Antiviral Agents

This section covers the mechanisms of action of antiviral agents and the mechanisms by which viruses develop resistance to these drugs

Mechanisms of Action and Resistance for Antiviral Agents

Definition: Antiviral agents are medications used to treat viral infections by interfering with specific steps in the viral life cycle. However, viruses can develop resistance to these drugs through various mechanisms

General Mechanisms of Action of Antiviral Agents

Inhibition of Viral Attachment and Entry
- Mechanism: These drugs block the virus from attaching to host cells or entering the cells
- Examples
  - Enfuvirtide (HIV): Binds to the gp41 protein of HIV, preventing fusion with the host cell membrane
  - Maraviroc (HIV): Binds to the CCR5 receptor on host cells, blocking HIV entry
Inhibition of Viral Nucleic Acid Synthesis
- Mechanism: These drugs interfere with the synthesis of viral DNA or RNA
- Examples
  - Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs/NtRTIs) (HIV, HBV): These drugs are incorporated into the growing DNA chain during reverse transcription, causing chain termination
    - Examples: Zidovudine (AZT), Lamivudine (3TC), Tenofovir
  - Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (HIV): These drugs bind directly to reverse transcriptase, inhibiting its activity
    - Examples: Efavirenz, Nevirapine
  - Nucleoside/Nucleotide Analogs (Herpesviruses, HBV): These drugs are incorporated into the growing DNA chain during viral DNA synthesis, causing chain termination
    - Examples: Acyclovir, Valacyclovir, Ganciclovir, Sofosbuvir
  - Non-Nucleoside Polymerase Inhibitors (HCV): These drugs bind directly to the viral polymerase, inhibiting its activity
    - Examples: Dasabuvir
Inhibition of Viral Protein Synthesis and Processing
- Mechanism: These drugs interfere with the synthesis or processing of viral proteins
- Examples
  - Protease Inhibitors (PIs) (HIV, HCV): These drugs inhibit the viral protease enzyme, which is essential for cleaving viral polyproteins into functional proteins
    - Examples: Ritonavir, Atazanavir
Inhibition of Viral Assembly and Release
- Mechanism: These drugs prevent the assembly of new viral particles or their release from infected cells
- Examples
  - Neuraminidase Inhibitors (Influenza): These drugs inhibit the neuraminidase enzyme, which is essential for the release of new viral particles from infected cells
    - Examples: Oseltamivir, Zanamivir
Inhibition of Viral Integrase
- Mechanism: These drugs block the viral integrase, preventing viral DNA from integrating into the host cell’s DNA
- Examples
  - Integrase Strand Transfer Inhibitors (INSTIs) (HIV): These drugs bind to the viral integrase enzyme, preventing the integration of viral DNA into the host cell’s DNA
    - Examples: Raltegravir, Elvitegravir, Dolutegravir

Mechanisms of Antiviral Resistance

Definition: Antiviral resistance occurs when viruses develop the ability to replicate in the presence of antiviral drugs that would normally inhibit their replication
Mechanisms
- Mutations in the Viral Genome
  - Mechanism: Mutations in the viral genes encoding the drug target can alter the structure of the target, reducing the drug’s ability to bind and inhibit its function
  - Examples
    - HIV: Mutations in the reverse transcriptase gene can cause resistance to NRTIs and NNRTIs. Mutations in the protease gene can cause resistance to protease inhibitors. Mutations in the integrase gene can cause resistance to integrase inhibitors
    - HCV: Mutations in the NS3/4A protease, NS5A protein, or NS5B polymerase can cause resistance to direct-acting antivirals (DAAs)
    - Herpesviruses: Mutations in the viral thymidine kinase or DNA polymerase genes can cause resistance to acyclovir and ganciclovir
    - Influenza: Mutations in the neuraminidase gene can cause resistance to neuraminidase inhibitors
- Increased Viral Replication
  - Mechanism: Increased viral replication can overwhelm the inhibitory effects of the antiviral drug
- Altered Viral Entry
  - Mechanism: Mutations that alter the viral entry process can bypass the inhibitory effects of entry inhibitors
- Increased Efflux of the Drug
  - Mechanism: Some viruses can increase the expression of efflux pumps, which pump the antiviral drug out of the cell, reducing its intracellular concentration
- Compensatory Mutations
  - Mechanism: Some mutations that cause drug resistance can also reduce viral fitness. Compensatory mutations can restore viral fitness without reversing drug resistance
Factors Contributing to Antiviral Resistance
- High Viral Replication Rate: Viruses with high replication rates are more likely to develop resistance mutations
- Lack of Proofreading Ability: Viruses with error-prone polymerases (e.g., HIV) are more likely to generate resistance mutations
- Suboptimal Drug Levels: Inadequate drug dosing or poor adherence can lead to suboptimal drug levels, which can promote the development of resistance
- Prolonged Drug Exposure: Prolonged exposure to antiviral drugs can increase the selective pressure for resistance mutations
- Cross-Resistance: Resistance to one drug in a class can sometimes confer resistance to other drugs in the same class

Clinical Significance of Antiviral Resistance

Treatment Failure: Antiviral resistance can lead to treatment failure, resulting in continued viral replication, disease progression, and increased risk of transmission
Limited Treatment Options: Antiviral resistance can limit the available treatment options, particularly if resistance develops to multiple drugs
Increased Morbidity and Mortality: In some cases, antiviral resistance can lead to increased morbidity and mortality

Strategies to Prevent and Manage Antiviral Resistance

Combination Therapy: Using multiple antiviral drugs with different mechanisms of action can reduce the risk of resistance
Adherence to Therapy: Ensuring that patients adhere to their prescribed antiviral regimen is essential for maintaining adequate drug levels and preventing resistance
Drug Resistance Testing: Performing drug resistance testing can help guide treatment decisions and avoid the use of drugs to which the virus is resistant
Development of New Drugs: Continued development of new antiviral drugs with novel mechanisms of action is essential for overcoming resistance
Public Health Measures: Implementing public health measures, such as vaccination and infection control, can help reduce the spread of viral infections and the need for antiviral drugs

Key Terms

Antiviral Agent: A medication used to treat viral infections
Mechanism of Action: The way in which a drug exerts its therapeutic effect
Antiviral Resistance: The ability of a virus to replicate in the presence of an antiviral drug that would normally inhibit its replication
Mutation: A change in the genetic material of a virus
Drug Target: The specific viral protein or process that an antiviral drug inhibits
Cross-Resistance: Resistance to one drug in a class that confers resistance to other drugs in the same class
Drug Resistance Testing: Laboratory tests used to identify mutations in the viral genome that confer resistance to antiviral drugs
Combination Therapy: Using multiple antiviral drugs with different mechanisms of action
Adherence: The extent to which a patient follows their prescribed treatment regimen
Viral Load: The quantity of virus present in a specific amount of a patient’s body fluid (e.g., copies/mL)
Reverse Transcriptase: An enzyme used by retroviruses to convert RNA into DNA
Protease: An enzyme used by viruses to cleave viral proteins
Integrase: An enzyme used by viruses to integrate viral DNA into the host cell’s genome
Neuraminidase: An enzyme used by influenza viruses to release new viral particles from infected cells
Nucleoside/Nucleotide Analog: A synthetic compound that resembles a naturally occurring nucleoside or nucleotide
Efflux Pump: A protein that pumps drugs out of cells
Compensatory Mutation: A mutation that restores viral fitness without reversing drug resistance
Direct-Acting Antiviral (DAA): A drug that targets specific viral proteins or processes

Direct Detection

Procedures