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Low NNRTI Levels Before Drug Breaks Predict Resistance
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XVI International HIV Drug Resistance Workshop
June 12-16, 2007
Barbados
Mark Mascolini
Falling concentrations of the nonnucleoside (NNRTI) efavirenz or nevirapine before a CD4 and plasma viral load guided structured treatment interruption (STI) more than quadrupled the risk that a major new NNRTI-related mutation would emerge during the next drug break [1]. TIBET trial investigators warned colleagues that "even in virological responders, decreasing drug concentrations close to the lowest limit of the therapeutic range should be avoided" because of the high risk of selecting major NNRTI mutations.
In the TIBET study Barcelona clinicians tracked 50 virologic responders who resumed treatment when their CD4 count fell below 350 or their viral load topped 100,000 copies [2]. The TIBET team conducted population-based and clonal sequencing of peripheral blood mononuclear cells during periods of viral control and sequenced HIV RNA in plasma during viral rebounds.
For this substudy Laila Darwich and colleagues analyzed plasma concentrations of efavirenz or nevirapine measured at various points before treatment breaks. When drug levels were not available, they estimated concentrations with linear interpolation equations. Then they figured the degree of drug level increase or decrease over consecutive weeks.
New NNRTI mutations emerged in plasma samples from 7 of 50 people (14%) during planned drug holidays. Drug levels close to the low end of the therapeutic range for efavirenz (1500 micrograms/mL) and nevirapine (3400 micrograms/mL) before a treatment break favored selection of the major NNRTI mutations K103N, Y181C, and G190S during drug interruptions. Continuously low or undetectable NNRTI concentrations spurred selection of minor mutations including V106I/A, K103R/E, and Y188C/D during the next treatment suspension.
Compared with stable or rising NNRTI concentrations, a drop from one measure to the next raised the risk that a major NNRTI mutation would emerge 4.22 times (95% confidence interval [CI] 1.15 to 15.6, P = 0.03). This enhanced risk rose to 4.4 when the lower concentration stood below the therapeutic range for efavirenz or nevirapine (95% CI 1.18 to 16.32, P = 0.027).
This study appears to be the first linking low NNRTI concentrations just before a treatment break to emergence of major and minor mutations during the break.The result sounds surprising if one assumes good NNRTI levels are more dangerous than subtherapeutic levels if an NNRTI and two nucleosides are stopped at the same time. The danger of stopping an NNRTI simultaneously with nucleosides is that levels of slowly eliminated NNRTIs will likely persist well after nucleoside levels drop out of sight. The resulting NNRTI "monotherapy" persists as nonnuke levels dwindle into subtherapeutic realms sure to evoke resistance.
So if NNRTI levels are already low before a drug break, one might figure they will fade safely in tandem with nucleoside concentrations if people stop all drugs at the same time. And in TIBET people did stop all their drugs simultaneously. If this reasoning is right, one might guess that HIV had begun to evolve to an NNRTI-resistant genotype as NNRTI levels fell during on-treatment periods.
Whatever the explanation for the link between falling NNRTI levels before a drug break and emergence of resistance during the break, the results buttress advice to avoid NNRTIs in people who may need drug breaks or take drug breaks without medical advice--or to "cover" the slowly waning NNRTI concentration after a drug break with prolonged nucleoside therapy or even with a protease inhibitor.
References
1. Darwich L, Bellido R, Blanco A, et al. Non-nucleoside reverse transcriptase inhibitor (NNRTI) plasma concentrations determine different NNRTI-resistance pattern in virological responders during treatment interruptions. Antiviral Therapy. 2007;12:S73.
2. Ruiz L, Paredes R, Gomez G, et al. Antiretroviral therapy interruption guided by CD4 cell counts and plasma HIV-1 RNA levels in chronically HIV-1-infected patients. AIDS. 2007;21:169-178.
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