gs-5816 and grazoprevir

Topics: Amides; Antibodies, Monoclonal, Humanized; Benzofurans; Carbamates; Cyclopropanes; Drug Approval; Drug Therapy; gamma-Cyclodextrins; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Peptides; Phenylalanine; Quinoxalines; Sofosbuvir; Sugammadex; Sulfonamides; Sulfones; Thioglycolates; Triazoles; United States; United States Food and Drug Administration

There has been a revolution in the treatment of chronic hepatitis C. Several oral regimens combining direct-acting antivirals (DAAs) from different families [NS5B nucleotide inhibitors, NS5B non-nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A protease inhibitors (PI)] have been developed. These regimens result in an increase in sustained virological response (SVR) rates to above 90% and reduce the duration of treatment to 12 weeks or less. As of 2016 several regimens will be approved with additive potencies, without cross-resistance and with a good safety profile. Remaining issues will include increasing screening and access to care so that HCV may become the first chronic viral infection eradicated worldwide. This review summarizes results obtained with oral DAA combinations that have been approved and/or have completed phase 3 clinical trials for HCV infection and discusses future perspectives.

Topics: 2-Naphthylamine; Amides; Anilides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Protease Inhibitors; Quinoxalines; Sofosbuvir; Sulfonamides; Uracil; Valine; Viral Nonstructural Proteins

The treatment of chronic hepatitis C virus (HCV) has undergone a period of rapid evolution. The era of combination direct antivirals has led to high rates of sustained viral response (SVR), limited toxicities, and more broad applicability across patient demographics. Even current therapies have their limitations, however, including genotype specificity and variable durations of treatment depending on the presence or absence of cirrhosis. Developing a fixed-duration pangenotypic regimen that can broadly treat all stages of fibrosis with equal rates of SVR in all patients, irrespective of treatment experience, is the goal of future therapies. This article reviews antivirals in development.

Topics: Amides; Antiviral Agents; Benzazepines; Benzofurans; Carbamates; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Discovery; Drug Therapy, Combination; Forecasting; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Indoles; Isoquinolines; MicroRNAs; Molecular Targeted Therapy; Nucleic Acid Synthesis Inhibitors; Protease Inhibitors; Pyrrolidines; Quinoxalines; RNA, Viral; Sofosbuvir; Sulfonamides; Valine; Viral Nonstructural Proteins

SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir.

Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19 Drug Treatment; Hepacivirus; Hepatitis C; Humans; Lung; Nucleosides; SARS-CoV-2; Sofosbuvir

Second generation direct acting antivirals (DAAs) drastically changed the landscape of chronic HCV (CHCV). Aim of this paper was to assess the effectiveness of DAAs, also looking at the demographic characteristics of subjects enrolled.. Ambispective multi-center real-life study conducted among patients with CHCV treated with DAAs in Campania Region (Southern Italy). Patient were enrolled in two cohorts according to time of enrolment.. 1,479 patients were enrolled. Patients aged ≥60 years were 74.7% in the historic cohort (953 patients) and 70.2% in the prospective cohort (526 patients. Patients aged ≥ 60 years showed a higher prevalence of genotype 1b (p<0.001) and 2 (p<0.001), while patients aged < 60 years showed a higher prevalence of genotype 1a (p<0.001), 3 (p<0.001) and 4 (p<0.05). SVR12 was 98.5% in both cohorts. SVR12 was similar among patients of the prospective cohort aged < and ≥ 60 years (99.4% vs 98.1%). SVR12 among patients with and without cirrhosis was 96.0% and 98.9%, respectively.. DAAs provide high efficacy also in harder to treat patients. The effectiveness of DAAs is leading to a shift in patients characteristics with a greater prevalence of younger subjects and persons with mild liver disease.

Topics: Adult; Age Distribution; Aged; Amides; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Italy; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Quinoxalines; Retrospective Studies; Sulfonamides; Sustained Virologic Response

A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs.. PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment.. Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements.. In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities.. Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Amides; Anilides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Patient Reported Outcome Measures; Proline; Prospective Studies; Quinoxalines; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Young Adult