HIV RESISTANCE AND RESISTANCE TESTING
The Origins of HIV Resistance When specific substitutions occur at certain codons in the part of the HIV
genome that encodes the reverse transcriptase and protease enzymes that are the targets of current therapy,
these mutations can alter the binding of the drug to the enzyme or produce other biochemical changes that
result in some degree of resistance to the therapy.
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Resistance occurs because HIV has a rapid replication rate (approximately 1 to 10 billion viral
particles are produced every day in the average infected individual), and as the virus replicates, it
mutates. Roughly one mutation is introduced into proviral DNA each time the HIV genome is
reverse transcribed. Because HIV reverse transcriptase has no proofreading function, all mutations
are carried in the progeny virions that emerge from that infected cell.
Therefore, mutations occur whether or not a patient is taking medication, and probably exist prior
to the initiation of treatment. Because mutations in these viral enzymes impede the efficiency of
HIV replication, the resistant virus is present at concentrations that are too low to measure in the
absence of treatment. However, once the patient starts on therapy, if incomplete suppression of
HIV replication occurs, the low numbers of virus with the resistance mutations that provide a
survival advantage is selected for and it rapidly becomes the dominant population of virus.
The probability that virus will develop resistance to any particular drug is influenced by the
activity of the combination, the number of mutations needed for the virus to become resistant (it
often requires several in combination), and the impact of the mutations on the “fitness” of the
virus. Fitness refers to the efficiency of viral replication. Mutations that adversely influence the
virus’ fitness will develop more slowly than others that have less impact
Measuring HIV Resistance
Genotypic resistance refers to the mutations that are selected for by drugs when a patient has virologic
failure. Phenotypic resistance refers to the concentration of drug required to inhibit a given amount of virus
replication in vitro. Phenotypic resistance data typically cite an IC50 or IC90, the concentration of drug that
is required to inhibit 50% or 90% of virus replication. There are advantages and disadvantages of analyzing
resistance from either perspective.
General problems with HIV resistance testing today.
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Neither the genotypic and phenotypic assay is good at detecting mutant virus that is present in low
concentrations.
2. The tests are only helpful at detecting virus with resistance relative to the combination that the
patient is currently taking. Mutations or phenotypic resistance to a drug can be undectable when a
patient switches to another combination, only to rapidly emerge if the patient is rechallenged with
the drug later on.
Specific problems with the types of HIV resistance testing today.
Genotypic Resistance Testing
Advantages: relatively fast and relatively inexpensive
Disadvantages
1. Occasionally certain combinations can interact to restore sensitivity though
individually they confer resistance.
2. New mutations are being characterized
3. Requires an expert to interpret
Phenotypic Resistance Testing
Advantages: Easy to interpret
Disadvantages
1. Expensive and time consuming
2. High degree of variability ( 2.5 to 4 fold)
3. Can’t identify trends or small changes
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Does not take into effect pharmacokinetics: some drugs may be clinically ineffective
if 2x phenotypic change while others 10x.
Does resistance testing help?
Several studies in patients with virologic failure have compared the outcomes of combinations that were
selected based on genotyping or phenotyping virus versus combinations that were selected by patients’
treatment history alone. Each trial has shown that having the resistance data available influences the
antiretroviral combination that is selected. In three of four large trials that have been published, patients
who had a combination selected on the basis of resistance testing had a greater reduction in viral load, and
were more likely to have an undetectable viral load, compared with patients whose combination was based
solely on knowledge of the treatment history.
Studies comparing treatment decisions based on genotyping versus phenotyping are underway,
and more data are needed to examine the utility of these assays in patients who have failed multiple
combinations.
Guidelines for obtaining resistance testing
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To get information on patient adherence
To help pick a new regimen when a person is having a virologic failure on the present regimen
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