XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications Seville, Spain, 2–5 July 2002

BACKGROUND: Response to abacavir is reduced significantly with ≥4 nucleoside reverse transcriptase inhibitor (NRTI)-associated substitutions. Response to didanosine or stavudine is reduced with ≥3 thymidine analogue mutations (TAMs). Drug susceptibility to abacavir, didanosine and stavudine is evaluated relative to viral genotype and related to biological cutoff (3.0-, 3.5-, 3.0-fold, respectively).

METHODS: 301 of 433 Virco datasets were analysed after multidrug-resistance complexes or mixtures at NRTI-resistance residues were censored. Substitutions were defined: TAMs: 41L, 67N, 70R, 210W, 215Y/F, 219Q/E; abacavir and/or didanosine: 65R, 74V, 115F, 184V; stavudine: TAMs and 75T. 44D and 118I were also evaluated. Significance was set at P=0.001.

RESULTS: Most samples had 3–4 TAMs (168/301, 56%), with M184V in 147 samples (49%) and L74V in 59 (20%). 65R, 75T, 115F and samples with six TAMs were too rare for evaluation. 118I ±44D were present in 123 samples. The median number of TAMs and abacavir/didanosine substitutions per sample was four (range 0–8). In presence of wild-type residues 74, 44, 118 and 184, the median level of resistance with any number of TAMs was <3-fold. Overall, TAMs supplemented with 184V alone contributed significantly to resistance to didanosine (1.8-fold) and abacavir (1.6-fold), but not to stavudine (0.8-fold). 74V with 3–4 TAMs and wild-type M184 showed similar changes (abacavir 2.2-fold; didanosine 2.6-fold; stavudine 1.1-fold). 44D ±118I with 3–4 TAMs showed small, non-significant increases for all drugs (1.2–1.6- fold). Log-transformed fold-resistance was compared between groups with different numbers of TAMs (0–5). Abacavir: the difference between samples with and without TAMs was statistically significant when three or four TAMs were present (geometric mean ratios [95% CIs]: 0 vs 3 TAMs: 1.54 [1.01, 2.36]; 0 vs 4 TAMs: 2.58 [1.85,3.61] – adjusted for baseline: 2.4 and 4.0, respectively). Didanosine: a significant difference was not found between any groups of samples with and without TAMs. Stavudine: significant increases were observed in samples with 3, 4 and 5 TAMs (geometric mean ratios [95% CIs] for 0 vs 3 TAMs: 1.89 (1.30,2.76); 0 vs 4 TAMs: 1.99 [1.46, 2.73] and 0 vs 5 TAMs: 2.33 [1.43, 3.81], – adjusted for baseline: 1.8, 1.9 and 2.2, respectively).

CONCLUSION: Despite extensive genotypic resistance mutation, only abacavir exceeded the assay biological cut-off, and this was observed only with ≥4 TAMs when 184V or 74V were included. Didanosine and stavudine susceptibilities remained below the biological cut-off with up to seven substitutions, despite statistically significant increases in foldresistance relative to samples without TAMs in the case of stavudine. Therefore, phenotype may have limited utility for detection of clinically significant resistance particularly to stavudine and didanosine.

PRESENTING AUTHOR: C Craig

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2002-07-02
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