what is the treatment of genome 1a for hcv with cirrhosis

Simeprevir (brand name: Galexos), a NS3/4A protease inhibitor like the already available DAAs telaprevir and boceprevir, was recently approved by Health Canada for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis

, who are treatment-naïve or who have failed previous interferon therapy (peglyated or non-pegylated) with ribavirin.

Full Answer

How is hepatitis C virus (HCV) genotype 1a treated in compensated cirrhosis?

The fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) was approved by the FDA for the treatment of genotype 1 infection in treatment-naive patients based on two registration trials: ION-1 (865 treatment-naive patients; those with cirrhosis were included) and ION-3 (647 treatment-naive patients; those with cirrhosis were excluded).

What is the recommended treatment regimen for human hepatocellular virus (HCV)?

Quick Reference Treatment of HCV Genotype 1 Core Concepts. Introduction; HCV Genotype 1: Initial Treatment; Studies of Initial Treatment of Adults with HCV Genotype 1; HCV Genotype 1: Retreatment of Persons who Failed Prior Therapy; Studies of Retreatment of Adults with HCV Genotype 1; Summary Points; Activity 1B. AASLD-IDSA Hepatitis C Guidance; Activity 1C.

How to treat genotype 1a without cirrhosis?

Feb 25, 2022 · HCV genotype 1a treatment-naïve patients with compensated cirrhosis Recommended regimens Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for those with no b......

What are the treatment options for herpes simplex virus 1A without cirrhosis?

Recommendations for patients infected with HCV genotype 1a or genotype 1b with compensated cirrhosis, in whom prior INF and RBV treatment has failed are: (1) daily fixed-dose combination of Ledipasvir/Sofosbuvir for 24 weeks, (2) daily fixed dose of Ledipasvir/Sofosbuvir plus weight-based RBV for 12 weeks, (3) daily fixed dose of Paritaprevir/Ritonavir/Ombitasvir plus twice …

Which medication is only approved for genotype 1 treatment of HCV?

Is HCV genotype 1a curable?

What does HCV genotype 1a mean?

Which HCV genotype is easiest to treat?

What is recommended treatment for a patient who is treatment naïve and does not have cirrhosis?

Can HCV genotype change?

Why is HCV genotype important?

Is chronic hep C curable?

What is the difference between interferon and peginterferon?

Which HCV genotype is hardest to treat?

Which cluster of side effects are commonly found in HCV treatments?

What is a high viral count for hep C?

What is the phase 3 of POLARIS-2?

POLARIS-2: In this phase 3, open-labeled trial, individuals with chronic HCV genotype 1, 2, 3, or 4 infection who were naïve to DAA therapy (prior peginterferon and ribavirin allowed) were randomized to receive either 8 weeks of sofosbuvir-velpatasvir-voxilaprevir or 12 weeks of sofosbuvir-velpatasvir. [ 27] Among the 941 participants, 18% had compensated cirrhosis and 49% had HCV genotype 1 infection. Sustained virologic response (SVR) occurred in 95% and 98% in sofosbuvir-velpatasvir-voxilaprevir and sofosbuvir-velpatasvir arms, respectively. Notably, SVR occurred in 90% of persons with cirrhosis in the 8-week arm compared with 99% in the 12-week sofosbuvir-velpatasvir arm. [ 27] The investigators concluded that this study did not establish sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks. [ 27]

How long is the Peginterferon retreatment?

Persons with HCV genotype 1 and compensated cirrhosis who are treatment-experienced with peginterferon and ribavirin (with or without an early DAA) are not eligible for the 8-week glecaprevir-pibrentasvir retreatment option; the 8-week treatment course can be used in treatment-naïve persons with genotype 1 and compensated cirrhosis if they do not have HIV infection.

What are the factors that affect the choice of treatment for HCV genotype 1?

For individuals with chronic HCV genotype 1 infection, the main factors that influence the choice and duration of therapy are cirrhosis status and prior treatment experience . With the use of certain regimens for persons with HCV genotype 1a, namely elbasvir-grazoprevir, the genotype 1 subtype (1a or 1b) also impacts the choice of therapy, as elbasvir-grazoprevir is only recommended for persons with HCV genotype 1a who do not have baseline NS5A resistance-associated substitutions (RASs). In addition, the HCV RNA level and the patient’s HIV status can impact the duration of ledipasvir-sofosbuvir, but does not affect the duration of other regimens. Finally, the cost of the regimen, insurance coverage, and provider preference can play a major role in the regimen choice. The following treatment recommendations are based on the AASLD-IDSA HCV Guidance for initial treatment of adults with HCV genotype 1 and for retreatment of adults in whom prior therapy failed, including those with HCV genotype 1. [ 4, 5]

How long does it take to treat HCV genotype 1A?

For initial therapy of HCV genotype 1a infection in adults who have compensated cirrhosis, three 12-week regimens with similar efficacy are recommended: elbasvir-grazoprevir (if no key resistance-associated substitutions are detected on pretreatment NS5A testing); ledipasvir-sofosbuvir; or sofosbuvir-velpatasvir. One 8-week regimen is also recommended: glecaprevir-pibrentasvir.

What are the factors that influence the choice of treatment for HCV?

For treatment-naïve adults with chronic HCV genotype 1 infection, the main factors that influence the choice and duration of therapy are (1) presence or absence of cirrhosis, and (2) medication cost or insurance considerations. In the case of elbasvir-grazoprevir use, the HCV genotype 1 subtype (1a or 1b) is also important, as the presence of specific baseline NS5A RASs significantly reduces SVR12 rates in persons with HCV genotype 1a. [ 10, 11, 12] In cases where the genotype 1 subtype is not known, the individual should be treated as HCV genotype 1a. The baseline HCV RNA level generally does not influence the treatment choice or duration, except in treatment-naïve noncirrhotic patients in whom 8 or 12 weeks of ledipasvir-sofosbuvir is being considered. [ 13] Additional data from the HCV-TARGET registry and the Veterans Affairs National Healthcare System demonstrated comparable SVR rates of 94 to 98% for adults without cirrhosis treated with either 8 or 12 weeks of ledipasvir-sofosbuvir if the baseline HCV RNA levels were less than 6 million IU/mL. [ 14, 15, 16] In addition to the factors noted above, drug interactions may also influence the choice of therapy, particularly for individuals with HIV coinfection who are taking antiretroviral medications. Of note, individuals with HCV and HIV coinfection, depending on their specific antiretroviral therapy, are eligible for most of the same regimens for initial treatment of genotype 1 as for persons with HCV monoinfection, except that persons with HIV should not receive (1) any 8-week option of ledipasvir-sofosbuvir, or (2) the 8-week option of glecaprevir-pibrentasvir if cirrhosis is present. [ 11, 12, 17, 18]

What is the treatment for genotype 1?

From 1998-2013, therapy evolved from interferon monotherapy, to peginterferon monotherapy, to peginterferon plus ribavirin, to triple therapy with peginterferon plus ribavirin plus an NS3/4A protease inhibitor ( boceprevir or telaprevir ). [ 6, 7, 8, 9] Since 2014, the standard of care for HCV genotype 1 has consisted of all-oral therapy with a combination of DAAs. As of 2017, there have been multiple safe, convenient, and highly effective all-oral regimens recommended for the treatment of HCV genotype 1, most of which do not require ribavirin.

What is genotype 1?

In the United States, genotype 1 hepatitis C virus (HCV) accounts for approximately 70 to 75% of all HCV infections. [ 1] . Accordingly, treatment of genotype 1 has the most extensive data and highest clinical relevance for hepatitis C treatment issues in the United States. In recent years, multiple studies using direct-acting antiviral (DAA) ...

How long does it take to take sofosbuvir?

Sofosbuvir/Velpatasvir. The fixed-dose combination of 12 weeks of sofosbuvir (400 mg)/velpatasvir (100 mg) was approved by the FDA for the treatment of genotype 1 infection in treatment-naive patients based on ASTRAL-1.

What genotype is NS5A resistance tested for?

Based on known inferior response in patients with baseline NS5A RASs, NS5A resistance testing is recommended in genotype 1a patients who are being considered for elbasvir/grazoprevir therapy. If baseline RASs are present (ie, substitutions at amino acid positions 28, 30, 31, or 93), another recommended regimen should be used (additional information is available in the RAS section).

Does NS5A reduce SVR12?

The presence of certain baseline NS5A RASs significantly reduces SVR12 rates with a 12-week course of elbasvir/grazoprevir in genotype 1a-infected patients ( Zeuzem, 2017 ). Baseline NS5A RASs were identified in 12% (19/154) of genotype 1a-infected patients enrolled in the C-EDGE study, of which 58% (11/19) achieved SVR12 compared to an SVR12 rate of 99% (133/135) in patients without these RASs receiving 12 weeks of elbasvir/grazoprevir ( Zeuzem, 2017 ). Among treatment-naive patients, the presence of baseline NS5A RASs with >5-fold reduced sensitivity to elbasvir was associated with the most significant reduction in SVR12 with only 22% (2/9) of genotype 1a patients with these RASs achieving SVR12.

How to determine HCV genotype?

The determination of HCV genotype is based on isolation of HCV viral RNA and cDNA synthesis followed by PCR amplification of the 5′ untranslated region (5′ UTR). Viral RNA is isolated from infected serum after HCV viral load determination using the MagNA Pure Total Nucleic Acids Extraction Kit (Roche Diagnostics) or the Qiagen EZ1 BioRobot. The extracted nucleic acids are subjected to RT-PCR using primers specific for 5′ UTR sequence that is conserved among all known HCV genotypes. The RT-PCR step is performed using an Applied Biosystems GeneAmp 9600 PCR System (block cycler). A second PCR amplification using a seminested pair of primers is accomplished in the LightCycler in the presence of a pair of FRET oligonucleotide probes. The FRET detection probe allows the discrimination of HCV genotypes 1a/b, 2a/c, 2b, 3a, and 4 during melting curve analysis ( Fig. 30.3) because it hybridizes with differential affinity to a region of the 5′ UTR that varies among the different HCV genotypes. Magnesium concentration is critical for optimal genotype discrimination. Primer and probe design and PCR details have been described. For method validation, patient samples analyzed by an independent reference laboratory were used. Positive QC materials consisted of pooled patient serum samples of previously determined genotype (genotypes 1, 2a/c, 2b, and 3a). Negative QC material consisted of pooled patient serum samples previously determined to be HCV negative. A water blank is also always included with each run. A serial limiting dilution of positive patient samples with known viral titers was used to determine the limits of detection. The seminested method described will fail when viral titers are less than 12,600 IU per mL. A more sensitive fully nested PCR method was developed and is able to genotype specimens with 130 IU per mL. The fully nested PCR method uses the freshly extracted RNA and the same RT and the first PCR steps used for the seminested approach. The second PCR step uses a new set of nested primers and is done in the block cycler. The products of this reaction are subjected to melting curve analysis in the LightCycler to determine genotype using the same set of FRET probes described for the semi-nested genotyping method. The fully nested approach is rarely needed because patients usually have high viral loads on initial presentation, and this is the ideal time to assess the HCV genotype.

How does autophagy affect HCV replication?

Autophagy acts as a proviral factor and positively regulates HCV replication. We have reported the inhibition of infectious virus particle production in autophagy knockdown virus-infected cells in immortalized human hepatocytes, suggesting that autophagy contributes to HCV infectious particle assembly in hepatocytes ( Shrivastava et al., 2011 ). Immunity-associated GTPase family M (IRGM) protein is able to directly interact with several autophagy proteins and is involved in the initial steps of autophagy induction. Reduced expression of IRGM prevented the accumulation of autophagosomes and LC3 lipidation upon HCV infection ( Grégoire et al., 2011 ). Silencing of IRGM compromised the production of infectious HCV particles by more than 70%; similar to the absence of Atg5, suggesting that IRGM-mediated autophagy induction favors infectious viral particle production. The autophagy machinery may be required for the early steps of HCV infection, most likely at viral RNA translation and/or replication ( Dreux et al., 2009 ). Silencing of autophagy proteins, LC3 or Atg7, inhibits replication of the HCV JFH1 genomic RNA in Huh-7.5 cells ( Sir et al., 2008 ). On the other hand, Tanida et al. (2009) showed that Atg7 and Beclin 1 siRNA treatment in virus-infected cells resulted in a decrease in the production of the infectious HCV particles in the medium, however, the intracellular production of HCV mRNA and HCV proteins remained unchanged. There are conflicting reports about HCV replication in autophagic vacuoles ( Dreux et al., 2009; Tanida et al., 2009; Ke and Chen, 2011 ). Chloroquine and Bafilomycin A1 treatment led to reduction of HCV RNA replication and infectious virus production ( Ke and Chen, 2011 ). We, and others, have observed that several HCV proteins (NS3, NS4B, and NS5A) induce autophagy ( Gregoire et al., 2011; Shrivastava et al., 2012 ), implying that HCV viral proteins might facilitate interaction with various autophagy-associated proteins to play a positive role in autophagosome formation. HCV has been shown to exploit autophagy machinery as a survival mechanism in hepatocytes. We have observed that knockdown of Beclin 1 or Atg7 leads to cell death in virus-infected hepatocytes ( Shrivastava et al., 2011 ). A similar finding was reported in HCV replicon cells ( Taguwa et al., 2011 ), indicating that HCV circumvents cell death by inducing autophagy in hepatocytes.

What is boceprevir used for?

Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor , which reversibly binds to the active site of HCV non-structural protein 3 (NS3) [31r,35E]. In vitro, boceprevir has potent activity against HCV genotypes 1a and 1b; it is principally metabolized by the aldoketoreductase pathway and also by CYP3A4 [36E].

What is the BILN-2061 inhibitor?

In a substrate-based development programme, a specific and potent peptidomimetic inhibitor, ciluprevir (BILN-2061), of the hepatitis C virus NS2/3 protease lowered serum HCV-RNA markedly in patients chronically infected with the HCV genotype 1, and less pronouncedly and more variably in patients with HCV genotypes 2 and 3. In a small prospective, multicenter, double-blind, placebo-controlled, proof-of-principle study in eight patients, adverse events that were possibly drug related included mild constitutional symptoms, such as a drunken feeling, fatigue, somnolence, and mild gastrointestinal symptoms [7 ].

What genotypes are associated with NS5A?

HCV genotypes 1 a and 3 are associated with a high prevalence of NS5A mutations at baseline, which necessitate evaluation depending on planned NS5A-inhibitor treatment regimen and clinical presentation.

Which genotype has higher relapse rates?

Patients with HCV genotype 1a tend to have higher relapse rates than patients with genotype 1b with certain regimens. Genotype 1 HCV infection that cannot be subtyped should be treated as a genotype 1a infection [38,40–58].

Where is HCV endemic?

Recent studies have reported that HCV genotype 5a, once believed to be restricted to South Africa, has been endemic for a long time in isolated areas of Central France and West Flanders ( Verbeeck et al., 2006 ). In contrast, HCV strains found in restricted geographic areas are highly divergent.

How long does Sofosbuvir last?

Sofosbuvir plus ledipasvir is a coformulated, once-daily, single-pill regimen for the treatment of Gt 1 HCV infection. The recommended treatment duration is 12 weeks, except for people with cirrhosis who have not responded to pegIFN therapy, who should receive treatment for 24 weeks (Table 3).

How often should you monitor hemoglobin levels during ribavirin?

Patients with renal impairment have increased risk of anaemia during ribavirin therapy. Monitoring of haemoglobin levels is recommended every 2–4 weeks during ribavirin therapy in people with decompensated liver disease. As ribavirin is teratogenic, both women and men should be counselled about the risks of pregnancy and advised that two forms ...

What are the most common adverse effects of ribavirin?

Headache, nausea and fatigue were the most common adverse effects, but were typically mild and occurred at the same frequency as in people who were treated with placebo. Typical ribavirin-related adverse events were observed in those who received ribavirin.

What are the genotype specific regimens for HCV?

Genotype-specific regimens for the treatment of people with HCV infection are still listed on the PBS. Elbasvir plus grazoprevir and sofosbuvir plus ledipasvir are genotype-specific treatment regimens, and HCV genotype should be determined before prescribing either of these regimens.

Is Sofosbuvir safe for liver disease?

Combination sofosbuvir and ledipasvir is safe even with decompensated cirrhosis (see treatment of decompensated liver disease ). Fatigue, headache and nausea are the most common adverse effects, but are uncommon and typically mild. [33,34] As noted, sofosbuvir and its main metabolite GS-331007 are renally excreted.

Is HCV tolerated in Australia?

Several other genotype-specific regimens for the treatment of HCV infection are no longer marketed in Australia and have been removed from this consensus statement.

Treatment

Clinical significance

Prevention

Administration

• The following is a summary of the AASLD-IDSA HCV Guidance for adults with hepatitis C genotype 1a or 1b infection who are treatment experienced and failed prior therapy, including those without cirrhosis and those with compensated cirrhosis.[41,42,43,44,45,46,47] For individuals with cirrhosis, the AASLD-IDSA HCV Guidance defines compensated cirrho...

See more on hepatitisc.uw.edu

Research

Analysis

• For genotype 1a-infected, treatment-naive patients without cirrhosis, there are 4 recommended regimens with comparable efficacy. Four regimens are classified as alternative because, compared to the recommended regimens, they require a longer duration of treatment, involve greater prescribing complexity, are potentially less efficacious, and/or ther...

See more on hcvguidelines.org

Contraindications

Pharmacology

Medical uses