Protease Inhibitors Drug Resistance Mutations in Turkish Patients with Chronic Hepatitis C

Background. The development of direct acting antivirals (DAAs) has spurred a revolution in treatment of patients with chronic hepatitis C. However, there are cases showing no response to treatment. In 5% of cases, the viral breakthrough is most likely caused by DAA resistance mutations in the hepatitis C virus genome.The purpose of the study is to detect drug resistance mutations of hepatitis C virus in patients with DAA treatment failure.Materials and methods. The study was performed on plasma samples from 3 patients diagnosed with chronic hepatitis C virus infection and demonstrating DAA virological treatment failure. All isolates had genotype 1b. Drug resistance mutations were detected by using direct sequencing of NS3, NS5A, and NS5B genome regions. The detection technique was developed at the Pasteur Research Institute of Epidemiology and Microbiology.Results. Drug resistance mutations were detected in all cases. By using the Geno2pheno [hcv] 0.92 tool, nucleotide substitutions were detected in different viral genome regions and presumably caused resistance or decreased sensitivity to antivirals both present and absent in the sofosbuvir + daclatasvir combination therapy. Antiviral treatment failure in patients with chronic hepatitis C is caused by drug resistance mutations.Conclusions. The developed technique is efficient for detection of drug resistance mutations in NS3, NS5A, and NS5B regions in cases of virological failure of DAA treatment.

Download Full-text

1224 TIMING AND CHARACTERISTICS OF DRUG RESISTANCE MUTATIONS (DRMS) IN CHRONIC HEPATITIS C PATIENTS DURING AND AFTER TREATMENT WITH PROTEASE INHIBITOR THERAPY AT A SINGLE CENTRE

Journal of Hepatology ◽

10.1016/s0168-8278(13)61225-8 ◽

2013 ◽

Vol 58 ◽

pp. S497 ◽

Cited By ~ 1

Author(s):

C. Velazquez ◽

M. Macartney ◽

D. Irish ◽

S. Tanwar ◽

P. Trembling ◽

...

Keyword(s):

Drug Resistance ◽

Chronic Hepatitis ◽

Hepatitis C ◽

Protease Inhibitor ◽

Chronic Hepatitis C ◽

Protease Inhibitor Therapy ◽

Resistance Mutations ◽

Single Centre ◽

Drug Resistance Mutations ◽

Chronic Hepatitis C Patients

Download Full-text

Detection of anti-protease inhibitors resistance mutations in HCV strains infecting treatment-naïve chronic patients from Romania

Revista Romana de Medicina de Laborator ◽

10.2478/rrlm-2018-0029 ◽

2018 ◽

Vol 26 (4) ◽

pp. 443-449

Author(s):

Sorin Dinu ◽

Grațiela Țârdei ◽

Emanoil Ceaușu ◽

Simin Aysel Florescu ◽

Laurențiu Micu ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Treatment Failure ◽

Protease Inhibitors ◽

Chronic Hepatitis C ◽

Resistance Mutation ◽

Cross Resistance ◽

Resistance Mutations ◽

Chronic Patients ◽

Subtype 1B

Abstract Background: Severe complications of chronic hepatitis C – i.e. cirrhosis and hepatocellular carcinoma – are important causes of morbidity and mortality worldwide. Despite the overwhelming rates of sustained virologic response achieved after therapy with different combinations of direct-acting antiviral drugs (DAAs), treatment failure is still recorded, and is due to the mutations harboured by hepatitis C virus (HCV) resistance associated variants (RAVs) selected during therapy. Baseline RAVs testing was found significant for guiding treatment in the cases of treatment failure and, sometimes, in naïve patients. Methods: Romanian chronic hepatitis C patients unexposed to DAAs and infected with subtype 1b HCV were studied. Serum samples were used for Sanger population sequencing of a fragment containing NS3 viral protease, known to harbour resistance mutation against protease inhibitors (PIs). Results: Catalytic triad and zinc-binding site in the studied sequences were conserved. Low-intermediate resistance mutations to first generation PIs were detected either alone or in conjunction with resistance substitutions associated with second generation PIs. Cross-resistance and reduced susceptibility to certain DAAs were observed. Discussion: This study focused on HCV patients infected with subtype 1b strains, the most prevalent in Romania. The rate of RAVs found in this work is consistent with the results reported by similar studies from other countries. Noticeably, numerous polymorphisms of unknown significance to DAAs resistance, but reflecting the high genetic variability of HCV, were found in the studied sequences. Testing for RAVs can be a useful method for guiding treatment in a cost-efficient manner in developing countries where access to DAAs is limited.

Download Full-text

Ultradeep Pyrosequencing of NS3 To Predict Response to Triple Therapy with Protease Inhibitors in Previously Treated Chronic Hepatitis C Patients

Journal of Clinical Microbiology ◽

10.1128/jcm.02547-14 ◽

2014 ◽

Vol 53 (2) ◽

pp. 389-397 ◽

Cited By ~ 5

Author(s):

Sylvie Larrat ◽

Om Kulkarni ◽

Jean-Baptiste Claude ◽

Réjane Beugnot ◽

Michaël G. B. Blum ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Triple Therapy ◽

Protease Inhibitors ◽

Chronic Hepatitis C ◽

Mononuclear Cells ◽

Resistance Mutations ◽

Serum Samples ◽

Peripheral Blood Mononuclear ◽

Previously Treated

Despite the gain in sustained virological responses (SVR) provided by protease inhibitors (PIs), failures still occur. The aim of this study was to determine if a baseline analysis of the NS3 region using ultradeep pyrosequencing (UDPS) can help to predict an SVR. Serum samples from 40 patients with previously nonresponding genotype 1 chronic hepatitis C who were retreated with triple therapy, including a PI, were analyzed. Baseline UDPS of the NS3 gene was performed on plasma and peripheral blood mononuclear cells (PBMC). Mutations conferring resistance to PIs were sought. The overall diversity of the quasispecies was evaluated by calculating the Shannon entropy (SE). Resistance mutations were found in plasma and PBMC but were not discriminating enough to predict an SVR. NS3 quasispecies heterogeneity was significantly lower at baseline in patients achieving an SVR than in those not achieving an SVR (SE of 26.98 ± 16.64 × 10−3versus 44.93 ± 19.58 × 10−3,P= 0.0047). With multivariate analysis, the independent predictors of an SVR were fibrosis of stage F ≤2 (odds ratio [OR], 13.3; 95% confidence interval [CI], 1.25 to 141.096;P< 0.03) and SE below the median (OR, 5.4; 95% CI, 1.22 to 23.87;P< 0.03). More than the presence of minor mutations at the baseline in plasma or in PBMC, the NS3 viral heterogeneity determined by UDPS is an independent factor for an SVR in previously treated patients receiving triple therapy that includes a PI.

Download Full-text

Nationwide Experience of Treatment with Protease Inhibitors in Chronic Hepatitis C Patients in Denmark: Identification of Viral Resistance Mutations

PLoS ONE ◽

10.1371/journal.pone.0113034 ◽

2014 ◽

Vol 9 (12) ◽

pp. e113034 ◽

Cited By ~ 10

Author(s):

Christina Sølund ◽

Henrik Krarup ◽

Santseharay Ramirez ◽

Peter Thielsen ◽

Birgit T. Røge ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Protease Inhibitors ◽

Chronic Hepatitis C ◽

Viral Resistance ◽

Resistance Mutations ◽

Chronic Hepatitis C Patients

Download Full-text

743 NATURALLY OCCURRING DRUG RESISTANCE MUTATIONS IN THE HEPATITIS C VIRUS NS3 PROTEASE IN HIV/HCV COINFECTED PATIENTS TREATED WITH HIV PROTEASE INHIBITORS

Journal of Hepatology ◽

10.1016/s0168-8278(10)60745-3 ◽

2010 ◽

Vol 52 ◽

pp. S289 ◽

Cited By ~ 1

Author(s):

M. Bottecchia ◽

A. Madejón ◽

M. Sánchez-Carillo ◽

P. Labarga ◽

J. García-Samaniego ◽

...

Keyword(s):

Drug Resistance ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Protease Inhibitors ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Naturally Occurring ◽

Ns3 Protease

Download Full-text

Major drug resistance mutations to HIV-1 protease inhibitors (PI) among patients exposed to PI class failing antiretroviral therapy in São Paulo State, Brazil

PLoS ONE ◽

10.1371/journal.pone.0223210 ◽

2019 ◽

Vol 14 (10) ◽

pp. e0223210

Author(s):

Giselle de Faria Romero Soldi ◽

Isadora Coutinho Ribeiro ◽

Cintia Mayumi Ahagon ◽

Luana Portes Ozório Coelho ◽

Gabriela Bastos Cabral ◽

...

Keyword(s):

Drug Resistance ◽

Antiretroviral Therapy ◽

Protease Inhibitors ◽

Sao Paulo ◽

Resistance Mutations ◽

Paulo State ◽

Drug Resistance Mutations ◽

São Paulo State ◽

Major Drug ◽

Hiv 1

Download Full-text

Hepatitis C virus vaccine development: old challenges and new opportunities

National Science Review ◽

10.1093/nsr/nwv040 ◽

2015 ◽

Vol 2 (3) ◽

pp. 285-295 ◽

Cited By ~ 20

Author(s):

Dapeng Li ◽

Zhong Huang ◽

Jin Zhong

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Chronic Hepatitis C ◽

Vaccine Development ◽

Rna Virus ◽

Antiviral Agents ◽

Resistance Mutations ◽

Direct Acting Antiviral ◽

Direct Acting

Abstract Hepatitis C virus (HCV), an enveloped positive-sense single-stranded RNA virus, can cause chronic and end-stage liver diseases. Approximately 185 million people worldwide are infected with HCV. Tremendous progress has been achieved in the therapeutics of chronic hepatitis C thanks to the development of direct-acting antiviral agents (DAAs), but the worldwide use of these highly effective DAAs is limited due to their high treatment cost. In addition, drug-resistance mutations remain a potential problem as DAAs are becoming a standard therapy for chronic hepatitis C. Unfortunately, no vaccine is available for preventing new HCV infection. Therefore, HCV still imposes a big threat to human public health, and the worldwide eradication of HCV is critically dependent on an effective HCV vaccine. In this review, we summarize recent progresses on HCV vaccine development and present our views on the rationale and strategy to develop an effective HCV vaccine.

Download Full-text