Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection

Ghany, Marc G.; Morgan, Timothy R.

doi:10.1002/hep.31060

Cited by 620 publications

(656 citation statements)

References 396 publications

(748 reference statements)

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“…therapies with direct-acting antivirals (DAAs) against essential viral proteins NS3/4A, NS5A, and NS5B have significantly improved treatment options and outcomes (2)(3)(4)(5) with cure rates of ϳ95% for treatment-naive patients (6)(7)(8)(9)(10)(11)(12). However, even the most recent DAA combinations, still in 2019, fail to cure some patients (4,5,13,14). Especially for DAA-experienced patients, baseline polymorphisms among diverse genotypes and preexisting resistance-associated substitutions (RASs) negatively impact treatment outcomes (3-5, 14, 15).…”

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confidence: 99%

“…Especially for DAA-experienced patients, baseline polymorphisms among diverse genotypes and preexisting resistance-associated substitutions (RASs) negatively impact treatment outcomes (3-5, 14, 15). Treatment failure is highly associated with RASs in the therapeutic target (4,5,(14)(15)(16)(17)(18)(19). With the WHO goal to increase treatment from 13% (2016) to 80% (2030) of the 71 million infected globally (1,20), even a small failure rate will result in many HCV-infected patients failing therapy due to drug resistance (3, 14-19, 21, 22).…”

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confidence: 99%

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Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Matthew

Zephyr

Rao

et al. 2020

mBio

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Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles. IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.

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confidence: 99%

mentioning

confidence: 99%

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Matthew

Zephyr

Rao

et al. 2020

mBio

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“…T A B L E 1 Univariate analysis of patients' and hospital characteristics, and immunosuppressive comorbidities of hospitalized patients with a vaccinepreventable disease and chronic liver disease ALD, alcoholic liver disease; APR-DRG, all patients refined-diagnosis related groups; NALD, non-alcoholic liver disease; SD, standard deviation.American Association for the Study of Liver Diseases (AASLD) recommends in all patients with HBV and HCV (whether acute or chronic)should have an HAV vaccination and individuals with chronic HCV infection who are at risk for HBV infection should have an HBV vaccination only 14,15. In our study, HBV was noted to be the most frequent VPD in patients with CLD, highlighting the importance of HBV immunization in this patient population.…”

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confidence: 57%

The important role of immunization in alcoholic and non‐alcoholic chronic liver disease: A population‐based study

Nasir

Vinsard

Wakefield

et al. 2020

J of Digest Diseases

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To determine differences in frequencies of vaccine-preventable diseases between alcoholic liver disease (ALD) and non-alcoholic liver disease (NALD) patients. Methods: This population-based cohort study used USA national inpatient sample ICD-9 codes from January 2012 to September 2015. Frequencies of admissions for ALD and NALD in patients with pneumococcal pneumonia, influenza, herpes zoster virus, varicella zoster virus, hepatitis A, hepatitis B, human papilloma virus, meningococcal meningitis, diphtheria, pertussis and tetanus were measured. Frequencies and patients' characteristics were compared for ALD and NALD using χ 2 test and multivariate logistic regression analysis. Results: There was no difference in admissions for hepatitis A and pneumococcal pneumonia between the ALD and NALD groups. There were fewer admissions for hepatitis B (1.17% vs 1.80%, odds ratio [OR] 0.64, P < 0.01), herpes zoster (0.12% vs 0.17%, OR 0.69, P < 0.01), influenza (0.16% vs 0.26%, OR 0.59, P < 0.01) and all others (0.005% vs 0.015%, OR 0.36, P = 0.01) in the ALD group than the NALD group. The extreme all patient refined-diagnosis related groups mortality risk was 15.24% in ALD and 7.77% in NALD admissions (P < 0.0001). Conclusions: The most frequent vaccine-preventable disease in both groups was hepatitis B. Patients with NALD had higher odds of admissions for hepatitis B, herpes zoster virus, influenza and other vaccine-preventable disease than ALD patients. However, the ALD group had a higher risk of mortality when admitted to hospital with a vaccine-preventable disease than the NALD group. K E Y W O R D S vaccination, vaccine-preventable disease, alcoholic liver diseases, non-alcoholic liver diseases, hepatitis B 1 | INTRODUCTION Chronic liver disease (CLD) has affected over 45 million people worldwide, contributing a significant disease burden to both individuals and institutions. 1 The liver, owing to its high degree of vascularity and a capillary system that is lined with immune cells, plays a major role in the immune system and liver disease may result in decreased opsonization, reticuloendothelial cellular activity and neutrophil mobilization with increased bacterial translocation. 2 In alcoholic liver disease (ALD) in particular, hepatic dendritic cells may become impaired, impacting their cell-mediated response towards certain viral infections. 3,4 CLD, including ALD and non-alcoholic liver disease (NALD),

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“…Although once not recommended in patients with advanced CKD (estimated GFR (eGFR) <30 mL/min/1.73 m 2 ), a new meta‐analysis demonstrated that sofosbuvir, which is mainly eliminated via the kidneys, can be used safely and effectively in patients with CKD Stages 4‐5 97 . Sofosbuvir‐based regimens were recently amended for use with eGFR < 30 mL/min or on dialysis by the US Food and Drug Administration in November 2019 98 . Renal function and CNI levels must be monitored carefully both during and after completion of therapy, as CNI levels can fluctuate even after HCV treatment with DAA is completed 94 .…”

Section: Hepatitis C (Hcv) In Eskdmentioning

confidence: 99%

“…Most clinicians opt to wait until transplant recipients have stable renal function and CNI levels before embarking on HCV therapy, usually initiating therapy around 3 months post‐transplant; however, in patients with proteinuria, glomerular lesions related to HCV infection, or signs of hepatic dysfunction, earlier initiation of treatment is reasonable. The American Association for the Study of Liver Diseases and Infectious Diseases Society of America recently updated their HCV guidelines 98 . There is no dose adjustment in DAAs required when using recommended regimens for patients with renal impairment including both CKD and dialysis patients.…”

Section: Hepatitis C (Hcv) In Eskdmentioning

confidence: 99%

Current state of kidney transplantation in patients with HIV, hepatitis C, and hepatitis B infection

Sawinski

Wong

Goral

2020

Clinical Transplantation

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Human immunodeficiency virus (HIV), hepatitis C (HCV), and hepatitis B (HBV) are common chronic viral infections in the end‐stage kidney disease (ESKD) patient population that were once considered relative contraindications to kidney transplantation. In this review, we will summarize the current state of kidney transplantation in patients with HIV, HCV, and HBV, which is rapidly evolving. HIV+ patients enjoy excellent outcomes in the modern transplant era and may have new transplant opportunities with the use of HIV+ donors. Direct‐acting antivirals for HCV have substantially changed the landscape of care for patients with HCV infection. HBV+ patients now have excellent patient and allograft survival with HBV therapy. Currently, kidney transplantation is a safe and appropriate treatment for the majority of ESKD patients with HIV, HCV, and HBV.

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Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection

Cited by 620 publications

References 396 publications

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

The important role of immunization in alcoholic and non‐alcoholic chronic liver disease: A population‐based study

Current state of kidney transplantation in patients with HIV, hepatitis C, and hepatitis B infection

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