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November 2000
It is possible that Alex’s virus has become resistant to the antiretroviral medications. This can occur because of intermittent adherence, continued low-level virus replication and mutational events despite undetectability of virus in plasma, and/or interindividual variability in the pharmacokinetics of the antiretroviral agents (especially protease inhibitors). Because Alex has an extensive antiretroviral medication history, genotypic resistance testing should be considered as a next step in choosing a new treatment regimen.
You obtain results of a genotypic resistance assay showing amino acid substitutions at codons 41, 70, 184, and 215 of the HIV reverse transcriptase, and codons 46 and 82 of the HIV protease. Which of the following treatment regimens would be the best choice for Alex?
A. AZT, ddI, saquinavir
B. AZT, 3TC, lopenavir/ritonavir
C. d4T, ddI and efavirenz
Answer:
C. Two types of resistance testing are available: genotypic assays and phenotypic assays. Phenotypic assays provide data similar to that from bacterial susceptibility testing. Genotyping compares relevant genetic regions of the HIV protease and reverse transcriptase with a consensus wild-type sequence. The results report any amino acid substitutions at the codons tested. Both types of resistance testing have many drawbacks. They both are based on in vitro and not in vivo testing, so may not predict precisely the way an individual patient will respond to medications. Neither test will detect minority mutant populations. For example, genotypic resistance assays typically will not detect HIV minority populations representing ten percent or less of circulating virus. If there is no ongoing exposure to a given antiretroviral agent, resistant virus may become a progressively smaller percentage of the total circulating virus, only to re-appear after treatment with the agent is re-instituted. The assays are complex and can be difficult to interpret, although algorithms and database driven programs are available. Experienced technicians are needed to perform the test accurately. In addition, experienced physicians should interpret resistance tests in the context of an individual patient’s clinical and treatment history. Finally, resistance testing can be very expensive.
In Alex’s case, there were several codon substitutions, as is expected in a patient who has been exposed to several different antiretroviral agents. Alex’s genotype reveals resistance to AZT (codons 41, 70, and 215), 3TC (codon 184), and indinavir (codons 46 and 82). Hence, choosing any of these medications will decrease the likelihood of a complete and durable virologic response to treatment. Alex’s virus did not show any resistance to d4T. There is increasing data supporting the existence of in vitro cross-resistance between d4T and AZT, however little clinical resistance to d4T has been demonstrated. Mutations at codon 184 may be associated with low-grade resistance to ddI, but this mutation generally does not eliminate ddI as a treatment option. Hence, d4T and ddI are the best choices for a nucleoside backbone.
While therapy with a new protease inhibitor such as saquinavir is a possibility, there is often cross-resistance between the protease inhibitors. Hence, a new protease inhibitor may only transiently lower Alex’s viral load, and then allow rebound with another mutant strain. The new protease inhibitor combination of lopinavir/ritonavir has been shown to be effective in salvage regimens. However, the nucleoside backbone in answer B is not the best choice. In addition, there is another class of antiretroviral medications (non-nucleoside reverse transcriptase inhibitors) to which Alex has never been exposed. Adding one of these agents (e.g., efavirenz) to the nucleoside backbone probably will provide the best likelihood of regaining viral suppression.
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