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Background:  We examined the patterns and frequencies of HIV-1 protease (PR) and reverse transcriptase (RT) gene mutations and mutation combinations in clinical samples and sequences received for routine resistance analysis from July 1998 to June 2004.

Methods:  The mutations considered were those confirmed to be associated with a decrease in phenotypic susceptibility in the vircoTYPE analysis. Codons showing a mixture of wild-type and mutant amino acids were considered as mutant, while codons showing a mixture of two mutant amino acids were considered as distinct mutants. Mutation patterns were analyzed in 6-month intervals.

Results:  Of the 128,456 samples or sequences received during the 6-year period, the percentage of samples with any nucleoside reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) mutation or ³ 1 mutation for all 3 classes declined from an interval high of 79% to 63%, 82% to 74%, and 42% to 32%, respectively. The percentage of samples with any non-NRTI (NNRTI) mutation (~50%) remained constant, while the percentage of samples with no resistance mutations increased from an interval low of 6% to 10%. The median number of samples received in each 6-month interval from July 2000 to June 2004 with combinations of NRTI, NNRTI, or PI mutations unobserved in any previous interval (back to July 1998) was 980, 151, and 1337, respectively. During the 6 year period, > 22,700 samples with unique combinations of PI mutations, > 17,200 samples with unique combinations of NRTI mutations, and > 3300 samples with unique combinations of NNRTI mutations were received. Over the 6-year period, 95.3%, 87.2%, and 97.3% of all mutation combinations occurred in £ 10 (rare) samples for NRTI, NNRTI, and PI mutations, respectively. Conversely, more common mutation combinations (> 100 samples) comprised 0.5%, 2.4%, and 0.3% of NRTI, NNRTI, and PI mutation combinations, respectively.

Conclusions:  Analysis of HIV-1 mutations in PR and RT genes in this data set shows resistance trends similar to those previously described with either genotype or predicted phenotype analysis. Although the frequency of samples with any mutation combination associated with NRTI or PI resistance is declining, the appearance of previously unobserved combinations continues to occur at a steady rate. In this dataset, these combinations show high mutational diversity and are rare in prevalence, suggesting that the virus continues to discover new genetic pathways to facilitate the evasion of antiviral drug pressure.

Keywords: HIV resistance; mutation diversity; genotype