Resistance detection and re-treatment options in hepatitis C virus-related chronic liver diseases after DAA-treatment failure

Starace, Mario; Minichini, Carmine; Pisaturo, Mariantonietta; Macera, Margherita; Sagnelli, Caterina; Coppola, Nicola

doi:10.1007/s15010-018-1188-3

Cited by 22 publications

(15 citation statements)

References 166 publications

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“…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%

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%

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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“…While the treatment for HCV infection has significantly improved, one major threat to the clinical efficacy of all currently available anti-HCV drugs is the emergence of drug resistance. 9-10, [18][19][20][21] In fact, single and double RASs can cause resistance to the entire class of protease inhibitors. [18][19][20] The most common RASs in the NS3/4A protease occur at residues R155, A156, and D/Q168.…”

Section: ) So Far Structural and Most Biochemical Studies Focused Onmentioning

confidence: 99%

“…9-10, [18][19][20][21] In fact, single and double RASs can cause resistance to the entire class of protease inhibitors. [18][19][20] The most common RASs in the NS3/4A protease occur at residues R155, A156, and D/Q168. While substitutions at A156 reduce replicative fitness of the virus drastically, the other RASs do not significantly impair substrate processing and allow robust viral replication.…”

Section: ) So Far Structural and Most Biochemical Studies Focused Onmentioning

confidence: 99%

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Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir

et al. 2019

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Hepatitis C virus (HCV), causative agent of chronic viral hepatitis, infects 71 million people worldwide and is divided into seven genotypes and multiple subtypes with sequence identities between 68 to 82%. While older generation direct-acting antivirals (DAAs) had varying effectiveness against different genotypes, the newest NS3/4A protease inhibitors including glecaprevir (GLE) have pan-genotypic activity. The structural basis for pan-genotypic inhibition and effects of polymorphisms on inhibitor potency were not well known due to lack of crystal structures of GLE-bound NS3/4A or genotypes other than 1. In this study, we determined the crystal structures of NS3/4A from genotypes 1a, 3a, 4a and 5a in complex with GLE. Comparison with the highly similar grazoprevir (GZR) indicated the mechanism of GLE's drastic improvement in potency. We found that while GLE is highly potent against wild type NS3/4A of all genotypes, specific resistance-associated substitutions (RASs) confer orders of magnitude loss in inhibition. Our crystal structures reveal molecular mechanisms behind pan-genotypic activity of GLE, including potency loss due to RASs at D168. Our structures permit for the first time analysis of changes due to polymorphisms among genotypes, providing insights into design principles that can aid future drug development and potentially can be extended to other proteins.

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“…Due to sequence diversity and variation of hepatitis C genome, no vaccine is available against HCV infection. No decisive antiviral therapy is available against HCV infection even through recent direct acting antiviral (DAA) therapy (12).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of hepatitis C virus among HIV-infected patients

Zayedi¹,

Makvandi²,

Teimoori³

et al. 2020

IJM

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Background and Objectives: Hepatitis C virus and Human Immunodeficiency Virus (HIV) share the same rate of transmis- sion. HIV/HCV co-infected individuals may result in faster progression of liver fibrosis and highly increase the risk of cir- rhosis, hepatocellular carcinoma development. Thus this study was conducted to determine co-infection of HCV genotypes in positive HIV patients in Ahvaz city, Iran. Materials and Methods: The sera samples were collected from confirmed 78 infected HIV, 67 (85.89%) males and 11 (14.1%) females. All sera samples were tested for HCV Ab using ELISA test. The HCV Ab positive samples were tested for detection of 5' untranslated (UTR) and core regions of HCV genome using nested RT-PCR. The PCR products of 5UTR and core regions were sequenced to determine HCV genotypes. Results: Among the 78 infected HIV, 25 (32.05%) cases including 20 (25.64%) males and 5 (6.41%) females were positive for HCV Ab (p=0.316). 53 (67.94%) of HIV patients were negative for HCV Ab. Among 25 positive HCV Ab, 19 (24.35%) cases including 15 (19.23%) males and 4 (5.12%) females were positive for HCV RNA (p=0.447). The PCR products of 5 positive samples were randomly sequenced. The results of sequences and alignments showed that the detected HCV geno- types were three 3a and two 1a. The occurrence of genotype HCV 1a was found in one male injecting drug user Injecting Drug User (IDU) and one female. The HCV 3a genotype was detected in the three males IDU. Conclusion: The results of this survey indicated that 32.05% of HIV patients were positive for HCV Ab, among them 24.35% were positive HCV RNA. HCV genotype 3a was dominant and detected in the three males IDU. Regarding the consequences of HIV/HCV co-infection, it is suggested that HCV RNA detection should be regularly checked in individuals infected with HIV.

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Resistance detection and re-treatment options in hepatitis C virus-related chronic liver diseases after DAA-treatment failure

Cited by 22 publications

References 166 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

Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir

Prevalence of hepatitis C virus among HIV-infected patients

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