Randomized, controlled trial of daily trimethoprim-sulfamethoxazole or weekly chl

描述(申请人提供)：每日服用抗菌药物甲氧苄氨嘧啶-磺胺甲恶唑(TS)，通过预防包括菌血症、肺炎、肠炎和疟疾在内的机会性感染，减少撒哈拉以南非洲艾滋病毒携带者的疾病和死亡。目前尚不清楚在接受抗逆转录病毒治疗(ART)的艾滋病毒感染者免疫重建后这种保护作用是否持续，或者通过TS预防的感染(包括疟疾)是否影响艾滋病毒疾病的进展。随着非洲抗逆转录病毒治疗规模的扩大，公共卫生当局需要知道，对于那些对抗逆转录病毒治疗稳定的人来说，是否有必要预防TS。抗逆转录病毒治疗与显著降低典型艾滋病相关机会性感染的风险有关。因此，我们假设，在这种情况下，如果在免疫重建后预防TS有好处，这将是由于预防疟疾感染，并且用高效抗疟疾药物(氯喹，目前在马拉维对疟疾有99%的疗效)预防将优于每天用抗疟疾效果较低的抗菌药物(TS，在马拉维最近的研究中对疟疾有80%的效率)预防。 这一应用的总体公共卫生目标是确定在ART免疫重建后是否可以安全地停止TS。主要的研究问题是，临床上对抗逆转录病毒治疗稳定的人是否从抗菌预防、抗疟疾预防、两者都受益，或者两者都不受益。次要问题侧重于了解抗菌素预防通过预防与艾滋病毒病毒载量上升相关的感染而在改善抗逆转录病毒治疗的持续反应中可能发挥的作用，以及评估抗疟疾药物的疗效和艾滋病毒感染者的耐药性选择。为了解决这些问题，我们设计了一项三臂随机开放标签临床试验，对服用抗逆转录病毒治疗6-12个月后临床稳定的成年人进行每日TS预防疟疾和每周氯喹预防疟疾的比较。 在以前的资助下，已经为这项试验编写了一份方案，并获得了IRB的批准。R34将支持完成这项研究的规划，并导致提交U01赠款申请，以支持马拉维布兰太尔的布兰太尔疟疾项目恩迪兰德研究诊所进行临床试验。

DESCRIPTION (provided by applicant): A daily regimen of the antibacterial drug trimethoprim-sulfamethoxazole (TS) reduces disease and death among people living with HIV in sub-Saharan Africa by preventing opportunistic infections including bacteremia, pneumonia and enteritis as well as malaria. It is not known whether this protective effect persists after immune reconstitution in HIV-infected persons receiving antiretroviral therapy (ART) or if infections prevented by TS, including malaria, influence the progression of HIV disease. With the scaling up of ART in Africa, public health authorities need to know if TS prophylaxis is necessary for those who are stable on ART. ART is associated with a dramatically reduced risk of typical AIDS-associated opportunistic infections. We therefore hypothesize that if there is a benefit of TS prophylaxis after immune reconstitution in this setting it will be due to the prevention of malaria infection, and that prophylaxis with a highly efficacious antimalarial drug (chloroquine, which now has 99% efficacy against malaria in Malawi) will be superior to daily prophylaxis with an antibacterial drug with lower antimalarial efficacy (TS, which had 80% efficacy against malaria in recent studies in Malawi). The overall public health objective of this application is to determine if TS can safely be stopped after immune reconstitution on ART. The primary research question is whether persons who are clinically stable on ART benefit from antibacterial prophylaxis, antimalarial prophylaxis, both, or neither. Secondary questions focus on understanding the role that antimicrobial prophylaxis may play in improving sustained responses to ART by preventing infections associated with rises in HIV viral load, and assessing antimalarial drug efficacy and selection for drug resistance in HIV-infected persons. To address these questions, we have designed a three-arm randomized open-label clinical trial comparing daily TS prophylaxis for prevention of malaria and bacterial infections, with weekly chloroquine prophylaxis to prevent only malaria, compared to no prophylaxis, in adults who are clinically stable after 6-12 months on ART. Under previous funding a protocol for this trial has been written and IRB approval obtained. This R34 will support completion of planning for the study and lead to submission of a U01 grant application to support the conduct of the clinical trial at the Blantyre Malaria Project Ndirande Research Clinic in Blantyre, Malawi.