Prevalence and clinical significance of HIV drug resistance mutations by ultra-deep sequencing in antiretroviral-naïve subjects in the CASTLE study.
Prevalence and clinical significance of HIV drug resistance mutations by ultra-deep sequencing in antiretroviral-naïve subjects in the CASTLE study.
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DOI：
10.1371/journal.pone.0010952
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发表时间：
2010-06-03
期刊：
影响因子：
3.7
通讯作者：
Kozal M
中科院分区：
文献类型：
--
作者：
Lataillade M;Chiarella J;Yang R;Schnittman S;Wirtz V;Uy J;Seekins D;Krystal M;Mancini M;McGrath D;Simen B;Egholm M;Kozal M
CASTLE比较了阿扎那韦/利托那韦与洛匹那韦/利托那韦联合替诺福韦-恩曲他滨治疗来自5大洲的ARV初治受试者的疗效。在CASTLE的ARV初治受试者中使用超深度测序（UDS）确定TDR突变的基线率和临床意义。对第48周病毒学失败（VF）的所有53例受试者和随机选择并通过CD 4计数和病毒载量匹配的95例病毒学成功（VS）受试者的基线样本进行病例对照研究。使用454 Life Sciences/Roche技术进行UDS。在148例样本中，141例成功进行了UDS（86例亚型B，55例非B亚型）。总体而言，30.5%的受试者在基线时存在TDR突变; 15.6%的受试者仅在<20%的病毒群体中存在TDR。B亚型（30.2%）或非B亚型（30.9%）的TDR率无差异。VF（51例）和VS（90例）的任何TDR（25.5% vs. 33.3%）、NNRTI TDR（11.1% vs. 11.8%）和NRTI TDR（24.4% vs. 25.5%）的发生率相似。在9例（6.4%）M184 V/I受试者（7例水平<20%）中，6例发生VF。16例（11.3%）受试者有多个TAM，7例发生VF。3例（2.1%）受试者同时发生多个TAM + M184 V，并且均发生VF。在14例（9.9%）PI TDR受试者中（11例水平<20%）：仅1例发生病毒学失败。大多数PI TDR以<20%的水平孤立存在（例如，46 I），并且具有低电阻算法评分。在CASTLE的ARV初治受试者的代表性样本中，TDR突变很常见（30.5%）; B和非B亚型的TDR发生率相似。多个PI TDR的受试者不常见。总体而言，TDR不影响第48周时接受加强PI的受试者的病毒学应答;然而，一小部分具有广泛NRTI主干TDR模式的受试者发生病毒学失败。
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.
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