Chronic Hepatitis C Genotype 1a

Initial Treatment Of Hcv Infection

Determining Genotype in Hepatitis C Determines Treatment Course

This section addresses treatment of patients with chronic hepatitis C who are naive to any type of therapy. Although regimens containing peginterferon and ribavirin plus direct-acting antiviral drugs are approved by the FDA for many HCV genotypes, the initial regimen for patients who are treatment-naive with HCV genotype 1 generally has been superseded by treatments incorporating regimens using only DAAs. Recommended treatments are viewed as equivalent, and the decision of which to use may involve consideration of drug interactions between the DAAs and concomitant medications . For example, the daily fixed-dose combination of ledipasvir and sofosbuvir has a potential interaction with proton pump inhibitors. Similarly, the daily fixed-dose combination of paritaprevir , ritonavir , and ombitasvir plus twice-daily dosed dasabuvir has a substantial interaction with the long-acting inhaled beta-adrenoceptor agonist salmeterol and other drugs that interface with the cytochrome P450 3A4 isoenzyme.

Factors Associated With The Two Distinct Subtype 1a Clades

Table summarizes the analysis of the association of some demographic, epidemiological, and virological factors with segregation of European HCV 1a into clade I or II. We found no significant association with known risk factor and time from HCV diagnosis, calendar year of sampling, or HCV viral load, whereas clade II tended to be associated with the presence of HIV coinfection.

Evolutionary Rate Estimates Time

Bayes factor analysis showed that the relaxed clock fitted the data significantly better than the strict clock . Under the relaxed clock, the BF analysis showed that the constant model was better than the other models . Under the relaxed log-normal clock and constant model, the analysis of the HCV subtype 1a NS3 gene led to a mean evolutionary rate estimate of 3.24 × 103 .

Bayesian phylogenetic tree of the complete dataset 1A) showed a clear separation between 2 clades, which were labeled as clade I and II in agreement with original designation .

Bayesian phylogenetic tree. A, Bayesian maximum clade credibility tree of all hepatitis C virus 1a subtype sequences with branch lengths scaled in time by enforcing a relaxed molecular clock. Branches labeled with asterisks are well supported, having a posterior probability > 0.90. Tip dates for each node represent the year of isolate collection. B, Geographic origin of the sequences on the phylogenetic tree based on a subset of 192 sequences from Europe and the Americas with known geographic origin and sequencing date. Abbreviations: BR, Brazil EU, Europe US, United States.

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Medications Used To Treat Hcv Genotype 1

The HCV Medications section on this website provides detailed information for each of the Food and Drug Administration -approved medications listed in the treatment recommendations, including links to the full prescribing information and to patient assistance programs. The DAAs exert their action at specific steps in the HCV life cycle. There are three major classes of direct-acting antiviral medications: nonstructural proteins 3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors the NS5B polymerase inhibitors include the nucleoside analogs and nonnucleoside analogs . Adherence with the treatment regimen is of paramount importance. Persons receiving treatment for HCV should receive detailed counseling regarding the importance of adherence prior to starting therapy as well as intensive monitoring and follow-up during therapy.

Which Treatment Works For Each Genotype

Chronic Hepatitis: Chronic Hepatitis C Genotype 1a

All Genotypes: see Epclusa fact sheet
Genotypes 1 through 4: see Sovaldi, Viekira XR and Technivie, Harvoni, Olysio fact sheets
Genotypes 1 or 4: see Zepatier fact sheet
Genotypes 2 or 3: see Sovaldi, Daklinza fact sheets
Genotype 6: see Harvoni fact sheets

Ribavirin causes birth defects and miscarriage. HCV treatment regimens that include RBV should not be used by pregnant women or by male partners of pregnant women. RBV stays in a persons body for months, so women and their male partners should avoid pregnancy until six months after stopping it .

This fact sheet is current as of December 2016. It is recommended to be read alongside the Adherence and HCV Diagnostics fact sheets. Always check for updated information.

How Is Genotype Determined

A simple blood test can be used to determine your hepatitis C genotype. The test doesnt have to be repeated because once someone has been infected with HCV, the genotype remains the same. It is possible to be infected by more than one HCV genotype. However, this occurs rarely.

Learn more about recommended treatment based on HCV genotype.

First Combination Tablet For Chronic Hepatitis C Genotype 1 Infection

On October 10, 2014, the FDA approved the fixed-dose combination capsule of ledipasvir plus sofosbuvir for the treatment of patients with chronic HCV genotype 1 infection., Ledipasvir plus sofosbuvir is the first combination tablet approved for the treatment of patients with chronic HCV genotype 1 infection, as well as the first approved regimen that does not require the use of interferon or ribavirin. Ledipasvir and sofosbuvir interfere with the enzymes that HCV needs to be able to multiply.

Ledipasvir was a new agent that was approved for use in combination with sofosbuvir., Ledipasvir plus sofosbuvir combination therapy was reviewed under the FDA’s priority review program, which expedites the review of drugs that treat serious conditions and that, if approved, would provide significant improvement in the safety or efficacy of the treatment.

With the development and approval of new treatments for hepatitis C virus, we are changing the treatment paradigm for Americans living with the disease, said Edward Cox, MD, MPH, Director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.Until last year, the only available treatments for hepatitis C virus required administration with interferon and ribavirin. Now, patients and health care professionals have multiple treatment options, including a combination pill to help simplify treatment regimens.

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H77s Virus Challenge In Chimpanzee 4×0193

The original cell culture-adapted genotype 1a H77S clone contains 5 cell culture-adaptive mutations located in NS3, NS4A, and NS5A . Cells transfected with synthetic H77S RNA release virus into supernatant culture fluid that has a buoyant density of â¼1.13 gm/cm3 and is capable of infecting naive Huh-7.5 cells . To determine whether this virus was infectious in the chimpanzee, we concentrated H77S virus from supernatant fluids by centrifugal filtration. A sterile 10-ml suspension containing 104 FFU H77S virus was inoculated intravenously into a 25-year-old, previously HCV-naive female chimpanzee . Subsequent monitoring of the animal over a period of 28 weeks revealed an isolated increase in serum alanine aminotransferase from a baseline of 30 Â± 5.9 U/liter to 88 U/liter 3 weeks postinoculation but no evidence of HCV viremia or anti-HCV seroconversion . The results led us to conclude that the H77S inoculum did not contain sufficient chimpanzee-infectious virus to initiate an infection.

Structural Context Of Amino Acid Substitutions Occurring During H77s2 Infection In 4×0193

Genotype 1 Hepatitis C is Common with Increasingly Effective Treatment

Experimental high-resolution models exist for the three-dimensional structures of several nonstructural HCV proteins, including the NS2 protease, the NS3 protease-helicase, NS5A domain I, and the NS5B RNA-dependent RNA polymerase . To gain insight into the selective forces driving evolution of the H77S.2 genome in 4×0193, we assessed the structural context of substitutions occurring within these nonstructural proteins. We considered it likely that amino acid substitutions influencing interactions with host cell proteins would be located at or near the solvent-accessible surface of the nonstructural proteins. In contrast, mutations reflecting escape from T cell recognition of peptide epitopes presented on class I molecules may be more randomly distributed between surface-exposed and nonexposed residues. Surprisingly, each of the nonsynonymous substitutions occurring within domains of the nonstructural proteins for which structural information exists involved amino acid residues that were at least partially surface exposed.

Why Do Genotypes Matter For Treatment

Knowing your HCV genotype is important information that can help patients and doctors find the most effective treatment.

All HCV genotypes cause the same amount of liver damage. However, people infected with genotype 1, particularly subtype 1b, may have a greater chance of developing cirrhosis, or severe liver scarring, than other genotypes. Genotypes 1b and 3 may increase the risk of liver cancer.

HCV can now be cured by all oral, direct-acting antivirals , medications that prevent the hepatitis C virus from make copies of itself. DAAs do this by sticking to proteins in the virus and blocking steps in the virus life cycle. This allows your immune system to clear the virus out of your body. How well a DAA works depends on where it sticks to the target proteins in the virus.

Some of the latest DAA treatments are pangenotypic, which means they can cure all genotypes at nearly the same rates.

Screening And Linkage To Care

To increase the identification of the large proportion of persons living with undiagnosed HCV, we recommend that screening be both risk-based and target the birth cohort of individuals born from 1945 to 1975, which currently encompasses the majority of persons chronically infected with HCV in Canada .

A high proportion of Canadians with chronic HCV infection remain undiagnosed, with credible estimates ranging from 44% to 70%., The asymptomatic nature and slow progression of the infection require that individuals be identified through screening. Individuals at increased risk of infection should be tested for HCV . In addition, based on a high prevalence and low testing rate among baby boomers, a strategy of one-time screening of all individuals born between 1945 and 1975 has been shown to be cost-effective and should be implemented in Canada.

Recommended regimens and durations for patients with compensated cirrhosis who have never been treated, according to HCV genotype*

For each HCV genotype, multiple approved regimens are available. The comprehensive efficacy and safety data supporting the recommendation of each regimen for each population are provided in Appendix 1.

Genotype 1

Genotype 2

Genotype 3

Genotypes 4, 5, 6

Posttreatment follow-up

Patients who achieve sustained virologic response and do not have cirrhosis require no specific liver-related follow-up. In those with ongoing risk exposures, annual HCV RNA testing to assess for reinfection is suggested .

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What Are Hepatitis C Genotypes

A variable for those with chronic hepatitis C virus is the genotype, or the strain of the virus when they contracted an infection. The genotype is determined by a blood test.

The genotype doesnt necessarily play a role in progression of the virus, but rather as a factor in selecting the right medications for treating it.

According to the

Origin And Spread Of Hcv In The World

Epidemiological and phylogenetic studies have shown that the initial epidemic spread of HCV in Japan occurred in the 1920s1930s through mass campaigns of parenteral antischistosomal therapy , followed during World War II by intravenous drug use , transfusion, and unsafe invasive medical and surgical procedures. Similarly, in Europe, the initial spread of the virus started during the last century through the use of unsafe parenteral injections, invasive medical and surgical procedures and transfusion of blood products. An epidemic explosion of IDU shortly followed the iatrogenic spread in the early 1960s both in the United States and Europe .

The divergence of subtype variants is estimated to have occurred less than 100 years ago, whereas the numerous subtypes of HCV are proposed to have diverged some 300 years ago while the major HCV genotypes would have originated at least 5002000 years ago.

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Validation Of Hepatitis C Virus Genotyping

Figure 30.3. HCV genotyping assay. Comparison of samples from patients infected with HCV genotypes 1b, 2a/c, 2b, and 3a. Shown are genotype-specific melting transitions for four samples in 2 mM MgCl2. Data were obtained by monitoring the fluorescence of the LCRed640-labeled FRET sensor probe during heating from 40 to 80 °C at a temperature transition rate of 0.1 °C/s.

Management Of Competing Interests

Members of the guideline panel have financial relationships with pharmaceutical companies related to HCV therapeutics. All members signed a commitment and competing interest statement at the outset of guideline development. Individuals with relevant disclosures were not excluded from voting on recommendations. However, in order to manage competing interests, the final guideline was vetted by the Canadian Association for the Study of the Liver membership, and specifically by the associations executive, to evaluate the presence of commercial bias. No funding, direct or in kind, was provided to the guideline panel for this work.

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Retreatment Of Persons With Prior Peginterferon And Ribavirin Failure

The latest version of the AASLD-IDSA HCV Guidance no longer provides specific recommendations for retreatment of persons with a history of peginterferon plus ribavirin therapy, with or without an earlier generation direct-acting antiviral agent . The AASLD-IDSA HCV Guidance notes that these individuals respond to retreatment similar to treatment-naïve persons, thus implying the treatment approach should be the same as with treatment-naïve individuals. Although the pool of persons with a history of failure with a peginterferon-based regimen who need retreatment is small and diminishing, there are some individuals with this treatment history who need retreatment and may require special consideration that differs from that of treatment-naïve individuals. The following outlines a few of these key considerations based on available data and previous guidance that should be noted when retreating an individual with a history of prior treatment failure with peginterferon plus ribavirin, with or without an earlier generation DAA . Note that except for the 8-week option of glecaprevir-pibrentasvir , when retreating these individuals with first-line DAA combinations that have pangenotypic activity , the treatment will be the same as their treatment-naïve counterparts.

Hepatitis C And Health

A Simple HCV Treatment

How can health-care personnel avoid exposure to HCV?

Avoiding occupational exposure to blood is the primary way to prevent transmission of bloodborne illnesses among health-care personnel. To promote blood safety in the workplace, health-care personnel should consult infectious-disease control guidance from the National Institute for Occupational Safety and Health and from CDC. Depending on the medical procedure involved, Standard Precautions may include the appropriate use of personal protective equipment .

What is the risk of acquiring hepatitis C after being accidentally exposed to HCV-contaminated blood or body fluids in the workplace?

Although sharps injuries have decreased in recent decades due to improved prevention measures, they continue to occur, placing health-care personnel at risk for several bloodborne pathogens like hepatitis C. A recent analysis of several studies revealed an overall 0.2% risk for infection among those exposed to HCV-antibody-positive blood through needlestick or sharps injuries . Updated guidelines for management and treatment of hepatitis Cexternal icon are available to provide guidance for health-care personnel who become infected via exposure to contaminated blood at the workplace.

Other than needlesticks, do other exposures place health-care personnel at risk for hepatitis C?

Should HCV-infected health-care personnel be restricted in their work?

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Chemistry Mechanism Of Action Spectrum And Resistance

Simeprevir is an inhibitor of the NS3/4A serine protease of HCV, which is necessary for the proteolytic cleavage of the HCV-encoded polyprotein and is essential for viral replication. Simeprevir has demonstrable in vitro activity against HCV genotypes 1a, 1b, and 4 using different cell-based replicon assays.

Several amino acid substitutions at NS3 protease positions confer reducted activity, including F43, Q80, S122, R155, A156, and D168. The baseline prevalence of Q80K is 30% in genotype 1ainfected patients, but is less than 1% in genotype 1binfected patients. The Q80K polymorphism is associated with a lower sustained virologic response in clinical trials. Baseline determination of the Q80K polymorphism should be obtained before initiation of treatment with simeprevir.

Jean-Michel Pawlotsky, in, 2013

The Management Of Chronic Hepatitis C: 2018 Guideline Update From The Canadian Association For The Study Of The Liver

Hepatitis C is a major public health problem in Canada that is underdiagnosed and undertreated birth cohort screening would benefit population health outcomes.
Pretreatment evaluation of an infected patient should include clinical evaluation, viral load, genotype and a fibrosis stage assessment.
The treatment of hepatitis C has become safer, better tolerated and more effective owing to the availability of direct-acting antivirals for nearly all patients this guideline advocates against the use of any interferon-based treatment regimens and for the use of all-oral regimens for all infected patients.
The treatment of infected patients should be individualized to maximize chance of success, especially for difficult-to-cure populations, including patients with renal failure, decompensated cirrhosis, and active substance use disorders.
After treatment, the follow-up of successfully treated patients depends on whether they are cirrhotic patients with cirrhosis require life-long surveillance for the development of hepatocellular cancer.

Since the last Canadian guideline on the management of chronic HCV infection from the Canadian Association for the Study of the Liver was published in 2015, there have been remarkable treatment advances. Thus, there was a need for an updated, evidence-based guideline.

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Chronic Hepatitis C Genotype1

Department of Genetics and Biotechnology, Osmania University, Hyderabad, India.

*Corresponding Author:Chandapure SindhuraDepartment of Genetics and Biotechnology, Osmania University, Hyderabad, IndiaTel: 917702877625

Received: November 05, 2020 Accepted: November 16, 2020 November 23, 2020

Citation:Sindhura C Chronic hepatitis C genotype1. , J Liver Disease Transplant 9:5. 185. doi: 10.37532/jldt.2020.9.185

Phylogenetic Diversity In Core Region Of Hepatitis C Virus Genotype 1a As A Factor Associated With Fibrosis Severity In Hiv

Jorge Quarleri

1Instituto de Investigaciones Biomédicas en Retrovirus y Sida , Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 11, C1121ABG Buenos Aires, Argentina

2Laboratorio de Virología y Genética Molecular , Facultad de Ciencias Naturales y Ciencias de la Salud Sede Trelew, Universidad Nacional de la Patagonia San Juan Bosco, 9 de Julio y Belgrano S/N, Chubut, 9100 Trelew, Argentina

3Consejo Nacional de Investigaciones Científicas y Técnicas, Av. Rivadavia 1917, C1083ACA Buenos Aires, Argentina

Abstract

1. Introduction

Hepatitis C virus is an enveloped, positive-stranded RNA virus belonging to the genus Hepacivirus in the family Flaviviridae. HCV infection is the major cause of chronic liver disease. Total global viraemic HCV infections were estimated in 80 million infections . Of them, more than 4 million are coinfected with the human immunodeficiency virus as both viruses share common transmission routes .

HCV-chronic infection is responsible for different hepatic damage including oxidative stress, insulin resistance, steatosis, fibrosis, apoptosis, and hepatocellular carcinoma . Such alterations are attributed to changes in gene expression patterns in the liver due to virus replication dynamics .