Drug Resistance

Drug resistance occurs when microorganisms, such as viruses or bacteria, become resistant to the drugs that are typically effective against them. Hepatitis C (HCV) drug resistance occurs when HCV becomes resistant to one or more direct-acting antiviral agents (DAA). DAAs are powerful tools in the fight against HCV. They have dramatically improved the chances of a successful cure for most people with HCV. However, drug resistance is one of the important challenges that HCV treatment faces.1

HCV and genetic mutations

HCV replicates very quickly in the body, producing billions of viruses daily. Each time the virus replicates, a copy of the virus’s genetic material is made. This copying process isn’t precise. Small errors can occur, creating genetic mutations, or small changes to the genetic code.1

Some genetic mutations that occur during replication have no effect on the virus or may even create a virus that no longer replicates. However, certain genetic mutations can create a virus that is no longer susceptible to particular antiviral drugs. These kinds of mutations can result in the drug no longer being able to stop the virus from replicating.1

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Because HCV is able to mutate rapidly, the immune system is constantly trying to catch up with the virus as it produces slightly different versions of itself. Once the body has successfully eradicated one version of HCV, another slightly modified version takes its place. Experts believe that this process is the reason why so many people who are infected with HCV develop chronic disease and why infection has been so difficult to cure.2 Additionally, this genetic diversity interferes with HCV vaccine development.

HCV drug resistance and DAAs

When a person with HCV receives a DAA, the drug may successfully eradicate most of the virus. The number of viral copies may even fall below detectable levels, suggesting that a cure has been achieved. However, if some of the virus had a genetic mutation and survived attack by the DAA, this mutated virus will continue to reproduce, and eventually re-establish the viral infection. This is what happens when a person achieves an initial response to treatment, followed by a viral breakthrough.3

Drug resistant HCV is more likely to occur when the levels of medication in the body are lower than recommended, which may occur if a person doesn’t take the recommended dose at the proper time. Drug resistance is also more common in people for whom a certain treatment fails to work.1

Certain genetic mutations can result in drug resistance not only to one medication, but to all medications that work in a similar way. For example, if someone with HCV has been treated with a NS5A inhibitor (such as ledipasvir, which is in Harvoni®) and the virus undergoes a change, the virus may become resistant to other NS5A inhibitors.4

Strategies to overcome HCV drug resistance

There are tests that can detect if HCV has specific mutations that are known to make it resistant to certain medications. Testing may be used in patients with HCV who have had prior treatment, as well as in people who have not yet had treatment for HCV. The results of these tests can help doctors choose which medications are more likely to be effective in an individual case.1

Another strategy to overcome HCV drug resistance is to combine several drugs with different mechanisms of action to attack the virus in multiple ways. The length of treatment may also be increased in cases where the HCV has resistance to certain medications.1 Lastly, it is important to adhere to your medication as prescribed by your healthcare professional, without missing any doses to decrease the chances of drug resistance.

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Written by: Emily Downward | Last reviewed: March 2021