Thymidine analogue mutations (TAMs; RT codons 41, 67, 70, 210, 215, 219) are a prevalent form of transmitted drug resistance (TDR) in Europe and North America, commonly occurring as singleton revertants of T215Y/F (e.g., T215E), and thought to often represent onward transmission from ART-naive subjects. Although PI/r-based therapy is recommended for patients with transmitted TAMs, it is not known whether alternative regimens carry an increased risk of virologic failure (VF). The study aim was to analyze ART outcomes in subjects with ≥1 TAM (and no other resistance) vs. subjects without evidence of resistance.
Subjects underwent genotypic resistance testing in 1998-2012 prior to starting TDF or ABC + 3TC or FTC + PI/r (ATV, DRV, FPV, LPV) or NNRTI (EFV, NVP, RPV). VF definition: confirmed viral load >50 (or 200) cps/mL after ≥6 months of ART, or one viral load >50 (or 200) cps/mL followed by a treatment change. Time to VF was analyzed using Kaplan Meier plots (figure) and Cox models adjusted for age, ethnicity, risk group, pre-ART viral load and CD4 count, and ABC use.
Of 6926 patients evaluated before ART initiation, 6345 (92%) had no resistance; 271 (4%) had ≥1 TAM, including 204/271 (75%) with singleton TAMs, most commonly T215 revertants (112/271, 41%). VF risks at the 50 cps cut-off were 808/6345 (13%) in subjects with no resistance vs. 33/271 (12%) in subjects with ≥1TAM (P=0.53, log rank test). VF risks in subjects with no resistance were 304/1591 (19%) for PI/r use vs. 504/4754 (11%) for NNRTI use (adjHR=2.2; 95% CI 1.9-2.5; P<0.001). The same direction of effect was observed with ≥1TAM: 16% (21/131) for PI/r vs. 9% (12/140) for NNRTI (adjHR=1.7; 0.8-3.4, P=0.15). At the 200 cps cut-off, VF risks were 401/6345 (6%) in subjects with no resistance vs. 12/271 (4%) in subjects with ≥1TAM (P=0.14, log rank test). VF risks in subjects with no resistance were 149/1591 (9%) for PI/r use vs. 252/4754 (5%) for NNRTI use (adjHR=1.9; 1.6-2.4, P<0.001). With ≥1TAM, VF risks were 6/131 (5%) for PI/r vs. 6/140 (4%) for NNRTI (adjHR=0.9; 0.3-2.8, P=0.87).
This cohort analysis supports the hypothesis that in patients with ≥1 TAM as the sole form of TDR (predominantly singleton T215 revertants), there was no apparent virologic advantage of starting ART with a PI/r-based regimen. As the influence of confounding factors cannot be excluded, the data should be regarded as providing a framework for designing a controlled trial.