September 28, 2006
Understanding the relationship between the acquisition of antiretroviral-associated resistance mutations and the reduced activity of antiretroviral drugs continues to be important for HIV practitioners. In a poster presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy,1 Lisa L. Ross, of GlaxoSmithKline, and colleagues attempted to determine how the number of primary nucleoside reverse transcriptase inhibitor (NRTI) mutations in the HIV-1 reverse transcriptase (RT) gene affects a patient's susceptibility to NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). To do so, Ross et al analyzed resistance data from blood samples submitted to Monogram Biosciences, Inc., for the PhenoSense GT assay between 2003 and 2005.
The total number of samples received during the study period was 35,222, although samples with mutation mixtures were excluded, leaving 26,852 in the analysis. Data for emtricitabine (FTC, Emtriva), tipranavir (TPV, Aptivus) and zalcitabine (ddC, Hivid) were not available. For analysis purposes, the 2005 International AIDS Society-USA guidelines were used to determine whether mutations were defined as either "primary" or "secondary."
The results showed that no samples had more than eight RT mutations. As the number of NRTI mutations increased, the number of thymidine associated mutations (TAMs) and secondary NRTI, NNRTI and PI mutations increased. The prevalence of multidrug RT mutations never increased past 5.5% regardless of the number of NRTI mutations.
Replication capacity decreased incrementally as the number of primary NRTI mutations increased. This may reflect the fact that 60% to 80% of samples with two or more NRTI mutations had M184V, which is known to be associated with decreased replication capacity. Specific mutations -- such as K65R, Q151M and 69 insertions -- were associated with a lower number of NRTI mutations.
Loss of phenotypic susceptibility to at least one NNRTI was found in 33% of samples (n = 14,363) that had no NRTI mutations and in 54% of samples (n = 4,092) that had just one NRTI mutation. The average number of NNRTI mutations in these groups as a function of the number of major NRTI mutations present in the samples was 0.3 and 0.8, respectively.
As the number of NRTI mutations increased, so did the number of NNRTI and PI mutations. In samples with one NRTI mutation, 35% had K103N and 9.5% had Y181C. The prevalence of K103N did not increase above 40%, even in the face of a growing number of NRTI mutations. In addition, as the number of NRTI mutations increased, so did the percentage of samples with reduced susceptibility to at least one PI, as well as the total number of PIs with reduced susceptibility.
There were a number of limitations to this study. For one thing, the clinical and antiretroviral history of the patient samples were not known. Nor was the context for why these antiretroviral resistance tests were obtained, or what (or how many) antiretroviral regimens were taken on an individual patient basis that contributed to the aggregation of the various mutations.
In sum, this study found that the number of NRTI mutations correlates directly with the number of NNRTI and PI mutations, as well as with the loss of susceptibility to all three of these antiretroviral classes. The results are fairly consistent with what is seen in clinical practice: Namely, that the more regimens a patient fails, the greater the number of mutations and the smaller the number of active antiretroviral agents that are available.
Certainly, the prevalence of NNRTI resistance that was discovered in this study is higher than what has been reported in acute infection studies, as well as some other studies that investigated the prevalence of resistance. However, we were not given any information about these patients, nor do we have any context explaining why phenotypes were ordered. Were these samples all from acutely infected patients? Chronically infected, antiretroviral-naive patients? Antiretroviral-experienced patients not currently on treatment? Patients with previous NNRTI or NRTI exposure who are not currently on treatment? Patients currently on NNRTI treatment? The number of questions surrounding the apparently higher proportion of patients with NNRTI resistance makes it difficult to put any clinical context around this finding.
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