Background: Transmitted drug resistance (TDR) is increasing in some areas of Africa. Detection of TDR may predict virologic failure of first-line non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART). We evaluated the utility of a relatively inexpensive oligonucleotide ligation assay (OLA) to detect clinically relevant TDR at time of ART initiation.
Methods: Pre-ART plasmas from ART-naive Kenyans initiating an NNRTI-based fixed-dose combination ART in a randomized adherence trial conducted in 2006 were retrospectively analyzed by OLA for mutations conferring resistance to NNRTI (K103N, Y181C, and G190A) and lamivudine (M184V). Post-ART plasmas were analyzed for virologic failure (>=1,000 copies/mL) at 6 month intervals over 18-month follow-up. Pre-ART plasmas of those with virologic failure were evaluated for drug resistance by consensus and 454-pyrosequencing.
Results: Among 386 participants, TDR was detected by OLA in 3.89% [95% Confidence Interval (CI), 2.19-6.33], and was associated with a 10-fold higher rate of virologic failure [Hazard Ratio (HR), 10.39; 95% CI, 3.23-32.41; p<0.001) compared to those without TDR. OLA detected 24 TDR mutations (K103N, n=13; Y181C, n=5; G190A, n=3; M184V, n=3) in 15 subjects (NNRTI, n=15; 3TC, n=3). Among 51 participants who developed virologic failure, consensus sequencing did not detect additional TDR mutations conferring high-level resistance, and pyrosequencing only detected additional mutations at frequencies <2%. Mutant frequencies <2% at ART initiation were significantly less likely to be found at the time of virologic failure compared to frequencies >=2% (22% vs. 63%; p<0.001).
Conclusions: Detection of TDR by a point mutation assay may prevent use of sub-optimal ART.
(C) 2014 by Lippincott Williams & Wilkins