Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria

Babalwa Zani, Michael Gathu, Sarah Donegan, Piero L Olliaro, David Sinclair, Babalwa Zani, Michael Gathu, Sarah Donegan, Piero L Olliaro, David Sinclair

Abstract

Background: The World Health Organization (WHO) recommends Artemisinin-based Combination Therapy (ACT) for treating uncomplicated Plasmodium falciparum malaria. This review aims to assist the decision-making of malaria control programmes by providing an overview of the relative effects of dihydroartemisinin-piperaquine (DHA-P) versus other recommended ACTs.

Objectives: To evaluate the effectiveness and safety of DHA-P compared to other ACTs for treating uncomplicated P. falciparum malaria in adults and children.

Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) up to July 2013.

Selection criteria: Randomized controlled trials comparing a three-day course of DHA-P to a three-day course of an alternative WHO recommended ACT in uncomplicated P. falciparum malaria.

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 gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach.

Main results: We included 27 trials, enrolling 16,382 adults and children, and conducted between 2002 and 2010. Most trials excluded infants aged less than six months and pregnant women. DHA-P versus artemether-lumefantrineIn Africa, over 28 days follow-up, DHA-P is superior to artemether-lumefantrine at preventing further parasitaemia (PCR-unadjusted treatment failure: RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, high quality evidence), and although PCR-adjusted treatment failure was below 5% for both ACTs, it was consistently lower with DHA-P (PCR-adjusted treatment failure: RR 0.42, 95% CI 0.29 to 0.62, nine trials, 5417 participants, high quality evidence). DHA-P has a longer prophylactic effect on new infections which may last for up to 63 days (PCR-unadjusted treatment failure: RR 0.71, 95% CI 0.65 to 0.78, two trials, 3200 participants, high quality evidence).In Asia and Oceania, no differences have been shown at day 28 (four trials, 1143 participants, moderate quality evidence), or day 63 (one trial, 323 participants, low quality evidence).Compared to artemether-lumefantrine, no difference was seen in prolonged QTc (low quality evidence), and no cardiac arrhythmias were reported. The frequency of other adverse events is probably similar with both combinations (moderate quality evidence). DHA-P versus artesunate plus mefloquineIn Asia, over 28 days follow-up, DHA-P is as effective as artesunate plus mefloquine at preventing further parasitaemia (PCR-unadjusted treatment failure: eight trials, 3487 participants, high quality evidence). Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials, but lower with DHA-P in two trials (PCR-adjusted treatment failure: RR 0.41 95% CI 0.21 to 0.80, eight trials, 3482 participants, high quality evidence). Both combinations contain partner drugs with very long half-lives and no consistent benefit in preventing new infections has been seen over 63 days follow-up (PCR-unadjusted treatment failure: five trials, 2715 participants, moderate quality evidence).In the only trial from South America, there were fewer recurrent parastaemias over 63 days with artesunate plus mefloquine (PCR-unadjusted treatment failure: RR 6.19, 95% CI 1.40 to 27.35, one trial, 445 participants, low quality evidence), but no differences were seen once adjusted for new infections (PCR-adjusted treatment failure: one trial, 435 participants, low quality evidence).DHA-P is associated with less nausea, vomiting, dizziness, sleeplessness, and palpitations compared to artesunate plus mefloquine (moderate quality evidence). DHA-P was associated with more frequent prolongation of the QTc interval (low quality evidence), but no cardiac arrhythmias were reported.

Authors' conclusions: In Africa, dihydroartemisinin-piperaquine reduces overall treatment failure compared to artemether-lumefantrine, although both drugs have PCR-adjusted failure rates of less than 5%. In Asia, dihydroartemisinin-piperaquine is as effective as artesunate plus mefloquine, and is better tolerated.

Conflict of interest statement

None known.

Figures

**Figure 2**
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

**Analysis 1.1**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 1 Total failure (*P. falciparum*) Day 28 PCR‐unadjusted.

**Analysis 1.2**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 2 Total failure (*P. falciparum*) Day 28 PCR‐adjusted.

**Analysis 1.3**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 3 Total failure (*P. falciparum*) Day 42 PCR‐unadjusted.

**Analysis 1.4**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 4 Total failure (*P. falciparum*) Day 42 PCR‐adjusted.

**Analysis 1.5**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 5 Total failure (*P. falciparum*) Day 63 PCR‐unadjusted.

**Analysis 1.6**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 6 Total failure (*P. falciparum*) Day 63 PCR‐adjusted.

**Analysis 1.7**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 7 Gametocyte carriage.

**Analysis 1.8**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 8 Gametocyte development (in those negative at baseline).

**Analysis 1.9**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 9 Serious adverse events (including deaths).

**Analysis 1.10**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 10 Other adverse events: Gastrointestinal.

**Analysis 1.11**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 11 Other adverse events: Neuro‐psychiatric.

**Analysis 1.12**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 12 Other adverse events: Cardio‐respiratory.

**Analysis 1.13**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 13 Other adverse events: Musculoskeletal/dermatological.

**Analysis 1.14**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 14 Sensitivity analysis: Total failure Day 63 PCR‐unadjusted.

**Analysis 1.15**
Comparison 1 Dihydroartemisinin‐piperaquine versus Artesunate plus mefloquine, Outcome 15 Sensitivity analysis: Total failure Day 63 PCR‐adjusted.

**Analysis 2.1**
Comparison 2 Dihydroartemisinin‐piperaquine dose analysis: 3 dose versus 4 dose regimen, Outcome 1 Total failure PCR‐unadjusted.

**Analysis 2.2**
Comparison 2 Dihydroartemisinin‐piperaquine dose analysis: 3 dose versus 4 dose regimen, Outcome 2 Total failure PCR‐adjusted.

**Analysis 3.1**
Comparison 3 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 1 Total failure Day 28 PCR‐unadjusted.

**Analysis 3.2**
Comparison 3 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 2 Total failure Day 28 PCR‐adjusted.

**Analysis 3.3**
Comparison 3 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 3 Total failure Day 42 PCR‐unadjusted.

**Analysis 3.4**
Comparison 3 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 4 Total failure Day 42 PCR‐adjusted.

**Analysis 3.5**
Comparison 3 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 5 Total failure Day 63 PCR‐unadjusted.

**Analysis 3.6**
Comparison 3 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 6 Total failure Day 63 PCR‐adjusted.

**Analysis 4.1**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 1 Total failure (*P. falciparum*) Day 28 PCR‐unadjusted.

**Analysis 4.2**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 2 Total failure (*P. falciparum*) Day 28 PCR‐adjusted.

**Analysis 4.3**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 3 Total failure (*P. falciparum*) Day 42 PCR‐unadjusted.

**Analysis 4.4**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 4 Total failure (*P. falciparum*) Day 42 PCR‐adjusted.

**Analysis 4.5**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 5 Total failure (*P. falciparum*) Day 63 PCR‐unadjusted.

**Analysis 4.6**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 6 Total failure (*P. falciparum*) Day 63 PCR‐adjusted.

**Analysis 4.7**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 7 Gametocyte development (in those negative at baseline).

**Analysis 4.8**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 8 Gametocyte carriage.

**Analysis 4.9**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 9 Anaemia.

**Analysis 4.10**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 10 Serious adverse events (including deaths).

**Analysis 4.11**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 11 Other adverse events: Gastrointestinal.

**Analysis 4.12**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 12 Other adverse events: Neuro‐psychiatric.

**Analysis 4.13**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 13 Other adverse events: Cardio‐respiratory.

**Analysis 4.14**
Comparison 4 Dihydroartemisinin‐piperaquine versus Artemether‐lumefantrine, Outcome 14 Other adverse events: Musculoskeletal/dermatological.

**Analysis 5.1**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 1 Total failure (*P. falciparum*) Day 28 PCR‐unadjusted.

**Analysis 5.2**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 2 Total failure (*P. falciparum*) Day 28 PCR‐adjusted.

**Analysis 5.3**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 3 Total failure (*P. falciparum*) Day 42 PCR‐unadjusted.

**Analysis 5.4**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 4 Total failure (*P. falciparum*) Day 42 PCR‐adjusted.

**Analysis 5.5**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 5 Total failure (*P. falciparum*) Day 63 PCR‐unadjusted.

**Analysis 5.6**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 6 Total failure (*P. falciparum*) Day 63 PCR‐adjusted.

**Analysis 5.7**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 7 Serious adverse events (including deaths).

**Analysis 5.8**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 8 Other adverse events: Gastrointestinal.

**Analysis 5.9**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 9 Other adverse events: Neuro‐psychiatric.

**Analysis 5.10**
Comparison 5 Dihydroartemisinin‐piperaquine versus Artesunate plus amodiaquine, Outcome 10 Other adverse events: Cardio‐respiratory.

**Analysis 6.1**
Comparison 6 Dihydroartemisinin‐piperaquine versus Artesunate plus sulfadoxine‐pyrimethamine, Outcome 1 Total failure (*P. falciparum*) Day 28 PCR‐unadjusted.

**Analysis 6.2**
Comparison 6 Dihydroartemisinin‐piperaquine versus Artesunate plus sulfadoxine‐pyrimethamine, Outcome 2 Total failure (*P. falciparum*) Day 28 PCR‐adjusted.

**Analysis 6.3**
Comparison 6 Dihydroartemisinin‐piperaquine versus Artesunate plus sulfadoxine‐pyrimethamine, Outcome 3 Total failure (*P. falciparum*) Day 42 PCR‐unadjusted.

**Analysis 6.4**
Comparison 6 Dihydroartemisinin‐piperaquine versus Artesunate plus sulfadoxine‐pyrimethamine, Outcome 4 Total failure (*P. falciparum*) Day 42 PCR‐adjusted.

References

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References to studies excluded from this review

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References to studies awaiting assessment

1. Borrmann S, Sasi P, Mwai L, Bashraheil M, Abdallah A, Muriithi S, et al. Declining responsiveness of Plasmodium falciparum infections to artemisinin‐based combination treatments on the Kenyan coast. PloS One 2011;6(11):e26005.

References to ongoing studies

1. Tekete M, Djimde A, Borrmann S. A phase IIIb/IV comparative, randomised, multi‐centre, open label, parallel 3‐arm clinical study to assess the safety and efficacy of repeated administration of four artemisinin‐based combination therapy (ACT) over a two‐year period in children and adult patients with acute uncomplicated Plasmodium sp. malaria. Chemotherapie Journal. 2012; Vol. Conference: 9.

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Source: PubMed

Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria

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