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

非洲艾滋病相关卡波西肉瘤的抗逆转录病毒治疗

基本信息

批准号：
7483264
负责人：
JEFFREY N MARTIN
金额：
$ 48.02万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483264
关键词：
AIDS with Kaposi&apos s sarcoma Active Sites Address Africa Africa South of the Sahara African Animal Model Anti-Retroviral Agents Antibodies Antigens Area Aspartic Endopeptidases Biological Blinded Blood CD4 Positive T Lymphocytes CD8B1 gene Cell Count Clinical Communicable Diseases Cytotoxic T-Lymphocytes DNA Data Development Disease Disease regression Epidemic Etiology Evaluation Fibroblast Growth Factor Frequencies Gelatinase A Guidelines HIV HIV Infections Herpesviridae Infections High Prevalence Highly Active Antiretroviral Therapy Human Herpesvirus 8 Immune Immune response In Vitro Incidence Individual Inflammatory Institutes Iris Kaposi Sarcoma Laboratories Lamivudine/Zidovudine Lesion Lopinavir/Ritonavir Lytic Phase Malignant Neoplasms Measurement Mediating Nature Outcome Pathogenesis Patient Care Patients Persons Pharmaceutical Preparations Plasma Protease Inhibitor Public Health RNA Randomized Randomized Controlled Clinical Trials Research Infrastructure Research Personnel Resources Saliva Salivary Syndrome System T-Lymphocyte Treatment Protocols Tumor Burden Uganda United States Dept. of Health and Human Services Universities Vascular Endothelial Growth Factors Week Work antiretroviral therapy base chemotherapy clinically relevant efavirenz falls in vivo insight multidisciplinary non-nucleoside reverse transcriptase inhibitors pathogen programs reconstitution response sarcoma tumor

项目摘要

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.

描述（由申请人提供）：在撒哈拉以南非洲，艾滋病毒流行与卡波西肉瘤相关的疱疹病毒（KSHV）感染之间的相交使卡波西的肉瘤（KS）在该地区许多地区成为最常见的恶性肿瘤。在资源丰富地区的HIV感染患者中，即使在没有常规化学疗法的情况下，使用高活性的抗逆转录病毒疗法（HAART）也经常会导致KS的消退。但是，尚不清楚哪种特定的抗逆转录病毒药物对于传达HAART对KS的影响以及HAART如何实现这种影响至关重要。特别是，来自体外系统和动物模型的最新数据表明，最初开发的蛋白酶抑制剂（PIS）也具有直接的抗KKS效应，该蛋白酶抑制剂（PIS）最初开发的蛋白酶抑制剂（PIS）也具有直接的抗KES效应。既然在非洲抗逆转录病毒疗法已经可以使用，那么解决含Pi的HAART的假设非常重要，即含有PI的HAART优于促进KS回归的HAART。因此，我们的多学科团队提出了这四个目标： (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非洲的KS；（2）评估哪些HAART参数可预测非洲HAART处理的KS患者之间的KS回归以及HAART启动后这些参数的变化如何预测KS回归；（3）检查HAART的影响，当用于与KSHV相关病毒学活性的非洲非洲患者中，并宿主对KSHV的免疫反应，包括使用HAART是否会降低KSHV唾液脱落的水平，从而潜在地减少KSHV的KSHV感染；和（4）估计非洲与HAART治疗的非洲艾滋病相关KS患者KS相关免疫重建炎症综合征的发病率和决定因素。为了实现这些目标，我们将对基于PI的HAART方案进行随机试验，而在乌干达坎帕拉的224名具有非化学疗法的艾滋病相关的KS的抗逆转录病毒NATVE患者中，与基于NNRTI的HAART方案进行了随机试验。受试者将以四周的间隔持续48周，主要结果将是对KS肿瘤负担的变化的盲目测量。我们还将在唾液和血液中KSHV DMA水平的变化，宿主的体液和细胞免疫反应以及VEGF，BFGF和MMP-2的等离子体水平方面纵向评估对HAART的反应。这项工作的发现都将有助于为非洲与艾滋病相关的KS患者提供临床护理，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。