Page 27 - HIV/AIDS Guidelines

HIV Drug Resistance Database (http://hivdb.stanford.edu) also provides helpful guidance for interpreting
genotypic resistance test results. Various tools are now available to assist the provider in interpreting genotypic
test results. 2-5 Clinical trials have demonstrated the benefit of consultation with specialists in HIV drug
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resistance in improving virologic outcomes. Clinicians are thus encouraged to consult a specialist to facilitate
interpretation of genotypic test results and the design of an optimal new regimen.
Phenotypic Assays

Phenotypic assays measure the ability of a virus to grow in different concentrations of ARV drugs. RT and
PR gene sequences and, more recently, integrase and envelope sequences derived from patient plasma HIV
RNA are inserted into the backbone of a laboratory clone of HIV or used to generate pseudotyped viruses
that express the patient-derived HIV genes of interest. Replication of these viruses at different drug
concentrations is monitored by expression of a reporter gene and is compared with replication of a reference
HIV strain. The drug concentration that inhibits viral replication by 50% (i.e., the median inhibitory
concentration [IC] ) is calculated, and the ratio of the IC 50 of test and reference viruses is reported as the
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fold increase in IC 50 (i.e., fold resistance).

Automated phenotypic assays are commercially available with results reported in 2–3 weeks. However,
phenotypic assays cost more to perform than genotypic assays. In addition, interpretation of phenotypic assay
results is complicated by incomplete information regarding the specific resistance level (i.e., fold increase in
IC ) that is associated with drug failure, although clinically significant fold increase cutoffs are now
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available for some drugs. 7-11 Again, consultation with a specialist can be helpful for interpreting test results.
Further limitations of both genotypic and phenotypic assays include lack of uniform quality assurance for all
available assays, relatively high cost, and insensitivity for minor viral species. Despite being present, drug-
resistant viruses constituting less than 10%–20% of the circulating virus population will probably not be
detected by available assays. This limitation is important because after drugs exerting selective pressure on
drug-resistant populations are discontinued, a wild-type virus often re-emerges as the predominant
population in the plasma. As a consequence, the proportion of virus with resistance mutations decreases to
below the 10%–20% threshold. 12-14 For some drugs, this reversion to predominantly wild-type virus can
occur in the first 4–6 weeks after drugs are stopped. Prospective clinical studies have shown that, despite this
plasma reversion, reinstitution of the same ARV agents (or those sharing similar resistance pathways) is
usually associated with early drug failure, and the virus present at failure is derived from previously archived
resistant virus. Therefore, resistance testing is of greatest value when performed before or within 4 weeks
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after drugs are discontinued (AII). Because detectable resistant virus may persist in the plasma of some
patients for longer periods of time, resistance testing beyond 4 to 6 weeks after discontinuation may still
reveal mutations. However, the absence of detectable resistance in such patients must be interpreted with
caution in designing subsequent ARV regimens.

Use of Resistance Assays in Clinical Practice (Table 4)
No definitive prospective data exist to support using one type of resistance assay over another (i.e., genotypic
vs. phenotypic) in different clinical situations. In most situations genotypic testing is preferred because of the
faster turnaround time, lower cost, and enhanced sensitivity for detecting mixtures of wild-type and resistant
virus. However, for patients with a complex treatment history, results derived from both assays might
provide critical and complementary information to guide regimen changes.

Use of Resistance Assays in Determining Initial Treatment
Transmission of drug-resistant HIV strains is well documented and associated with suboptimal virologic
response to initial ART. 16-19 The likelihood that a patient will acquire drug-resistant virus is related to the
prevalence of drug resistance in HIV-infected persons engaging in high-risk behaviors in the community. In

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents C-9

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