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Artemisinin-based combination therapy for treating uncomplicated malaria

  • Review
  • Intervention

Authors


Abstract

Background

The World Health Organization recommends uncomplicated P. falciparum malaria is treated using Artemisinin-based Combination Therapy (ACT). This review aims to assist the decision making of malaria control programmes by providing an overview of the relative benefits and harms of the available options.

Objectives

To compare the effects of ACTs with other available ACT and non-ACT combinations for treating uncomplicated P. falciparum malaria.

Search methods

We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) to March 2009.

Selection criteria

Randomized head to head trials of ACTs in uncomplicated P. falciparum malaria.

This review is limited to: dihydroartemisinin-piperaquine; artesunate plus mefloquine; artemether-lumefantrine (six doses); artesunate plus amodiaquine; artesunate plus sulfadoxine-pyrimethamine and amodiaquine plus sulfadoxine-pyrimethamine.

Data collection and analysis

Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on P. vivax, gametocytes, haemoglobin, and adverse events.

Main results

Fifty studies met the inclusion criteria. All five ACTs achieved PCR adjusted failure rates of < 10%, in line with WHO recommendations, at most study sites.

Dihydroartemisinin-piperaquine performed well compared to the ACTs in current use (PCR adjusted treatment failure versus artesunate plus mefloquine in Asia; RR 0.39, 95% CI 0.19 to 0.79; three trials, 1062 participants; versus artemether-lumefantrine in Africa; RR 0.39, 95% CI 0.24 to 0.64; three trials, 1136 participants).

ACTs were superior to amodiaquine plus sulfadoxine-pyrimethamine in East Africa (PCR adjusted treatment failure versus artemether-lumefantrine; RR 0.12, 95% CI 0.06 to 0.24; two trials, 618 participants; versus AS+AQ; RR 0.44, 95% CI 0.22 to 0.89; three trials, 1515 participants).

Dihydroartemisinin-piperaquine (RR 0.32, 95% CI 0.24 to 0.43; four trials, 1442 participants) and artesunate plus mefloquine (RR 0.30, 95% CI 0.21 to 0.41; four trials, 1003 participants) were more effective than artemether-lumefantrine at reducing the incidence of P.vivax over 42 days follow up.

Authors' conclusions

Dihydroartemisinin-piperaquine is another effective first-line treatment for P. falciparum malaria.

The performance of the non-ACT (amodiaquine plus sulfadoxine-pyrimethamine) falls below WHO recommendations for first-line therapy in parts of Africa.

In areas where primaquine is not being used for radical cure of P. vivax, ACTs with long half-lives may provide some benefit.

摘要

背景

以Artemisinin作為基礎之組合療法用於治療非重症瘧疾

世界衛生組織(The World Health Organization)建議使用以Artemisinin作為基礎之組合療法(Artemisininbased Combination Therapy;ACT)治療非重症惡性瘧疾。本回顧之目標係藉著綜觀諸等可選擇之效益及害處以協助制定瘧疾控制計畫。

目標

比較ACTs與其他可用之ACT及非ACT組合對於治療非重症惡性瘧疾的效應。

搜尋策略

我們搜尋直到2009年3月為止的Cochrane Infectious Diseases Group Specialized Register、Cochrane Central Register of Controlled Trials (CENTRAL)、MEDLINE、EMBASE、 LILACS以及meta Register of Controlled Trials(mRCT)。

選擇標準

針對非重症惡性瘧疾之隨機平行對照試驗。本回顧限定於:dihydroartemisininpiperaquine;artesunate加mefloquine;artemetherlumefantrine(6劑);artesunate加amodiaquine;artesunate加sulfadoxinepyrimethamine;以及amodiaquine加sulfadoxinepyrimethamine。

資料收集與分析

由2名作者獨立評估試驗適用性及偏差風險並摘錄數據。茲遵照WHO之‘Protocol for assessing and monitoring antimalarial drug efficacy(評估及監測抗瘧疾藥物功效之操作流程)’分析首要結果,並使用風險比(risk ratio;RR)及95%信賴區間(confidence interval;CI)比較藥物。次級結果為對於間日瘧之效應、配子體、血紅素、及不良作用。

主要結論

共有50項研究符合收錄標準。在大部分之研究地點,全部5項ACTs皆達成< 10%之PCR調整後失敗率,符合WHO之建議。相較於目前所用之ACTs,dihydroartemisininpiperaquine具有良好之表現(PCR調整後失敗率:在亞洲相對於artesunate加mefloquine; RR 0.39, 95% CI 0.19 – 0.79; 3項試驗, 1062名參與者; 在非洲相對於artemetherlumefantrine; RR 0.39,95% CI 0.24 – 0.64; 3項試驗, 1136名參與者)。ACTs在東非優於amodiaquine加sulfadoxinepyrimethamine(PCR調整後失敗率:相對於artemetherlumefantrine; RR 0.12,95% CI 0.06 – 0.24; 2項試驗, 618名參與者; 相對於AS+AQ; RR 0.44, 95% CI 0.22 – 0.89;3項試驗, 1515名參與者)。在42天之追蹤中,dihydroartemisininpiperaquine (RR0.32, 95% CI 0.24 – 0.43; 4項試驗, 1442名參與者)以及artesunate加mefloquine (RR 0.30, 95% CI 0.21 – 0.41; 4項試驗, 1003名參與者)可較artemetherlumefantrine更為有效的降低間日瘧之發生。

作者結論

對於惡性瘧疾,dihydroartemisininpiperaquine是另一種有效之第一線治療。在非洲部分區域,非ACT (amodiaquine加sulfadoxinepyrimethamine)之表現低於WHO針對第一線治療之建議。在並未使用primaquine以根治間日瘧之地區,具有長半生期之ACTs可能提供某些效益。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

在諸多世界上最貧窮之國家中,瘧疾是疾病及死亡的主要肇因之一。其係由受到經瘧原蟲感染之蚊子叮咬而在人和人之間傳播。惡性瘧原蟲(P. falciparum)是全世界最為常見之瘧疾肇因,且其造成大部分之死亡。非重症瘧疾是該疾病之輕微形式,如不予治療,其可快速惡化成為威脅性命之疾病。傳統用於治療非重症瘧疾之藥物在世界上之諸多區域已經因為產生抗藥性而變為無效。世界衛生組織現今建議使用Artemisinin基礎性組合療法(Artemisininbased Combination Therapy;ACT)以治療非重症瘧疾。ACTs係組合一種artemisinin衍生物(一種相對較新類型之藥物,其極為有效)與另一種較長效之藥物,以試著降低產生進一步抗藥性之風險。本回顧共針對4種常用之ACTs、1種相對較新之ACT (dihydroartemisinin加piperaquine)、以及1種不含artemisinin衍生物但仍在某些非洲國家使用之組合,摘述其相對效益及害處。全部5種ACTs皆顯示可在大部分其進行研究之地區高度有效的治療惡性瘧疾。然而,亦有數項其中ACTs顯示高治療失敗率之試驗其皆強調必須繼續監測其效能。該種新的ACT,dihydroartemisinin加piperaquine,顯示至少與目前廣泛用於亞洲及非洲之該等ACTs同樣有效,且其可為治療瘧疾之另一選擇。在東非國家中,ACTs顯示要較amodiaquine加sulfadoxinepyrimethamine更為有效,這可能代表此區域中對於此種組合之2種藥物皆具有高抗藥性。第二常見之瘧疾形式,間日瘧,亦可以ACTs治療,但其需要額外之其他治療始可完全治癒病患。這是因為間日瘧寄生蟲可在肝臟中休眠數月或數年之後再度變為活動性狀態。其中該夥伴藥物具有長作用期的ACTs可能可協助延後此等復發情形。ACTs似乎是為相對安全之治療,僅具有極少數之嚴重副作用。輕微之副作用較為常見,但其可能不易與瘧疾之症狀區隔。本回顧共收錄50項試驗,但其並未收錄最為脆弱之族群:懷孕婦女及幼嬰(年齡< 6個月)。

Plain language summary

Artemisinin-based combination treatments for uncomplicated malaria

Malaria is a major cause of illness and death in many of the world's poorest countries. It is spread from person to person by the bite of mosquitoes infected with a microorganism called Plasmodium. The Plasmodium species P. falciparum is the most common cause of malaria worldwide and causes the majority of deaths. Uncomplicated malaria is the mild form of the disease which, if left untreated, can progress rapidly to become life threatening. The drugs traditionally used to treat uncomplicated malaria have become ineffective in many parts of the world due to the development of drug resistance.

The World Health Organization now recommends Artemisinin-based Combination Therapy (ACTs) for treating uncomplicated malaria. The ACTs combine an artemisinin-derivative (a relatively new group of drugs which are very effective) with another longer-lasting drug to try and reduce the risk of further resistance developing.

This review summarizes the relative benefits and harms of the four ACTs in common use, one relatively new ACT (dihydroartemisinin plus piperaquine), and one combination which does not contain an artemisinin derivative but remains in use in some African countries (amodiaquine plus sulfadoxine-pyrimethamine).

All five ACTs were shown to be highly effective at treating P. falciparum in most places where they have been studied. However, there were several trials where ACTs had high levels of treatment failure, which emphasises the need to continue to monitor their performance.

The new ACT, dihydroartemisinin plus piperaquine, was shown to be at least as effective as the ACTs currently in widespread use in Asia and Africa, and represents another option for malaria treatment.

ACTs were shown to be more effective than amodiaquine plus sulfadoxine-pyrimethamine in countries from East Africa which probably represents high levels of resistance, to both drugs in this combination, in this region.

The second most common form of malaria, P. vivax, can also be treated with ACTs but requires additional treatment to cure the patient completely. This is because the P. vivax parasite can lie dormant in the liver for months or years before becoming active again. ACTs where the partner drug has a long duration of action may help to delay these relapses.

The ACTs seem to be relatively safe with few serious side effects. Minor side effects are more common but can be difficult to distinguish from the symptoms of malaria itself. Fifty trials were included in this review but did not include the most vulnerable populations; pregnant women and young infants (age < six months).

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