ritonavir and grazoprevir

Chronic HCV infection is a non-traditional (but modifiable) risk factor for chronic kidney disease and has been implicated in glomerular injury and nephrosclerotic disease. Three HCV direct-acting antiviral regimens are available for patients with severe kidney impairment: ombitasvir, paritaprevir with the pharmacokinetic enhancer ritonavir, and dasabuvir; glecaprevir plus pibrentasvir; and elbasvir plus grazoprevir. In patients with severe kidney impairment, sofosbuvir-free regimens are preferred because sofosbuvir accumulation has been associated with a progressive worsening of renal function. In this Review, we provide our expert opinion on the current HCV treatment paradigm and highlight the remaining issues that need to be overcome to improve the treatment of HCV in this population.

Topics: 2-Naphthylamine; Amides; Aminoisobutyric Acids; Anilides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Disease Management; Drug Therapy, Combination; Expert Testimony; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Practice Guidelines as Topic; Proline; Pyrrolidines; Quinoxalines; Renal Insufficiency, Chronic; Risk Factors; Ritonavir; Sulfonamides; Uracil; Valine

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

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

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