype 3, and the OBV/PTV/R regimen was the best choice for genotype 4, with the highest SVR of 98.1% (95% CI, 94.4%-99.9%). In the pan-genotypic DAAs comparison, the G/P regimen showed the best pooled SVR of 99.4% (95% CI, 98.6%-100%). DAA regimens without Ribavirin or SOF showed the lowest rates of AEs (49.9%; 95% CI, 38.4%-61.5%) in HCV-infected ESRD patients.. The G/P could be recommended as the best option for the treatment of pan-genotypic HCV-infected ESRD patients. The OBV/PTV/R plus DSV, SOF/Velpatasvir (VEL), SOF/Ledipasvir (LDV), and SOF/DCV would be reliable alternatives for HCV treatment with comparable efficacy and safety profiles.. https://www.crd.york.ac.uk/prospero/#searchadvanced, PROSPERO: CRD42021242359.

Topics: Antiviral Agents; Bayes Theorem; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Male; Network Meta-Analysis; Ritonavir; Treatment Outcome

Over 3 million paediatric patients globally and ~50 000 in the United States are estimated to be infected with HCV. Eradicating HCV in children helps prevent liver fibrosis, cirrhosis and hepatocellular carcinoma; reduces extra-hepatic manifestations of HCV; improves quality of life; and increases survival. The 2019 American Association for the Study of Liver Diseases-Infectious Diseases Society of America (AASLD-IDSA) guidelines now recommend direct-acting antiviral (DAA) treatment with an approved regimen for all children and adolescents with HCV infection aged ≥3 years. We conducted a descriptive review of the new DAA treatments for HCV infection in the paediatric population. Ledipasvir/sofosbuvir (LDV/SOF) and sofosbuvir with ribavirin (SOF/RBV) are now approved for those ≥3 years old under specific clinical scenarios; sofosbuvir/velpatasvir (SOF/VEL) is the only pangenotypic agent approved for those ≥6 years or ≥17 kg, and glecaprevir/pibrentasvir (GLE/PIB) is approved for adolescents ≥12 years old or ≥45 kg. These DAA regimens are well-tolerated and have comparable sustained virologic response rates at 12 weeks post-treatment compared to those reported in adults (close to 100%). The introduction of DAAs has significantly changed the landscape of HCV treatment in adults and children with HCV infection and has increased confidence that the 2030 World Health Organization elimination goal may be attainable. Further studies are warranted to determine the optimal treatment for children with HCV infection, including timing, regimen and duration. Additionally, with the recent paediatric approvals, long-term safety data are needed.

Topics: Adolescent; Adult; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Child; Child, Preschool; Cyclopropanes; Disease Eradication; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Leucine; Pediatrics; Proline; Pyrrolidines; Quality of Life; Quinoxalines; Ribavirin; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; World Health Organization

Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.

Topics: Animals; Antiviral Agents; DNA-Directed RNA Polymerases; Enzyme Inhibitors; Hepatitis C; Humans; Molecular Structure; Molecular Targeted Therapy; Protease Inhibitors

Direct acting antivirals (DAA's) have revolutionized the treatment of hepatitis C (HCV). However, questions persist concerning their efficacy in minority populations.. In this review, the authors review outcomes for treatment of HCV by race and ethnicity among the clinical trials that have led to the current recommended treatments for HCV. The authors highlight the efficacy and safety differences by race and ethnicity. They also highlight deficiencies within the literature including small populations of racial/ethnic minorities within HCV clinical trials. DAA's can achieve cure rates for HCV over 95% with the use of once daily medications that have minimal side effects and few significant drug-drug interactions. Regimens with high pan-genotypic efficacy have further simplified treatment paradigms. The purpose of this review is to describe the data on DAA's in treating HCV in racial/ethnic populations.. While the overall data in racial/ethnic minority populations is sparse, DAA's appear to have high efficacy in curing HCV in diverse racial/ethnic populations. Although achieving high sustained virologic response (SVR) rates, there are also data that suggests that some disparities in SVR persist, especially when considering shorter regimens for HCV treatment in racial/ethnic populations.

Topics: Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles

Ledipasvir and sofosbuvir are new direct-acting antiviral agents for patients with HCV infection. Ledipasvir inhibits the HCV non-structural 5A protein, while sofosbuvir is a nucleotide polymerase inhibitor. Many studies have evaluated the safety and efficacy of ledipasvir and sofosbuvir combination with and without ribavirin for patients with chronic HCV genotype-1.. A computer literature search of PubMed, SCOPUS, Web of Knowledge and Cochrane CENTRAL has been conducted. Studies were screened for eligibility and data were extracted. Sustained virological response (SVR) rate and commonly reported adverse events were pooled as risk ratio (RR) using Review Manager version 5.3 for windows and OpenMeta (Analyst) software.. Eight randomized controlled trials (n=1,892) were pooled in the final analysis. A 12-week ledipasvir and sofosbuvir regimen achieved SVR in 97.5% and 89% of non-cirrhotic and cirrhotic patients, respectively. A 24-week ledipasvir and sofosbuvir regimen achieved SVR in 99.6% and 92.6% in non-cirrhotic and cirrhotic patients, respectively. When ribavirin was added to the treatment regiment, the SVR did not differ significantly in either of the treatment regimens (12-week SVR: 93.9% versus 96.7%, RR=0.97, P=0.19 and 24-week SVR: 94.8% versus 97.2%, RR=0.98, P=0.24).. The combination of sofosbuvir and ledipasvir achieved high SVR rates (>90%) in both cirrhotic and non-cirrhotic patients with HCV genotype-1. The addition of ribavirin to this regimen did not significantly increase the SVR rates.

Topics: Animals; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Publication Bias; Recurrence; Ribavirin; RNA, Viral; Sofosbuvir; Time Factors; Treatment Outcome; Viral Load

Treatment for hepatitis C virus genotype 4 infection has undergone a major advance over the past 5 years with the emergence of direct-acting antiviral agents. Previously, genotype 4 treatment had been limited to the combination of pegylated interferon and ribavirin, with low rates of sustained virological response. The combinations of new direct-acting agents have resulted in a radical improvement in hepatitis C therapy. Much of the currently available efficacy and safety information in the treatment of genotype 4 has been extrapolated through the results of genotype 1. In this report, we review the efficacy and safety data obtained in recent studies focusing on genotype 4 patients, including special populations, such as those with decompensated cirrhosis.

Topics: Antiviral Agents; Benzimidazoles; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Simeprevir; Sofosbuvir; Sustained Virologic Response

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

Reactivation of occult or inactive Hepatitis B virus (HBV) infection during immunosuppressant treatments is well known and widely described in literature. The same observation has been made in Hepatitis C (HCV)-infected patients previously exposed to HBV and treated with interferon-free DAA treatments. Because of common transmission routes, persons may have been exposed to HCV, HBV and HIV, but few cases have been reported in this scenario to date. Frequency of HBV reactivation in HIV/HCV co-infected patients previously exposed to HBV and treated with DAA remains unclear. Herein, we report an episode of HBV reactivation in an HIV/HCV co-infected patient prescribed with sofosbuvir/ledipasvir for HCV.. This case-report highlights the risk of HBV reactivation with interferon-free DAA treatment in HIV/HCV co-infected patients previously exposed to HBV and who have contraindications for treatment with nucleoside/nucleotide reverse transcriptase Inhibitors because of comorbid conditions. In the setting of HIV infection, clinicians prescribing DAA should be aware of this risk, and HBV assessment at treatment start as well as virological monitoring during DAA treatment is recommended. Large epidemiological and virological studies are needed to investigate reactivation of occult HBV infection more in depth.

Topics: Antiviral Agents; Benzimidazoles; Coinfection; Female; Fluorenes; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis C; HIV Infections; Humans; Middle Aged; Sofosbuvir

We report an HIV-positive patient post liver transplant for non-alcoholic steatohepatitis. Posttransplant liver enzymes became persistently elevated, however HCV antibody was repeatedly negative. Nucleic acid testing subsequently revealed ongoing HCV viremia. Exposure to HCV was on the basis of sexual transmission. The patient was subsequently successfully treated with sofosbuvir/ledipasvir.

Topics: Antiviral Agents; Benzimidazoles; Fluorenes; Hepatitis C; Hepatitis C Antibodies; HIV Infections; Humans; Liver Transplantation; Male; Middle Aged; RNA, Viral; Sexually Transmitted Diseases, Viral; Sofosbuvir; Transaminases; Transplant Recipients; Treatment Outcome

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

Sofsobuvir is the first-in-class NS5B nucleotide inhibitor to be launched as a treatment for the hepatitis C virus (HCV). Its viral potency, pan genotypic activity and high barrier to resistance make it the ideal candidate to become a backbone for several IFN-free regimens. Ledipasvir is a NS5A inhibitor with multi genotypic activity but modest barrier to resistance. The once-daily fixed-dose combination of sofosbuvir plus ledipasvir is the first-in-market single-tablet regimen for the treatment of hepatitis C infection. Recent data demonstrated that this FDC alone, or in combination with ribavirin, is able to achieve HCV cure of at least 90% or more among genotype 1,4, 5 and 6 patients. This combination appears to be suboptimal in genotype 3 patients and other direct acting antiviral combinations with sofosbuvir will help to fulfill this gap in the near future. The safety profile of the fixed dose combination is good. Resistance is not an issue with sofosbuvir but may be a significant issue with regards to ledipasvir for those rare individuals who harbor baseline HCV NS5A resistance-associated variants that conferred a high resistance level. The rational for using FDCs and the available clinical data are reviewed.

Topics: Antiviral Agents; Benzimidazoles; Drug Combinations; Drug Resistance, Viral; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Ribavirin; Sofosbuvir

About 150,000,000 people worldwide are chronically infected with hepatitis C virus (HCV). HCV infection can lead to liver cirrhosis, hepatocellular carcinoma and death. Treatment was based previously only on pegylated interferon combined with other antiviral drugs. Recently, the first interferon-free combination for patients with genotype 2 or 3 was approved in the USA and Europe, and several molecules are in an advanced phase of clinical development.. This review focuses on the pharmacokinetics, pharmacodynamics and tolerability of ledipasvir , an inhibitor of HCV nonstructural 5A protein. The authors also highlight the drug's safety and resistance profile.. The pharmacokinetic profile and antiviral activity of ledipasvir are ideal. However, given the high rate of natural and drug-related ledipasvir-resistant HCV mutations, ledipasvir is administered in combination regimens with other antiviral drugs, which resulted in a cure rate up to 100%. While ledipasvir is effective in patients with genotype 1 chronic hepatitis C, its efficacy remains to be established in patients with genotype 4, 5 or 6, in subjects with HIV coinfection, in hemodialyzed and elderly patients and in subjects with decompensated cirrhosis. If the excellent results of combination therapy be confirmed in larger trials, hepatologists will have the possibility to cure most HCV-positive patients in the near future.

Topics: Animals; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Fluorenes; Hepatitis C; Humans; Interferon-alpha; Polyethylene Glycols; Recombinant Proteins; Viral Nonstructural Proteins

A key to effective interferon- (IFN-) free therapy for hepatitis C virus (HCV) infection is a direct-acting antiviral (DAA) with a high barrier to resistance that can act as the backbone to any regimen. Ideally, this agent should also be active against all HCV genotypes, be well tolerated and have few drug interactions. Nucleoside/nucleotide analogues (NAs) that inhibit the function of the HCV RNA-dependent-RNA polymerase fit these requirements and thus hold promise as a cornerstone for new IFN-free regimens. To date, the issue with this class of agents has been toxicity. Numerous NAs in early clinical development have led to significant toxicity leading to their abandonment. However, sofosbuvir, a prodrug of a uridine NA, has moved through development with a clean-safety profile leading to its recent approval. When combined with ribavirin (RBV) alone, sofosbuvir is effective against genotype 2 and even genotype 3 if duration is extended. There are currently limited data with this combination in genotype 1; however, when sofosbuvir is combined with other DAAs of different classes, it is highly effective in almost all patients. To date, sofosbuvir has been studied with protease, NS5A, and nonnucleoside HCV polymerase inhibitors, including as part of a fixed-dose combination single tablet with the NS5A inhibitor ledipasvir, with very high rates of SVR with as little as 8 weeks of therapy. Combining two DAAs to sofosbuvir may shorten therapy even further. Because of the poor replicative fitness of the S282T sofosbuvir-resistant variant, resistance to sofosbuvir has not been a significant clinical issue in trials thus far. In addition to sofosbuvir, other NAs are in early-stage development. Provided unanticipated toxicity does not emerge, NAs are likely to play a major role as a backbone for future HCV therapy. The rationale for using this class of agents and the clinical data available to date are reviewed.

Topics: Animals; Antiviral Agents; Benzimidazoles; Drug Design; Drug Resistance, Viral; Fluorenes; Hepacivirus; Hepatitis C; Humans; Interferons; Molecular Targeted Therapy; Nucleosides; Nucleotides; Protease Inhibitors; Sofosbuvir; Treatment Outcome; Uridine Monophosphate; Viral Nonstructural Proteins

Eliminating hepatitis C virus (HCV) will require effective treatment delivery to persons with substance use disorders (SUDs). We evaluated the relationship between ledipasvir/sofosbuvir treatment persistence (receiving 84 tablets), adherence, and sustained virologic response (SVR) in persons with human immunodeficiency virus (HIV)/HCV coinfection.. Of the 144 participants with HIV/HCV and SUDs, 110 initiated a 12-week treatment course under 1 of 3 conditions (usual care, peer mentors, and cash incentives). We used self-report, pharmacy pill counts, and expected date of refill to examine adherence. Persistent participants were categorized as high adherence (taking ≥90% of doses) or low adherence (taking <90% of doses).. Most participants persisted on treatment after initiation (n = 105), with 95% (n = 100) achieving SVR. One third (34%) of participants had moderate/heavy alcohol use by the biomarker phosphatidylethanol ([Peth] ≥50 ng/mL), and 44% had urine toxicology positive for cocaine or heroin at enrollment. The proportion of persons with high adherence was 72% (n = 76), and the proportion of persons with low adherence was 28%. Although low adherence was associated with moderate/heavy alcohol use by PEth (relative risk = 2.77; 95% confidence interval, 1.50-5.12), SVR did not vary according to adherence (P = .702), and most participants (97%) with low adherence achieved SVR.. Treatment persistence led to high SVR rates among persons with HIV/HCV, despite imperfect adherence and SUDs.

Topics: Antiviral Agents; Benzimidazoles; Coinfection; Fluorenes; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; HIV; HIV Infections; Humans; Pharmaceutical Preparations; Sofosbuvir; Substance-Related Disorders; Sustained Virologic Response; Treatment Outcome

COVID-19 is a pandemic disease caused by SARS-CoV-2, which is an RNA virus similar to the hepatitis C virus (HCV) in the replication process. Sofosbuvir/ledipasvir is an approved drug to treat HCV infection. This study investigates the efficacy of Sofosbuvir/ledipasvir as a treatment for patients with moderate COVID-19 infection. This is a single-blinded parallel-randomized controlled trial. The participants were randomized equally into the intervention group that received Sofosbuvir/ledipasvir (S.L. group), and the control group received Oseltamivir, Hydroxychloroquine, and Azithromycin (OCH group). The primary outcomes were the cure rate over time and the incidence of serious adverse events. The secondary outcomes included the laboratory findings. 250 patients were divided equally into each group. Both groups were similar regarding gender, but age was higher in the S.L. group (p=0.001). In the S.L. group, 89 (71.2%) patients were cured, while only 51 (40.8%) patients were cured in the OCH group. The cure rate was significantly higher in the S.L. group (RR=1.75, p<0.001). Kaplan-Meir plot showed a considerably higher cure over time in the S.L. group (Log-rank test, p=0.032). There were no deaths in the S.L. group, but there were six deaths (4.8%) in the OCH group (RR=0.08, p=0.013). Seven patients (5.6%) in the S.L. group and six patients (4.8%) in the OCH group were admitted to the intensive care unit (ICU) (RR=1.17, P=0.776). There were no significant differences between treatment groups regarding total leukocyte and neutrophils count, lymph, and urea. Sofosbuvir/ledipasvir is suggestive of being effective in treating patients with moderate COVID-19 infection. Further studies are needed to compare Sofosbuvir/ledipasvir with new treatment protocols.

Topics: Antiviral Agents; Benzimidazoles; COVID-19 Drug Treatment; Drug Therapy, Combination; Egypt; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Ribavirin; SARS-CoV-2; Sofosbuvir; Treatment Outcome; Uridine Monophosphate

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.

Topics: Amides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Nausea; Quinoxalines; Sofosbuvir; Sulfonamides

Guidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.gov/ct2/show/NCT02707601) was to evaluate the safety/efficacy of ledipasvir/sofosbuvir (LDV/SOF) co-administered with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/F/TAF (R/F/TAF) in HIV-1/HCV co-infected participants.. Participants with HIV-1 RNA <50 copies/mL and chronic HCV-genotype (GT) 1 (HCV treatment-naïve ± compensated cirrhosis or HCV treatment-experienced non-cirrhotic) were randomized 1:1 to switch to E/C/F/TAF or R/F/TAF. If HIV suppression was maintained at Week 8, participants received 12 weeks of LDV/SOF. The primary endpoint was sustained HCV virologic response 12 weeks after LDV/SOF completion (SVR12).. Of 150 participants, 148 received ≥1 dose of HIV study drug and 144 received LDV/SOF (72 in each F/TAF group; 83% GT1a, 94% HCV treatment-naïve, 12% cirrhotic). Overall, SVR12 was 97% (95% confidence interval: 93-99%). Black race did not affect SVR12. Of four participants not achieving SVR12, one had HCV relapse, one had HCV virologic non-response due to non-adherence, and two missed the post-HCV Week 12 visit. Of 148 participants, 96% receiving E/C/F/TAF and 95% receiving R/F/TAF maintained HIV suppression at Week 24; no HIV resistance was detected. No participant discontinued LDV/SOF or E/C/F/TAF due to adverse events; one participant discontinued R/F/TAF due to worsening of pre-existing hypercholesterolemia. Renal toxicity was not observed in either F/TAF regimen during LDV/SOF co-administration. In conclusion, high rates of HCV SVR12 and maintenance of HIV suppression were achieved with LDV/SOF and F/TAF-based regimens.. This study supports LDV/SOF co-administered with an F/TAF-based regimen in HIV-1/HCV-GT1 co-infected patients.

Topics: Adenine; Adult; Aged; Alanine; Benzimidazoles; Coinfection; Drug Combinations; Drug Resistance, Viral; Emtricitabine; Female; Fluorenes; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Male; Middle Aged; RNA, Viral; Sofosbuvir; Tenofovir

Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women.. This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants. A reference group of women who had participated in pharmacokinetic studies of ledipasvir-sofosbuvir during phase 2 and 3 trials was used. Participants were enrolled at Magee-Womens Hospital (Pittsburgh, PA, USA) between 23 and 24 weeks' gestation and had a 12-week course of oral ledipasvir-sofosbuvir (daily 90 mg ledipasvir plus 400 mg sofosbuvir). Three 12-h intensive pharmacokinetic visits were done at 25-26, 29-30, and 33-34 weeks' gestation and individual pharmacokinetics were summarised by geometric mean across the three visits. The primary outcome, analysed in all participants without suspected dosing errors, was the ledipasvir-sofosbuvir area under the concentration-time curve of the dosing interval (AUC. From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Eight (89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the pregnant women versus the non-pregnant reference group (geometric mean ratio of AUC. Ledipasvir-sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women.. National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health/Office of Research on Women's Health, and Gilead Sciences.

Topics: Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Infant; Pregnancy; Pregnant Women; Sofosbuvir; Treatment Outcome

In the ION-4 trial, hepatitis C virus relapse was rare, occurring only in African American patients, 80% receiving efavirenz for human immunodeficiency virus infection. We observed no indication that CYP2B6 polymorphisms associated with increased plasma efavirenz exposure explained the relapses.

Topics: Alkynes; Antiviral Agents; Benzimidazoles; Benzoxazines; Black or African American; Cohort Studies; Coinfection; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Therapy, Combination; Female; Fluorenes; Genome-Wide Association Study; Genotype; Hepacivirus; Hepatitis C; HIV Infections; Humans; Male; Polymorphism, Single Nucleotide; Recurrence; Sofosbuvir

Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side-effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection.. In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (≥18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918.. Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations.. Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF).

Topics: Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Germany; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Prospective Studies; RNA, Viral; Sofosbuvir

Postmarketing cases of hepatitis B virus (HBV) reactivation during hepatitis C treatment have been reported. We analyzed serum samples from patients in a clinical trial of ledipasvir-sofosbuvir in Taiwan and Korea. Of the 173 patients enrolled, 103 (60%) had been previously infected with HBV. None showed evidence of HBV reactivation.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Coinfection; Drug Therapy, Combination; Female; Fluorenes; Hepatitis B; Hepatitis B virus; Hepatitis C; Humans; Male; Middle Aged; Sofosbuvir; Virus Activation

Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs.. To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis.. Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882).. Single-center.. 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups.. 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks.. The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12).. Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up.. Nonrandomized study design and small sample of patients with early-stage fibrosis.. Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates.. National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

Topics: Antiviral Agents; Benzimidazoles; Drug Resistance, Viral; Drug Therapy, Combination; Female; Fluorenes; Furans; Genotype; Hepatitis C; Hepatitis C, Chronic; Humans; Male; Middle Aged; Quinolines; RNA, Viral; Sofosbuvir; Thiophenes; Treatment Outcome; Viral Load

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.

Topics: Administration, Oral; Animals; Antiviral Agents; Base Sequence; Benzimidazoles; DNA Primers; Double-Blind Method; Fluorenes; Half-Life; Hepatitis C; Humans; Macaca fascicularis; Male; Placebos; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Viral Nonstructural Proteins

We evaluated an all-oral regimen comprising the nucleotide polymerase inhibitor sofosbuvir (SOF) with the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with genotype 1 hepatitis C virus (HCV) infection.. A total of 113 patients were enrolled. Sofosbuvir (400 mg once daily) and LDV (90 mg once daily) plus ribavirin (RBV) were given for 12 weeks to treatment-naïve (TN) patients (n = 25) and those who did not respond to previous therapy (prior null responders, n = 9). Sofosbuvir and GS-9669 (500 mg once daily) plus RBV were given for 12 weeks to TN patients (n = 25) and prior null responders (n = 10). Additionally, prior null responders with cirrhosis were randomly assigned to groups given a fixed-dose combination of SOF and LDV, with RBV (n = 9) or without RBV (n = 10). Finally, a group of TN patients received SOF, LDV, and RBV for 6 weeks (n = 25). The primary efficacy end point was sustained virologic response 12 weeks after therapy (SVR12).. SVR12 was achieved by 25 of 25 (100%) TN patients receiving SOF, LDV, and RBV and 23 of 25 (92%) of those receiving SOF, GS-9669, and RBV. Of TN patients receiving 6 weeks of SOF, LDV, and RBV, 17 of 25 (68%) achieved SVR12. All noncirrhotic prior null responders receiving 12 weeks of SOF along with another direct-acting antiviral agent plus RBV achieved SVR12-9 of 9 (100%) of those receiving SOF, LDV, and RBV and 10 of 10 (100%) of those receiving SOF, GS-9669, and RBV. Among cirrhotic prior null responders, SVR12 was achieved by 9 (100%) of those receiving SOF, LDV, and RBV and 7 (70%) of those receiving SOF and LDVD without RBV. The most common reported adverse events were headache, fatigue, and nausea.. The combination of SOF and a second direct-acting antiviral agent is highly effective in TN patients with HCV genotype 1 infection and in patients that did not respond to previous treatment. ClinicalTrials.gov ID NCT01260350.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Enzyme Inhibitors; Fatigue; Female; Fluorenes; Furans; Genotype; Headache; Hepacivirus; Hepatitis C; Humans; Incidence; Male; Middle Aged; Nausea; Sofosbuvir; Thiophenes; Treatment Outcome; Uridine Monophosphate; Viral Nonstructural Proteins

A patient with genotype 1b chronic hepatitis C virus who had been treated with pegylated interferon and ribavirin (RBV) was treated with glecaprevir/pibrentasvir (GLE/PIB) for 12 weeks. A sustained virological response at post-treatment week 12 (SVR12) was achieved, but relapse occurred approximately 31 weeks after the end of treatment. The patient had a history of allergy to RBV and was treated with ledipasvir/sofosbuvir (LDV/SOF), achieving SVR12 and remaining hepatitis C virus-negative until 24 weeks after the completion of treatment. LDV/SOF can thus be a secondary treatment for GLE/PIB.

Topics: Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Neoplasm Recurrence, Local; Ribavirin; Sofosbuvir

Insurers manage the cost of specialty medicines via rebates, however it is unclear if the savings are passed on to patients, and whether reducing rebates may lead to changes in patient out-of-pocket (OOP) costs and medication adherence. This study examined two drug classes to understand the impact of reducing list prices to net prices, via lower-priced national drug codes (NDCs) or authorized generics, on patient OOP costs and adherence.. This retrospective analysis assessed IQVIA PharMetrics ® Plus adjudicated medical and pharmacy claims for commercially insured patients. Patient OOP costs per prescription and payer drug costs were assessed for evolocumab or alirocumab (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9is]) or velpatasvir/sofosbuvir or ledipasvir/sofosbuvir (hepatitis C virus [HCV] medications). For PCSK9is and HCV medications, the original and lower-priced versions were compared. Adherence was estimated based on proportion of days covered (PDC) (PCSK9is) and receipt of full treatment regimen (HCV medications).. In total, 10,640 patients were included (evolocumab, 5,042; alirocumab, 1,438; velpatasvir/sofosbuvir, 2,952; ledipasvir/sofosbuvir,1,208). After list price reductions, mean payer drug costs decreased by over 60%, while patient OOP cost reductions ranged from 14% to 55% (evolocumab: 55%, p < 0.01; alirocumab: 51%, p < 0.01; velpatasvir/sofosbuvir: 30%, p < 0.01; ledipasvir/sofosbuvir: 14%, p = 0.03). Patients with coinsurance as the largest contributor to their OOP costs had the largest reductions in OOP costs, ranging from adjusted, mean values of US$135 to US$379 (>60% reductions). Six-month PDC for PCSK9is and proportion receiving full HCV treatment regimen were high with the original versions and did not substantially differ with the new, lower-priced versions.. Reducing list prices to approximate net prices (as a proxy for reducing rebates) resulted in lower patient OOP costs, particularly for those with coinsurance. Our findings suggest that future reduction of rebates may assist in patient affordability, although additional transparency is needed.

Topics: Drug Costs; Health Expenditures; Hepatitis C; Humans; Medication Adherence; Retrospective Studies; Sofosbuvir

Human pegivirus (HPgV) is a single-stranded RNA virus​ that is closely related to hepatitis C virus (HCV)​. HPgV has also been shown to infect patients with human immunodeficiency virus (HIV). The mechanisms and disease outcomes of HPgV infections are largely unknown, although it has been implicated in both cancer and neurological diseases. There are no established therapies for HPgV.. To estimate the prevalence of HPgV in a cohort of HCV/HIV co-infected patients undergoing treatment for HCV with direct acting antivirals (DAA) and investigate the effect of DAA therapy on HPgV infection.. RNA was extracted from plasma samples collected at time points before, during, and after DAA. HPgV RNA abundance was quantified by droplet digital PCR assays targeting the NS5A and 5'UTR domains and confirmed by RT-qPCR. Clinical, demographic and treatment data were analysed.. HPgV RNA was detected and quantified in 26 of 100 patients' plasma (26%) before starting DAA. Patients with detectable HPgV were more likely to be male, had higher peak HIV plasma levels, and a history of injection drug use. Patients receiving sofosbuvir/ledipasvir (n = 9) displayed significantly lower HPgV levels at time of DAA completion and had lower post-DAA HPgV rebound​ levels compared to patients receiving sofosbuvir/velpatasvir (n = 11) although both regimens significantly reduced viremia directly following DAA completion. Sustained suppression of HPgV was ​also observed among patients (n = 2) receiving pegylated-interferon.. HPgV RNA ​was frequently detected in HCV/HIV co-infected patients and ​was​ supressed by DAA and pegylated interferon therapies with sofosbuvir-ledipasvir showing greatest antiviral activity. These findings suggest potential treatment strategies for HPgV infections​.

Topics: Antiviral Agents; Coinfection; Female; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; HIV; HIV Infections; Humans; Interferons; Male; Pegivirus; Polyethylene Glycols; RNA, Viral; Sofosbuvir; Viremia

For patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up.. In Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either less than the lower limit of quantification (LLOQ, 20 IU/mL) to equal to or more than LLOQ or equal to or more than LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2× upper limit of normal. Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis.. All patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12, whereas clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and hepatitis B surface antigen (HBsAg) levels were associated with HBV virologic reactivation and baseline ALT and HBV DNA, and HBsAg levels were associated with HBV clinical reactivation.. Among HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy.. NCT02613871.

Topics: Antiviral Agents; Benzimidazoles; Coinfection; DNA, Viral; Fluorenes; Follow-Up Studies; Hepacivirus; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis C; Hepatitis C, Chronic; Humans; Sofosbuvir; Taiwan

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

The use of complementary medicine (CMD) for liver support in Hepatitis C virus (HCV) patients sometimes coincides with the administration of oral antiviral drugs to eradicate the virus. This calls for a deep investigation of CMD effects on the pharmacokinetic parameters of these drugs to ensure their safety and efficacy. Silymarin (SLY), as a CMD, was selected to be given orally to healthy male rats with sofosbuvir (SFB) and ledipasvir (LED), a common regimen in HCV treatment. A new and sensitive LC-MS method was validated for the bioassay of SLY, LED, SFB and its inactive metabolite, GS-331007, in spiked plasma with lower limits of quantitation of 10, 1, 4 and 10 ng/ml, respectively. Moreover, the method was further applied to conduct a full pharmacokinetic profile of SFB, GS-331007 and ledipasvir with and without SLY. It was found that co-administration of SLY may expose the patient to unplanned high serum concentrations of SFB and LED. This could be accompanied by a decrease in SFB efficacy, potentially leading to therapeutic failure and the emergence of viral resistance.

Topics: Animals; Antiviral Agents; Benzimidazoles; Chromatography, Liquid; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C; Male; Rats; Silymarin; Sofosbuvir; Tandem Mass Spectrometry

We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis.. Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs).. Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment.. Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Drug Administration Schedule; Female; Fluorenes; Hepatitis C; Humans; Kidney Failure, Chronic; Male; Middle Aged; Sofosbuvir; Sustained Virologic Response; 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

Ledipasvir/sofosbuvir (LDV/SOF) shows high efficacy and safety in patients with genotype 1-hepatitis C virus (HCV). We aimed to investigate the efficacy and safety of LDV/SOF in real-world Mongolian patients.. Between 2015 to 2019, 23 (0.5%) and 5,005 patients (99.5%) with genotype 1a and 1b HCV, respectively, were treated with a fixed-dose tablet containing 90 mg ledipasvir and 400 mg sofosbuvir for 12 weeks, and 81 patients (1.6%) with previous experience of interferon (IFN)-based treatment received additional 1,000 mg ribavirin. HCV RNA was measured at 4, 12, and 24 weeks after the first dose to determine rapid virologic response, end of treatment response (ETR), and sustained virologic response at 12 weeks after end of treatment (SVR12).. Most patients (n=5,008; 99.6%) achieved ETR and SVR12 without virologic relapse. Patients with genotype 1a showed low rates of ETR and SVR12 in only 16 patients (69.6%). There was no significant difference in SVR12 rate between patients regardless of IFN experience (n=81; 1.6%), cirrhosis (n=1,151; 22.9%), HCV RNA >6×106 IU/mL (n=866; 17.2%), or liver stiffness >9.6 kPa (n=1,721; 34.2%) (100.0%, 99.3%, 99.4%, and 99.4%, respectively). No severe adverse events (AEs) were reported, and there was no dose reduction or interruption due to AE. The most common AEs were headache (n=472; 9.4%), fatigue (n=306; 6.2%), abdominal discomfort (n=295; 5.9%), and skin rash (n=141; 2.8%).. LDV/SOF showed high efficacy and safety for patients with genotype 1, especially 1b HCV, in Mongolia. The real-world data might be applicable to patients in other Asian-Pacific countries.

Topics: Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Mongolia; Sofosbuvir; Treatment Outcome

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

Topics: Antiviral Agents; Benzimidazoles; Child; Female; Fluorenes; Gain of Function Mutation; Genotype; Hepatitis C; Humans; Sofosbuvir; STAT3 Transcription Factor

The aim of this study was to evaluate the efficacy and safety of sofosbuvir/ledipasvir ± ribavirin in Malagasy patients with hepatitis C virus genotypes 1 and 2, in real conditions.. This was a retrospective monocentric clinical study, carried out over a period of 3 years from March 1, 2017 to February 28, 2020, in a hospital hepato-gastroenterology department.. In total, 26 patients (M/F: 11/15) with hepatitis C virus genotype 1 (n = 13) or genotype 2 (n = 13), were treated with sofosbuvir/ledipasvir without (n = 21) or with (n = 5) ribavirin for 12 weeks. The mean age was 61.38 ± 7.09 years. Seventeen patients (65.4%) had cirrhosis. The overall sustained virological response was 96.2% (95% CI = 80.4-99.9%). There was no significant difference between the sustained virological responses of genotypes 1 and 2 (92.3% vs 100%; p = 0.31) or those of cirrhotic or non-cirrhotic patients (94.1% vs 100%; p = 0.46). A relapse was observed in one patient (5.9%) - cirrhotic and genotype 1b - under sofosbuvir/ledipasvir with ribavirin. Seven patients (26.9%) experienced mild adverse reactions, including asthenia (57.1%) and insomnia (42.9%).. Treatment with sofosbuvir/ledipasvir ± ribavirin for infection with hepatitis C virus genotype 1 has been shown to be safe and effective, even in the presence of cirrhosis. The sofosbuvir/ledipasvir combination is a good option for genotype 2 non-cirrhotic patients.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Developing Countries; Drug Interactions; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Retrospective Studies; Sofosbuvir; Treatment Outcome; Young Adult

In this study, we aimed to investigate the efficacy and safety of sofosbuvir-based therapies in the treatment of chronic hepatitis C in real-world clinical practice.. Data from patients with chronic hepatitis C treated with SOF/LDV ± RBV or SOF/RBV in 31 centers across Turkey between April 1, 2017, and August 31, 2018, were recorded in a nationwide database among infectious disease specialists. Demographics, clinical, and virological outcomes were analyzed.. A total of 552 patients were included in the study. The mean age of the patients was 51.28 ± 14.2, and 293 (55.8%) were female. The majority had HCV genotype 1b infection (65%), 75.04% of the patients underwent treatment, and non-cirrhosis was present at baseline in 381 patients (72.6%). SOF/LDV ± RBV treatment was given to 477 patients and 48 patients received SOF/RBV according to HCV genotype. The total SVR12 rate was 99% in all patients. Five patients experienced disease relapse during the study and all of them were genotype 2. In patients infected with HCV GT2, SVR12 was 77.3%. SVR was 100% in all patients infected with other HCV genotypes. All treatments were well tolerated by patients without causing severe adverse events. Side effects and side effects-associated treatment discontinuation rates were 28.2% and 0.4%, respectively. Weakness (13.7%) was the common side effect.. The present real-world data of 525 patients with HCV genotypes 1, 1a, 1b, 3, 4, and 5 who underwent SOF/LDV ± RBV treatment in Turkey demonstrated a high efficacy and safety profile. HCV GT2 patients should be treated with more efficacious treatment.

Topics: Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Ribavirin; Sofosbuvir; Treatment Outcome; Turkey

Hepatitis C virus (HCV) infected adolescents with beta-thalassemia major (BTM) are considered a potential population for HCV micro-elimination model development where BTM may negatively impact the pharmacokinetic exposure parameters of sofosbuvir/ledipasvir (SOF/LED).. The study aimed at studying the effect of BTM on SOF/LED and SOF metabolite (GS-331007) pharmacokinetics.. A prospective, controlled study recruiting BTM and control HCV infected adolescents (Clinicaltrials.gov identifier-NCT04353986). Pharmacokinetic exposure to GS-331007 and LED was the primary pharmacokinetic outcome. No-effect boundaries were set to 90% confidence interval (CI) of exposure geometric mean ratio (GMR) within 70-143%. Dose suitability was based on the 90% CI of exposure GMR within 50-200% compared to adults. The percentage of patients achieving sustained virologic response 12 weeks post-treatment (SVR12) was the primary efficacy endpoint.. Thirteen patients were enrolled per study group. All patients were included in the pharmacokinetic analysis (n=26). BTM patients showed lower GS-331007 and LED exposure that could, respectively, be as low as 45.4% and 36.1% compared to their control group. GS-331007 exposure in BTM patients was nearly half (56.8%, 90% CI 45.3-71.2%) that observed in adults. Despite that low drug exposure in 46.2% of BTM patients may alert dose unsuitability, they achieved SVR12. Moreover, patients with total bilirubin ≥1.93 mg/dL were predicted to have low GS-331007 exposure (0.913 receiver operating characteristic area under the curve with sensitivity and specificity >80%).. The identified systematically lower drug exposure in BTM patients might partially explain relapses or treatment failures among BTM patients reported in other studies. BTM may be a hurdle towards implementing HCV micro-elimination model that may necessitate dose-adjustment.

Topics: Adolescent; Adult; Antiviral Agents; Benzimidazoles; beta-Thalassemia; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Pharmaceutical Preparations; Prospective Studies; Sofosbuvir; Treatment Outcome; Uridine Monophosphate

Topics: Benzimidazoles; Child; Child, Preschool; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Sofosbuvir

Topics: Benzimidazoles; Fluorenes; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sofosbuvir; Waldenstrom Macroglobulinemia

Hepatitis C (HCV) infection is a significant health threat, with increasing incidence rates in the setting of the opioid crisis. Many patients miss appointments and cannot initiate treatment. We implemented financial incentives to improve appointment attendance in a primary care-based HCV treatment setting.. We conducted a systems-level financial incentives intervention at the Adult Primary Care HCV Treatment Program at Boston Medical Center which provides care to many patients with substance use disorders. From April 1 to June 30, 2017, we provided a $15 gift card to patients who attended appointments with an HCV treatment provider. We evaluated the effectiveness of the incentives by 1) conducting a monthly interrupted time series analysis to assess trends in attendance January 2016-September 2017; and 2) comparing the proportion of attended appointments during the intervention to a historical comparison group in the previous year, April 1 to June 30, 2016.. 327 visits were scheduled over the study period; 198 during the intervention and 129 during the control period. Of patient visits in the intervention group, 72.7% were attended relative to 61.2% of comparison group visits (p = 0.03). Appointments in the intervention group were more likely to be attended (adjusted odds ratio 1.94, 95% confidence interval 1.16-3.24). Interrupted time series analysis showed that the intervention was associated with an average increase of 15.4 attended visits per 100 appointments scheduled, compared to the period prior to the intervention (p = 0.01).. Implementation of a financial incentive program was associated with improved appointment attendance at a safety-net hospital-based primary care HCV treatment program. A randomized trial to establish efficacy and broader implementation potential is warranted.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Benzimidazoles; Carbamates; Female; Fluorenes; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Middle Aged; Odds Ratio; Primary Health Care; Program Evaluation; Reward; Safety-net Providers; Sofosbuvir; Sustained Virologic Response; Young Adult

Data on direct-acting antiviral agent (DAA) treatment for mixed genotype hepatitis C virus (HCV) infection are scant. This study examined the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) and ledipasvir/sofosbuvir (LDV/SOF) for mixed HCV genotype infection in a real-world setting in Taiwan. We analysed the data from all patients with mixed HCV genotype infections treated with GLE/PIB or LDV/SOF from 2017 to 2019 in three Chang Gung Memorial Hospitals in Taiwan. The primary treatment outcome was sustained virologic response 12 weeks after treatment cessation (SVR12). Adverse events (AEs) were also evaluated. A total of 5190 HCV patients received DAA treatment during this time period. Among them, 116 patients (2.2%) had mixed infections of any 2 or 3 genotypes of 1a, 1b, 2, 3 and 6. Fifty-four patients received GLE/PIB and 62 received LDV/SOF. SVR12 rates for LDV/SOF vs GLE/PIB therapy were 96.6% (56/58) vs 100% (51/51) by the per-protocol analysis and 90.3% (56/62) vs 94.4% (51/54) by the evaluable population analysis. Two patients with 1b + 6 and 1b + 2 genotype infections in the LDV/SOF group had relapse. Evaluating the GLE/PIB vs LDV/SOF groups for the most common AEs revealed pruritus (16.7% vs 4.8%), abdominal discomfort (5.6% vs 8%) and fatigue (5.6% vs 4.8%). One patient with AE-related treatment discontinuation presented with liver decompensation after 4-week GLE/PIB therapy. DAA-related significant laboratory abnormalities occurred in two patients with >3× elevated bilirubin level in the GLE/PIB group. GLE/PIB and LDV/SOF are well tolerated and achieve high SVR12 rates for patients with mixed HCV genotype infection.

Topics: Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Cyclopropanes; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Proline; Pyrrolidines; Quinoxalines; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Taiwan

Topics: Benzimidazoles; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Renal Insufficiency, Chronic; Ribavirin; Sofosbuvir

Topics: Antiviral Agents; Benzimidazoles; Betacoronavirus; Carbamates; Coronavirus Infections; COVID-19; Drug Repositioning; Fluorenes; Hepatitis B virus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Pandemics; Peptide Hydrolases; Pneumonia, Viral; SARS-CoV-2; Severe acute respiratory syndrome-related coronavirus; Spain

Topics: Acute Kidney Injury; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Sofosbuvir; Treatment Outcome

One-third of the Australian population lives outside major cities and this group has worse health outcomes. Telehealth is becoming an accepted way to improve patient access to specialist healthcare. Over 200,000 Australian’s have hepatitis C virus (HCV) and new treatments are very effective and well tolerated. We aim to demonstrate that HCV treatment utilising telehealth support for care delivery has cure rates similar to onsite care in clinical trials. We also report length of consultation and calculate reductions in travel and carbon output.. Patient demographic, clinical, and treatment outcome data were collected prospectively from hospital software and analysed retrospectively. This was an audit of all patients treated for HCV in one year from a single tertiary hospital that included telehealth in their care delivery.. Sustained virological response was achieved in 51/52 (98%) patients with completed treatment courses, and 51/58 (88%) of those who had a planned telehealth consultation as part of their management. A median of 634 km of patient travel was saved per telehealth consultation.. We found that a telehealth-supported outreach programme for patients in regional Australia with HCV produced similar outcomes to clinical trials. There was a considerable saving in time and cost for the patients and significant environmental benefit through the reduction in carbon footprint associated with travel to distant specialist health services. We conclude that telehealth facilitated outreach is a feasible and effective way to access HCV treatment and cure in regional Australia.

Topics: Adult; Aged; Antiviral Agents; Australia; Benzimidazoles; Carbamates; Delivery of Health Care; Female; Fluorenes; Health Services Accessibility; Hepatitis C; Humans; Imidazoles; Male; Middle Aged; Pyrrolidines; Retrospective Studies; Sofosbuvir; Telemedicine; Treatment Outcome; Valine

Topics: Aged; Animals; Anti-HIV Agents; Antiviral Agents; Atazanavir Sulfate; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzimidazoles; Caco-2 Cells; Carbamates; Drug Interactions; Female; Fluorenes; Hepatitis C; HIV Infections; Humans; Imidazoles; Intestines; Lopinavir; Male; Maraviroc; Middle Aged; Pyrrolidines; Rats; Rats, Wistar; Ritonavir; Saquinavir; Valine; Zidovudine

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

There have been a few reports on the treatment of patients infected with recombinant hepatitis C virus (HCV) genotype 2/1 strains with direct-acting antivirals (DAAs). We experienced three patients, with genotype 2/1 recombinant HCV, treated with DAAs successfully. The first, a 39-year-old man, was infected with recombinant HCV genotype 2a/1b, a rare variant. The sequence of the relapsed virus showed chimeric HCV 2a/1b with the recombinant breakpoint found at nucleotide +49 from the start of the NS3 region. Sofosbuvir plus ribavirin, a regimen recommended for HCV genotype 2, did not lead to a sustained viral response (SVR). Retreatment with grazoprevir plus elbasvir resulted in an SVR. The second case, a 70-year-old woman, was infected with recombinant HCV genotype 2b/1b. DAA therapy with sofosbuvir plus ledipasvir resulted in an SVR. The third case, a 48-year-old woman, was also infected with recombinant HCV genotype 2b/1b. DAA therapy with daclatasvir plus asunaprevir resulted in an SVR. The baseline sequences of the viruses from both the second and third cases showed chimeric HCV 2b/1b with the recombinant breakpoint found at nucleotide +10 from the NS3 start. We report three cases with 2/1 chimeras and discuss the prevalence and response to therapy.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Isoquinolines; Male; Middle Aged; Pyrrolidines; RNA; Sofosbuvir; Sulfonamides; Valine

The emergence of a deletion mutant at hepatitis C virus (HCV) NS5A-P32 (P32del) has recently been reported in a subset of chronic hepatitis C patients who experience virologic failure after direct-acting antiviral drug (DAA) treatment. This mutation confers extremely high resistance to NS5A inhibitors. No effective treatment has been established for cases with this mutation.. We used a JFH1-based recombinant virus with NS5A from a genotype 1b strain to introduce a P32del mutation. We inoculated human hepatocyte chimeric mice with sera from a patient with ledipasvir/sofosbuvir therapy failure carrying a genotype 1b HCV with NS5A L31M and P32del or from a DAA-naïve patient carrying wild-type virus.. JFH1-based chimeric viruses with P32del showed sufficient levels of replication for in vitro assay despite the suppression of viral growth and infectious virus production. Variants with P32del exhibited severe resistance to all tested NS5A inhibitors, including daclatasvir, ledipasvir, elbasvir and velpatasvir, but were as susceptible to NS3/4A inhibitors, NS5B inhibitors, interferon alfa-2b, and ribavirin as wild-type viruses in the in vitro assay. The P32del mutant virus caused persistent infection in all inoculated chimeric mice with high viral titer and frequency. The virus was resistant to the ledipasvir/GS-558093 (a nucleotide analog inhibitor of NS5B polymerase) regimen but susceptible to either simeprevir plus GS-558093 or peg-interferon alfa-2b, compared to the wild-type virus.. Therapies combining at least two drugs among NS3/4A inhibitors, NS5B inhibitors and non-selective antiviral agents may be effective for HCV-infected patients with NS5A-P32del.

Topics: Aged; Animals; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cell Line; Chimera; Drug Resistance, Viral; Drug Therapy, Combination; Fluorenes; Guanosine Monophosphate; Hepacivirus; Hepatitis C; Hepatocytes; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Interferon alpha-2; Interferon-alpha; Male; Mice; Middle Aged; Polyethylene Glycols; Pyrrolidines; Recombinant Proteins; Ribavirin; Sequence Deletion; Serine Proteases; Simeprevir; Valine; Viral Nonstructural Proteins

Direct-acting antiviral drugs to cure infections with Hepatitis C virus (HCV) achieve a sustained virological response (SVR) in more than 90% of adult patients. At present, clinical trials are ongoing and real-life data are still limited in children. Herein, we report two cases of pediatric patients treated with fixed-dose combination of sofosbuvir/ledipasvir, already approved to treat HCV4 genotype. Both young girls achieved SVR even though HCV4 isolates carried L28M and M31L NS5A resistance-associated substitutions (RASs). Therefore, possible effects of these RASs merit further study, especially in children.

Topics: Adolescent; Benzimidazoles; Child; Drug Resistance, Viral; Female; Fluorenes; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C; Humans; Phylogeny; Sofosbuvir; Treatment Outcome; Viral Nonstructural Proteins

 The urgent need in HCV-infected patients with liver disease mandated the rapid implementation of IFN-free DAA combination therapies following their regulatory approval in 2014 and 2015 without full knowledge of the optimal combinations and regimens. Investigating the evolution of the DAA utilization patterns and treatment outcomes could provide learnings for future situations..  This was an analysis of a prospective observational database from the German Hepatitis C Registry (DHC-R) covering a period from May 2014 to September 2015. Adult patients had evidence of chronic HCV GT1 or GT4 infection and were treated with an IFN-free combination regimen of simeprevir (SMV) + sofosbuvir (SOF) or other IFN-free regimens: daclatasvir + sofosbuvir (DCV + SOF), ledipasvir/sofosbuvir (SOF/LDV), paritaprevir/r + ombitasvir ± dasabuvir (PrOD), with or without ribavirine (R)..  A total of 5496 subjects were followed during the period. During this period, clinical recommendations and treatment patterns evolved rapidly in response to new evidence from clinical trials and clinical routine and regulatory approval of additional regimens. High SVR12 rates were seen in this cohort, even in hard-to-treat patient subgroups. In the multivariate analysis, gender, age, advanced cirrhosis, and intensified treatment for cirrhotics were associated with treatment outcome..  Despite limited knowledge of the optimal utilization of the newly approved DAA combinations and treatment durations as well as their comparative efficacy and safety profiles, high SVR rates were achieved regardless of the DAA combination. These outcomes were facilitated by the rapid adaptation of clinical recommendations. Future situations with high unmet medical need may follow a similar approach..  Die dringende Behandlungsbedürftigkeit HCV-infizierter Patienten mit Lebererkrankung verlangte die rasche Einführung IFN-freier DAA-Kombinationstherapien nach ihrer Zulassung in 2014 und 2015 trotz unvollständigem Wissen über deren optimalen Einsatz. Die Untersuchung der Evolution des Einsatzes und der Ergebnisse könnte wichtige Erkenntnisse für zukünftige Situationen bergen..  Diese Analyse einer prospektiven Kohorte des Deutschen Hepatitis C-Registers (DHC-R) deckt den Zeitraum von Mai 2014 bis September 2015 ab. Erwachsene Patienten mit chronischer HCV-GT1 oder GT4-Infektion wurden mit einer IFN-freien Therapie aus Simeprevir (SMV) + Sofosbuvir (SOF), oder anderen IFN-freien Regimen: Daclatasvir + Sofosbuvir (DCV + SOF), Ledipasvir/Sofosbuvir (SOF/LDV), Paritaprevir/r + Ombitasvir ± Dasabuvir (PrOD), mit oder ohne Ribavirin (R) behandelt..  5496 Patienten wurden während des Zeitraums beobachtet. In dieser Periode wandelten sich die klinischen Leitlinien und Behandlungsmuster rasch in Folge neuer Evidenz aus klinischen Studien und klinischer Erfahrung und der Zulassung von neuen Regimen. Hohe SVR12-Raten wurden in dieser Kohorte, selbst in schwierig zu behandelnden Patienten-Subgruppen, beobachtet. Die multivariate Analyse zeigte, dass Geschlecht, Alter, fortgeschrittene Zirrhose und die intensivierte Therapie bei Patienten mit Zirrhose mit dem Behandlungserfolg assoziiert waren..  Trotz begrenzten Wissens um den optimalen Einsatz von neu zugelassenen DAA-Kombinationen und deren Behandlungsdauer sowie dem Vergleich ihrer Wirksamkeits- und Sicherheits-Profile wurden hohe SVR12-Raten mit verschiedenen DAA-Kombinationen erzielt. Diese Ergebnisse wurden unterstützt von einer raschen Adaption klinischer Therapie-Empfehlungen. Zukünftige Szenarien mit einem erheblichen ungedeckten medizinischen Bedarf könnten einem ähnlichen Ansatz folgen.

Topics: Adult; Antiviral Agents; Benzimidazoles; Drug Combinations; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Prospective Studies; Registries; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

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

This study evaluates the safety and efficacy of direct-acting antivirals (DAAs) including sofosbuvir, ledipasvir and daclatasvir in patients with hepatitis C viraemia who were on maintenance haemodialysis.. Data on patients who received sofosbuvir and ribavirin were analysed. Patients who experienced treatment failure with the above regimen received sofosbuvir and ledipasvir for infection with hepatitis C virus (HCV) genotype 1. Those having HCV genotype 3 infection received sofosbuvir and daclatasvir. All treatment regimens were of 12 weeks duration. Side-effects were investigated. The HCV viral load was determined by RT-PCR at 4,16 and 24 weeks after the initiation of therapy; haemoglobin levels and liver function tests were monitored at regular intervals during therapy.. Of the 22 subjects initially treated with sofosbuvir and ribavirin, 72.72% attained sustained virologic response at 12 weeks (SVR12). Four patients experienced treatment failure and received genotype specific therapy. Patients with HCV genotype one received sofosbuvir with ledipasvir. One patient with HCV genotype 3 infection received sofosbuvir and daclatasvir. All of them attained SVR12. A statistically significant reduction in the median serum glutamic-oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (SGPT) were observed from the baseline until the end of treatment. Anaemia was observed in 45% of patients receiving ribavirin.. Our study demonstrates that sofosbuvir-based therapy is efficacious for HCV viraemia in patients on maintenance haemodialysis. The therapy was found to be reasonably safe with no major adverse effects noted with the use of sofosbuvir, ledipasvir or daclatasvir. However, larger studies are needed to validate our results.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; India; Kidney Diseases; Male; Middle Aged; Pyrrolidines; Renal Dialysis; Retrospective Studies; Ribavirin; Sofosbuvir; Sustained Virologic Response; Time Factors; Treatment Outcome; Valine; Viral Load

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 evaluate the impact of ledipasvir on both tenofovir plasma trough concentration and estimated glomerular renal function in human immunodeficiency virus-hepatitis C virus coinfected patients receiving a tenofovir-based antiretroviral regimen and treated with ledipasvir/sofosbuvir. Twenty-six patients [81% male, median age: 51 years; hepatitis C virus genotype 1(75%)/4(15%)] were included. Tenofovir trough concentration (interquartile range) increased from 78 ng ml

Topics: Antiviral Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzimidazoles; Drug Interactions; Drug Therapy, Combination; Female; Fluorenes; Glomerular Filtration Rate; Hepatitis C; HIV Infections; Humans; Male; Middle Aged; Retrospective Studies; Tenofovir

Topics: Adult; Antineoplastic Agents; Antiviral Agents; Benzimidazoles; Drug Therapy; Female; Fluorenes; Hematologic Neoplasms; Hepatitis C; Humans; Male; Middle Aged; Sofosbuvir

Direct-acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon-based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified.. Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation-related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real-time polymerase chain reaction or luciferase assay.. Addition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P ≤ .01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P ≤ .01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT.. For patients with HCV GT2a, GT3a, or GT4a infection, mTOR-based immunosuppressive therapy may be beneficial. CNI-based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection.

Topics: Antiviral Agents; Benzimidazoles; Calcineurin Inhibitors; Carbamates; Cell Line; Cyclosporine; Everolimus; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Immunosuppressive Agents; Liver Transplantation; Pyrrolidines; Sirolimus; Sofosbuvir; Valine; Virus Replication

The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA-positive donor organs are typically not given to patients who have cleared HCV. A 64-year-old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA <15 IU/mL by week 10. At week 18 of a planned 24-week treatment course, the patient underwent deceased-donor LT and received an organ from an anti-HCV-positive donor. Treatment was stopped at LT. At week 3 post LT, HCV RNA was detectable and revealed a genotype 3 HCV infection, compatible with transplantation of an organ with established infection. With retreatment with sofosbuvir, daclatasvir, and ribavirin for 12 weeks, the patient achieved a sustained virologic response. This report highlights how antiviral therapies can be used to optimize the outcomes of HCV-infected transplant patients.

Topics: Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Liver; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Ribavirin; RNA, Viral; Sofosbuvir; Sustained Virologic Response; Tissue Donors; Transplant Recipients; Viral Load

Topics: Adult; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Male; Polyethylene Glycols; Recombinant Proteins; Retreatment; Ribavirin; Sofosbuvir

Hepatitis C Virus (HCV) is a diverse human pathogen which displays ~15% divergence at the subtype level. To facilitate development of antivirals with pan-genotype activity, we developed the first genotype 4d subgenomic replicon, as well as new replicons for genotypes 5a, and 6a. Adaptive mutations developed in these replicons differ greatly across genotypes. Their impacts on the replication capacity were tested using site-directed mutants. In the genotype 4d replicon, single mutations have moderate effect, but the double mutation NS4A-Q34R+NS5A-S232G increased the replication capacity by 161-fold. These new stable replicon cell lines were used to determine the antiviral activity of HCV inhibitors. The NS3 protease inhibitor voxilaprevir, NS5A second generation inhibitor velpatasvir, and NS5B nucleoside analog inhibitor sofosbuvir, had similar antiviral activities across the different genotypes/subtypes tested, while the NS5A first generation inhibitor, ledipasvir, had very good antiviral activity against GT1, 4, 5, and 6 in vitro.

Topics: Antiviral Agents; Benzimidazoles; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Replicon; Viral Nonstructural Proteins; Virus Replication

Hepatitis C virus (HCV) is a highly divergent virus currently classified into seven major genotypes and 86 subtypes (ICTV, June 2017), which can have differing responses to therapy. Accurate genotyping/subtyping using high-resolution HCV subtyping enables confident subtype identification, identifies mixed infections and allows detection of new subtypes. During routine genotyping/subtyping, one sample from an Equatorial Guinea patient could not be classified into any of the subtypes. The complete genomic sequence was compared to reference sequences by phylogenetic and sliding window analysis. Resistance-associated substitutions (RASs) were assessed by deep sequencing. The unclassified HCV genome did not belong to any of the existing genotype 1 (G1) subtypes. Sliding window analysis along the complete genome ruled out recombination phenomena suggesting that it belongs to a new HCV G1 subtype. Two NS5A RASs (L31V+Y93H) were found to be naturally combined in the genome which could limit treatment possibilities in patients infected with this subtype.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Drug Resistance, Viral; Equatorial Guinea; Female; Fluorenes; Gene Expression; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Microbial Sensitivity Tests; Middle Aged; Mutation; Phylogeny; Proline; Pyrrolidines; Sequence Analysis, DNA; Sulfonamides; Uracil; Valine; Viral Nonstructural Proteins

The performances of core-shell 2.7 μm and fully porous sub-2 μm particles packed in narrow diameter columns were compared under the same chromatographic conditions. The stationary phases were compared for fast separation and determination of five new antiviral drugs; daclatasvir, sofosbuvir, velpatasvir, simeprevir, and ledipasvir. The gradient elution was done using ethanol as green organic modifier, which is more environmentally friendly. Although both columns provided very good resolution of the five drugs, core-shell particles had proven to be of better efficiency. Under gradient elution conditions, core-shell particles exhibited faster elution, better peak shape, and enhanced resolution adding to lower system backpressure. The column backpressure on sub-2 μm particles was more than twice that on core-shell particles. This gives a chance to use conventional high-performance liquid chromatography conditions without needing special instrumentation as that required for ultra-high performance liquid chromatography. The method was validated for determination of the five drugs by gradient elution using mobile phase composed of organic modifier ethanol and aqueous part containing 0.75 g sodium octane sufonate and 3.0 g sodium dihydrogen phosphate per liter at pH of 6.15. Detection was done using UV-detector set at 210 nm. The linearity, accuracy, and precision were found very good within the concentration range of 2-200 μg/mL.

Topics: Antiviral Agents; Benzimidazoles; Carbamates; Chromatography, High Pressure Liquid; Fluorenes; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Imidazoles; Molecular Conformation; Particle Size; Porosity; Pyrrolidines; Simeprevir; Sofosbuvir; Surface Properties; Valine

Anti-PD-1 monoclonal antibodies have shown durable long-term survival benefit in patients with metastatic melanoma. Limited evidence exists on the safety and efficacy of PD-1 inhibitors in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections as these patients have traditionally been excluded from clinical trials because of a theoretical risk of immune reconstitution inflammatory syndrome. We aim to determine the safety and efficacy of treatment with PD-1 inhibitors in seven patients with HBV/HCV infection and concurrent metastatic melanoma or non-small-cell lung cancer (NSCLC). We describe seven patients treated with PD-1 inhibitors nivolumab and pembrolizumab for either metastatic melanoma or metastatic NSCLC in the setting of chronic or past HBV/HCV infection. The safety and efficacy of treatment were analysed retrospectively by examining response to treatment, alanine transaminase (ALT) trends and viral load trends. One patient showed an increase in ALT of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 severity that returned to the normal range following treatment of his HCV infection with ledipasvir 90 mg/sofosbuvir 400 mg. An additional four patients showed an increase in ALT of CTCAE grade 1 severity. The remaining two patients experienced no hepatic toxicity, with stable disease continuing after more than 24 cycles of nivolumab. Efficacy was similar to the data of published trials. Our results indicate that patients with metastatic melanoma and NSCLC can be treated safely with PD-1 inhibitors in the context of HBV/HCV infection. However, we recommend that those with active viral hepatitis be monitored closely in consultation with a hepatologist and treated with antiviral therapy if indicated.

Topics: Aged; Antibodies, Monoclonal, Humanized; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Fluorenes; Hepatitis B; Hepatitis C; Humans; Interferons; Lung Neoplasms; Male; Melanoma; Middle Aged; Nivolumab; Programmed Cell Death 1 Receptor; Skin Neoplasms; Sofosbuvir

Topics: Aged; Antiviral Agents; Benzimidazoles; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Male; Sequence Deletion; Sofosbuvir; Treatment Failure; Viral Nonstructural Proteins

Topics: Antiviral Agents; Benzimidazoles; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Fluorenes; Hepatitis C; Humans; Kidney Failure, Chronic; Renal Dialysis; Sofosbuvir

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Cross Infection; Disease Outbreaks; Female; Fluorenes; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Ribavirin; Sofosbuvir; Sustained Virologic Response; Time Factors

A rapid and specific spectrofluorimetric method with higher sensitivity was developed for determination of ledipasvir (LDS) in tablets and human plasma. The proposed method relies on hydrogen bonding formations between the hydroxyl groups of polyoxyethylene 50 stearate and LDS, causing significant enhancement of its native fluorescence. The fluorescence intensity was measured at 430 nm after excitation at 340 nm. The fluorescence-concentration plot was rectilinear over the range 1-400 ng mL

Topics: Benzimidazoles; Chemistry, Pharmaceutical; Drug Stability; Fluorenes; Hepatitis C; Humans; Hydrogen-Ion Concentration; Limit of Detection; Reproducibility of Results; Solvents; Spectrometry, Fluorescence; Sunlight; Surface-Active Agents; Time Factors

Topics: Benzimidazoles; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Japan; Red Cross; Sofosbuvir

Topics: Antiviral Agents; Benzimidazoles; Fluorenes; Hepacivirus; Hepatitis C; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Male; Middle Aged; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Recurrence; Sofosbuvir

Topics: Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Fluorenes; Genotype; Health Status Disparities; Hepacivirus; Hepatitis C; Humans; Sofosbuvir

Topics: Antiviral Agents; Benzimidazoles; Fluorenes; Hepatitis C; Humans; RNA; Sofosbuvir

We experienced two patients with serious arrhythmias associated with the administration of ledipasvir (LDV) and sofosbuvir (SOF). Neither patient took amiodarone, an agent for which concomitant use is prohibited. One patient was 82 years old and hypertensive; the other was 72 years old and had no cardiovascular risk factors such as hypertension or diabetes mellitus. The arrhythmias were both serious ventricular tachycardia (VT) that converted spontaneously to sinus rhythm, without treatment, and both patients had good outcomes. These cases suggest that LDV/SOF may be associated with an increased risk of heart-related events.

Topics: Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Hepatitis C; Humans; Risk Factors; Sofosbuvir; Tachycardia, Ventricular

Topics: Antiviral Agents; Benzimidazoles; Drug Administration Schedule; Drug Therapy, Combination; Evidence-Based Medicine; Fluorenes; Hepatitis C; Humans; Sofosbuvir; Tenofovir; Treatment Outcome

Topics: Benzimidazoles; Coinfection; Fluorenes; Hepacivirus; Hepatitis B virus; Hepatitis C; HIV Infections; Humans; Sofosbuvir

To evaluate the effectiveness and safety of ledipasvir/sofosbuvir (LDV/SOF)±ribavirin (RBV) regimen in a real-world setting.. Patients received a fixed-dose combination tablet containing LDV and SOF with or without RBV, for 8, 12 or 24 weeks. Patients were assessed at baseline, end of treatment, and 12 weeks after the end of treatment. The primary effectiveness endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12).. Of the 86 patients, aged 20-80 years, 82.6% were HCV genotype 1b-infected and 50.0% were cirrhotic. More than half (52.3%) had previously followed pegylated interferon-containing (PEG-IFN) treatment regimens, and 38.5% were null-responders. SVR12 was achieved by 94.2% of patients. All non-responders were cirrhotic: two demonstrated virologic breakthrough and the remaining three relapsed. All patients treated with an 8-week regimen achieved SVR12 despite having high viral load at baseline (HCV RNA of >1 million IU/mL in 8/10 patients, including one with a viral load of >6 million IU/mL). Adverse events were generally mild and transient. Most frequently, fatigue (22.1%), headache (15.1%), and arthralgia (7.0%) were observed. Laboratory abnormalities included anemia and hyperbilirubinemia.. Treatment with LDV/SOF±RBV is an effective and safe option for patients with HCV, including those with advanced liver disease or a history of non-response to PEG-IFN-based therapy.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Female; Fluorenes; Follow-Up Studies; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Ribavirin; Safety; Sofosbuvir; Treatment Outcome

In January 2017, counterfeits of the hepatitis C drug 'HARVONI

Topics: Antiviral Agents; Benzimidazoles; Chromatography, Liquid; Counterfeit Drugs; Drugs, Chinese Herbal; Ephedrine; Fluorenes; Gas Chromatography-Mass Spectrometry; Glycyrrhizic Acid; Hepatitis C; Japan; Magnetic Resonance Spectroscopy; Mass Spectrometry; Sofosbuvir; Tablets; Uridine Monophosphate; Vitamins

We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)-negative donor to three HCV-negative recipients-two renal transplants and one liver. Both renal recipients underwent standard deceased-donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39-year-old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV-infected male partner. Recipient 1 was a 45-year-old man with a history of end-stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62-year-old woman with a history of end-stage renal disease caused by hypertension and insulin-dependent diabetes. Recipient 3 was a 42-year-old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post-transplant follow-up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipient's liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor-derived HCV in transplant recipients.

Topics: Acetaminophen; Adult; Allografts; Antiviral Agents; Benzimidazoles; Blood-Borne Pathogens; Chemical and Drug Induced Liver Injury; Disease Transmission, Infectious; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C; Humans; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Polymerase Chain Reaction; Ribavirin; RNA, Viral; Sofosbuvir; Transplant Recipients; Viral Load

Second-generation direct-acting antiviral agents are integral to treatment of hepatitis C (HCV) infection. Eight-week courses of ledipasvir/sofosbuvir (LDV/SOF) have been supported in some studies, but data are limited on efficacy in real-world use. Controversy exists regarding applicability of clinical trials to real-world effectiveness. We report virologic responses of patients with HCV genotype 1 infection receiving LDV/SOF for 8 or 12 weeks in a large integrated healthcare system.. All patients receiving LDV/SOF, without ribavirin, were identified from pharmacy records, and outcomes are reported. Only treatment-naïve patients without evidence of cirrhosis and hepatitis C viral load less than 6 million IU/ml were candidates for 8-week therapy. Treatment was at clinician discretion, but delivered by a multidisciplinary team and reviewed for appropriateness and adherence to these criteria by one of the authors, all experienced in hepatitis C treatment. Sustained viral response at 12 weeks (SVR 12) was contrasted between those receiving 8 and those receiving 12 weeks of treatment.. Completed prescriptions for LDV/SOF, without ribavirin, as of 30 September 2015 were identified in 1021 patients. Five patients discontinued therapy due to medical reasons and 35 had incomplete follow-up viral load data, thus there were 981 evaluable patients: 377 treated for 8 weeks and 604 treated for 12 weeks. SVR 12 was virtually identical at 93.6 and 93.5%, respectively. Baseline characteristics differed between the two groups, as only treatment-naïve, non-cirrhotic, non-HIV-infected patients were eligible for an 8-week course of therapy.. Eight-week courses of LDV/SOF are comparable to 12-week courses in real-world use among selected patients supported by a multidisciplinary team.

Topics: Antiviral Agents; Benzimidazoles; Delivery of Health Care, Integrated; Fluorenes; Hepatitis C; Humans; Sofosbuvir; Time Factors

New hepatitis C virus (HCV) therapies report cure rates of ~90% but are expensive. Identification of predictors for treatment failure could help decrease health care costs, limit unnecessary drug exposure and adverse events, and prevent drug-drug interactions. Failure to achieve rapid viral response (RVR), defined as detectable viral load at 4 weeks, has previously been identified as a predictor of treatment failure with some previous HCV therapies.. To evaluate RVR, and other potential variables, as predictors of treatment failure in patients treated with ledipasvir and sofosbuvir (LDV/SOF).. A retrospective, case-control analysis of adult veterans treated with LDV/SOF was conducted. Included patients had a viral load obtained between weeks 3 and 6 of therapy (RVR) and between weeks 12 and 16 after the end of therapy for sustained viral response (SVR12) evaluation. Identified SVR12 failures (viral load detectable) constituted the case population. The control population was randomly selected in a 1:4 case: control ratio from all identified SVR12 successes.. In all, 12 SVR12 failures were identified; 48 of 144 SVR12 successes were randomly selected for inclusion. Overall failure rate was 7.7% (12/156). Univariate analysis identified histamine-2 receptor antagonist, previous treatment failure, and pretreatment creatinine clearance (CrCl; Cockcroft-Gault) >90 mL/min as potential predictors of SVR12 failure; these variables were included in the regression model with RVR per protocol. In multivariate analysis, pretreatment CrCl >90 mL/min was independently associated with SVR12 failure (odds ratio = 7.27; 95% CI = 1.33 to 39.72; P = 0.022).. Patients with pretreatment CrCl >90 mL/min were more likely to fail SVR12 than patients with CrCl <90 mL/min.

Topics: Aged; Antiviral Agents; Benzimidazoles; Case-Control Studies; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Odds Ratio; Retrospective Studies; Sofosbuvir; Treatment Failure; Treatment Outcome; Viral Load

Hepatitis C virus (HCV) infection is associated with a particularly poor outcome after liver transplantation. In December 2014, sofosbuvir/ledipasvir (SOF/LDV) fixed-dose combination (FDC) was approved for HCV genotype 1 and 4 in Europe. In orthotopic liver transplantation (OLT) recipients, the interferon-free treatment of HCV re-infection with novel direct-acting antivirals has been demonstrated to be safe and effective in clinical trials, but real-world data are missing. The aim of this study was to investigate the safety and efficacy of SOF/LDV FDC in OLT recipients in the real-life setting.. All consecutive OLT patients started on SOF/LDV FDC for 12 or 24 weeks at the University Medical Center Hamburg-Eppendorf and Medical School Hannover between October 2014 and August 2015 were retrospectively analyzed (n = 30). The primary efficacy endpoint was sustained virological response (SVR), i.e., absence of viremia 12 weeks after end of treatment (SVR 12). Liver function tests, creatinine, blood count, and HCV RNA (by polymerase chain reaction assay) were determined at each visit.. SVR was achieved in 29/30 patients (96.67%) treated with SOF/LDV ± ribavirin (RBV) for 12 (n = 4) or 24 weeks (n = 25). Twenty-five patients (86.2%) received RBV. However, in 15 of the 25 patients, RBV administration had to be discontinued because of severe anemia (57.7%). One RBV-treated patient died of a myocardial infarction during antiviral therapy; this event was most likely not directly related to SOF/LDV. Aside from RBV-associated anemia, no severe side effects of the antiviral regimen were observed.. Antiviral treatment with SOF/LDV is highly effective, safe, and well tolerated in OLT recipients. The addition of RBV often results in severe anemia, requiring dose reduction or discontinuation.

Topics: Aged; Alanine Transaminase; Antiviral Agents; Aspartate Aminotransferases; Benzimidazoles; Europe; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Ribavirin; Sofosbuvir; Treatment Outcome

Topics: Antiviral Agents; Benzimidazoles; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Therapy, Combination; Fluorenes; Hepatitis C; HIV Infections; Humans; Sofosbuvir

Little is known on the cost-effectiveness of novel regimens for hepatitis C virus (HCV) compared with standard-of-care with pegylated interferon (pegIFN) and ribavirin (RBV) therapy in developing countries. We evaluated cost-effectiveness of sofosbuvir/ledipasvir for 12 weeks compared with a 48-week pegIFN-RBV regimen in Chinese patients with genotype 1b HCV infection by economic regions.. A decision analytic Markov model was developed to estimate quality-adjusted-life-years, lifetime cost of HCV infection and incremental cost-effectiveness ratios (ICERs). SVR rates and direct medical costs were obtained from real-world data. Parameter uncertainty was assessed by one-way and probabilistic sensitivity analyses. Threshold analysis was conducted to estimate the price which can make the regimen cost-effective and affordable.. Sofosbuvir/ledipasvir was cost-effective in treatment-experienced patients with an ICER of US$21,612. It varied by economic regions. The probability of cost-effectiveness was 18% and 47% for treatment-naive and experienced patients, and it ranged from 15% in treatment-naïve patients in Central-China to 64% in treatment-experienced patients in Eastern-China. The price of 12-week sofosbuvir/ledipasvir treatment needs to be reduced by at least 81% to US$18,185 to make the regimen cost-effective in all patients at WTP of one time GDP per capita. The price has to be US$105 to make the regimen affordable in average patients in China.. Sofosbuvir/ledipasvir regimen is not cost-effective in most Chinese patients with genotype 1b HCV infection. The results vary by economic regions. Drug price of sofosbuvir/ledipasvir needs to be substantially reduced when entering the market in China to ensure the widest accessibility.

Topics: Asian People; Benzimidazoles; China; Costs and Cost Analysis; Female; Fluorenes; Hepacivirus; Hepatitis C; Humans; Male; Markov Chains; Models, Economic; Sofosbuvir

Currently there are no all-oral treatment regimens for HCV in patients coinfected with HBV. In this pilot study, we evaluated whether ledipasvir and sofosbuvir therapy can suppress HCV infection in patients coinfected with HBV.. Patients with HBV and genotype-1 HCV received 90 mg ledipasvir and 400 mg sofosbuvir daily for 12 weeks. The efficacy end point was sustained virological response (HCV RNA <15 IU/ml) 12 weeks after the end of treatment.. Of the eight patients enrolled, six (75%) were male, five (63%) were Polynesian, seven (88%) had the CC IL28B genotype and two (25%) had cirrhosis. All eight patients (100%; 95% CI 63%, 100%) reached the primary end point of HCV RNA <15 IU/ml 12 weeks after treatment. In seven of eight patients (88%), serum HBV DNA levels increased during treatment, but none of the increases were greater than 20,000 IU/ml, and none were associated with clinical HBV flares or required treatment. The most common adverse events were viral infection (63%), fatigue (25%) and upper respiratory tract infection (25%). No patients had serious adverse events and none discontinued treatment for any reason.. In this small sample, 12 weeks of ledipasvir/sofosbuvir was a safe and effective treatment for genotype-1 HCV infection in patients coinfected with HBV. Larger studies with longer follow-up are warranted.

Topics: Aged; Antiviral Agents; Benzimidazoles; Coinfection; DNA, Viral; Drug Therapy, Combination; Female; Fluorenes; Hepatitis B; Hepatitis C; Humans; Male; Middle Aged; Pilot Projects; Sofosbuvir

Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection, with superior efficacy and safety compared to interferon-based therapies. Despite these improvements, drug interactions with DAAs exist and may be clinically relevant in human immunodeficiency virus (HIV)-coinfected patients. We present a case of nephrotoxicity associated with concomitant use of tenofovir disoproxil fumarate (TDF) and ledipasvir-sofosbuvir (LDV-SOF). A 56-year-old woman with HIV infection who had been taking efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) for 6 years developed acute kidney injury 8 weeks after initiating LDV-SOF for the treatment of HCV infection. Her serum creatinine concentration peaked at 10 mg/dL, compared with her baseline concentration of 0.9-1 mg/dL. Kidney biopsy revealed acute tubular necrosis and acute interstitial nephritis. Both LDV-SOF and TDF were discontinued, and the patient's serum creatinine concentration decreased to 1.3 mg/dL over the following 6 weeks. We postulate that this adverse drug reaction may have been secondary to the known interaction between ledipasvir and TDF, which results in increased TDF exposure. Despite knowledge of this interaction, LDV-SOF is commonly prescribed in patients with HIV-HCV coinfection, as patients who received LDV-SOF- and TDF-containing regimens in trials have not demonstrated adverse clinical consequences related to this interaction. This case highlights the rare but potentially serious nephrotoxicity that can result from TDF toxicity and serves as a reminder to clinicians to implement close renal function monitoring in patients receiving both LDV-SOF and TDF. Clinicians prescribing LDV-SOF to HCV-HIV-coinfected patients receiving TDF should be cautious about use with concomitant nephrotoxic medications and monitor markers of tubular dysfunction, including urinary phosphorus excretion, and renal injury at baseline and week 4 of therapy. Tenofovir alafenamide and alternative DAAs may also have a role in the management of patients at high risk for renal adverse effects from TDF.

Topics: Antiviral Agents; Benzimidazoles; Coinfection; Drug Therapy, Combination; Female; Fluorenes; Hepatitis C; HIV Infections; Humans; Kidney; Middle Aged; Sofosbuvir; Tenofovir

Topics: Antiviral Agents; Benzimidazoles; Female; Fluorenes; Hepacivirus; Hepatitis C; Humans; Middle Aged; Sofosbuvir

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

Topics: Antiviral Agents; Benzimidazoles; Cost-Benefit Analysis; Costs and Cost Analysis; Drug Costs; Drug Industry; Fluorenes; Hepatitis C; Humans; Sofosbuvir; United Kingdom

Hepatitis C (HC) is a very relevant negative prognosis factor for graft and transplant recipient survival. New direct-acting antivirals (DAAs) allow us to solve this problem in an effective way. It is crucial to understand their real impact in our daily practice. We analyzed treatment results with DAA, free of interferon, in kidney transplant recipients (KTRs) from 15 Spanish hospitals (Grupo Español de Actualización en Trasplante), regarding effectiveness, tolerance, and impact on immunosuppression, renal function-proteinuria, and diabetes. One hundred nineteen KTRs were included (9 combined liver-kidney transplants). The main DAA used was sofobusvir (91%) combined with ledipasvir (55%), simeprevir (14%), or daclatasvir (13%); in 9 cases (7%), a paritaprevir-ritonavir-ombitasvir-dasabuvir combination (3D) was used; Ribavirin was used as a coadjuvant in 18%. Side effects were limited (23.5%) and without relevance in general, except in 7 patients for whom we needed to interrupt the treatment due to neurotoxicity (1) caused by drug interaction (3D and tacrolimus) or anemia (3) by Ribavirin or others. Ninety-four patients had completed the treatment when data were analyzed: virological response was seen in 97.8% % of cases. Liver function analysis improved: 84% normal versus 21% before starting the treatment (P < .001). Renal function and proteinuria did not change. Tacrolimus level at the end of DAA-treatment was significantly lower with respect to the beginning (5.8 ± 2.1 ng/mL vs. 7.4 ± 1.8 ng/mL, P = .03), despite a slight increase in the dose (2.6 mg/d vs. 2.3 mg/d, P = .17). DAA are highly effective in the treatment of hepatitis C in KTRs with good tolerance in general, making it possible to solve the problem and have a good chance to improve the prognosis in our transplantation patients. The use of these therapies in KTRs requires special control and coordination with digestive professionals, especially if 3D or Ribavirin is used.

Topics: Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C; Humans; Imidazoles; Immunosuppression Therapy; Kidney Transplantation; Lactams, Macrocyclic; Macrocyclic Compounds; Postoperative Complications; Proline; Prospective Studies; Pyrrolidines; Retrospective Studies; Ribavirin; Simeprevir; Sofosbuvir; Spain; Sulfonamides; Treatment Outcome; Valine

It has been reported that several baseline polymorphisms of direct-acting antivirals (DAAs) agents resistance-associated variants (RAVs) would affect the treatment outcomes of patients chronically infected with hepatitis C virus (CHC). The aim of this study is to investigate the prevalence of DAAs RAVs in treatment-naÏve GT1b CHC patients.. Direct sequencing and ultra-deep sequencing of the HCV NS3, NS5A, and NS5B gene were performed in baseline serum samples of treatment-naÏve patients infected with genotype 1b hepatitis C virus (HCVs).. One hundred and sixty CHC patients were studied. Complete sequence information was obtained for 145 patients (NS3), 148 patients (NS5A), and 137 patients (NS5B). Treatment-failure associated variants of DAAs were detected: 56.6% (82/145) of the patients presented S122G for simeprevir (NS3 protease inhibitor); 10.1% (14/148) of the patients presented Y93H for daclatasvir and ledipasvir (NS5A protein inhibitors); 94.2% (129/137) of the patients presented C316N for sofosbuvir (NS5B polymerase inhibitor). Nearly, all of the DAAs RAVs detected by ultra-deep sequencing could be detected by direct sequencing.. The majority of genotype 1b CHC patients in China present a virus population carrying HCV DAAs RAVs. Pretreatment sequencing of HCV genome might need to be performed when patients infected with GT1b HCV receiving DAAs-containing regimens in China. Population sequencing would be quite quantified for the work.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Carbamates; China; Drug Resistance, Viral; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; Male; Middle Aged; Polymorphism, Genetic; Pyrrolidines; Simeprevir; Valine

Topics: Acute-On-Chronic Liver Failure; Aged; Antiviral Agents; Benzimidazoles; End Stage Liver Disease; Fatal Outcome; Fluorenes; Hepacivirus; Hepatitis C; Humans; Male; Sofosbuvir

Topics: Antiviral Agents; Benzimidazoles; Drug Combinations; Fluorenes; Hepatitis C; Humans; Prescription Fees; Sofosbuvir; United States; Uridine Monophosphate