mk-8742 and Hepatitis-C

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

Therapeutic options for patients with HCV-related liver disease have increased over the last two decades. In fact, the old standard of care based on the combination of pegylated interferon and ribavirin did not result in satisfactory eradication rates, particularly in patients with liver cirrhosis. With the advent of direct-acting antivirals (DAAs), higher rates of viral clearance became possible and, patients with contraindications to interferon obtained access to treatment. However, several concerns have been raised regarding first-generation DAAs, namely their high costs, and the emergence of resistant-associated variants with low susceptibility to these drugs.. In this review, the authors discuss the data about the efficacy and safety of the main anti-HCV direct-acting antivirals currently in the pipeline. Furthermore, they evaluate the impact of these drugs on the therapeutic options currently available for HCV patients.. The results of trials evaluating the effectiveness of new DAAs are encouraging. These new antivirals lead to high rates of viral eradication without relevant adverse reactions and seem to be effective regardless of viral genotypes, presence of resistant-associated variants or advanced liver disease. Consequently, with the advent of this new family of drugs, chronic HCV-related hepatitis may become a curable disease.

Topics: Amides; Antiviral Agents; Benzazepines; Benzofurans; Carbamates; Cyclopropanes; Drugs, Investigational; Hepatitis C; Humans; Imidazoles; Indoles; Isoquinolines; Quinoxalines; Sofosbuvir; Sulfonamides

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Fatigue; Hepatitis C; Humans; Imidazoles; Nausea; Quinoxalines; Sulfonamides

Chronic hepatitis C virus (HCV) infection is a leading cause of health care utilization in the USA. Incidence of cirrhosis from HCV is expected to rise in the near future, further increasing this burden. There is a high medical need for effective, tolerable, safe, all-oral, short-duration therapy. To this end, several new direct-acting antiviral agents have been developed and have shown excellent sustained virologic response rates. However, patients who have previously failed treatment or who have developed cirrhosis, renal failure, or human immunodeficiency virus coinfection remain difficult-to-treat subgroups. An all-oral agent that is effective in many of these subgroups would simplify treatment of HCV greatly. Here we review currently available data on the efficacy, treatment duration, tolerability, and safety of combination of grazoprevir and elbasvir.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Hepatitis C; Humans; Imidazoles; Quinoxalines; Sulfonamides

Hepatitis C virus (HCV) infection is an increasing public health concern with an estimated 184 million people infected worldwide and approximately 350,000 deaths yearly from HCV-related complications. There is a compelling medical need for new anti-HCV therapeutic agents that are potent, tolerable, safe, completely oral and with shorter treatment duration. To this end, a plethora of direct-acting antivirals have been developed and regulatory authorities have approved nine new molecules for the treatment of chronic hepatitis C (CHC). In January 2016, the U.S. Food and Drug Administration approved the fixed-dose combination medication incorporating the NS3/NS4A inhibitor grazoprevir (formerly MK-5172) and the NS5A inhibitor elbasvir (formerly MK-8742), with or without ribavirin, for the treatment of CHC genotypes 1 and 4 infection in adult patients. This all-oral combination has proven potent and safe even in patients with advanced kidney disease. Herein, we review the pharmacokinetics, clinical efficacy and safety profile pertaining to grazoprevir/elbasvir fixed-dose combination for CHC.

Topics: Amides; Animals; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Combinations; Hepacivirus; Hepatitis C; Humans; Imidazoles; Quinoxalines; Sulfonamides

About 2% of the world's population is estimated to be chronically infected with hepatitis C virus (HCV). These chronic carriers are at risk of developing liver cirrhosis and its complications. Successful treatment of HCV infection is associated with improved quality of life and increased survival. Antiviral approaches were formerly based on interferon and therefore all patients with a contraindication to interferon were excluded from treatment (e.g., patients with decompensated disease, severe impairment of other organs). Very recently, interferon-free combinations have become available for genotypes 2 and 3. This review focuses on the most recently reported data on the various interferon-free combinations used (namely, sofosbuvir-based combinations, the ABT-450/ombitasvir/dasabuvir/ribavirin combination, the daclatasvir/asunaprevir combination, and the MK-5172/MK-8742 combination). All these combinations yielded amazing results in terms of efficacy (90-100%), tolerability and safety. If the problem of the high cost is overcome, interferon-free therapies will lead to what has long been a chimera, namely, an HCV-free world.

Topics: 2-Naphthylamine; Amides; Anilides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials as Topic; Cyclopropanes; Disease Eradication; Drug Combinations; Hepacivirus; Hepatitis C; Humans; Imidazoles; Isoquinolines; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Pyrrolidines; Quinoxalines; Ribavirin; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine

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

Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of 8 weeks fixed-dose combination of grazoprevir-elbasvir in treatment-naïve patients, with non-severe fibrosis.. HCV mono-infected and treatment naïve patients with non-severe fibrosis (Fibroscan. Naïve patients with genotype 1b and non-severe fibrosis can achieve an SVR12 of 97% and an SVR24 of 95%. Then, these patients can be treated with grazoprevir-elbasvir for 8 weeks.

Topics: Adult; Aged; Amides; Antiviral Agents; Asia; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Europe; Female; Fibrosis; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Ribavirin; Sulfonamides

Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection.. To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir.. Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg.. The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir.. Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Topics: Adult; Amides; Antiretroviral Therapy, Highly Active; Antiviral Agents; Benzofurans; Carbamates; Chromatography, Liquid; Coinfection; Cyclopropanes; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Imidazoles; Male; Mass Spectrometry; Middle Aged; Oxazines; Piperazines; Pyridones; Quinoxalines; Raltegravir Potassium; Sulfonamides; Treatment Outcome; Young Adult

Direct-acting antivirals effectively treat chronic hepatitis C virus (HCV) infection but there is a paucity of data on their efficacy for acute HCV, when immediate treatment could prevent onward transmission. We assessed the efficacy of grazoprevir plus elbasvir treatment in acute HCV infection and investigated whether treatment can be shortened during the acute phase of HCV infection.. The Dutch Acute HCV in HIV study number 2 (DAHHS2) study was a single-arm, open-label, multicentre, phase 3b trial. Adult patients (≥18 years) with acute HCV genotype 1 or 4 infection (duration of infection 26 weeks or less, according to presumed day of infection) were recruited at 15 HIV outpatient clinics in the Netherlands and Belgium. All patients were treated with 8 weeks of grazoprevir 100 mg plus elbasvir 50 mg administered as one oral fixed drug combination tablet once daily. The primary efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12; HCV RNA <15 IU/mL) in all patients who started treatment. Reinfection with a different HCV virus was not considered treatment failure in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT02600325.. Between Feb 15, 2016, and March 2, 2018, we assessed 146 patients with a recently acquired HCV infection for eligibility, of whom 86 were enrolled and 80 initiated therapy, all within 6 months after infection. All patients who initiated treatment completed treatment and no patients were lost to follow-up. 79 (99%, 95% CI 93-100) of 80 patients achieved SVR12. All 14 patients who were infected with a virus carrying a clinically significant polymorphism in NS5A were cured. If reinfections were considered treatment failures, 75 (94%, 86-98) of 80 patients achieved SVR12. Two serious adverse events not considered related to the treatment were reported (traumatic rectal bleeding and low back surgery). The most common adverse event was a new sexually transmitted infection (19 [24%] of 80 patients). The most common reported possibly drug-related adverse events were fatigue (11 [14%] patients), headache (seven [9%] patients), insomnia (seven [9%] patients), mood changes (five [6%] patients), dyspepsia (five [6%] patients), concentration impairment (four [5%] patients), and dizziness (4 [5%] patients), all of which were regarded as mild by the treating physician. No adverse events led to study drug discontinuation.. 8 weeks of grazoprevir plus elbasvir was highly effective for the treatment of acute HCV genotype 1 or 4 infection. The ability to treat acute HCV immediately after diagnosis might help physicians to reach the WHO goal of HCV elimination by 2030.. Merck Sharp and Dohme and Health-Holland.

Topics: Acute Disease; Administration, Oral; Adult; Amides; Antiviral Agents; Belgium; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Incidence; Male; Middle Aged; Netherlands; Quinoxalines; Sexually Transmitted Diseases; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Failure; Treatment Outcome

Topics: Adult; Amides; Antiviral Agents; Atazanavir Sulfate; Benzofurans; Carbamates; Cyclopropanes; Darunavir; Drug Interactions; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; Lopinavir; Male; Middle Aged; Quinoxalines; Ritonavir; Sulfonamides; Viral Nonstructural Proteins; Young Adult

The advent of direct-acting antiviral therapy for hepatitis C virus (HCV) has generated tremendous interest in transplanting organs from HCV-infected donors. We conducted a single-arm trial of orthotopic heart transplantation (OHT) from HCV-infected donors into uninfected recipients, followed by elbasvir/grazoprevir treatment after recipient HCV was first detected (NCT03146741; sponsor: Merck). We enrolled OHT candidates aged 40-65 years; left ventricular assist device (LVAD) support and liver disease were exclusions. We accepted hearts from HCV-genotype 1 donors. From May 16, 2017 to May 10, 2018, 20 patients consented for screening and enrolled, and 10 (median age 52.5 years; 80% male) underwent OHT. The median wait from UNOS opt-in for HCV nucleic-acid-test (NAT)+ donor offers to OHT was 39 days (interquartile range [IQR] 17-57). The median donor age was 34 years (IQR 31-37). Initial recipient HCV RNA levels ranged from 25 IU/mL to 40 million IU/mL, but all 10 patients had rapid decline in HCV NAT after elbasvir/grazoprevir treatment. Nine recipients achieved sustained virologic response at 12 weeks (SVR-12). The 10th recipient had a positive cross-match, experienced antibody-mediated rejection and multi-organ failure, and died on day 79. No serious adverse events occurred from HCV transmission or treatment. These short-term results suggest that HCV-negative candidates transplanted with HCV-infected hearts have acceptable outcomes.

Topics: Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Female; Genotype; Graft Rejection; Heart Failure; Heart Transplantation; Heart-Assist Devices; Hepacivirus; Hepatitis C; Humans; Imidazoles; Male; Middle Aged; Postoperative Period; Quinoxalines; RNA, Viral; Sulfonamides; Sustained Virologic Response; Time Factors; Tissue and Organ Procurement; Treatment Outcome; Viral Load; Waiting Lists

Despite highly effective direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection, some patients experience virological relapse. Salvage regimens should include multiple agents to suppress emergence of resistance-associated substitutions (RAS) and minimise treatment failure. The combination of sofosbuvir (SOF) and elbasvir/grazoprevir (ELB/GZR) ±ribavirin (RBV) is an effective retreatment strategy for HCV genotype (GT)1 and 4 infection. We hypothesised that SOF and ELB/GZR (±RBV) would also be an effective salvage regimen for DAA-experienced GT3 patients.. We evaluated the efficacy and safety of SOF/ELB/GZR ± RBV in DAA-experienced participants with chronic HCV infection who had prior relapse. Participants were treated at four hospitals between December 2016 and March 2018 for either 12- or 16-weeks. The primary endpoint was sustained virological response at week 12 post-treatment (SVR12) using intention-to-treat analysis.. There were 40 participants included in the analysis. The mean age was 53 years, 53% had GT3, 33% had GT1 infection and 63% had cirrhosis. Fifty-eight percent were treated for 12 weeks, 42% were treated for 16 weeks and 90% received RBV. The SVR12 rate was 98% overall, 100% in non-GT3 participants and 95% in GT3 participants. One GT3 cirrhotic participant relapsed. ELB/GZR was stopped at week 6 in one GT3 cirrhotic participant who switched to SOF/velpatasvir/RBV for a further 12 weeks and achieved SVR12. RBV dose reduction was required in two participants. Treatment was otherwise well tolerated.. The combination of SOF/ELB/GZR ± RBV is effective and safe for difficult-to-cure patients who relapse after first-line DAA, including those with cirrhosis and GT3 infection.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Recurrence; Ribavirin; Salvage Therapy; Sofosbuvir; Sulfonamides; Sustained Virologic Response

Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource.. To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non-HCV-infected recipients (that is, HCV D+/R- transplantation).. Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649).. Single center.. 10 HCV D+/R- kidney transplant candidates older than 50 years with no available living donors.. Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR-EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR-EBR for 12 weeks of triple therapy.. The primary safety outcome was the incidence of adverse events related to GZR-EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis.. Among 10 HCV D+/R- transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment.. Nonrandomized study design and a small number of patients.. Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R- kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection.. Merck Sharp & Dohme.

Topics: Adolescent; Adult; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Feasibility Studies; Female; Genotype; Graft Rejection; Graft Survival; Hepatitis C; Humans; Imidazoles; Kidney; Kidney Transplantation; Male; Middle Aged; Quinoxalines; RNA, Viral; Sofosbuvir; Sulfonamides; Tissue Donors; Treatment Outcome

Direct-acting antivirals (DAAs) targeting NS5A are broadly effective against hepatitis C virus (HCV) infections, but sustained virological response rates are generally lower in patients infected with genotype (gt)-1a than gt-1b viruses. The explanation for this remains uncertain. Here, we adopted a highly accurate, ultra-deep primer ID sequencing approach to intensively study serial changes in the NS5A-coding region of HCV in gt-1a- and gt-1b-infected subjects receiving a short course of monotherapy with the NS5A inhibitor, elbasvir. Low or undetectable levels of viremia precluded on-treatment analysis in gt-1b-infected subjects, but variants with the resistance-associated substitution (RAS) Y93H in NS5A dominated rebounding virus populations following cessation of treatment. These variants persisted until the end of the study, two months later. In contrast, while Y93H emerged in multiple lineages and became dominant in subjects with gt-1a virus, these haplotypes rapidly decreased in frequency off therapy. Substitutions at Q30 and L31 emerged in distinctly independent lineages at later time points, ultimately coming to dominate the virus population off therapy. Consistent with this, cell culture studies with gt-1a and gt-1b reporter viruses and replicons demonstrated that Y93H confers a much greater loss of replicative fitness in gt-1a than gt-1b virus, and that L31M/V both compensates for the loss of fitness associated with Q30R (but not Y93H) and also boosts drug resistance. These observations show how differences in the impact of RASs on drug resistance and replicative fitness influence the evolution of gt-1a and gt-1b viruses during monotherapy with an antiviral targeting NS5A.

Topics: Antiviral Agents; Benzofurans; Drug Resistance, Viral; Genetic Fitness; Genotype; Hepacivirus; Hepatitis C; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; Phylogeny; Replicon; Sustained Virologic Response; Treatment Outcome; Viral Nonstructural Proteins; Viremia; Virus Replication

Direct-acting antiviral agents (DAAs) represent the standard of care for patients with hepatitis C virus (HCV) infection. Combining DAAs with different mechanisms may allow for shorter treatment durations that are effective across multiple genotypes. The aim of the C-SWIFT study was to identify the minimum effective treatment duration across multiple genotypes. C-SWIFT was an open-label, single-center trial in treatment-naïve patients with chronic HCV genotype (GT)1 or 3 infection. All patients received elbasvir (EBR) 50 mg/grazoprevir (GZR) 100 mg with sofosbuvir (SOF) 400 mg for 4-12 weeks. Patients with GT1 infection who failed therapy were eligible for retreatment with EBR/GZR+SOF and ribavirin for 12 weeks. The primary efficacy endpoint was sustained virological response [SVR]12 (SVR of HCV RNA <15 IU/mL 12 weeks after the end of therapy). Rates of SVR12 were 32% (10 of 31) and 87% (26 of 30) in patients without cirrhosis with GT1 infection treated for 4 and 6 weeks and 80% (16 of 20) and 81% (17 of 21) in GT1-infected patients with cirrhosis treated for 6 and 8 weeks. Among GT3-infected patients without cirrhosis, SVR12 was 93% (14 of 15) and 100% (14 of 14) after 8 and 12 weeks. SVR12 in GT3-infected patients with cirrhosis was 83% (10 of 12) after 12 weeks of treatment. Twenty-three GT1-infected patients who relapsed following initial treatment completed retreatment; all achieved SVR12. In the initial treatment phase, there was one serious adverse event of pneumonia, which led to treatment discontinuation, and during retreatment, 1 patient discontinued ribavirin because of pruritus.. Data from this study support the use of 8-week treatment regimens that maintain high efficacy, even for patients with HCV GT3 infection. Retreatment of patients who failed short-duration therapy was achieved through extended treatment duration and addition of ribavirin. (Hepatology 2017;65:439-450).

Topics: Adult; Aged; Amides; Benzofurans; Carbamates; Confidence Intervals; Cyclopropanes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Prospective Studies; Quinoxalines; RNA, Viral; Sulfonamides; Time Factors; Treatment Outcome; Viral Load

The recommended treatment duration of hepatitis C virus (HCV) genotype 1a (GT1a) infection with elbasvir/grazoprevir (EBR/GZR) in the presence of a high baseline viral load and resistance associated substitutions (RAS) is 16 weeks with ribavirin added. The objective of this study was to evaluate the real-world effectiveness of 12 weeks of EBR/GZR without ribavirin and regardless of baseline viral load and RAS testing.. This retrospective, observational cohort study was performed at five Norwegian hospitals that did not systematically utilize RAS testing. All adult patients with chronic HCV GT1a and compensated liver disease who had received 12 weeks of EBR/GZR without ribavirin and baseline RAS testing, were included. The primary endpoint was sustained virologic response at week 12 (SVR12), or if not available, at week 4 (SVR4).. We included 433 patients and attained SVR data on 388. The mean age was 45.7 years (22-73 years). 67.2% were male. HIV co-infection was present in 3.8% (16/424) and cirrhosis in 4% (17/424). The viral load was >800 000 IU/mL in 55.0% (235/427) of patients. Overall SVR was achieved in 97.2% (377/388). SVR was achieved in 98.3% (169/172) of those with viral load ≤800 000 IU/mL and in 96.2% (202/210) of those with viral load >800 000 IU/mL.. We observed high SVR rates among patients with HCV GT1a infection treated with EBR/GZR for 12 weeks without ribavirin, with no regard to baseline viral load and no RAS testing.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Male; Middle Aged; Retrospective Studies; Ribavirin

Topics: Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Quinoxalines; Sulfonamides

Approximately 3.5 million children and adolescents worldwide are chronically infected with HCV. This study uses pharmacokinetic modeling to identify pediatric doses of elbasvir/grazoprevir (EBR/GZR) that achieve plasma concentrations similar to those seen in adults receiving the approved fixed-dose combination regimen of EBR/GZR.. We conducted a nonrandomized, single-arm, multicenter, open-label phase 2b trial in children and adolescents aged 3 to <18 years with chronic HCV genotype 1 or 4 infection (NCT03379506). Pharmacokinetic data were used to bridge efficacy and safety data from adults to children in a stepwise (oldest to youngest) manner. A total of 57 participants were enrolled: cohort 1 (aged 12 to <18 y), n=22; cohort 2 (aged 7 to <12 y), n=17; and cohort 3 (aged 3 to <7 y), n=18.. Steady-state plasma exposures were achieved by week 4 for EBR and GZR in all cohorts and daily dosing achieved geometric mean steady-state area under the concentration-time curve at 0-24 hours that fell within comparability bounds established for adults. All participants achieved sustained virologic response 12 weeks after completing treatment (ie, undetectable HCV RNA 12 wk following completion of treatment). Headache (n=4), fatigue (n=4), and nausea (n=2) were the most common treatment-related adverse events (all mild or moderate); no participant discontinued because of an adverse event.. Pediatric EBR/GZR pharmacokinetic models were successfully developed based on complex adult population pharmacokinetic models. At appropriate age-related doses, EBR/GZR is safe and effective in pediatric and adolescent participants with HCV infection.

Topics: Adolescent; Adult; Antiviral Agents; Child; Genotype; Hepacivirus; Hepatitis C; Humans; Quinoxalines

Direct Acting Antivirals(DAAs) achieve the highest rate of sustained viral response(SVR) in patients with genotype-1b(G1b) Hepatitis C virus(HCV) infection. Reducing treatment duration can simplify the management and improve adherence of therapy.. The study evaluates the efficacy of 8 weeks of elbasvir/grazoprevir regimen in 75 treatment-naïve(TN), G1b patients with mild-moderate fibrosis(Liver Stiffness by Fibroscan® <9.0 kPa). Viral load(VL) has been evaluated by Roche TaqMan RT-PCR(LLOQ<15 IU/ml).. Mean age was 61.0 ± 14.2 years, 44% were male, mean LS by Fibroscan® was 6.1 ± 1.8 kPa. Twenty-eight patients(37.3%) had an HOMA>2.5. Two patients were excluded from analysis(one dropped out and the other one had diagnosed genotype 2c at genotyping by sequencing performed after relapse). At 8 weeks(EOT), 71 out of 73 patients(97.3%) had undetectable HCV-RNA, while in two cases HCV-RNA was detectable but with VL<15 IU/ml. Both of them achieved SVR. Two G1b patients relapsed at 12 weeks of follow-up, both with baseline VL>800,000 IU/ml and HOMA score 1.3 and 3.8 respectively. Both had undetectable HCV VL at 4th week and at the EOT. Modified intention-to-treat SVR12 for G1b patients was 71/73(97.3%).. In naïve, genotype-1b HCV-infected patients with mild/moderate liver fibrosis, short course of 8 weeks of EBR/GZR appears to achieve high efficacy regardless of features of insulin resistance.

Topics: Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Glucose; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Ribavirin; RNA; Sulfonamides

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Transplantation; Middle Aged; Quinoxalines; Sulfonamides

Topics: Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Combinations; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Lactams, Macrocyclic; Opioid-Related Disorders; Quinoxalines; Sulfonamides

Grazoprevir/elbasvir and glecaprevir/pibrentasvir (G/P) are the two preferred treatment options for patients with chronic hepatitis C virus (HCV) infection and a glomerular filtration rate (GFR) <30 mL/min. Both therapies have been separately analyzed in different real-life cohorts; however, a direct comparison has not been performed so far. We, therefore, analyzed safety and effectiveness of both regimens in a concerted real-life population.. The Germany Hepatitis C-Registry is a prospective national real-world registry. The analysis is based on 2773 patients with documented GFR at baseline treated with grazoprevir/elbasvir (N = 1041), grazoprevir/elbasvir + ribavirin (N = 53) and glecaprevir/pibrentasvir (N = 1679).. A total of 93 patients with GFR <30 mL/min were treated with grazoprevir/elbasvir (N = 56), grazoprevir/elbasvir + ribavirin (N = 4), and glecaprevir/pibrentasvir (N = 33). They suffered significantly more frequent from diabetes mellitus, hypertension, and coronary heart disease than individuals with GFR >30 mL/min and showed the following baseline characteristics: 20.4, 55.9, 3.2, 12.9, and 5.3% were infected with HCV-genotypes 1a, 1b, 2, 3, and 4; 12.9% suffered from liver cirrhosis; 80.1% were treatment-naïve. Baseline characteristics except distribution of HCV-genotype 1b (n = 43/52 treated with grazoprevir/elbasvir) and sustained virologic response rates (SVR12) did not differ significantly between glecaprevir/pibrentasvir (SVR12: 100%) and grazoprevir/elbasvir (SVR12: 97.9%).Fatigue, headache, abdominal discomfort, and arthralgia were the most frequently reported adverse events without a statistical difference between grazoprevir/elbasvir and glecaprevir/pibrentasvir.. In patients with chronic hepatitis C and a baseline GFR ≤30 mL/min grazoprevir/elbasvir and glecaprevir/pibrentasvir show an equally favorable safety profile and antiviral efficacy and can both be recommended for real-life use.

Topics: Amides; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Lactams, Macrocyclic; Leucine; Proline; Prospective Studies; Pyrrolidines; Quinoxalines; Registries; Renal Insufficiency, Chronic; Ribavirin; Sulfonamides; Sustained Virologic Response

For treatment of genotype 1a (GT1a) infection with elbasvir/grazoprevir, the German guidelines recommend a differentiated approach depending on baseline viral load (BVL). For low BVL ≤800 000 IU/mL, treatment with 12 weeks elbasvir/grazoprevir should be considered, whereas for high BVL >800 000 IU/mL, this regimen is only recommended in nonstructural protein 5A (NS5A) resistance-associated substitutions (RAS) absence. With present NS5A RAS or when RAS-testing is not available, 16 weeks elbasvir/grazoprevir + ribavirin is preferred. Here, we investigated the adherence to these recommendations and the effectiveness of elbasvir/grazoprevir in a large German Hepatitis C-Registry GT1a cohort.. From September 2016 until July 2018, 195 GT1a-infected patients were treated with elbasvir/grazoprevir ± ribavirin for 12-16 weeks. The primary outcome was per protocol SVR12 or SVR24.. Mean age was 50 years, 89% were male, 19% had cirrhosis, 72% were treatment-naïve. Forty-five percent had low BVL ≤800 000 IU/mL, 55% high BVL >800 000 IU/mL, of whom 49 vs. 42% were baseline RAS-tested. Four patients with high (7.7%) and two with low BVL (5%) had NS5A RAS of whom 50% received elbasvir/grazoprevir+ribavirin, respectively. Ninety-four percent of patients with low and 65% with high BVL received elbasvir/grazoprevir without ribavirin. Thirty-five percent of patients with high BVL received ribavirin, mostly without prior RAS-testing. Per protocol sustained virologic response (SVR) by low vs. high BVL was 98.8 and 95.1%. All patients with NS5A RAS achieved SVR.. In German, real-world most patients received elbasvir/grazoprevir without ribavirin. Ribavirin was mainly added in GT1a patients >800 000 IU/mL, who were not NS5A RAS tested. SVR rates were consistently high and comparable to clinical trial results.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Registries; Sulfonamides; Sustained Virologic Response

This study aimed to establish the real-world effectiveness and safety of grazoprevir/elbasvir (EBR/GZR) therapy in South Korea.. A total of 242 patients with chronic hepatitis C virus (HCV) genotype 1 or 4 infection who started EBR/GZR were consecutively enrolled from seven tertiary hospitals. Retrospective analysis of the fractions of patients that achieved sustained virological response (SVR) was performed, and the incidence of adverse events was noted.. The mean age of enrolled patients was 59.0 ± 12.6 years and 47.5% were males. Patients with HCV genotype 1b accounted for 93.8% (n = 227), and patients with HCV of unspecified genotype 1 accounted for 5.8% (n = 14). Hypertension was the most common comorbid disease (29.8%) followed by diabetes (22.7%) and chronic kidney disease (CKD, 12.4%). SVR rates of treatment-naïve and treatment-experienced patients were 85.5% (182/213) and 93.1% (27/29), respectively, in the intention-to-treat analyses, whereas in the per-protocol analyses, those were 97.8% (179/183) and 100% (28/28), respectively. Fewer patients with HCV genotype 1 of unspecified subtype achieved SVR (81.8%, n = 11) compared to the patients with SVR infected with genotype 1b (99%, n = 198, p < 0.001). All patients with CKD showed SVR. Itching (12%) and dyspepsia (4.1%) were common adverse events. Of the four patients who discontinued the antiviral therapy, one experienced mild fatigue but neither treatment withdrawal was because of an adverse event.. EBR/GZR showed high real-world effectiveness and safety in Korean patients with chronic HCV infection regardless of the previous antiviral treatment, liver cirrhosis, or CKD status.

Topics: Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Republic of Korea; Retrospective Studies; Sulfonamides

Elbasvir/grazoprevir (EBR/GZR) use in drug users on opiate agonist therapy (OAT) is supported by the C-EDGE Co-STAR trial. SVR rates in this study were within those found in the rest of patients included by the EBR/GZR development programme. In clinical practice, however, efficacy could theoretically be lower. Thus, we aimed at evaluating the SVR rates of EBR/GZR among people who injected drugs (PWID) with and without OAT in clinical practice. Patients starting EBR/GZR included in the HEPAVIR-DAA (NCT02057003), recruiting HIV/HCV-coinfected patients or the GEHEP-MONO (NCT02333292), including HCV-monoinfected individuals, prospective cohorts were analysed. Overall SVR12 (ITT), discontinuations due to adverse effects and drop-outs were evaluated. The same analysis was carried out for PWID with and without OAT. 336 patients had started EBR/GZR and reached the SVR12 evaluation date. 318 [95%, 95% confidence interval (95% CI): 92%-98%] patients achieved SVR12. SVR12 was 97% (95% CI: 93%-99%, n/N = 141/145) among people who never used injecting drugs, 94% (95% CI: 88%-97%, n/N = 117/125) among PWIDs without OAT and 91% (95% CI: 81%-97%, n/N = 60/66) among PWIDs with OAT (p = 0.134). Five (1.5%) patients showed relapses, and two (0.6%) individuals showed viral breakthrough. The SVR12 rate for recent drug users was 69% (n/N = 18/26) compared with 97% (n/N = 276/284) for individuals without recent drug use (in the prior year) (p < 0.001). Among recent drug users, three (12%) showed relapses, and five (19%) were lost-to-follow-up. The SVR rates achieved with EBR/GZR were high in real-world conditions of use. However, PWID with recent drug use reach suboptimal response rates with EBR/GZR.

Topics: Amides; Analgesics, Opioid; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Pharmaceutical Preparations; Prospective Studies; Quinoxalines; Sulfonamides

Hepatitis C virus (HCV) infection is known to affect long-term patient survivals. Elbasvir/grazoprevir (EBR/GZR) has shown a high cure rate in hemodialysis patients with HCV infection. However, the combination is rarely used in peritoneal dialysis patients. Herein, we report a case of successful treatment with EBR/GZR in a peritoneal dialysis patient with HCV genotype 1 b infection. A 54-year-old woman on peritoneal dialysis（PD）with HCV genotype 1 b infection had been received EBR (100 mg) and GZR (50 mg) once daily for 12 weeks. Hepatitis C virus RNA was undetectable 4 weeks after the treatment. She achieved a sustained virological response at 12 weeks after the end of treatment. Only fatigue was reported as side effect during the treatment. Thus, elbasvir/grazoprevir was effective and safe in this PD patient with HCV genotype 1 b infection.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Middle Aged; Peritoneal Dialysis; Quinoxalines; Sulfonamides; Sustained Virologic Response

The combination of elbasvir and grazoprevir (EBR/GZR) has been approved for treating HCV infection. This study aimed to evaluate the efficacy of EBR/GZR in terms of sustained virological response (SVR) and improvement of liver fibrosis in Thai patients with HCV genotype-1 (GT1). The utility of serum HCV core antigen (HCVcAg) as an alternative to HCV RNA in assessing SVR was also investigated.. A total of 101 HCV GT1-infected patients (65 monoinfection and 36 HIV coinfection) who received EBR/GZR for 12-16 weeks were included. Liver stiffness (LS) and controlled attenuation parameter (CAP) were measured by transient elastography. Serum HCVcAg was measured in parallel with HCV RNA.. The overall SVR12 and SVR24 rates in the cohort were 98.0% and 95.0%, respectively. SVR24 rates were consistently high (90.0% to 100%) across all subgroups of patients. A significant LS decline ³30% was observed more frequently in cirrhotic than non-cirrhotic individuals who achieved SVR (63.3% versus 30.3%; P=0.003). The magnitude of LS decline following HCV eradication was comparable between HCV monoinfection and HCV-HIV coinfection. The reduction of CAP was also observed in responders who had significant steatosis at baseline. Compared with HCV RNA, HCVcAg testing displayed high sensitivity (100%) and specificity (99.0-100%) in determining SVR12 and SVR24.. This study confirms that EBR/GZR is effective for HCV GT1-infected Thai patients with or without HIV infection. HCV eradication is associated with LS and CAP improvement regardless of HIV status. HCVcAg testing could be a potential replacement for HCV RNA for assessing SVR in resource-limited settings.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; HIV Infections; Humans; Imidazoles; Quinoxalines; Sulfonamides

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

In the Republic of Korea, an estimated 231,000 individuals have chronic hepatitis C virus (HCV) infection. The aim of the present analysis was to evaluate the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) administered for 12 weeks in Korean patients who were enrolled in international clinical trial phase 3 studies.. This was a retrospective, integrated analysis of data from patients with HCV genotype (GT) 1b infection enrolled at Korean study sites in four EBR/GZR phase 3 clinical trials. Patients were treatment-naive or had previously failed interferon-based HCV therapy, and included those with human immunodeficiency virus coinfection or ChildPugh class A cirrhosis. All patients received EBR 50 mg/GZR 100 mg once daily for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12, HCV RNA <15 IU/mL).. SVR12 was achieved by 73 of 74 (98.6%) patients. No patients had virologic failure and one discontinued from the study after withdrawing consent. SVR12 rates were uniformly high across all patient subgroups. A total of 16 patients had nonstructural protein 5A resistance-associated substitutions at baseline (16/73, 22%), all of whom achieved SVR12. Adverse events (AEs) reported in >5% of patients were fatigue (6.8%), upper respiratory tract infection (5.4%), headache (5.4%), and nausea (5.4%). Thirteen patients (17.6%) reported drug-related AEs, two serious AEs occurred, and two patients discontinued treatment owing to an AEs.. In this retrospective analysis, EBR/GZR administered for 12 weeks was well-tolerated and highly effective in Korean patients with HCV GT1b infection.

Topics: Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Resistance, Viral; Fatigue; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Republic of Korea; Retrospective Studies; Sulfonamides; Sustained Virologic Response; Viral Nonstructural Proteins

Elbasvir/grazoprevir (EBR/GZR) is an all-oral direct-acting antiviral agent (DAA) with high sustained virologic response (SVR) in clinical trials. This study's primary objective was to evaluate effectiveness of EBR/GZR among HCV-infected patients in a real-world clinical setting. We conducted a nationwide retrospective observational cohort study of HCV-infected patients in the US Department of Veterans Affairs (VA) using the VA Corporate Data Warehouse. The study population included patients with positive HCV RNA who initiated EBR/GZR from February 1 to August 1, 2016. We calculated the 95% confidence interval for binomial proportions for SVR overall and by demographic subgroups. Clinical and demographic characteristics were also evaluated. We included 2436 patients in the study cohort. Most were male (96.5%), African American (57.5%), with mean age of 63.5 (SD = 5.9) and 95.4% infected with genotype (GT) 1 [GT1a (34.7%), GT1b (58.6%)]. Other comorbidities included diabetes (53.2%), depression (57.2%) and HIV (3.0%). More than 50% had history of drug or alcohol abuse (53.9% and 60.5%, respectively). 33.2% of the cohort had cirrhosis. A total of 95.6% (2,328/2,436; 95% CI: 94.7%-96.4%) achieved SVR. The SVR rates by subgroups were: male, 95.5% (2245/2350); female, 96.5% (83/86); GT1a, 93.4%, GT1b, 96.6%, GT4, 96.9%, African American, 95.9% (1,342/1,400); treatment-experienced, 96.3% (310/322); cirrhosis, 95.6% (732/766); stage 4-5 CKD, 96.3% (392/407); and HIV, 98.6% (73/74). SVR rates were high overall and across patient subgroups regardless of gender, race/ethnicity, cirrhosis, renal impairment or HIV. This study provided important data regarding the effectiveness of EBR/GZR in a large clinical setting.

Topics: Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Retrospective Studies; Sulfonamides; Sustained Virologic Response; United States; Veterans

In this issue, Alric and colleagues demonstrate through real-world experience that grazoprevir-elbasvir is safe and effective for treating hepatitis C in advanced kidney disease patients with higher comorbidity burdens. This commentary highlights that this and similar studies have primarily focused on treatment safety and efficacy, rather than the clinical impact of viral eradication. Critical knowledge gaps including which patients to treat, and when, as well as potential management strategies that may improve outcomes, are discussed.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Goals; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Quinoxalines; Sulfonamides

There are rare reports of association between hepatitis C virus (HCV) infection and dermatomyositis although cause and effect remains to be proven. We present a clinical case with a probable cause and effect association between these two entities. A 71-year-old woman developed an erythematous exanthem with pruritic and scaly lesions located at the torso and upper limbs associated with heliotrope and Gottron's papules. At the same time, she notice a significant loss of muscular strength. Skin and muscular biopsies made the diagnosis of dermatomyositis and the patient started with prednisolone (60 mg/day) with poor symptoms control. Paraneoplastic syndrome, HIV, hepatitis B virus and syphilis infections were excluded. HCV serology was positive, with a viral load of 58 159 IU/mL (genotype 1a). Therefore, the patient underwent a 12-week treatment with grazoprevir 100 mg and elbasvir 50 mg achieving a sustained virological response with regression of skin lesions and complete recovery of muscular strength (photodocumented before/after treatment). Additionally it was possible to reduce prednisolone dosage to 5 mg/day.

Topics: Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Dermatomyositis; Diagnosis, Differential; Female; Hepatitis C; Humans; Imidazoles; Quinoxalines; Sulfonamides; Viral Load

Elbasvir (EBR; HCV NS5A inhibitor) and grazoprevir (GZR; HCV NS3/4A protease inhibitor) are approved as a fixed-dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+GZR was assessed in HCV GT3-infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+GZR with ribavirin (RBV) in treatment-naïve, noncirrhotic HCV GT3-infected patients. Randomized patients received open-label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy (SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+GZR+RBV for 12 weeks or 18 weeks, respectively. On-treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance-associated substitutions (RASs) with a >five-fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+GZR+RBV was suboptimal in HCV GT3-infected patients due to a high rate of on-treatment virologic failure and treatment-emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+GZR+RBV in GT3-infected patients.clinicaltrials.gov: NCT01717326.

Topics: Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Quinoxalines; Ribavirin; RNA, Viral; Sulfonamides; Time Factors; Treatment Failure; Treatment Outcome; Viral Load

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Evaluation, Preclinical; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Quinoxalines; Sulfonamides; Virus Activation

To describe the use of nonantiretroviral comedication and combination antiretroviral therapy (cART) in patients coinfected with HIV/hepatitis C virus (HCV) and to predict the potential for drug-drug interactions (DDIs) with direct-acting antivirals (DAAs) against HCV.. This is a retrospective, cross-sectional study, using the Dutch, nationwide ATHENA observational HIV cohort database. All patients with a known HIV/HCV coinfection on January 1, 2015, were included. Comedication and cART registered in the database were listed. The potential for DDIs between DAAs and comedication/cART were predicted using http://hep-druginteractions.org. DDIs were categorized as: (1) no clinically relevant DDI; (2) possible DDI; (3) contraindication; or (4) no information available.. We included 777 patients of whom 488 (63%) used nonantiretroviral comedication. At risk for a category 2/3 DDI with nonantiretroviral comedications were 299 patients (38%). Most DDIs were predicted with paritaprevir/ritonavir, ombitasvir ± dasabuvir (47% of the drugs) and least with grazoprevir/elbasvir (11% of the drugs). Concerning cART, daclatasvir/sofosbuvir is the most favorable combination as no cART is contraindicated with this combination. In genotype 1/4 patients, grazoprevir/elbasvir is least favorable as 75% of the patients must alter their cART.. This study showed that comedication use in the aging HIV/HCV population is frequent and diverse. There is a high potential for DDIs between DAAs and comedication/cART.

Topics: Adult; Aged; Aged, 80 and over; Amides; Anti-Retroviral Agents; Antiviral Agents; Benzofurans; Carbamates; Coinfection; Combined Modality Therapy; Cross-Sectional Studies; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Hepacivirus; Hepatitis C; HIV; HIV Infections; Humans; Imidazoles; Middle Aged; Quinoxalines; Retrospective Studies; Ritonavir; Sulfonamides; Young Adult

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.

Topics: Antiviral Agents; Dose-Response Relationship, Drug; Drug Discovery; Genotype; Hepacivirus; Hepatitis C; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship; Viral Nonstructural Proteins; Virus Replication

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl "Z group" modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.

Topics: Animals; Antiviral Agents; Benzofurans; Dose-Response Relationship, Drug; Hepacivirus; Hepatitis C; Imidazoles; Male; Microbial Sensitivity Tests; Molecular Structure; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Viral Nonstructural Proteins; Virus Replication