Clinical trial of trimethoprim-sulfamethoxazole or chloroquine in adults on ART

描述（由申请人提供）：负责非洲艾滋病毒感染者护理的临床医生和政策制定者缺乏证据来指导决定是否以及何时停止对正在接受抗逆转录病毒治疗（ART）的患者使用甲氧苄啶-磺胺甲恶唑（TS，复方新诺明）进行抗菌预防。此外，预防疟疾的相对重要性，以及在ART背景下TS预防的任何益处在多大程度上归因于疟疾预防，也是未知的。该临床试验的总体公共卫生目标是确定ART成功启动后持续TS预防的益处（如果有的话），以及任何这样的益处是否是由于预防HIV相关的机会性感染、疟疾或两者。为了解决这些问题，我们设计了一项三臂、随机、开放标签的临床试验，在两年内开始ART的HIV病毒载量不可检测且CD 4计数>250个细胞/mm 3的成人中，将每日TS预防用于预防疟疾和HIV相关的机会性感染与每周氯喹预防用于仅预防疟疾与无预防进行比较。创新的研究设计部分是基于我们的观察，即氯喹抗药性疟疾在马拉维停止使用后已经消失，使其成为疟疾特异性预防的理想药物。这项研究将使我们能够确定接受抗逆转录病毒治疗的病毒载量检测不到的人是否受益于抗疟疾预防、预防HIV相关机会性感染的抗生素预防、两者兼而有之，或者两者都不受益。次要目标集中于了解抗菌预防在维持ART的病毒抑制和免疫改善方面可能发挥的作用，评估预防在高度耐药微生物背景下的疗效，并测量预防对HIV感染者耐药性选择的影响。这项研究与NIH艾滋病研究办公室优先考虑的战略直接一致，以1）确定停止不同机会性感染和合并感染预防的最佳时机，2）评估在艾滋病毒感染的背景下预防流行机会性和地方性感染的策略。相关性（参见说明）：这项研究的结果将与马拉维和该地区的决策者直接和直接相关，通过提供证据来确定1）是否停止对接受ART的人进行TS预防;和2）在稳定接受ART的人中预防HIV相关的机会性感染和疟疾的重要性，从而影响数百万当前和未来ART接受者的健康。 相关性（由申请人提供）：本研究的结果将与马拉维和该地区的决策者直接和直接相关，通过提供证据来确定1）是否停止对接受ART的人进行TS预防;和2）预防HIV相关机会性感染和疟疾在接受ART的稳定人群中的重要性，从而影响数百万当前和未来ART接受者的健康。

DESCRIPTION (provided by applicant): Clinicians and policymakers responsible for the care of people living with HIV in Africa lack evidence to guide decisions about whether and when to stop antimicrobial prophylaxis with trimethroprim-sulfamethoxazole (TS, co-trimoxazole) in patients who are on antiretroviral therapy (ART). Moreover, the relative importance of preventing malaria, and the extent to which any benefit of TS prophylaxis in the context of ART is due to malaria prevention, are also unknown. The overall public health objective of this clinical trial is to determine the benefit, if any, of continued TS prophylaxis after ART has been successfully initiated, and whether any such benefit is due to preventing HlV-associated opportunistic infections, malaria, or both. To address these questions, we have designed a three-arm, randomized, open-label clinical trial comparing daily TS prophylaxis for prevention of malaria and HlV-associated opportunistic infections, with weekly chloroquine prophylaxis to prevent only malaria, compared to no prophylaxis, in adults with undetectable HIV viral load and a CD4 count of >250 cells/mm3 who initiated ART within two years. The innovative study design is based in part on our observation that chloroquine-resistant malaria has disappeared from Malawi following its withdrawal from use, making it an ideal agent for malaria-specific prophylaxis. The study will allow us to determine whether persons on ART with undetectable viral load benefit from antimalarial prophylaxis, antimicrobial prophylaxis to prevent HlV-associated opportunistic infections, both, or neither. Secondary objectives focus on understanding the role that antimicrobial prophylaxis may play in maintaining viral suppression and immunologic improvement on ART, assessing the efficacy of prophylaxis in the context of highly resistant organisms, and measuring the effect of prophylaxis on the selection of drug resistance in HIV-infected persons. This research aligns directly with the strategy prioritized by the NIH Office of AIDS Research to 1) determine the optimal timing for discontinuing prophylaxis for different opportunistic infections and coinfections and 2) to evaluate strategies for prevention of prevalent opportunistic and endemic infections in the context of HIV infection. RELEVANCE (See instructions): Results of this study will be of direct and immediate relevance to decision-makers in Malawi and the region, affecting the health of millions of current and future ART recipients by providing evidence to determine 1) whether to stop TS prophylaxis in persons on ART; and 2) the importance of preventing HlV-associated opportunistic infections and malaria in persons who are stable on ART. RELEVANCE (provided by applicant): Results of this study will be of direct and immediate relevance to decision-makers in Malawi and the region, affecting the health of millions of current and future ART recipients by providing evidence to determine 1) whether to stop TS prophylaxis in persons on ART; and 2) the importance of preventing HlV-associated opportunistic infections and malaria in persons who are stable on ART.