作者：tomato来源：生物谷2014-3-10 21:29:00

关键词： 默沙东 艾滋病 HIV Isentress 整合酶抑制剂

2014年3月7日讯/生物谷BIOON/ --默沙东（Merck & Co）在第21届逆转录病毒和机会性感染大会（CROI 2014）上公布了已获批HIV药物Isentress首个大规模III期临床比较研究ACTG的数据。ACTG研究旨在比较3种不同的非核苷类逆转录酶抑制剂（NMRTI）治疗方案用于初治HIV患者的疗效和耐受性，研究数据证明了3种方案的病毒学疗效和耐受性具有等价性，达到了主要终点。

ACTG是一项96周、开放标签、AIDS临床试验组研究，涉及1809例初治HIV-1患者，将Isentress（raltegravir）与2种蛋白酶抑制剂类治疗方案（利用ritonavir增效）进行了对比。研究中，患者随机接受Isentress（400mg，每日2次）、atazanavir/ritonavir（300mg/100mg，每日一次）、darunavir/ritonavir（800mg/100mg，每日1次），同时还接受emtricitabine/tenofovir（恩曲他滨/替诺福韦，200/300mg，每日1次）治疗。

研究的主要目的是证明这3种方案在96周病毒学疗效和耐受性的等价性。病毒学疗效终点是病毒学失败（VF）时间，定义为从接受治疗开始至确认病毒载量高于1000拷贝/毫升（16周后和24周前）的时间，或病毒载量高于200拷贝/毫升（在24周或24周后）的时间。耐受性终点是耐受失败（TF）时间，定义为接受治疗开始至因毒性而停止给药的时间。关键次要复合终点是，首次VF或TF的时间。

研究数据表明，ACTG研究中，92%的患者完成了96周治疗，3种方案均取得了高的、同等程度的病毒学疗效，病毒学控制具有同等控制率。Isentress治疗组、atazanavir/r组、darunavir/r组分别有94%、88%、89%在96周时维持病毒载量小于50拷贝/毫升，因毒性而停药的比例分别为1%、16%、5%。共同主要终点TF，Isentress、darunavir/ritonavir方案由于atazanavir/ritonavir方案。此外，关键次要终点即首次VF或TF的时间，Isentress方案优于2种蛋白酶方案。

这些发现，为Isentress在初治HIV-1不同群体中的疗效和耐受性提供了额外的证据。

关于Isentress：

Isentress（raltegravir）由默沙东研发，是上市的首个HIV整合酶抑制剂，于2007年10月获FDA批准，该药是继鸡尾酒疗法出现10年之后HIV治疗领域的又一个里程碑，对初治患者、已产生耐药的艾滋病患者均有显著疗效。Isentress是对抗HIV/AIDS的新型药物，能够阻断HIV病毒遗传物质与人类细胞染色体的整合，该药常与其它抗逆转录病毒（ARV）药物联合用药，用于治疗HIV-1感染的成年患者。（生物谷Bioon.com）

英文原文：New 96-Week ACTG Study Results Presented at CROI 2014; First Large Study Comparing ISENTRESS? (raltegravir) Regimen to Two Protease Inhibitor Regimens in Previously Untreated Adults with HIV-1

BOSTON--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, said today that in a new 96-week, open-label AIDS Clinical Trials Group (ACTG) study designed to compare three different NNRTI-sparing HIV regimens in treatment-na?ve patients – one containing Merck’s twice-daily ISENTRESS? (raltegravir) and two containing different once-daily ritonavir-boosted protease inhibitors, atazanavir and darunavir -- all three regimens achieved high and equivalent levels of efficacy, as measured by time to virologic failure (VF), the study’s co-primary endpoint. On the other co-primary endpoint of failure due to tolerability, the ISENTRESS and darunavir/r regimens were superior to the atazanavir/r regimen. In addition, on the key secondary endpoint of the combination of VF and tolerability failure (TF), the regimen with ISENTRESS was superior to both of the protease inhibitor regimens. The results of this ACTG study were presented in an oral session today at the 21st Conference on Retroviruses and Opportunistic Infections (CROI).

“These findings provide additional evidence of the efficacy and tolerability of ISENTRESS in a diverse population of treatment-na?ve adults with HIV-1,” said Dr. Randi Leavitt, executive director, Infectious Diseases, Merck Research Laboratories, and co-author of the ACTG 5257 study. “We want to acknowledge the patients who participated in this study, the ACTG and the trial investigators for this important contribution to the therapeutic evaluation of medicines used to manage the consequences of HIV infection.”

The 1,809-patient ACTG 5257 open-label study is the first large, well-powered study to compare ISENTRESS (raltegravir) to protease inhibitor-based treatment regimens in a treatment-na?ve population. Patients were randomized to receive atazanavir/r (300 mg/100mg once daily), ISENTRESS (400 mg twice daily), or darunavir/r (800 mg once daily). All patients in the study also received emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily). The primary objective of this study was to demonstrate equivalence of the regimens with regard to virologic efficacy and tolerability over 96 weeks. The virologic endpoint was time to VF, defined from study entry to confirmed viral load above 1000 copies/mL (after week 16 and before week 24), or above 200 copies/mL (at or after week 24). Time to TF was defined from entry to discontinuation of the atazanavir/r, ISENTRESS or darunavir/r component of the regimen for toxicity. The key secondary composite endpoint was time to first of VF or TF.

In this Phase 3 prospective, randomized study, 34 percent of patients were non-Hispanic white, 42 percent were non-Hispanic black and 22 percent were Hispanic. Twenty-four percent were women. Mean entry viral load was 4.6 log 10 copies/mL; 31 percent had viral load above 100,000 copies/mL. Mean baseline CD4 cell count was 308/mm3; CD4 was below 200/mm3 for 30 percent.

Equivalence was declared if the two-sided 97.5 percent confidence interval (CI) on the difference in 96-week cumulative probability of VF in pairwise comparisons between each study regimen was entirely within +/- 10 percent. Comparisons of TF and a composite of VF/TF were similarly defined. In the event that equivalence was not shown, superiority was declared if the 97.5 percent CI excluded zero.

ACTG 5257 Trial Results

At CROI, the ACTG reported that 92 percent of patients completed 96 weeks of the study. Equivalent rates of virologic control were attained for all regimens. The percentage of patients maintaining ≤50 copies/mL at week 96 was 94 percent, 88 percent and 89 percent for ISENTRESS, atazanavir/r and darunavir/r, respectively, based on intent-to-treat analysis. One percent, 16 percent and five percent discontinued ISENTRESS, atazanavir/r and darunavir/r, respectively, for toxicity largely due to clinical jaundice and hyperbilirubinemia with atazanavir/r, and gastrointestinal symptoms with both atazanavir/r and darunavir/r. Other discontinuations were similarly distributed across all arms. The primary tolerability endpoint of discontinuation of the randomized treatment was equivalent between ISENTRESS and darunavir/r, while the incidence of discontinuation due to tolerability over 96 weeks in the atazanavir/r group was 13 percent (97.5% CI: 9.4%, 16%) higher than ISENTRESS and 9.2 percent (97.5% CI: 5.5%, 13%) higher than darunavir/r. In pairwise comparisons of the cumulative incidence to first of either VF or TF, ISENTRESS (raltegravir) was superior to both atazanavir/r (largely due to elevated bilirubin) and darunavir/r (driven by both virology and differences in gastrointestinal toxicity) when considering tolerability and virologic efficacy together. In this composite analysis, atazanavir/r was inferior to both ISENTRESS by 15 percent (97.5% CI: 10%, 20%) and darunavir/r by 7.6 percent (97.5% CI: 2.3%, 13%). Darunavir/r was inferior to ISENTRESS by 7.5 percent (97.5% CI: 3.2%, 12%).

About ISENTRESS

ISENTRESS is Merck’s integrase inhibitor indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adults. This indication is based on analyses of plasma HIV-1 RNA levels in three double-blind controlled studies of ISENTRESS. Two of these studies were conducted in clinically advanced, three-class ARV [non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)] treatment-experienced adult patients through 96 weeks, and one was conducted in treatment-na?ve adults through 240 weeks. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.

Important Safety Information

ISENTRESS does not cure HIV-1 infection or AIDS.

Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis. Immediately discontinue treatment with ISENTRESS and other suspect agents if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develop and monitor clinical status, including liver aminotransferases closely.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

Co-administration of ISENTRESS with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT1A1) may result in reduced plasma concentrations of raltegravir. Co-administration of ISENTRESS and other drugs may alter the plasma concentration of raltegravir. The potential for drug-drug interactions (DDIs) must be considered prior to and during therapy. Co-administration or staggered administration (by 2 hours) of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended. Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS (raltegravir) for adults should be increased to 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age.

The most commonly reported (≥2%) drug-related clinical adverse reactions of moderate to severe intensity in treatment-na?ve adult patients receiving ISENTRESS compared with efavirenz were insomnia (4% vs 4%), headache (4% vs 5%), nausea (3% vs 4%), fatigue (2% vs 3%) and dizziness (2% vs 6%), respectively. In treatment-experienced adult patients receiving ISENTRESS, the most commonly reported (≥2% in either treatment group) drug-related clinical adverse reactions of moderate to severe intensity and at a higher incidence compared with placebo was headache (2% vs 1%). Intensities were defined as follows: Moderate (discomfort enough to cause interference with usual activity); or Severe (incapacitating with inability to work or do usual activity).

Grade 2 to 4 creatine kinase laboratory abnormalities were observed in patients treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported.

Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS (raltegravir) plus darunavir/ritonavir, compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug-related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.