Gilbert P B, Ribaudo H J, Greenberg L, Yu G, Bosch R J, Tierney C, Kuritzkes D R
Center for Biostatistics in AIDS Research and Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
AIDS. 2000 Sep 8;14(13):1961-72. doi: 10.1097/00002030-200009080-00012.
At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared.
Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response.
Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511.
In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest.
A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.
目前，许多抗HIV-1疗法的临床试验通过测量HIV-1复制抑制持久性的主要终点来比较治疗方法。比较了几种持久性终点。
通过终点对临床结局替代指标的隐含假设、样本量要求以及对患者基线血浆HIV-1-RNA水平和初始治疗反应个体差异的适应性来比较终点。
病毒学失败定义为在预定随访时间T时病毒水平未被抑制（早期病毒学失败）或复发。将二元病毒学失败终点与三个病毒学失败时间终点进行比较：（i）随机分组后，将早期失败患者的失败时间设定为T周；（ii）随机分组后，对反应缓慢的患者延长早期失败时间T；（iii）病毒学反应，将无反应者的失败时间设定为0周。用阿古伦公司的511号试验来说明终点差异。
在阿古伦511号试验中比较高剂量与低剂量奈非那韦（NFV）方案时，对于终点（i）、（ii）和（iii），24周时未失败比例的Kaplan-Meier估计差异分别为16.7%（P = 0.048）、6.5%（P = 0.29）和22.9%（P = 0.0030）。结果不同是因为高剂量NFV能更快抑制病毒，且各终点对这种治疗差异的权重不同。这表明在选择能检测出感兴趣的治疗差异的主要终点时需要仔细考虑。
通常推荐采用随机分组后的时间终点，因为它在灵活性和样本量方面具有优势，尤其是在中期分析中，并且便于对患者管理进行解读。
