Amongst patients experiencing a rebound in viral load, those taking 3TC (lamivudine, Epivir) in combination with tenofovir (Viread) were more likely than those taking FTC (emtricitabine, Emtriva) and tenofovir to develop a number of key resistance mutations, report investigators in the online edition of AIDS.
Furthermore, virological failure with 3TC and tenofovir was associated with the emergence of a mutation that can confer resistance to the new non-nucleoside reverse transcriptase inhibitor (NNRTI), etravirine (Intelence).
Although most patients take FTC and tenofovir in a co-formulated pill (Truvada, or Atripla when efavirenz is also included), the investigators nevertheless believe that their results have clinical significance.
They write, “budget restrictions and the perception of a fundamental equivalence between 3TC and FTC may…lead to this possibly suboptimal prescription.”
3TC and FTC are nucleoside reverse transcriptase inhibitors (NRTIs) and are a key component in most first-line triple drug antiretroviral regimens in use today.
They are often regarded as being equally potent, and virological failure with both drugs has been associated with the emergence of the M184V resistance mutation.
However, laboratory studies suggest that FTC may have a longer half-life than 3TC. Moreover, there is evidence suggesting that FTC also has a favourable interaction with tenofovir, which further extends its half-life.
To see if such characteristics translated into significant differences in the activity of the two drugs in patients, Italian investigators looked at resistance mutations emerging in patients who took 3TC/tenofovir or FTC/tenofovir-containing regimens and experienced virological failure.
A total of 859 patients were included in the investigators’ analysis. All took 3TC/tenofovir or FTC/tenofovir as part of a triple-drug antiretroviral treatment regimen. This treatment suppressed viral load to undetectable levels for at least six months before rebounding to detectable levels. The period of analysis was 2002 to 2008.
Over two-thirds of patients had previously been treated with a sub-optimal combination of drugs. Moreover, at the time of virological failure, 20% were taking a triple NRTI combination and 10% an unboosted protease inhibitor.
Resistance tests were performed after viral load rebounded. Statistical analysis showed that patients taking 3TC/tenofovir were significantly more likely than those taking FTC/tenofovir-containing regimens to develop a number of key resistance mutations.
These included:
- K70R (3TC, 16% vs. FTC, 4%, p = 0.002).
- MI84V (3TC, 53% vs. FTC, 35%, p = 0.031).
- T215F (3TC, 11% vs. FTC, 4%, p = 0. 02).
Furthermore, patients treated with 3TC were more likely to develop combinations of these resistance mutations.
In addition, three NRTI resistance mutations emerged in 6% of 3TC treated patients but only 1% of those taking FTC.
The investigators also noted that the Y181C mutation, which confers resistance to NNRTIs, was found in 16% of those who took 3TC, but in only 8% of those who were treated with FTC.
“This finding is of clinical relevance”, write the investigators, “mutations at reverse transcriptase codon 181 strongly decrease efficacy of etravirine, the latest licensed and the first NNRTI expected to be active in many NNRTI-experienced patients.”
The investigators conclude, “failing a 3TC/tenofovir-containing regimen was associated with an increased risk of emergence of specific drug resistance mutations with respect to failing an FTC/tenofovir-containing regimen.”
Maserati R et al. Emerging mutations at virological failure of HAART combinations containing tenofovir and lamivudine or emtricitabine. AIDS 24 (advance, online publication), 2010.