HCV Drug resistance Flashcards
HCV RNA polymerase has low fidelity - high error rate leading to mutations
Resistance associated substitutions (RASs) in all HCV proteins are generated daily. However RASs that have a clinical impact are much more limited.
RASs can either be drug-specific resistance, or class-specific resistance
What factors affect the likely development of a significant RAS?
Viral genotype Drug class used Replication fitness of RAS
Patient characteristics -
Prior HCV treatment
Presence of cirrhosis
Given these multiple factors, treatment decisions should not be made solely on the basis of resistance testing. It is recommended that such decisions are made by a multidisciplinary team (MDT), which is likely to include hepatologists, infectious disease physicians, pharmacists, clinical nurse specialists and virologists.
In which genotypes is there most data about the impact of RASs?
Genotype 1 - more likely to have pre-existing (baseline) non-structural NS5A mutations
Genotype 3
Certain polymorphisms that confer resistance to some DAA drug classes are present with other HCV genotypes (eg, genotype 2). However, these polymorphisms have limited clinical impact and there is a lack of commercially available diagnostic testing options
Baseline (ie, prior to drug exposure) NS5A RASs are relatively prevalent
13% prevalence in genotype 1a infection
18% prevalence in genotype 1b infection
12%-17% prevalence in genotype 3 infection
What are indications for resistance testing?
- Failure following DAA therapy
- Occasionally used as baseline screening if high cases in local area
When clinically relevant RASs are identified (e.g NS5A mutation), and patient has had treatment failure, what are options for change in management?
- prolongation of DAA therapy – to 16 or 24 weeks
- intensification of therapy with an additional drug, such as weight-based ribavirin
- avoidance of a particular DAA regimen - including stopping therapy
Patient treated for genotype 1a HCV infection.
Failed on treatment
What viral investigations would you perform?
- HCV viral load
- HCV genotyping
- HCV sequencing for RASs -
- will definitely include NS5A
- but may test for NS3A/4A and NS5B depending on what treatment they are on. Although even if RAS detected, clinical
significance is low
Apart from RASs, what is another cause of treatment failure?
- dual infection
- infection with recombinant form
- Failure may not be due to a RAS, but may be due to using genotype-specific therapy, which did not cover for dual infection. – Emergence of previously undetected minor population of different genotype, may occur. May be mis-identified as a re-infection
- Use of a pan-genotypic DAA regimen increases the likelihood for successful cure of both infecting genotypes.
- A proportion of individuals with HCV are infected with two or more different HCV genotypes or subtypes (‘mixed infection’). Between 1-30% patients have mixed infection - higher rates in PWID.
-
What is a HCV recombinant form?
What is clinical significance of this/ what testing needs performed?
Rarely, recombinant strains of HCV have been described, representing HCV genomes comprised of two different viral genotypes.
The recombinant 2k/1b is the most frequently observed in real world settings (genotype 2k is combined with genotype 1b)
Therefore any specimen provisionally assigned by core sequencing to genotype 2 should be additionally sequenced for NS5B or for the whole genome, in order to exclude a recombinant form. Otherwise if you use genotype 2 specific DAAs, you may not successfully treat genotype 1b infection - resulting in treatment failure
NS3A/4A RASs are rare in absence of prior drug exposure
Less fit virus, so resistance rapidly removed following cessation of treatment
Does not provide cross-resistance to other NS3A/B inhibitors e.g if mutation provides resistance to one drug, then another drug might be effective
What is the most common RAS?
NS3A/4A
- Q80K
NS5B RASs are rare if not on sofosbuvir, and rarely occur if on treatment with sofosbuvir
Why is this?
NS5B codes for viral RNA dependent RNA polymerase.
Virus relies on this for survival, and any mutation is likely detrimental to the virus, making it less fit
clinically no difference in outcome to patients if have NS5B RAS
What is the most common NS5B RAS
NS5B
- S282T
Only evidence exist for NS5A RASs affecting treatment outcome
Class-resistance mutations occur commonly
Patient on NS5A therapy fails treatment. What is the likelihood of them having a RAS?
75-90% individuals who fail will have NS5A RAS
NS5A RASs persist in most individuals for more than 2 years following cessation of treatment
What are the key NS5A RASs by genotype?
1a
Genotype 1a
L31M/V
M28A/T/V
Q30E/H/K/R
Y93C/H/N
What are the key NS5A RASs by genotype?
1b
Genotype 1b
L31I/M/V
Y93H
What are the key NS5A RASs by genotype?
3
Genotype 3
A30K
Y93H
