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

描述(申请人提供)：在非洲，负责照顾艾滋病毒携带者的临床医生和政策制定者缺乏证据来指导是否以及何时停止对正在接受抗逆转录病毒治疗(ART)的患者进行甲氧基苯丙胺-磺胺甲恶唑(TS，co-trimoxazine)的抗菌药预防。此外，预防疟疾的相对重要性，以及在抗逆转录病毒治疗的背景下，TS预防的任何好处在多大程度上归因于疟疾预防，也是未知的。这项临床试验的总体公共卫生目标是确定在成功启动抗逆转录病毒疗法后继续进行TS预防的益处(如果有的话)，以及这种益处是否源于预防HLV相关的机会性感染、疟疾或两者兼而有之。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，比较了每日TS预防疟疾和HLV相关机会性感染的方法，与每周仅预防疟疾的氯喹预防方法相比，在两年内开始抗逆转录病毒治疗的成年人中，HIV病毒载量无法检测到且CD4计数为250个/mm3的成年人仅预防疟疾。这项创新的研究设计部分是基于我们的观察，即在马拉维停止使用氯喹抗药性疟疾后，这种疟疾已经消失，使其成为针对疟疾的特定预防的理想制剂。这项研究将使我们能够确定病毒载量无法检测的抗逆转录病毒治疗的患者是否受益于抗疟疾预防、抗菌预防以防止HLV相关的机会性感染，两者都有，或者两者都没有。次要目标侧重于了解抗菌素预防在维持抗逆转录病毒疗法的病毒抑制和免疫学改善方面可能发挥的作用，评估在高度耐药生物背景下预防的有效性，并衡量预防对艾滋病毒感染者耐药性选择的影响。这项研究与国立卫生研究院艾滋病研究办公室优先考虑的战略直接一致：1)为不同的机会性感染和混合感染确定停止预防的最佳时机；2)在艾滋病毒感染的背景下评估预防普遍的机会性和地方性感染的战略。相关性(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)是否停止对接受抗逆转录病毒治疗的患者进行TS预防；以及2)在接受抗逆转录病毒治疗的稳定患者中预防HLV相关机会性感染和疟疾的重要性，从而影响数百万当前和未来接受抗逆转录病毒治疗的人的健康。 相关性(由申请人提供)：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)是否停止对接受抗逆转录病毒治疗的患者进行TS预防；以及2)在接受抗逆转录病毒治疗的稳定患者中预防HLV相关机会性感染和疟疾的重要性。

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.