Department of Medicine, Norfolk and Norwich University Hospital, Norwich, UK.
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.
Cochrane Database Syst Rev. 2021 Jan 15;1(1):CD004529. doi: 10.1002/14651858.CD004529.pub3.
The World Health Organization (WHO) in 2015 stated atovaquone-proguanil can be used in travellers, and is an option in malaria-endemic areas in combination with artesunate, as an alternative treatment where first-line artemisinin-based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005.
To assess the efficacy and safety of atovaquone-proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children.
The date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal.
Randomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone-proguanil or atovaquone-proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection.
For this update, two review authors re-extracted data and assessed certainty of evidence. We meta-analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)-adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection.
Seventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South-America, and South-East Asia. Eight trials reported PCR-adjusted data to distinguish between new and recrudescent infection during the follow-up period. In this abstract, we report only the comparisons against the three WHO-recommended antimalarials which were included within these trials. There were two comparisons with artemether-lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone-proguanil compared to none with artemether-lumefantrine (PCR-adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR-adjusted treatment failures at day 42). There was only one comparison with artesunate-amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone-proguanil at day 28 and two with artesunate-amodiaquine (PCR-adjusted treatment failures at day 28: 9.4% with atovaquone-proguanil compared to 2.9% with artesunate-amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low-certainty evidence), although there was a similar number of PCR-unadjusted treatment failures (9 (14.1%) with atovaquone-proguanil and 8 (11.8%) with artesunate-amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low-certainty evidence). There were two comparisons with artesunate-mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi-resistant malaria. There were similar numbers of PCR-adjusted treatment failures between groups at day 42 (2.7% with atovaquone-proguanil compared to 2.4% with artesunate-mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high-certainty evidence). There were also similar PCR-unadjusted treatment failures between groups (5.3% with atovaquone-proguanil compared to 6.6% with artesunate-mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low-certainty evidence). When atovaquone-proguanil was combined with artesunate, there were fewer treatment failures with and without PCR-adjustment at day 28 (PCR-adjusted treatment failures at day 28: 2.16% with atovaquone-proguanil compared to no failures with artesunate-atovaquone-proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low-certainty evidence) and day 42 (PCR-adjusted treatment failures at day 42: 3.82% with atovaquone-proguanil compared to 2.05% with artesunate-atovaquone-proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate-certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate-atovaquone-proguanil group compared to the atovaquone-proguanil group at day 42 with PCR-adjustment. Whilst there were some small differences in which adverse events were more frequent in the atovaquone-proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone-proguanil is strongly associated with any specific adverse event.
AUTHORS' CONCLUSIONS: Atovaquone-proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone-proguanil may reduce treatment failure rates. Artesunate-atovaquone-proguanil and the development of parasite resistance may represent an area for further research.
2015 年，世界卫生组织（WHO）表示，在旅行者中可以使用阿托伐醌-普罗喹酮，并且在疟疾流行地区与青蒿琥酯联合使用，作为无法获得或无法有效使用一线基于青蒿素的联合治疗（ACT）时的替代治疗方法。本综述是对 2005 年 Cochrane 综述的更新。
评估阿托伐醌-普罗喹酮（单独使用和与青蒿素类药物联合使用）治疗成人和儿童无并发症恶性疟原虫疟疾的疗效和安全性。
最后一次试验检索日期为 2020 年 1 月 30 日。检索位置包括 Cochrane 传染病组专论、CENTRAL、MEDLINE、Embase 和 LILACS。为了包括最近发表的和未发表的试验，我们还检索了 ClinicalTrials.gov、metaRegister of Controlled Trials 和 WHO 国际临床试验注册平台搜索门户。
随机对照试验（RCTs）报告了阿托伐醌-普罗喹酮或阿托伐醌-普罗喹酮联合伴侣药物治疗无并发症恶性疟原虫感染的疗效和安全性数据，与至少一种其他抗疟药物进行比较。
对于本次更新，两名综述作者重新提取了数据并评估了证据的确定性。我们对数据进行了荟萃分析，以计算治疗失败的风险比（RR），并比较了不同比较之间和不同比较之间的安全性结果。结局指标包括未经调整的治疗失败和聚合酶链反应（PCR）调整的治疗失败。PCR 调整区分了新感染和复燃感染。
17 项 RCT 符合我们的纳入标准，纳入了来自非洲、南美洲和东南亚的 4763 名成人和儿童。八项试验报告了 PCR 调整数据，以区分随访期间的新感染和复燃感染。在本摘要中，我们仅报告了与 WHO 推荐的三种抗疟药进行比较的结果，这些药物均包含在这些试验中。有两个与青蒿琥酯-甲氟喹的比较，2008 年在埃塞俄比亚进行的一项试验有 60 名参与者的阿托伐醌-普罗喹酮治疗失败 2 例，而青蒿琥酯-甲氟喹无失败（PCR 调整的 28 天治疗失败）。2012 年在哥伦比亚进行的第二项试验有 208 名参与者，每个臂各有 1 例失败（PCR 调整的 42 天治疗失败）。仅有一项来自喀麦隆的 2014 年试验与青蒿琥酯-阿莫地喹进行了比较。28 天时阿托伐醌-普罗喹酮有 6 例治疗失败，青蒿琥酯-阿莫地喹有 2 例（PCR 调整的 28 天治疗失败率：阿托伐醌-普罗喹酮为 9.4%，青蒿琥酯-阿莫地喹为 2.9%；RR 3.19，95%CI 0.67 至 15.22；1 RCT，132 名参与者；低质量证据），尽管未经 PCR 调整的治疗失败率相似（阿托伐醌-普罗喹酮 9（14.1%），青蒿琥酯-阿莫地喹 8（11.8%）；RR 1.20，95%CI 0.49 至 2.91；1 RCT，132 名参与者；低质量证据）。有两项与青蒿琥酯-甲氟喹的比较来自 2012 年在哥伦比亚和 2002 年在泰国进行的试验，这些试验中存在高水平的多药耐药疟疾。42 天时两组之间的 PCR 调整的治疗失败率相似（阿托伐醌-普罗喹酮 2.7%，青蒿琥酯-甲氟喹 2.4%；RR 1.15，95%CI 0.57 至 2.34；2 RCTs，1168 名参与者；高质量证据）。两组之间未经 PCR 调整的治疗失败率也相似（阿托伐醌-普罗喹酮 5.3%，青蒿琥酯-甲氟喹 6.6%；RR 0.8，95%CI 0.5 至 1.3；1 RCT，1063 名参与者；低质量证据）。当阿托伐醌-普罗喹酮与青蒿琥酯联合使用时，PCR 调整后 28 天和无 PCR 调整的治疗失败率均较低（PCR 调整的 28 天治疗失败率：阿托伐醌-普罗喹酮为 2.16%，青蒿琥酯-阿托伐醌-普罗喹酮无失败；RR 5.14，95%CI 0.61 至 43.52；2 RCTs，375 名参与者，低质量证据）和 42 天（PCR 调整的 42 天治疗失败率：阿托伐醌-普罗喹酮为 3.82%，青蒿琥酯-阿托伐醌-普罗喹酮为 2.05%（RR 1.84，95%CI 0.95 至 3.56；2 RCTs，1258 名参与者，中等质量证据）。在泰国的 2002 年试验中，PCR 调整后，青蒿琥酯-阿托伐醌-普罗喹酮组的治疗失败率低于阿托伐醌-普罗喹酮组。虽然阿托伐醌-普罗喹酮组与对照组相比，某些不良事件的发生率更高，但没有反复出现的关联表明阿托伐醌-普罗喹酮与任何特定的不良事件密切相关。
阿托伐醌-普罗喹酮对无并发症恶性疟原虫疟疾有效，尽管在某些情况下，治疗失败率在 5%至 10%之间。添加青蒿琥酯可降低阿托伐醌-普罗喹酮的治疗失败率。青蒿琥酯-阿托伐醌-普罗喹酮和寄生虫耐药性可能是进一步研究的领域。
