Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

ABSTRACTDanoprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor that promotes multi-log10reductions in HCV RNA when administered as a 14-day monotherapy to patients with genotype 1 chronic HCV. Of these patients, 14/37 experienced a continuous decline in HCV RNA, 13/37 a plateau, and 10/37 a rebound. The rebound and continuous-decline groups experienced similar median declines in HCV RNA through day 7, but their results diverged notably at day 14. Plateau group patients experienced a lesser, but sustained, median HCV RNA decline. Baseline danoprevir susceptibility was similar across response groups but was reduced significantly at day 14 in the rebound group. Viral rebound in genotype 1b was uncommon (found in 2/23 patients). Population-based sequence analysis of NS3 and NS4A identified treatment-emergent substitutions at four amino acid positions in the protease domain of NS3 (positions 71, 155, 168, and 170), but only two (155 and 168) were in close proximity to the danoprevir binding site and carried substitutions that impacted danoprevir potency. R155K was the predominant route to reduced danoprevir susceptibility and was observed in virus isolated from all 10 rebound, 2/13 plateau, and 1/14 continuous-decline patients. Virus in one rebound patient additionally carried partial R155Q and D168E substitutions. Treatment-emergent substitutions in plateau patients were less frequently observed and more variable. Single-rebound patients carried virus with R155Q, D168V, or D168T. Clonal sequence analysis and drug susceptibility testing indicated that only a single patient displayed multiple resistance pathways. These data indicate the ascendant importance of R155K for viral escape during danoprevir treatment and may have implications for the clinical use of this agent.

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Spontaneous elimination of serum hepatitis C virus (HCV) RNA in chronic HCV carriers: A population-based cohort study

Journal of Medical Virology ◽

10.1002/jmv.10448 ◽

2003 ◽

Vol 71 (1) ◽

pp. 56-61 ◽

Cited By ~ 40

Author(s):

Hisayoshi Watanabe ◽

Takafumi Saito ◽

Haruhide Shinzawa ◽

Kazuo Okumoto ◽

Etsuko Hattori ◽

...

Keyword(s):

Cohort Study ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Population Based ◽

Hcv Rna ◽

Serum Hepatitis ◽

Chronic Hcv

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Hepatitis C Virus Prevalence and Risk Factors in a Village in Northeastern Romania—A Population-Based Screening—The First Step to Viral Micro-Elimination

Healthcare ◽

10.3390/healthcare9060651 ◽

2021 ◽

Vol 9 (6) ◽

pp. 651

Author(s):

Laura Huiban ◽

Carol Stanciu ◽

Cristina Maria Muzica ◽

Tudor Cuciureanu ◽

Stefan Chiriac ◽

...

Keyword(s):

Risk Factors ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Antiviral Treatment ◽

Population Based ◽

Hcv Infection ◽

World Health ◽

Hcv Rna ◽

Virus Eradication ◽

Tertiary Center

(1) Background: The World Health Organization adopted a strategy for the Global Health Sector on Viral Hepatitis in 2016, with the main objective of eliminating hepatitis C virus (HCV) by 2030. In this work, we aimed to evaluate the prevalence of HCV infection and risk factors in a Romanian village using population-based screening as part of the global C virus eradication program. (2) Methods: We conducted a prospective study from March 2019 to February 2020, based on a strategy as part of a project designed to educate, screen, treat and eliminate HCV infection in all adults in a village located in Northeastern Romania. (3) Results: In total, 3507 subjects were invited to be screened by rapid diagnostic orientation tests (RDOT). Overall, 2945 (84%) subjects were tested, out of whom 78 (2.64%) were found to have positive HCV antibodies and were scheduled for further evaluation in a tertiary center of gastroenterology/hepatology in order to be linked to care. In total, 66 (85%) subjects presented for evaluation and 55 (83%) had detectable HCV RNA. Of these, 54 (98%) completed antiviral treatment and 53 (99%) obtained a sustained virological response. (4) Conclusions: The elimination of hepatitis C worldwide has a higher chance of success if micro-elimination strategies based on mass screening are adopted.

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Characterization of Hepatitis C Virus Deletion Mutants Circulating in Chronically Infected Patients

Journal of Virology ◽

10.1128/jvi.01059-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12496-12503 ◽

Cited By ~ 34

Author(s):

Suwanna Noppornpanth ◽

Saskia L. Smits ◽

Truong Xuan Lien ◽

Yong Poovorawan ◽

Albert D. M. E. Osterhaus ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hcv Rna ◽

Deletion Mutants ◽

Genotype 3 ◽

Long Distance ◽

Bona Fide ◽

Chronic Hcv ◽

High Level

ABSTRACT Hepatitis C virus (HCV) has a linear positive-stranded RNA genome of ∼9,600 nucleotides in length and displays a high level of sequence diversity caused by high mutation rates and recombination. However, when we performed long distance reverse transcription-PCRs on HCV RNA isolated from serum of chronic HCV patients, not only full-length HCV genomes but also HCV RNAs which varied in size from 7,600 to 8,346 nucleotides and contained large in-frame deletions between E1 and NS2 were amplified. Carefully designed control experiments indicated that these deletion mutants are a bona fide natural RNA species, most likely packaged in virions. Moreover, deletion mutants were detected in sera of patients infected with different HCV genotypes. We observed that 7/37 (18.9%) of genotype 1, 5/43 (11.6%) of genotype 3, and 4/13 (30.7%) of genotype 6 samples contained HCV deletion mutant genomes. These observations further exemplify HCV's huge genetic diversity and warrant studies to explore their biological relevance.

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Pharmacokinetics, Safety, and Antiviral Effects of Hypericin, a Derivative of St. John's Wort Plant, in Patients with Chronic Hepatitis C Virus Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.2.517-524.2001 ◽

2001 ◽

Vol 45 (2) ◽

pp. 517-524 ◽

Cited By ~ 84

Author(s):

Jeffrey M. Jacobson ◽

Lawrence Feinman ◽

Leonard Liebes ◽

Nancy Ostrow ◽

Victoria Koslowski ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hcv Infection ◽

Hcv Rna ◽

Pharmacokinetic Data ◽

Serious Adverse Events ◽

Dosing Schedule ◽

Diarrhea Virus ◽

Chronic Hcv Infection ◽

Chronic Hcv

ABSTRACT Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log10. Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 μg/ml × hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection.

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Replication of Hepatitis C Virus (HCV) RNA in Mouse Embryonic Fibroblasts: Protein Kinase R (PKR)-Dependent and PKR-Independent Mechanisms for Controlling HCV RNA Replication and Mediating Interferon Activities

Journal of Virology ◽

10.1128/jvi.00586-06 ◽

2006 ◽

Vol 80 (15) ◽

pp. 7364-7374 ◽

Cited By ~ 78

Author(s):

Kyung-Soo Chang ◽

Zhaohui Cai ◽

Chen Zhang ◽

Ganes C. Sen ◽

Bryan R. G. Williams ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Rna Replication ◽

Hcv Infection ◽

Hcv Rna ◽

Protein Kinase R ◽

Mouse Embryonic Fibroblasts ◽

Embryonic Fibroblasts ◽

Chronic Hcv Infection ◽

Chronic Hcv

ABSTRACT Hepatitis C virus (HCV) infection causes chronic hepatitis and is currently treated with alpha interferon (IFN-α)-based therapies. The underlying mechanisms of chronic HCV infection and IFN-based therapies, however, have not been defined. Protein kinase R (PKR) was implicated in the control of HCV replication and mediation of IFN-induced antiviral response. In this report, we demonstrate that a subgenomic RNA replicon of genotype 2a HCV replicated efficiently in mouse embryonic fibroblasts (MEFs), as determined by cell colony formation efficiency and the detection of HCV proteins and both positive- and negative-strand RNAs. Additionally, the subgenomic HCV RNA was found to replicate more efficiently in the PKR knockout (PKR−/−) MEF than in the wild-type (PKR+/+) MEF. The knockdown expression of PKR by specific small interfering RNAs significantly enhanced the level of HCV RNA replication, suggesting that PKR is involved in the control of HCV RNA replication. The level of ISG56 (p56) was induced by HCV RNA replication, indicating the activation of PKR-independent antiviral pathways. Furthermore, IFN-α/β inhibited HCV RNA replication in PKR−/− MEFs as efficiently as in PKR+/+ MEFs. These findings demonstrate that PKR-independent antiviral pathways play important roles in controlling HCV replication and mediating IFN-induced antiviral effect. Our findings also provide a foundation for the development of transgenic mouse models of HCV replication and set a stage to further define the roles of cellular genes in the establishment of chronic HCV infection and the mediation of intracellular innate antiviral response by using MEFs derived from diverse gene knockout animals.

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Chronic hepatitis C virus infection: Is there a correlation between HCV genotypes and the level of viremia?

Medicinski pregled ◽

10.2298/mpns0606230d ◽

2006 ◽

Vol 59 (5-6) ◽

pp. 230-234 ◽

Cited By ~ 2

Author(s):

Dragan Delic ◽

Zorica Nesic ◽

Jasmina Simonovic ◽

Neda Svirtlih ◽

Ljubisa Dokic ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Objective Assessment ◽

Hcv Infection ◽

Hcv Rna ◽

Genotype 4 ◽

Hcv Genotypes ◽

Genotype 2 ◽

Chronic Hcv Infection ◽

Chronic Hcv

Introduction. Hepatitis C virus (HCV) RNA status and HCV genotypes have become extremely important for exact diagnosis, prognosis, duration of treatment and monitoring of antiviral therapy of chronic HCV infection. Material and methods. For the purpose of precise and objective assessment of virologic analyses, such as the determination of the number of virus copies and virus genotypes, 110 patients with chronic HCV infection were tested. Genotyping of HCV isolates and HCV RNA quantification were performed by using the PCR method. Genotype lb infection was verified in 49.1% of patients, genotype 3a infection was found in 28.2%, genotype 4 in 9.1%, genotype 2 in 4.5%, while mixed genotype infections were diagnosed in 9.1% of cases. Results. Patients infected by genotype lb had significantly higher serum HCV RNA level in relation to patients infected by other genotypes (p<0.05). Over 70% of patients infected by genotype lb had more than 2xl06 virus copies in 1 ml of blood, while in genotypes 2, 3a and 4, the percentage was 40%, 38.5% and 30%, respectively. Male patients had approximately 7.7x10.6 virus copies in 1 ml of blood, which was significantly higher in comparison with female patients (2.3xl06 copies/ml; p<0.05). Conclusion. Our results are in concordance with the results of other authors reporting that genotype lb is predominant in Europe, as well as significantly higher incidence of viremia in patients with genotype lb infection in relation to other HCV genotypes. Based on these results, we can conclude that our patients, most commonly, present with severe clinical course of chronic HCV infection and require longer treatment (48 weeks), which causes economic problems. .

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Association between chronic hepatitis C virus infection and myocardial infarction in people living with HIV in the United States

10.1101/453860 ◽

2018 ◽

Author(s):

Jessica Williams-Nguyen ◽

Stephen E Hawes ◽

Robin M Nance ◽

Sara Lindström ◽

Susan R Heckbert ◽

...

Keyword(s):

Myocardial Infarction ◽

Hepatitis C Virus ◽

Hepatitis C ◽

The United States ◽

Hcv Rna ◽

High Risk Population ◽

People Living With Hiv ◽

Extrahepatic Manifestations ◽

Chronic Hcv ◽

Living With Hiv

AbstractHepatitis C virus (HCV) is common among people living with HIV (PLWH). The potential for extrahepatic manifestations of HCV, including myocardial infarction (MI), is a topic of active research. MI is classified into types, predominantly atheroembolic Type 1 MI (T1MI) and supply-demand mismatch Type 2 MI (T2MI). We examined the association between HCV and MI in the CFAR Network of Integrated Clinical Systems (CNICS), a multi-center clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Universal MI definition. We estimated the association between chronic HCV (RNA+) and time to MI adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics and substance use. Among 24,755 PLWH aged ≥18, there were 336 T1MI and 330 T2MI during a median of 4.2 years of follow-up. HCV was associated with a 68% greater risk of T2MI (adjusted hazard ratio (aHR) 1.68, 95% CI: 1.22, 2.30) but not T1MI (aHR 0.96, 95% CI: 0.63, 1.45). In a cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR 2.26, 95% CI: 1.34, 3.81). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research.

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Risks of hepatitis C virus reactivation in a real-life population of oncology patients treated in an academic center

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155220969797 ◽

2020 ◽

pp. 107815522096979

Author(s):

Catherine-Audrey Boutin ◽

Jean-Philippe Adam ◽

Dominic Martel ◽

Stéphane Doucet ◽

Valérie Martel-Laferrière

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Real Life ◽

Viral Reactivation ◽

Hcv Rna ◽

Hepatic Decompensation ◽

Oncology Patients ◽

Chronic Hcv ◽

The Impact ◽

Hepatic Flare

Background Chemotherapy has been associated with a theoretical risk of hepatitis C virus (HCV) reactivation. However, little is known about the amplitude of viral replication and the incidence of subsequent hepatic exacerbation. Method We aimed to describe the occurrence of hepatitis flare and HCV reactivation at our center. We included, over a period of 5 years, adult patients with chronic HCV receiving intravenous chemotherapy. We excluded patients with undetectable HCV RNA, hepatocellular carcinoma, liver metastases or other etiologies of hepatic disease. The primary objective was to identify hepatic flares (elevation of alanine aminotransferase 3 times above the upper limit of normal). Secondary objectives were to assess viral reactivation (HCVr, HCV-RNA ≥1 log10 IU/mL when compared to baseline value), hepatic decompensation, mortality and the impact on the chemotherapy. Descriptive statistics were used. Results A total of 11 patients with chronic HCV were identified among the 5761 oncology patients. Five patients experienced a hepatic flare with median maximal ALT value of 139 U/L (IQR 133-237). Only 2 patients met criteria for HCVr with a median RNA increase of 1.16 log IU/mL (IQR 1.1-1.2). One patient presented with both HCVr and a hepatic flare. Only one patient required chemotherapy discontinuation following hepatic flare. No hepatic decompensation or related mortality were observed. Conclusion We identified a very small number of HCV cases among our population. We observed HCVr and hepatic flares, but only one consequence on cancer treatment. Nonetheless, HCV screening is encouraged among patients undergoing chemotherapy to allow close follow-up of hepatic function.

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Haplotype HLA-B8-DR3 Confers Susceptibility to Hepatitis C Virus-Related Mixed Cryoglobulinemia

Blood ◽

10.1182/blood.v91.6.2062 ◽

1998 ◽

Vol 91 (6) ◽

pp. 2062-2066 ◽

Cited By ~ 68

Author(s):

Marco Lenzi ◽

Magda Frisoni ◽

Vilma Mantovani ◽

Paolo Ricci ◽

Luigi Muratori ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Blood Chemistry ◽

Mixed Cryoglobulinemia ◽

Hcv Rna ◽

Hla Polymorphism ◽

Number Of Patients ◽

Host Genetic ◽

Chronic Hcv ◽

Normal Controls

Abstract Our aim was to investigate whether host genetic factors are involved in the onset of hepatitis C virus (HCV)-related mixed cryoglobulinemia (MC). We studied 25 consecutive patients presenting with a full-blown clinical picture of MC by physical examination, blood chemistry, assessment of cryoglobulins and their composition, nonorgan-specific autoantibodies, antibodies to HCV, serum HCV RNA, and HLA polymorphism. Biopsies of liver, bone marrow, and minor salivary glands were also performed in a number of patients. HLA results were compared with those of normal controls and patients with chronic HCV infection without MC and negative for autoimmune phenomena (pathological controls). Type II MC was found in 14 of 25 patients (56%), and type III MC was found in the remaining 11 (44%). All patients were positive for antibodies to HCV and/or serum HCV RNA. HLA-B8 was found in 40% (10 of 25) of patients compared with 10.1% (38 of 377) of normal controls (P = .00003, Pcorrected = .0005, relative risk [RR] 5.9) and 6.7% (2 of 30) of pathological controls (P = .007, Pcorrected = not significant). As for class II HLA molecules, only DR3 was significantly more frequent in MC patients (40%, 10 of 25) than in normal controls (15.1%, 57 of 377; P = .003, Pcorrected= .03, RR 3.7). Odds ratio (OR) for the risk of developing MC was calculated in patients positive for B8 and/or DR3, and the highest OR (8.2) was observed in individuals possessing both. The results suggest that the development of HCV-related MC is associated with HLA-B8 and DR3 markers.

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