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Better Etravirine Response Predicted After Efavirenz Than Nevirapine
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International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
People in whom efavirenz fails have a better chance of responding to the second-generation nonnucleoside etravirine than do people in whom nevirapine fails, according to results of an algorithm-based analysis of 7979 HIV-1 sequences [1]. Although certain etravirine-related mutations occurred more or less often in subtype C and G HIV-1 than in subtype B, subtype did not significantly affect etravirine resistance scores.
Researchers at academic centers in Belgium, Portugal, and Israel analyzed 7979 HIV-1 sequences from a pooled database of 7770 patients. The investigators divided sequences into five groups: 45% from people with no antiretroviral experience, 21% with no nonnucleoside experience, 19% with efavirenz experience, 12% with nevirapine experience, and 4% with both efavirenz and nevirapine experience. While 41% of sequences were subtype B, 26% were G, 14% were C, and the rest were subtypes or recombinant forms comprising less than 10% of all sequences.
Based on sequence analyses, Gertjan Beheydt (Rega Institute) and colleagues calculated expected resistance to etravirine with five prediction tools: ANRS (France), HIVdb (Stanford), Rega (Belgium), enhanced Monogram, and Tibotec. Predictions from all algorithms correlated relatively well, though correlations were lower with the ANRS algorithm (0.33 to 0.44) than with the other algorithms (0.68 to 0.86).
In sequences from patients with nevirapine experience, a median of 31% (range 6% to 49% depending on the algorithm) had intermediate resistance to etravirine, while a median of 4% (range 1% to 35%) had full resistance to etravirine. These resistance predictions were significantly higher (P < 0.001) than those in sequences from efavirenz-experienced people, of which a median of 17% (range 5% to 48%) had intermediate resistance to etravirine and 3% (range 1% to 25%) had full resistance.
Sequences from patients in whom both nevirapine and efavirenz failed had the highest predicted full resistance to etravirine, with a median of 25% (range 14% to 43%) scored as having intermediate resistance, and 11% (range 2% to 36%) scored fully resistant (P < 0.001 compared with both nevirapine-experienced sequences and efavirenz-experienced sequences).
HIV-1 subtype did not further affect etravirine resistance scores, although some etravirine-related mutations were more or less frequent in subtype C or subtype G than in subtype B: Antiretroviral-naive people with subtype C infection had significantly more 98G mutations than did naive people with subtype B infection. Compared with subtype B-infected individuals, subtype C-infected people with efavirenz or nevirapine experience had significantly more 106M mutations, and subtype G-infected people with efavirenz or nevirapine experience had significantly fewer 108I mutations. Antiretroviral-naive and efavirenz-experienced people infected with subtype G had more 179E mutations than people with subtype B. And subtype G-infected people with efavirenz experience had significantly fewer 179D mutations than people with subtype B.
The researchers believe their results suggest etravirine "may have limited activity in a substantial number of patients" in whom nevirapine or efavirenz failed. Because subtype did not directly influence predicted etravirine resistance, they proposed that "etravirine may be equally useful on all continents."
Reference
1. Beheydt G, Vercauteren J, levy I, et al. Expected HIV-1 etravirine resistance after treatment failure with efavirenz and/or nevirapine. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 54.
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