Resistance to antiretroviral therapy is an important cause of treatment failure, especially in the treatment-experienced patient. Its prevalence is also beginning to rise in both treatment-naive and newly infected patients.

The International AIDS Society panel and other experts recommend the use of resistance testing at both therapy initiation and treatment failure to help guide antiretroviral therapy selection. So, for every new agent, we have to understand genotypic algorithms and phenotypic cutoff points.

Emtricitabine (FTC, Emtriva) and lamivudine (3TC, Epivir) are both cytosine nuclear analogs approved for use in HIV-1 infection, with emtricitabine having a longer intracellular half-life. Both can select for the M184V/I mutation, which results in high-level resistance (>100 fold). Viruses with other nucleoside-associated reverse transcriptase (RT) mutations can also show reduced susceptibility to both drugs.

The objective of Borroto-Esoda's study was to compare the phenotypic resistance profiles of both emtricitabine and lamivudine against a panel of wild-type and mutant clinical isolates of HIV to further our understanding of emtricitabine resistance.

The study was jointly conducted by Gilead, the maker of emtricitabine, and ViroLogic, the maker of the Phenosense assay. Phenotypic evaluation was performed on viruses submitted for routine clinical testing in the ViroLogic Phenosense Assay -- 306 having nucleoside analog mutations (NRTI-R) and 100 wild-type without resistance mutations. Viruses with M184V or I were excluded, but those with a mixture were allowed.

The following genotypic profiles were obtained for the 306 samples with NRTI-R: 21% had mixtures of wild type and M184V/I, 72% had 1 or more thymidine analog mutations (TAMs), 14% had L74V/I and 7.5% had K65R. Results were expressed as fold change in IC₅₀ compared to NL4-3 reference. Concordance of fold change was evaluated based on both biological (emtricitabine and lamivudine) and clinical cutoffs (lamivudine).

Mean IC₅₀ values for emtricitabine and lamivudine against the NL4-3 reference were 1.01 +/- 0.14 and 2.79 +/- 0.37 micromolar, respectively. The fold change in 100 wild-type isolates was 0.9 and the biological cutoff was 1.4-fold for both emtricitabine and lamivudine. Emtricitabine-lamivudine concordance was quite high among NRTI-R isolates, ranging from 94-100% for biological cutoffs and 91-100% for clinical cutoffs for the NRTI-R mutations.

Emtricitabine and lamivudine demonstrate nearly identical phenotypic resistance profiles among NRTI-resistant clinical isolates of HIV-1. For NRTI-R isolates, there was a strong linear correlation between log-transformed emtricitabine and lamivudine fold change values (r² = 0.94). There was a greater than 90% concordance in resistance calls based on either the biological (1.4 fold) or clinical (3.5 fold) cutoffs among all NRTI-R isolates or isolates with M184V/I, TAMs, L74V or K65R. See table below.

In the absence of M184V/I, the majority of samples with resistance (>3.5 fold change) exhibited TAMs. When samples having the M184V/I mutation were excluded from analysis, there was a trend toward increased cross-resistance, with an increasing number of TAMs for both emtricitabine and lamivudine.

Both emtricitabine and lamivudine had identical biological cutoffs, as determined against a panel of 100 wild-type clinical isolates. Both also demonstrate nearly identical phenotypic resistance profiles among NRTI-resistant clinical isolates of HIV-1. Both showed a trend toward increased cross-resistance with increasing number of TAMs.

All of the above suggest similar genotypic interpretation algorithms and phenotypic cutoffs may apply to both drugs, although large studies in varied populations using different resistance assays are needed. While emtricitabine has been used extensively in other countries, it is still relatively new to American practitioners. The similarities between emtricitabine and lamivudine are important for both physicians and patients to be aware of since resistance to one agent most likely means resistance to the other. Viruses with other NRTI-R mutations may show reduced susceptibility to both drugs.