Principles of HIV Resistance
• Resistance variants pre-exist.
Resistant strains of HIV can be transmitted sexually, and thus can be detected in patients who have never been treated. Once therapy is initiated, the resistant variants can rapidly escape the drug.
• Partial suppression leads to resistance.
Resistance requires viral replication, but even a small amount of replication can eventually lead to resistance, despite the fact that numerous mutations are required to cause drug resistance.
• Reverse transcriptase and protease are flexible proteins.
HIV reverse transcriptase and protease are remarkably flexible in their ability to mutate to resistant forms without losing their function. So far, 23 amino acid substitutions have been associated with resistance to nucleoside analogs, 35 to non-nucleoside reverse transcriptase inhibitors, and 42 to protease inhibitors.
• Not all mutations lead to resistance.
Some mutations, rather, result only in impaired fitness of the virus and lead to reduced levels of propagation.
• Not all treatment failures result from resistance.
Other causes of failure may include drug intolerance, altered intracellular metabolism, individual variation in pharmokinetics, failure to adhere to the treatment regimen, incomplete viral suppression, change in viral phenotype, and progressive immune decline. Patients may progress with susceptible virus or may do well with resistant virus.
• Not all resistance leads to treatment failures.
Resistance may be overcome in some cases by raising the dosage of the antiretroviral agent to exceed the level of resistance.
• Resistance can be prevented.
The greater the degree of viral suppression, the less likely resistant mutants will arise.
• "Beware sins of the past."
A physician should base drug choice on a patient’s treatment history. Although a viral strain that develops resistance may be replaced by a wild-type (nonresistant) virus when the selective pressure of drug is removed, the resistant mutant may rapidly return when the drug is reinstated. Reinstat ing a drug to which resistance has developed previously is unlikely to provide long-term benefit.
Source: Presented by John Mellors at the 10th International Conference on Antiviral Research. Atlanta; April 9, 1997.