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: 7277230
• 负责人: JEFFREY N MARTIN
• 金额: $ 7.45万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7277230
• 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; 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

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）成为该地区许多地方最常见的恶性肿瘤。在资源丰富地区的艾滋病病毒感染的KS患者中，即使在没有常规化疗的情况下，使用高活性抗逆转录病毒治疗（HAART）也经常导致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递HAART对KS的作用至关重要，以及HAART是如何实现这种作用的。特别是，最近来自体外系统和动物模型的数据表明，蛋白酶抑制剂（Pis），最初是为了阻断HIV天冬氨酸蛋白酶的活性位点而开发的，也具有直接的抗ks作用。现在，抗逆转录病毒治疗在非洲变得可行，重要的是要解决含有Pi的HAART在促进KS回归方面优于不含Pi的HAART的假设。因此，我们的多学科团队提出了以下四个目标：