Sproat Michael, Pozniak Anton L, Peeters Monika, Winters Bart, Hoetelmans Richard, Graham Neil M, Gazzard Brian G
St Stephens Centre, Chelsea and Westminster Healthcare NHS Trust, London, UK.
Antivir Ther. 2005;10(2):357-61.
In vitro phenotypic resistance studies suggest that the presence of the M184V mutation leads to a reduction in HIV-1 susceptibility to didanosine (ddl). The relevance of this to clinical outcomes remains unclear. In this study, we compared the virological response of ddl- and non-ddl-containing regimens in the presence or absence of the M184V mutation.
Data from an observational cohort study of all HIV-1 patients who had phenotypic resistance testing following the emergence of virological failure to an existing highly active antiretroviral therapy (HAART) regimen were analysed. A total of 586 patients entered the study and were followed-up over 48 weeks; 281 (48%) were switched to ddl-containing HAART, of whom 105 had the M184V mutation at baseline. Virological efficacy of combination therapy was studied by reference to average area under the curve of viral load (VL) response and the proportion of patients attaining an undetectable VL (<400 copies/ml). Baseline characteristics and univariate analysis of changes in VL were compared using the Wilcoxon rank sum test. Multivariate analyses were performed using the Van Elteren test. Additional variables included the number of baseline nucleoside reverse transcriptase inhibitor mutations and the number of active antiretroviral drugs given to each group as compared by 'real phenotype' resistance test results.
Amongst patients on ddl-containing HAART, median fold changes in phenotypic susceptibility to ddl were greater in patients with the M184V mutation (fold changes of 2.2 vs 1.2, P<0.001). Nonetheless, the median change in VL and percentage of patients attaining an undetectable VL were similar in those taking ddl, irrespective of whether the M184V mutation was present at baseline. In the group of patients with the M184V mutation at baseline, the virological outcome was significantly better in those treated with ddl-containing HAART than in those on HAART without ddl (P<0.05).
While the M184V did increase the fold resistance of HIV to ddl, these changes appeared to be lower than the clinically relevant threshold for phenotypic resistance for this drug.
体外表型耐药性研究表明，M184V突变的存在会导致HIV-1对去羟肌苷（ddl）的敏感性降低。其与临床结果的相关性仍不明确。在本研究中，我们比较了含ddl和不含ddl方案在存在或不存在M184V突变情况下的病毒学反应。
对所有HIV-1患者进行观察性队列研究的数据进行分析，这些患者在现有高效抗逆转录病毒治疗（HAART）方案出现病毒学失败后接受了表型耐药性检测。共有586名患者进入研究并随访48周；281名（48%）患者改用含ddl的HAART方案，其中105名在基线时存在M184V突变。通过参考病毒载量（VL）反应曲线下的平均面积以及达到检测不到的VL（<400拷贝/毫升）的患者比例来研究联合治疗的病毒学疗效。使用Wilcoxon秩和检验比较基线特征和VL变化的单变量分析。使用Van Elteren检验进行多变量分析。其他变量包括基线核苷类逆转录酶抑制剂突变的数量以及根据“真实表型”耐药性检测结果比较每组给予的活性抗逆转录病毒药物的数量。
在接受含ddl的HAART方案的患者中，存在M184V突变的患者对ddl的表型敏感性的中位倍数变化更大（倍数变化分别为2.2和1.2，P<0.001）。尽管如此，接受ddl治疗的患者的VL中位变化和达到检测不到的VL的患者百分比相似，无论基线时是否存在M184V突变。在基线时存在M184V突变的患者组中，接受含ddl的HAART方案治疗的患者的病毒学结果明显优于未接受ddl的HAART方案治疗的患者（P<0.05）。
虽然M184V确实增加了HIV对ddl的耐药倍数，但这些变化似乎低于该药物表型耐药性的临床相关阈值。
