True prevalence of pre-existing reverse transcriptase inhibitor resistance in tre

描述（由申请人提供）：抗逆转录病毒治疗（ART）初治HIV感染者的抗逆转录病毒耐药性是一个日益严重的问题。在美国，多达18%的未接受过治疗的患者感染了HIV-1，对至少一种抗逆转录病毒药物具有耐药性。广泛遵循的治疗指南建议在开始ART之前进行耐药性检测;然而，临床使用的基于人群的基因型耐药性检测（PBGRT）仅在耐药病毒变异体占循环病毒群体的至少20%时才能检测到耐药病毒变异体。这提出了一个独特的和令人担忧的可能性，最近的初步研究结果支持，即在ART开始之前未被发现的耐药性可能会损害ART的最终疗效。这一建议背后的假设是，治疗中非核苷逆转录酶抑制剂（NNRTI）和核苷逆转录酶抑制剂（NRTI）耐药HIV的流行率可能与ART的治疗无关。5个个体的平均值高于目前使用的PBGRT检测值。本研究将证明，在开始ART治疗的个体中，有可能提高既存抗逆转录病毒耐药的检出率。这将通过在开始NNRTI-NRTI ART治疗前和治疗后7天使用PBGRT来实现。预计到第7天，野生型、药物敏感的HIV-1变异体的复制将被治疗抑制，而耐药变异体，在治疗的选择性压力下，将比药物敏感的人具有竞争优势，并且在绝对数量和HIV-1变异体循环库中的比例上都将增加。这种耐药变异体的“富集”将允许通过相同的PBGRT成功检测到它们，而在开始ART之前未能检测到它们。这些发现将通过在相同的时间点进行更灵敏的耐药测定来证实：克隆分析和最近开发的平行等位基因特异性测序（PASS）测定。还将对NNRTI-NRTI耐药的存在与NNRTI-NRTI治疗的短期（3个月）应答之间的相关性进行有限评估。后者将提供与无耐药性受试者的应答相比，具有未识别耐药性的受试者对ART的病毒学应答的一般意义。在初治患者中确定抗逆转录病毒耐药的发生率高于目前认识到的发生率，是一个重要的公共卫生问题。它使人们对当前耐药性检测策略的有效性产生了疑问，并提出了需要新方法或技术的可能性。最重要的是，未被认识到的耐药性可能会损害抗逆转录病毒疗法的疗效，及时发现耐药性可能会带来更好的治疗结果。

DESCRIPTION (provided by applicant): Antiretroviral resistance in antiretroviral therapy (ART) na¿ve HIV-infected individuals is a growing problem. As many as 18% of treatment-na¿ve patients in the United States are infected with HIV-1 with resistance to at least one antiretroviral drug class. Resistance testing prior to initiating ART is recommended by widely followed treatment guidelines; however, the population-based genotypic resistance testing (PBGRT) in clinical use can detect resistant viral variants only if they constitute at least 20% of the circulating viral population. This brings up the distinct and worrisome possibility, supported by recent preliminary findings, that undetected resistance that pre-dates the initiation of ART can compromise the eventual efficacy of ART. The hypothesis behind this proposal is that the prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) and nucleoside reverse transcriptase inhibitor (NRTI) resistant-HIV in treatment na¿ve individuals is higher than what is detected by PBGRT as it is currently used. This study will demonstrate that it is possible to increase the rate of detection of pre-existing antiretroviral resistance in individuals who are initiating ART. This will be accomplished through the use of PBGRT before and 7 days after starting NNRTI-NRTI ART. It is expected that by day 7, replication of wild-type, drug susceptible HIV-1 variants will have been suppressed by therapy whereas drug-resistant variants, under the selective pressure of therapy, will have a competitive advantage over drug-susceptible ones and will have increased both in absolute number and as a proportion of the circulating pool of HIV-1 variants. This "enrichment" of the resistant variants will allow for their successful detection through the same PBGRT that failed to detect them prior to initiating ART. These findings will be confirmed by performing more sensitive resistance assays at the same time points: a clonal analysis and the recently developed parallel allele-specific sequencing (PASS) assay. A limited assessment of the association between the presence of NNRTI-NRTI resistance and the short-term (3-month) response to NNRTI- NRTI therapy will also be performed. The latter will provide a general sense of the virological response to ART of subjects with unrecognized resistance compared to the response of subjects without resistance. Identification of a higher prevalence of antiretroviral resistance among treatment-na¿ve patients than what is currently recognized is an important public health issue. It brings into question the efficacy of current resistance detection strategies and raises the possibility that new methodologies or techniques are needed. Most importantly, unrecognized resistance might impair the efficacy of antiretroviral therapy, and its timely identification could lead to better treatment outcomes.