Drug resistance testing in the clinical management of HIV infection
- Michael J Kozal, MD
Michael J Kozal, MD
- Professor of Medicine
- Yale University School of Medicine
The development and transmission of HIV variants resistant to antiretroviral drugs continues to limit the efficacy of treatments for HIV infection. Factors influencing the development of HIV drug resistance and the role of genotypic and phenotypic testing in different clinical scenarios will be reviewed here .
The relative advantages and disadvantages of the tests and clinical trial data supporting their use, an introduction to the understanding of resistance mutations, and the issue of nevirapine resistance related to prevention of mother-to-child HIV transmission are discussed elsewhere. (See "Overview of HIV drug resistance testing assays" and "Clinical trials of HIV drug resistance testing" and "Primer on interpretation of HIV drug resistance testing".)
CONTRIBUTING FACTORS TO RESISTANCE
Multiple factors influence the development of HIV drug resistance, including the biology of HIV, genetic barriers to resistance, regimen potency, pharmacokinetics of antiretroviral drugs, and medication adherence.
HIV biology — HIV infection is characterized by high rates of replication, with more than 10(9) virions produced daily . In addition, HIV reverse transcriptase, which is responsible for replicating the viral genome, is error-prone. The combination of high rates of replication and frequent introduction of mutations during each round of replication leads to the frequent occurrence of randomly generated mutations, some of which confer drug resistance . The resulting population of genetically related, but distinct, HIV variants in a patient is referred to as a "quasispecies."
Some drug-resistant variants, which replicate less efficiently than drug-sensitive strains in the absence of drug, can pre-exist at low levels before drug therapy is initiated. If virus replication is not fully suppressed by the antiretroviral regimen, these mutants can emerge. Depending on their level of drug resistance, these mutants can either cause overt virologic failure, or, if replication in the presence of drug persists, become more drug resistant by the gradual accumulation of additional resistance mutations.
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- CONTRIBUTING FACTORS TO RESISTANCE
- HIV biology
- Genetic barriers to resistance
- Regimen potency
- Medication adherence
- CONSEQUENCES OF DRUG RESISTANCE
- Viral fitness
- Clinical impact
- RATIONALE FOR HIV SUSCEPTIBILITY TESTING
- INTERPRETATION OF RESISTANCE TESTING
- Choosing a regimen
- Assessing adherence
- Treatment history
- Expert advice
- False negative results
- Replication capacity
- WHEN TO OBTAIN RESISTANCE TESTING
- Treatment-naïve patients
- - Primary HIV infection
- Treatment-experienced patients
- Pregnant women
- CHOICE OF TESTING
- SUMMARY AND RECOMMENDATIONS