When and How to Use Resistance Testing

Taken as a whole, the available data provide a compelling rationale for the use of resistance testing in managing antiretroviral therapy (26). Resistance testing is recommended for patients failing a current regimen in order to aid in the selection of salvage therapy. Resistance testing should also be performed in patients with primary (acute) HIV-1 infection. This recommendation is based on the observation that the prevalence of drug resistance in virus samples from treatment-naïve patients with recently acquired HIV-1 infection is approximately 10% (27). Another use of resistance testing is to optimize therapy in HIV-1-infected pregnant women.

Whether or not to perform resistance testing in all patients prior to initiating antiretroviral therapy remains controversial. Because wild-type revertants are likely emerge and outgrow less fit drug-resistant variants over time, resistance testing may not be helpful in guiding therapy for treatment-naive patients with established HIV-1 infection of more than 6-12 months' duration.

For the same reason, possible resistance testing in patients experiencing treatment failure should be performed while the patient is still receiving the failing regimen, whenever possible. Once a regimen is stopped, there is the possibility that residual wild-type virus will rapidly overgrow the less fit drug-resistant mutants, giving a potentially misleading test result. Thus, results of resistance testing are most reliable for the drugs the patient is taking at the time the test is performed.

How should the results of resistance testing be interpreted? Tables of mutations that confer resistance to currently available drugs are provided in most recent reviews of drug resistance, including guidelines for use of drug resistance testing recommended by the International AIDS Society-USA (26). A number of web sites may also be helpful in interpreting resistance test results (Table 2). In the case of phenotypic testing, an increase in the IC50 of 10-fold or more (as compared to control isolates) is clear evidence for resistance in the case of most drugs. For certain drugs, however, increases in the IC50 as small as 1.7- to 4-fold may provide evidence of significant resistance. If resistance to a drug is identified, then that drug is likely to have little or no activity and should not be used in a salvage regimen. Similarly, if resistance to a drug has ever been identified, it is safe to assume that resistant virus persists, even if not detected in a current sample. (Remember, plasma virus populations change rapidly when drugs are started or stopped, but resistant viruses selected by prior regimens persist in latently infected resting CD4+ lymphocytes and can re-emerge promptly if these drugs are restarted).

Ultimately, the best choice of therapy for an individual patient should be determined by taking into account all of the information available, including history, disease stage, virus load, CD4 count, and patient preferences. Because industry-wide standards for proficiency testing and quality assurance are still evolving, clinicians should not hesitate to question the results of resistance tests that seem to be at odds with the treatment history of a given patient. It is important to remember that resistance testing is only a tool, and is never a substitute for sound clinical judgement.

4/15/01

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