Antiviral Drug Resistance

Question 1

Factors associated with the development of Antiviral Drug Resistance

Answer 1

1. The virus
   - Error-proneness of viral enzymes (polymerase, reverse transcriptase)
   - Kinetics of viral production
   - Kinetics of viral clearance
2. The Drug
   - Potency of antiviral drug
   - Pharmacokinetic (absorption, distribution, elimination) and pharmacodynamic (effects and side effects) properties
3. The patient
   - Prior drug experience
   - Compliance

Question 2

Effect of Nucleotide Changes

Answer 2

Nucleotide changes (mutations) —> Changes in amino acid sequence of a protein (enzyme) —> Changes in structure/function of the protein (e.g. PR or RT) —> Changes in ability of drug to inhibit target enzyme (resistance)

Question 3

Mutational Nomenclature

Answer 3

G48V :

G = Wild-type (wt) amino acid (consensus or reference)
48 = Codon position
V = Mutant amino acid

Question 4

Fitness rate

Answer 4

wild type (highest fitness rate)
mutant/variant A (reduced replication fitness)
mutant/variant B (reduced replication fitness)

Fitness is defined as a variant’s ability to contribute to successive generations

Question 5

Which antiviral drug has the highest probability of selecting drug resistance ?

Answer 5

• very poor or low antiviral activity —>does not put great selective pressure on the virus or the infecting agent; so the chances of actually selecting for drug resistance are low.
• intermediate antiviral activity is the one that actually puts the most pressure and results in the greatest probability of selecting for drug resistance.
• And that is only after getting down to the level of the maximum therapeutic efficacy for that particular organism (typically achieved by combination chemotherapy), where completely suppressed viral replication will be obtained. Obviously, there will be no chance for resistance to emerge.

Question 6

HIV-1 Genotypic Drug Resistance

Answer 6

regions of the HIV pol gene :

1) protease (PR)
2) reverse transcriptase (RT)
3) integrase (IN)

Question 7

Resistance to Antiretroviral Therapy (ART)

Answer 7

Reverse Transcriptase inhibitors (RTIs):
NNRTIs have low genetic barrier to resistance

Protease inhibitors (PIs)
PIs boosted with ritonavir have high genetic barrier to resistance

Question 8

Monitoring HIV Drug Resistance

Answer 8

1) Viral Load —> goal is a 1- to 2-log reduction in plasma viral load within 4 to 8 weeks after the initiation of drug therapy

If this GOAL is not achieved (Virologic Breakthrough = Viral rebound) = Treatment FAILURE OR Drug RESISTANCE

2) CD4+ T-cell count —> Persistently declining CD4 cell count —> measured on at least 2 separate occasions (= treatment failure)

3) Clinical Deterioration —> development of AIDS and severe symptoms indicates treatment failure

Question 9

HBV drug resistance

Answer 9

1) Lamivudine
- low genetic barrier to resistance
- long term use of lamivudine —> emergence of a resistant HBV (YMDD) mutant (15-30% of patients after 1 year of therapy, and 70% of patients after 5 years of therapy)

2) Tenofovir
- has a high genetic barrier to resistance (at least 4 mutations in the viral genome required to confer drug resistance)

BUT longitudinal study of Tenofovir therapy says —> no resistance development throughout 8 years of treatment.

3) Entecavir
- high genetic barrier to resistance (at least 3 mutations in the viral genome required to confer drug resistance)