Antiretroviral Therapy of AIDS-Related Kaposi's Sarcoma in Africa

描述(申请人提供)：在撒哈拉以南非洲，艾滋病毒流行和卡波西肉瘤相关疱疹病毒(KSHV)感染的地方性交叉导致卡波西肉瘤(KS)成为该地区许多地区最常见的恶性肿瘤。在资源丰富地区患有KS的HIV感染患者，即使在没有常规化疗的情况下，使用高效抗逆转录病毒疗法(HAART)也往往会导致KS的消退。然而，目前尚不清楚哪些特定的抗逆转录病毒药物对传达HAART对KS的影响至关重要，以及HAART如何实现这一效果。特别是，来自体外系统和动物模型的最新数据表明，最初开发用于阻断HIV天冬氨酸蛋白酶活性部位的蛋白酶抑制剂(Pis)也具有直接的抗KS作用。既然抗逆转录病毒治疗在非洲已经变得可行，重要的是要解决这样的假设，即含PI的HAART在促进KS回归方面优于不含PI的HAART。因此，我们的多学科团队提出了以下四个目标： (1)确定基于PI的HAART方案(洛匹那韦/利托那韦+齐多夫定/拉米夫定)在促进非洲艾滋病相关KS患者的KS肿瘤负担下降方面是否比基于非核苷逆转录酶抑制物(NNRTI)的HAART方案(Eefavirenz+齐多夫定/拉米夫定)更有效； (2)评价在接受HAART治疗的非洲KS患者中，哪些HAART前参数预测KS回归，以及HAART开始后这些参数的变化如何预测KS回归； (3)研究HAART用于非洲艾滋病相关KS患者时，对KSHV相关病毒学活性和宿主对KSHV的免疫反应的影响，包括使用HAART是否减少KSHV唾液脱落的水平，从而潜在地降低KSHV的传染性；以及 (4)评估接受HAART治疗的非洲艾滋病相关KS患者中KS相关免疫重建炎性综合征的发生率及其影响因素。为了实现这些目标，我们将在乌干达坎帕拉的224名不需要化疗的艾滋病相关KS患者中进行基于PI的HAART方案和基于NNRTI的HAART方案的随机试验。受试者将每隔4周接受为期48周的跟踪，主要结果将是对KS肿瘤负担变化的盲法测量。我们还将纵向评估HAART的反应，包括唾液和血液中KSHV DMA水平的变化，宿主对KSHV的体液和细胞免疫反应，以及血浆中血管内皮生长因子、碱性成纤维细胞生长因子和基质金属蛋白酶-2的水平。这项工作的发现将有助于为非洲艾滋病相关KS患者的临床护理提供信息，并为抗逆转录病毒治疗对潜在KSHV感染的影响提供生物学见解。

DESCRIPTION (provided by applicant): In sub-Saharan Africa, the intersection between the HIV epidemic and the endemic nature of Kaposi's sarcoma-associated herpesvirus (KSHV) infection has caused Kaposi's sarcoma (KS) to become the most common malignancy in many parts of the region. In HIV-infected patients with KS in resource-rich areas, use of highly active antiretroviral therapy (HAART) often causes regression of KS even in the absence of conventional chemotherapy. However, it is not known which specific antiretroviral drugs are critical to convey HAART's effect on KS and how HAART achieves this effect. In particular, recent data from in vitro systems and animal models suggest that protease inhibitors (Pis), originally developed to block the active site of HIV aspartyl protease, also have direct anti-KS effects. Now that antiretroviral therapy is becoming available in Africa, it is important to address the hypothesis that Pi-containing HAART is superior to Pi- sparing HAART in promoting KS regression. Hence, our multidisciplinary team proposes these four aims: (1) Determine whether a Pi-based HAART regimen (lopinavir/ritonavir plus zidovudine/lamivudine) is more efficacious than a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen (efavirenz plus zidovudine/lamivudine) in promoting the regression of KS tumor burden in persons with AIDS-related KS in Africa; (2) Evaluate which pre-HAART parameters are predictive of KS regression among HAART-treated patients with KS in Africa and how changes in these parameters after HAART is initiated predict KS regression; (3) Examine the effect of HAART, when used in African patients with AIDS-related KS, on KSHV-related virologic activity and host immune response to KSHV, including whether the use of HAART reduces levels of KSHV salivary shedding and therefore potentially reduces KSHV infectiousness; and (4) Estimate the incidence and determinants of KS-associated immune reconstitution inflammatory syndrome in patients with AIDS-related KS in Africa who are treated with HAART. To achieve these aims, we will perform a randomized trial of a Pi-based HAART regimen versus an NNRTI-based HAART regimen among 224 antiretroviral-naTve persons with non-chemotherapy-requiring AIDS-related KS in Kampala, Uganda. Subjects will be followed at four-week intervals for 48 weeks, and the primary outcome will be a blinded measurement of the change in KS tumor burden. We will also longitudinally assess the response to HAART in terms of changes in KSHV DMA levels in saliva and blood, host humoral and cellular immune response to KSHV, and plasma levels of VEGF, bFGF, and MMP-2. Findings from this work will both help to inform clinical care of patients with AIDS-related KS in Africa and provide biological insights into the effect of antiretroviral therapy on underlying KSHV infection.