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

• 批准号: 7656912
• 负责人: JEFFREY N MARTIN
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656912
• 关键词: AIDS with Kaposi' 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; Epidemic; Etiology; Evaluation; Fibroblast Growth Factor 2; 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; Lesion; Lopinavir/Ritonavir; Lytic Phase; Malignant Neoplasms; Measurement; Mediating; Nature; Pathogenesis; 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; Work; Zidovudine; antiretroviral therapy; base; chemotherapy; clinical care; clinically relevant; efavirenz; falls; in vivo; insight; multidisciplinary; non-nucleoside reverse transcriptase inhibitors; pathogen; primary outcome; programs; reconstitution; response; tumor

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，HIV流行与卡波西肉瘤相关疱疹病毒（KSHV）感染的地方性之间的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。在资源丰富地区的艾滋病毒感染的KS患者中，即使在没有常规化疗的情况下，使用高效抗逆转录病毒治疗（HAART）也经常导致KS消退。然而，目前尚不清楚哪些特定的抗逆转录病毒药物对HAART对KS的作用至关重要，以及HAART如何实现这种作用。特别是，最近的体外系统和动物模型的数据表明，蛋白酶抑制剂（PI），最初开发的阻断HIV乙酰基蛋白酶的活性位点，也有直接的抗KS的效果。现在抗逆转录病毒疗法在非洲变得可用，重要的是解决含Pi的HAART在促进KS消退方面上级Pi保留的HAART的假设。因此，我们的多学科团队提出了这四个目标： (1)确定在非洲艾滋病相关KS患者中，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KS肿瘤负荷消退方面是否比基于非核苷逆转录酶抑制剂（NNRTI）的HAART方案（依法韦仑+齐多夫定/拉米夫定）更有效; (2)评价HAART治疗前哪些参数可预测非洲HAART治疗的KS患者的KS消退，以及HAART开始后这些参数的变化如何预测KS消退; (3)检查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HAART的使用是否降低KSHV唾液脱落水平，从而可能降低KSHV的传染性; (4)评估非洲接受HAART治疗的艾滋病相关KS患者中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，我们将在乌干达坎帕拉的224名患有不需要化疗的艾滋病相关KS的抗逆转录病毒初治患者中进行一项基于Pi的HAART方案与基于NNRTI的HAART方案的随机试验。受试者将以4周间隔随访48周，主要结局将是KS肿瘤负荷变化的盲法测量。我们还将纵向评估HAART的反应，在唾液和血液中的KSHV DMA水平的变化，宿主对KSHV的体液和细胞免疫反应，以及VEGF，bFGF和MMP-2的血浆水平。这项工作的结果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。