Global Development and Medical Affairs, Bristol-Myers Squibb, Wallingford, Connecticut, USA.
PLoS One. 2010 Jun 3;5(6):e10952. doi: 10.1371/journal.pone.0010952.
CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents.
Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE.
A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology.
Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2%) or non-B subtypes (30.9%). VF (51) and VS (90) had similar rates of any TDRs (25.5% vs. 33.3%), NNRTI TDRs (11.1% vs.11.8%) and NRTI TDRs (24.4% vs. 25.5%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced VF. 16 (11.3%) subjects had multiple TAMs, and 7 experienced VF. 3 (2.1%) subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels): only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I) at <20% levels, and had low resistance algorithm scores.
Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure.
CASTLE 研究比较了初治患者中阿扎那韦/利托那韦与洛匹那韦/利托那韦的疗效，两种方案均联合使用替诺福韦-恩曲他滨。
采用超深度测序（UDS）技术确定 CASTLE 初治患者中治疗耐药相关突变（TDR）的基线发生率及其临床意义。
对 53 例 48 周时病毒学失败（VF）和 95 例随机选择并按 CD4 计数和病毒载量匹配的病毒学成功（VS）的患者进行了一项病例对照研究。采用 454 Life Sciences/Roche 技术进行 UDS。
148 例标本中，141 例 UDS 成功（86 例为亚型 B，55 例为非 B 亚型）。总体而言，30.5%的患者基线时存在 TDR 突变；15.6%的患者仅有 TDR（占病毒群体的<20%）。B 型（30.2%）和非 B 型（30.9%）的 TDR 发生率无差异。VF（51 例）和 VS（90 例）的任何 TDR 率（25.5% vs. 33.3%）、NNRTI TDR 率（11.1% vs. 11.8%）和 NRTI TDR 率（24.4% vs. 25.5%）均相似。9 例（6.4%）患者存在 M184V/I（7 例<20%水平），其中 6 例发生 VF。16 例（11.3%）患者存在多种 TAMs，其中 7 例发生 VF。3 例（2.1%）患者存在 M184V 和多种 TAMs，均发生 VF。14 例（9.9%）患者存在蛋白酶抑制剂 TDR（11 例<20%水平）：仅 1 例发生病毒学失败。大多数蛋白酶抑制剂 TDR 孤立存在（如 46I），且<20%水平，耐药算法评分较低。
在 CASTLE 初治患者的代表性样本中，TDR 突变较为常见（30.5%）；B 型和非 B 型患者的 TDR 发生率相似。存在多种蛋白酶抑制剂 TDR 的患者少见。总体而言，48 周时， boosted PI 方案并未影响 TDR 患者的病毒学应答；但少数存在广泛 NRTI 骨干 TDR 模式的患者发生了病毒学失败。
