编者按：在第20届欧洲艾滋病大会（EACS 2025）上，《感染医线》特别专访了荷兰乌得勒支大学医学中心Mafalda Miranda博士。作为Rosetta注册研究的日常协调员，Miranda博士在大会上分享了关于第二代整合酶抑制剂耐药性的重要研究进展。耐药性的产生与哪些关键因素相关？不同的病毒亚型是否会影响耐药模式？临床医生又应如何依据最新证据，调整治疗策略以应对挑战？本篇专访中，Miranda博士将结合其研究数据，为这些临床关切的问题带来深入解析。

 

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《感染医线》：Miranda博士，感谢您接受我们的邀请。首先，能否请您向观众介绍一下自己？能否概述您在EACS大会上展示的Rosetta注册研究（Rosetta Registry）的主要发现？在第二代整合酶抑制剂的耐药模式中，哪些模式尤为值得关注？这些模式对日常临床实践又有何意义？

 

Mafalda Miranda 博士

Rosetta注册研究日常协调员

 

大家好，我叫Mafalda Miranda，任职于荷兰乌得勒支大学医学中心，同时担任Rosetta注册研究的日常协调员。该注册研究主要收集第二代整合酶抑制剂病毒学失败的病例。

 

在此次欧洲艾滋病临床学会大会上，我展示了这项研究的第二次中期分析结果。本研究的主要结论是：耐药性总体上与既往接受过抗逆转录病毒治疗（ART）相关；具体而言，与在换用第二代整合酶抑制剂方案前曾使用过第一代整合酶抑制剂的情况也密切相关。也就是说，有既往治疗暴露史的患者更易产生耐药性。

 

关于具体的耐药突变模式，我们的分析揭示了一些与病毒亚型及既往治疗史相关的特点。值得注意的是，整合酶突变G118R和R263K在既往使用过第一代整合酶抑制剂的患者中检出的比例反而较低。相反，G140S突变在B亚型病毒感染者中比在非B亚型中更为常见，这可能与该突变具有更高的基因屏障有关。此外，对于含有恩曲他滨或拉米夫定的治疗方案，当出现第二代整合酶抑制剂耐药时，逆转录酶区的M184V突变也更为普遍，这提示了交叉耐药的可能。

 

Infectious Disease Frontier: Thank you, Dr. Miranda, for accepting our invitation. To begin with, could you please introduce yourself to our audience? Then, could you outline the key findings from the Rosetta Registry study you presented at the EACS Congress? What resistance patterns to second-generation integrase inhibitors were particularly notable, and what do they mean for day-to-day clinical practice?

 

Dr. Miranda: Hi, my name is Mafalda Miranda. I work at the University Medical Center Utrecht in the Netherlands, where I serve as the daily coordinator of the Rosetta Registry. This registry collects cases of virological failure to second-generation integrase inhibitors.

 

At the EACS Congress, I presented the results of our second interim analysis. Our main conclusion from this study was that resistance is associated with prior exposure to antiretroviral therapy (ART) in general, or specifically to first-generation integrase inhibitors before switching to a second-generation integrase inhibitor regimen. In other words, individuals with prior exposure are more likely to develop resistance.

 

Regarding specific mutational patterns, we observed that three mutations—R263K, G118R, and G140S—were linked to prior exposure and also related to viral subtype. In particular, the G118R mutation was not observed in subtype B cases, while the G140S mutation was more prevalent in subtype B, possibly due to a higher genetic barrier associated with this mutation.

 

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《感染医线》：基于您刚刚介绍的Rosetta注册研究结果，对于第二代整合酶抑制剂的耐药问题，临床医生应如何调整序贯使用策略？尤其是针对既往使用过第一代整合酶抑制剂的患者，该如何应对？

 

Mafalda Miranda 博士

Rosetta注册研究日常协调员

 

在开始任何新治疗方案前，基线耐药检测都至关重要。通过这项检测，医生能更好地了解患者的病毒特征，进而制定更有效的治疗策略。

 

至于您问的第二个问题，在不同病毒载量水平下都可能观察到耐药性，因此我们不应等到病毒完全反弹后才进行耐药检测。尽早开展检测对于防止耐药突变的累积十分关键。

 

此外，正如我之前提到的，既往治疗暴露史和病毒亚型可能与不同地理区域及治疗方式相关。因此，对患者进行密切监测，并结合临床因素进行仔细评估，是预防治疗失败的核心环节。

 

Infectious Disease Frontier: In view of the findings you have just presented from the Rosetta Registry, how should clinicians adjust their sequencing strategy to manage resistance to second-generation integrase inhibitors, especially in patients with prior exposure to first-generation agents?

 

Dr. Miranda: A baseline resistance test is always important before starting a new regimen, as it allows for a better understanding of the viral profile and thus helps in designing a more effective treatment strategy.

 

Regarding the second part of your question, resistance can be observed at various levels of viremia, so we should not wait until a full viral rebound occurs to perform resistance testing. It’s important to test earlier to prevent the accumulation of drug-resistant mutations.

 

Additionally, as I mentioned earlier, previous exposure and viral subtypes can be associated with different geographical regions and treatment approaches. Therefore, close monitoring of patients, along with careful evaluation of clinical factors, is crucial to prevent treatment failure.

 

来源：《感染医线》

 

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