Katzenstein D A, Holodniy M
Stanford University School of Medicine, California, USA.
AIDS Clin Rev. 1995:277-303.
We are moving rapidly beyond a "black box" understanding of the pathogenesis of HIV. The sites of virus replication, the molecular regulation of virus production in the host, and the dynamics between productive virus infection and immunological and clinical events are areas of intense study using powerful new tools. The quantitation of virus load and genetic characterization of replicating virus has important implications for the development and evaluation of drugs and treatment strategies for HIV. As new compounds are introduced, their ability to reduce virus load in vivo has become a primary consideration in the decision to initiate large efficacy trials and may soon be used, in combination with other markers, in the licensing of new agents. In parallel, rapid molecular evaluation of virus from patients, targeting those who break through drug-induced suppression, provides an explanation for the failure of drugs to sustain an effect on virus load. This approach has compressed the process of drug evaluation and set the stage for the evaluation of complex combinations and sequences of drugs to maintain suppression of virus and prevent the development of drug resistance. The most controversial question for the next few years is whether the measurement of virus load or detection of drug resistance can be incorporated into the practice of medicine and the management of individual patients. There is evidence that changes in virus load are the most proximate markers of drug response and that detection of resistance mutations can predict clinical and immunological decline. However, the window of time between a change in load or the development of drug resistance and a decline in CD4 cells is relatively short. With dideoxynucleoside therapies, a CD4 cell decline follows a rise in virus load or development of resistance within 3-6 months. In early studies with protease inhibitors and nonnucleoside reverse transcriptase inhibitors, the development of resistance and a return to baseline of virus load may occur within 2-3 months, mirrored by a fall in CD4 cells. The challenge to investigators is how to best use these new tools to determine whether changes or additions in therapy, initiated on the basis of virological measurements, result in more effective management of disease.
我们正迅速超越对HIV发病机制的“黑匣子”式理解。病毒复制位点、病毒在宿主体内产生的分子调控以及有生产性病毒感染与免疫和临床事件之间的动态关系，都是利用强大新工具进行深入研究的领域。病毒载量的定量以及复制病毒的基因特征分析，对于HIV药物和治疗策略的开发与评估具有重要意义。随着新化合物的推出，它们在体内降低病毒载量的能力已成为启动大型疗效试验决策中的主要考量因素，并且可能很快会与其他指标一起用于新药物的许可审批。与此同时，针对突破药物诱导抑制的患者进行病毒的快速分子评估，能够解释药物无法持续影响病毒载量的原因。这种方法压缩了药物评估过程，并为评估维持病毒抑制和预防耐药性发展的复杂药物组合及用药顺序奠定了基础。未来几年最具争议的问题是，病毒载量的测量或耐药性检测能否纳入医学实践及个体患者的管理中。有证据表明，病毒载量的变化是药物反应最直接的指标，而耐药突变的检测可以预测临床和免疫功能下降。然而，病毒载量变化或耐药性出现与CD4细胞下降之间的时间间隔相对较短。采用双脱氧核苷疗法时，CD4细胞下降会在病毒载量升高或出现耐药性后的3至6个月内发生。在早期使用蛋白酶抑制剂和非核苷类逆转录酶抑制剂的研究中，耐药性的出现和病毒载量恢复至基线可能在2至3个月内发生，同时伴有CD4细胞下降。研究人员面临的挑战是如何最好地利用这些新工具，来确定基于病毒学测量结果启动的治疗方案改变或添加是否能更有效地管理疾病。
