Resistance to HAART therapy has been a major obstacle in the long-term management of HIV infection. Increasingly, to guide drug selection, clinicians are testing for HIV resistance to antiretroviral agents as well as assessing patients’ detailed drug histories. This testing can use either genotypic or phe-notypic methods to determine whether patients have HIV mutations that confer resistance to currently available medications.
Genotypic Resistance Testing
Genotypic assays detect drug resistance mutations within the viral genome, either by sequencing specific genes or by using probes to find selected mutations that are most commonly associated with drug resistance. These assays are readily available, and genetic mutations usually occur before phenotypic changes.
Genotypic resistance testing following unsuccessful treatment is cost-effective at $17,900 per quality-adjusted life year (QALY) gained. Thus, when the prevalence of acquired resistance to HAART is high (e.g., 20% or greater), resistance testing might be cost-effective in treatment-naive individuals. Genotypic resistance assays are limited, because genotypic results do not always correlate with in vivo response and because the testing mechanism relies on known mutations in specific regions of the HIV genome.
Phenotypic Resistance Testing
Phenotypic assays quantify the ability of the patient’s HIV sample to grow in vitro in various concentrations of anti-retroviral drugs; this is a potential advantage because it is a direct measure of viral susceptibility. Phenotypic assays usually take longer than genotypic resistance testing and cost more, between $600 and $1,000 per test; in contrast, genotyping costs $300 to $550 per test. There is insufficient evidence to recommend the use of one type of resistance assay over the other.
The Role of Resistance Testing
The therapeutic role of antiretroviral resistance testing is still being evaluated. The DHHS Consensus Panel and the AIDS Society/USA Panel have made similar recommendations for HIV-infected adults. For treatment-experienced patients with virologic failure, resistance testing, in conjunction with clinical judgment, achieves an undetectable viral load when a new regimen is selected more frequently than when the regimens have been selected by clinical judgment alone.
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Although these studies appear encouraging, limitations to both genotypic and phenotypic assays include (1) cost, (2) limited experience interpreting the results, and (3) insensitivity for minor viral species. If less than 10% to 20% of the circulating viral population consists of mutant viruses, current resistance assays will probably be unable to detect them. This limitation leads to some concerns:
1. That resistance testing alone is not a replacement for clinical judgment; a detailed medication history and accounting of prior adherence will be fundamental factors in new drug selection.
2. Because of increased selection pressure for mutant viruses, antiretroviral resistance testing is best conducted while the patient is receiving antiretroviral therapy.
The DHHS Guidelines recommended antiretroviral resistance testing for patients experiencing virological failure while taking HAART. An example of virological failure would be a repeatedly detectable viral load following earlier suppression to undetectable levels. Resistance testing is recommended if, four weeks after initiating a new antiretroviral regimen, the log10 reduction in plasma HIV RNA is less than 0.5 to 0.75.
- the log10 reduction at eight weeks is less than 1.0.
- therapy does not suppress the viral load to undetectable levels four to six months after treatment is initiated.
A resistance assay should be considered in acute HIV infection to modify the initial regimen when transmission of a drug-resistant virus is suspected. The specific circumstances of HIV acquisition (e.g., from a partner who has undergone a heavy an-tiretroviral regimen) or the community prevalence of a drug-resistant virus may help to guide the decision. Generally, resistance assays are not recommended for chronic HIV infection in the following situations:
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- before drug therapy is begun
- after discontinuation of drug therapy
- when the plasma viral load is less than 1,000 copies/ml
Immune System Reconstitution
the sustainability of this reconstitution is still being evaluated.