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Antiretroviral Therapy: Emergence, Mechanisms, and Persistence of Resistance
Monday, 4 - 6:15 pm
Presentation Time: 4:00 pm
Background: The role of triple nucleoside analog reverse transcriptase inhibitor (NRTI) regimens remains uncertain for patients at various stages of HIV infection. We recently undertook a 24-week pilot study to evaluate the potency and safety of a once-daily regimen of didanosine EC (ddI) 250 mg, lamivudine (3TC) 300 mg, and tenofovir DF (TDF) 300 mg in treatment-naïve patients.
Methods: Patients were considered responders if a ³ 2 log10 reduction in plasma HIV-1 RNA from baseline was observed by week 12 of treatment. Genotyping was performed at baseline; genotyping and phenotyping (Phenosense GT) were performed at week 24 or time of study discontinuation.
Results: Of the 24 patients enrolled (20 males; 4 females; median age [range] of 39 [28 to 57] years), 1 withdrew consent and 1 was lost to follow up. Median (range) plasma log10 HIV‑1 RNA and CD4 count at baseline were 4.91 (3.31 to 6.02) copies/mL and 133 (4 to 475) cells/mm3; 38% had HIV‑1 RNA ³ 100,000 copies/mL, and 58% had CD4 < 200 cells/mm3 at baseline. Of 22 evaluable patients, 2 completed the study while 20 patients (91%) discontinued treatment early (median [range] 16 [7 to 23] weeks) due to a suboptimal response. At week 12, the change from baseline in log10 HIV-1 RNA ranged from -2.66 to 0.73 with a median of -0.61 (n = 20, p = 0.003) copies/mL; 1 patient responded (³ 2 log10 reduction in viral load) and 21 patients had a suboptimal response. Resistance testing (n = 20) showed M184I/V in all patients (100%) with 10 of these patients (50%) also having K65R. Of 19 patients who had phenotyping results available, all samples showed susceptibility to TDF (<1.4X WT), while 5 of 10 patients with K65R showed reduced susceptibility to ddI (>1.7X WT).
Conclusions: Use of a triple NRTI regimen of ddI + 3TC + TDF given QD resulted in a high frequency of suboptimal response with early emergence of resistance. While the primary cause is unclear, these findings are consistent with recent reports of other triple NRTI regimens showing high rates of suboptimal response and/or early failure and provide further evidence of the inferiority of such strategies.
Keywords: Triple Nucleosides; Tenofovir; Didanosine