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15th Annual Conference of the British HIV Association1-3 April 2009, Liverpool, UK |
LOW-FREQUENCY MUTATIONS STRENGTHEN THE IMPACT OF TRANSMITTED DRUG RESISTANCE (TDR) ON VIROLOGICAL RESPONSES TO FIRST-LINE EFAVIRENZ-OR NEVIRAPINE-BASED ANTIRETROVIRAL THERAPY
HIV Med 2009 Apr 1-3 (Suppl 1);15:10 (abstract no. O20)
AL Strang1, JA Johnson2, Z Fox1, CL Booth1, AN Phillips1, JF Li2, W Heneine2 and AM Geretti1
1Royal Free Hospital and University College Medical School, London, UK, 2Centers for Disease Control and Prevention, Atlanta, Georgia, USA
BACKGROUND: In the UK 10% of HIV-positive persons have evidence of TDR. However, routine genotyping fails to detect variants within the quasispecies if their frequency is <20–30%. Ultrasensitive resistance testing techniques have been developed, but evidence from clinical validation studies is not consistent.
AIM: To determine the impact of TDR on virological outcome of first-line HAART using sensitive real-time PCR.
DESIGN: Retrospective case-control study. Patients started NVP or EFV with ≥2 NRTIs in 1998–2007, had ≥24 weeks of follow-up, and either experienced virological failure (cases, n=18) or maintained virological suppression <50 copies/mL (controls, n=75).
METHODS: Stored plasma samples collected before starting HAART and at virological failure were tested by bulk genotyping. Pre-HAART samples were also tested by sensitive real-time PCR targeting RT K65R, K103N, Y181C, M184V, and G190A, using validated interpretation cut-offs for each mutation (0.5–1%).
RESULTS: Baseline characteristics were balanced. Overall, 7/18 cases and 0/75 controls showed resistance mutations in the pre-HAART sample, including 3 with high-frequency mutations also detectable by genotyping (2 K103Nhigh, 1 G190Ahigh), and 4 with low-frequency K103N detectable only by PCR (K103Nlow). Detection of either high (P=0.006) or low-frequency (P=0.001) mutants was significantly associated with the odds of virological failure. Combining high and low-frequency mutants markedly increased the strength of the association (P<0.0001). At failure, the patient with G190Ahigh, the 2 patients with K103Nhigh, and 2 patients with K103Nlow showed a genotype that included the baseline mutations plus additional RT mutations. The other 2 patients with K103Nlow showed K103R and V106M + F227L plus additional RT mutations, respectively.
CONCLUSIONS: Low-frequency K103N mutants were as prevalent as high-frequency variants in this UK cohort. The detection of low-frequency K103N was significantly associated with virological failure and, albeit not consistently, predicted the failure genotype.
2009-04-01
O20
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