 |
|
|
| |
Nevirapine and Slow Genotyping Raise Risk of Resistance to Etravirine
|
| |
| |
6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
People who took nevirapine (versus efavirenz) and those with a longer time between viral rebound and genotypic resistance testing ran a higher chance of harboring mutations that make HIV resistant to the newest nonnucleoside, etravirine [1]. A higher nadir (lowest-ever) CD4 count and treatment with lamivudine (3TC) or emtricitabine (FTC) lowered the risk of etravirine mutations in this study from the University of Brescia. A separate multicenter Italian study confirmed that nevirapine experience independently raised the risk of having one or more etravirine mutation, while efavirenz experience did not [2].
The Brescia researchers retrospectively scrutinized resistance readings in everyone genotyped 3 months or more after starting nevirapine or efavirenz from January 2001 through December 2006. They looked specifically for mutations reported to make HIV resistant to etravirine--V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S. The DUET trials found a higher risk of virologic failure in people with 3 or more etravirine-specific mutations [3,4].
Of the 248 people genotyped, 153 (61.7%) had an etravirine-linked mutation. But only 12 people (4.8%) had three of these mutations, while 53 (21.4%) had two, and 88 (35.5%) had 1. G190A, Y181C, and K101E were the most frequently detected etravirine mutations:
· G190A in 57 people (23%)
· Y181C in 57 people (23%)
· K101E in 35 people (14%)
Multivariate analysis figured that taking nevirapine instead of efavirenz almost tripled the risk of having an etravirine mutation (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.62 to 4.62, P < 0.001). Every extra month between a viral rebound above 500 copies and genotyping boosted the risk of etravirine mutations 5% (OR 1.05, 95% CI 1.01 to 1.09, P = 0.012).
Longer time between viral rebound and genotyping lets mutations accumulate. Among 35 people who had two genotypic tests after virologic failure, 25 were taking nevirapine, and 4 of them picked up more etravirine mutations. Antiretroviral experts stress the urgency of stopping a failing nonnucleoside quickly to prevent exactly this scenario.
Two factors lowered the risk of etravirine-related mutations. Every 100-cell higher nadir CD4 count trimmed the risk of resistance 19% (OR 0.81, 95% CI 0.67 to 0.98, P = 0.029). And taking 3TC or FTC cut the risk 43% (OR 0.57, 95% CI 0.37 to 0.87, P = 0.009), independently of M184V/I detection.
The multicenter study examined 5011 viral sequences from 2955 people who had taken nevirapine or efavirenz and had a complete treatment history on record [2]. Besides the etravirine mutations assessed in the Brescia study, the multicenter study also considered K103N. Of the 2955 patients, 2153 (72.9%) had at least one etravirine mutation, but only 253 (8.5%) had three or more. Among people with the Y181C mutation, 71% had two or more other etravirine mutations.
Multivariate analysis found that nevirapine experience independently raised the risk of one or more etravirine mutations more than 50% (OR 1.510, 95% CI 1.196 to 1.906). Higher viral load and male gender also made etravirine mutations more likely. Efavirenz raised the risk 17%, but that correlation lacked statistical significance (95% CI 0.928 to 1.478). Protease inhibitor experience lowered the etravirine mutation risk almost 25% (OR 0.768, 95% CI 0.609 to 0.967), and enfuvirtide experience lowered the risk more than 50% (OR 0.469, 95% CI 0.279 to 0.788).
References
1. Giuseppe L, Calabrese A, Castelnuovo F, et al. Prevalence and risk factors for etravirine resistance among patients failing to non-nucleoside reverse transcriptase inhibitors. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 55.
2. Di Vincenzo P, Rusconi S, Adorni F, et al. Prevalence of mutations and determinants of genotypic resistance to Etravirine (TMC125) in a large Italian resistance database (ARCA). 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 59.
3. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.
4. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.
|
| |
|
|
|
|
|
