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Lower M184V Rates With FTC/TDF Than With 3TC/TDF
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
Using tenofovir (TDF) or a ritonavir-boosted protease inhibitor (PI) with emtricitabine (FTC) may slow emergence of the M184V mutation with emtricitabine (FTC), according to results of cell-study and cohort analyses by Valentina Svicher and colleagues at the University of Rome Tor Vergata and Catholic University in Leuven, Belgium [1]. The investigators also confirmed their clinical observation of less frequent M184V emergence with FTC/TDF than with lamivudine (3TC)/TDF or 3TC without TDF.
Svicher and coworkers analyzed 1337 HIV-1 subtype B pol gene sequences from three groups, each of which included people taking their first regimen and people taking a later regimen:
· 168 people treated with FTC/TDF (35 first-line, 133 later)
· 249 people treated with 3TC/TDF (27 first-line, 222 later)
· 920 people treated with 3TC but naive to TDF (165 first-line, 755 later)
The three patient groups were similar in clinical and virologic characteristics, except for two: A significantly lower proportion of FTC/TDF patients took a nonnucleoside with their regimen (27.4%) when compared with the 3TC/TDF group (37.7%) or the 3TC-only group (39.0%) (P = 0.02), and a significantly higher proportion in the FTC/TDF group took a PI (70.2%) than did people in the 3TC/TDF group (47.8%) or the 3TC-only group (48.5%) (P < 0.001).
When these regimens failed as first-line therapy, no nucleoside-related mutations emerged in 82.9% of those taking FTC/TDF, in 51.8% of those taking 3TC/TDF, and in 47.9% of those taking 3TC but not TDF (P = 0.02).
M184V emergence proved less frequent in people treated with FTC/TDF than in those treated with 3TC/TDF or those treated with 3TC without TDF. This lower rate held true in people with multidrug experience (45.9%, 61 of 133, with FTC/TDF; 59.4%, 132 of 222, with 3TC/TDF; 71.9%%, 543 of 755, with 3TC alone, P < 0.01) and in people whose first regimen failed (11.4%, 4 of 35, with FTC/TDF; 25.9%, 7 of 27, with 3TC/TDF; 51.0%, 84 of 165, with 3TC alone, P < 0.001).
Overall prevalence of M184V was 38.7% with FTC/TDF, 55.8% with 3TC/TDF, and 68.0% with 3TC without TDF.
Statistical analysis considering numerous factors that may affect emergence of M184V found that two variables independently raised the risk of that mutation:
· Prior 3TC use more than doubled the risk: odds ratio (OR) 2.28, 95% confidence interval [CI 1.74- to 2.98, P < 0.001)
· Use of zidovudine or stavudine raised the risk 66%: OR 1.66, 95% CI 1.16 to 2.38, P = 0.004)
Two factors independently made emergence of M184V less likely:
· TDF use: OR 0.60, 95% CI 0.42 to 0.88, P = 0.008
· Boosted-PI use: OR 0.50, 95% CI 0.33 to 0.75, P = 0.0009
To elicit resistance mutations, the investigators exposed HIV in CEM cells to increasing doses of 3TC (0.025 to 0.25 microM) and FTC (0.025 to 0.25 microM) with or without TDF (1.25 to 10 microM). In these selection experiments, M184V did not emerge in up to 10 passages over 2 months with 3TC/TDF or FTC/TDF, a finding confirming the protective role of TDF.
The T69I mutation evolved in selection experiments with 3TC/TDF but not with FTC/TDF. When T69I arose without M184V in treatment-experienced patients in the Stanford database, it conferred 74.5-fold resistance to 3TC (P = 0.03). But T69I was rare in these patients, arising in only 4 of 432 (0.4%) of those in whom 3TC/TDF failed.
Svicher and coworkers suggested three explanations for less frequent M184V emergence with FTC/TDF than the other two regimens: greater potency of FTC than 3TC, different intracellular pharmacokinetics of FTC triphosphate than of 3TC triphosphate, and/or a lower mutation rate with FTC failure than with 3TC failure.
The investigators proposed that "mutational patterns, more complex than currently known, may contribute to resistance to NRTIs, including FTC/3TC."
Reference
1. Svicher V, Alteri C, Forbici F, et al. Different evolution and patterns of genotypic resistance profiles in emtricitabine plus tenofovir and lamivudine plus tenofovir containing regimen. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 23.
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