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Connection domain mutations are common in treatment-experienced patients and are associated with virologic outcome
Presented by Birgitt Dau, United States.
B. Dau1, D. Ayers2, M. Winters1, J. Singer2, R. Harrigan2, S. Brown3, W. Cameron4, T. Kyriakides5, B. Angus6, M. Holodniy1
1Stanford University and VA Palo Alto HCS, Palo Alto, United States, 2Canadian HIV Trials Network, Vancouver, Canada, 3Bronx VAMC, New York, United States, 4U Ottawa Hospital, Ottawa, Canada, 5West Haven VA CSPCC, West Haven, United States, 6UK MRC, London, United Kingdom
Background: Several mutations in the connection domain (cd) of HIV RT cause decreased NRTI and NNRTI susceptibility in vitro. We hypothesized that the frequency of these mutations would be higher in a population of heavily treated HIV-infected patients in the OPTIMA trial than in treatment-naïve patients, and that they would be correlated with virologic outcomes.
Methods: Frequencies of cd mutations were compared to treatment-naïve populations in the Stanford HIV database (chi-square). Fisher’s Exact Test was used in univariate analysis to determine if the most frequent cd mutations were associated with poorer virologic outcomes, defined as less than 1 log10/mL decrease at 24 weeks of a new antiretroviral regimen. Linkage to recognized mutations was not determined.
Results: 341 genotypes were analyzed. Significantly higher cd mutation rates were seen in OPTIMA patients compared to the treatment-naïve population. Mutations A371V and A376S were associated with worse virologic outcomes, while others were not. Having one of G333E, N348I, V365I, A371V, or A376S was associated with a worse virologic outcome compared to having none, P = 0.0071.
| Mutation | OPTIMA # (%) | ARV Naive # (%) (sample size) | P Value- Frequency | P Value- Virologic Failure | | Y318F | 13 (3.8) | 0 (0) (989) | < 0.0001 | 0.5547 | | G333D | 6 (1.8) | 4 (0.4) (910) | 0.0479 | 0.6697 | | G333E | 48 (14.1) | 69 (7.6) (910) | 0.0007 | 0.0743 | | G335D | 19 (5.6) | 10 (1.2) (851) | < 0.0001 | 0.7864 | | N348I | 44 (12.9) | 1 (0.2) (358) | < 0.0001 | 0.5782 | | A360V | 16 (4.7) | 6 (1.7) (352) | 0.0428 | 1.0000 | | V365I | 26 (7.6) | 13 (3.6) (352) | 0.0375 | 1.0000 | | A371V | 73 (21.4) | 19 (5.4) (349) | < 0.0001 | 0.0062 | | A376S | 53 (15.5) | 16 (4.5) (348) | < 0.0001 | 0.0239 |
Conclusions: Cd mutations are frequent in this treatment-experienced population, and have an effect on virologic outcome. Co-localization of cd mutations, linkage with primary RT mutational patterns, and treatment assignment will be presented.
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