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  16th CROI
Conference on Retroviruses and Opportunistic Infections Montreal, Canada
February 8-11, 2009
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K103N and Efavirenz vs Nevirapine Tied to Better Response to Etravirine
  16th Conference on Retroviruses and Opportunistic Infections,
February 8-11, 2009, Montreal
Mark Mascolini
A viral population featuring the nonnucleoside (NNRTI) K103N mutation--and failure of efavirenz rather than nevirapine--correlated with virologic response to etravirine, the newest NNRTI, in a study of 243 French patients [1]. The mutations E138A and Y181V (but not the more familiar Y181C) predicted a poor response to etravirine.
The study involved 243 people taking etravirine for at least 3 months. Anne-Genevieve Marcelin and colleagues defined virologic response as at least a 1.5-log drop in viral load or a load below 50 copies between month 2 and 3 of etravirine therapy. Most study participants (89%) had subtype B HIV-1. They had tried a median of 13 antiretrovirals (interquartile range [IQR] 11-15), including a median of 5 protease inhibitors and 1 NNRTI. While 60% had taken enfuvirtide, 12% had tried the integrase inhibitor raltegravir. Median pre-etravirine viral load stood at 4.4 log (about 25,000 copies, IQR 3.7 to 4.9 log) and median CD4 count at 175 (IQR 69 to 312).
Most people starting etravirine (73%) also started raltegravir, while 23% began enfuvirtide. The most frequently prescribe protease inhibitor was darunavir (79%), and the most frequent nucleosides lamivudine or emtricitabine (53%), tenofovir (49%), and abacavir (21%).
Among people who took only one NNRTI before etravirine, a significantly higher proportion who took nevirapine versus efavirenz had a poor virologic response (P = 0.03), regardless of the number of NNRTI mutations these people had. Compared with people who did not have the K103N mutation, those who did had fewer other NNRTI mutations (P = 0.054) and had taken efavirenz significantly more often than nevirapine (P = 0.004) but did not differ in the number of first-time drugs they took with etravirine. K103N independently predicted virologic response to the etravirine regimen. The better response to etravirine after efavirenz failure than nevirapine failure may reflect the tendency of efavirenz to select K103N upon failure.
Of the 17 mutations in the etravirine weighted mutation score, Y181I and Y181V had the highest weight, followed by L100I, K101P, Y181C, and M230L. Marcelin and coworkers identified all these mutations in pre-etravirine samples from their patients, but only Y181V had a negative impact on response to etravirine. E138A also independently predicted a poor response to etravirine.
Pre-etravirine viral load or CD4 count had no impact on response to etravirine. Response rates did not differ in patients taking an active PI with etravirine and those taking no PI or a PI predicted to be inactive by genotypic sensitivity score (85% vs 80%).
As in all earlier studies of new salvage drugs, the number of new drugs in the background regimen--in this case raltegravir, darunavir, or enfuvirtide--correlated with a better response to etravirine (P < 0.0001). Marcelin and colleagues recommended further study of why K103N, and perhaps mutations associated with K103N, appeared to make their patients more susceptible to etravirine.
1. Marcelin AG, Flandre P, Descamps D, et al. Factors associated with early virological response to etravirine in NNRTI-experienced HIV-infected patients. 16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal. Abstract 645.