Longitudinal studies show that transmitted drug resistance mutations are more durable than those that evolve during therapy (CID 2005;41:233; Antivir Ther 2006;11:173). These observations account for the current recommendations for baseline resistance testing to guide selection of the initial regimen (JAMA 2006;296:827; DHHS Guidelines Nov 3, 2008, www.aidsinfo.nih.gov/guidelines). Resistance tests are also the standard for changing therapy due to virologic failure. The limitations include the following:
- Resistance assays measure only dominant species at the time the test is performed; resistant variants that account for <20% of the total viral population in blood and strains in "sequestered havens" (CNS, latent CD4 cells,GI tract, genital tract, etc.) are not detected.
- Testing requires a viral load of ≥500 to 1,000 c/mL. It is technically possible to do clonal analysis to detect resistance mutations in minority species that account for as little as 0.1% of the viral pool, but these tests are expensive and time-consuming, and are not currently available for routine use by clinicians (JAIDS 2005;40:24; JID 2005;192:1).
- Genotypic assays may be difficult to interpret , especially in patients with multiple resistance mutations.
- Phenotypic assays are easier to interpret because they are more like antibacterial sensitivity results. However, clinically derived foldchange cut-offs are not available for all agents, and they are also less sensitive at detecting emerging resistance, which may be detectable by genotype assays in the form of wild-type/mutant mixtures.
As a result of these limitations, the following conclusions can be drawn:
- Resistance testing most reliably identifies drugs that should be avoided but is less reliable at detecting the drugs that are most likely to be active.
- Testing is most reliable for indicating activity of drugs the patient is taking or has recently taken, because discontinuation of therapy eventual- ly results in the reemergence and proliferation of wild-type virus. The time required for reappearance of wild-type virus after discon- tinuation of antiretrovirals appears to be at least 4 weeks, though this varies among drugs. Reversion of 184V within 20 days has been reported (JID 2005;192:1537).
- Interpretation of results in patients who have received prior antiretroviral agents is difficult, due to failure to detect "archived strains" or "minority species." Thus, prior drug history and outcome of prior resistance tests are important considerations in regimen selection. This was shown in ACTG 398, in which efavirenz (EFV) experienced patients failed EFV therapy despite baseline resistance tests showing NNRTI susceptibility. Single
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