18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

PRE-EXISTING LOW-LEVELS OF THE K103N HIV-1 RT MUTATION ABOVE A THRESHOLD IS ASSOCIATED WITH VIROLOGICAL FAILURE IN TREATMENT-NAÏVE PATIENTS UNDERGOING EFV-CONTAINING ANTIRETROVIRAL TREATMENT

Antivir Ther 2009; 14 Suppl 1:A43 (abstract no. 41)

DD Goodman¹, NA Margo², DJ McColl², MD Miller², K Borroto-Esoda¹ and ES Svarovskaia^1
1Gilead Sciences, Inc., Durham, NC, USA; ²Gilead Sciences, Inc., Foster City, CA, USA

BACKGROUND: Study GS-01-934 was a randomized open-label Phase III study comparing FTC+TDF+EFV to 3TC+ZDV+EFV in treatment-naïve HIV-1-infected patients. Patients with NNRTI resistance at baseline by standard population sequencing (22/509 [4.3%]) were excluded from the primary efficacy analysis. Through 144 weeks, 50/487 patients (FTC+TDF+EFV [n=19] and 3TC+ZDV+EFV [n=31]) experienced virological failure (VF). Here, we analysed all patients using allele-specific PCR (AS-PCR) to assess low levels of K103N at baseline and VF.

METHODS: A real-time PCR platform (EraGen Biosciences, Madison, WI, USA) that utilizes allele-specific PCR primers for K103K (AAA and AAG codons) and K103N (AAC and AAT codons) was developed. All available baseline plasma samples (n=485) were RT-PCR amplified and tested for K103N; assay cutoff was 0.5% for mutant detection.

RESULTS: AS-PCR results were obtained for 476/485 samples. Overall, 16/476 (3.4%) had detectable K103N by AS-PCR but not by population sequencing, increasing the percentage of treatment-naïve patients with NNRTI resistance to 7.5% (38/509). Six of 16 patients (37.5%) with low-level K103N showed VF (n=5 in the 3TC+ZDV group and n=1 in FTC+TDF group) and statistical analysis showed a strong correlation between pre-existing low-level K103N and VF within the 3TC+ZDV group (P=0.005). The size of the K103N subpopulation at baseline correlated with VF. Within the VF group, the K103N percentage detected by AS-PCR ranged from 0.8% to 15% (1,254–16,071 copies/ml of K103N in plasma), whereas in the non-VF group the K103N percentage ranged from 0.6% to 3.2% (51–5,535 copies/ml of K103N). The presence of K103N above 2,000 copies/ml strongly correlated with VF (5/6 with VF versus 1/10 without VF; P=0.008). For the one FTC+TDF patient with low-level K103N and VF, only 0.8% K103N (1,254 copies/ml) was detected; however, this patient had only 20 CD4+ T-cells/ml at baseline, which may also have contributed to VF.

CONCLUSIONS: Utilization of AS-PCR resulted in an overall increase in detection of K103N in treatment-naïve patients as compared with detection by population sequencing only. The presence of low-levels of K103N was associated with risk of VF within the 3TC+ZDV group. The results suggest a threshold quantity of K103N at baseline that is predictive of VF.

2009-06-09
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