Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area

f Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia's formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (C max ) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. NCT01624337.)

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confidence: 99%

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confidence: 99%

Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Two-Day Regimen of Dihydroartemisinin-Piperaquine for Malaria Prevention Halted for Concern over Prolonged Corrected QT Interval

Manning

Vanachayangkul

Lon

et al. 2014

“…In adults in Thailand, the protective efficacy of DHAPQ was 98% when DHAPQ was administered monthly and 86% when it was administered bimonthly (11). Despite extensive clinical evaluation and use of DHAPQ in Southeast Asia (12,13) and Africa (14)(15)(16), few studies have addressed pharmacokinetics of PQ in children (17)(18)(19). However, one of these studies suggested that children are underdosed with current regimens (17), which was also supported by a recent meta-analysis (20).…”

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confidence: 86%

Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulfadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso

Zongo

Milligan

Compaoré

et al. 2015

fThe WHO recommends that children living in areas of highly seasonal malaria transmission in the Sahel subregion should receive seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ). We evaluated the use of dihydroartemisinin-piperaquine (DHAPQ) as an alternative drug that could be used if SPAQ starts to lose efficacy. A total of 1,499 children 3 to 59 months old were randomized to receive SMC with SPAQ or DHAPQ over 3 months. The primary outcome measure was the risk of clinical malaria (fever or a history of fever with a parasite density of at least 3,000/l). A cohort of 250 children outside the trial was followed up as a control group. Molecular markers of drug resistance were assessed. The risk of a malaria attack was 0.19 in the DHAPQ group and 0.15 in the SPAQ group, an odds ratio of 1.33 (95% confidence interval [CI], 1.02 to 1.72). Efficacy of SMC compared to the control group was 77% (67% to 84%) for DHAPQ and 83% (74% to 89%) for SPAQ. pfdhfr and pfdhps mutations associated with antifolate resistance were more prevalent in parasites from children who received SPAQ than in children who received DHAPQ. Both regimens were highly efficacious and well tolerated. DHAPQ is a potential alternative drug for SMC. (This trial is registered at ClinicalTrials.gov under registration no. NCT00941785.) S ubstantial progress has been made in the control of malaria (1), but in most of sub-Saharan Africa, the disease remains a major public health problem. In Burkina Faso, malaria is still a leading cause of severe illness and mortality, accounting for 63% of hospital admissions and 71% of all deaths in hospital among children under 5 years of age in 2011 (2). Results from research studies indicate that the burden remains very high. In Boussé, in the Sahelian zone of the country, in 2011, 1,232 episodes of malaria were recorded over one transmission season in 1,500 children under 5 years of age who were using an insecticide-treated net (3). In such areas, new strategies for malaria control are needed. The WHO now recommends seasonal malaria chemoprevention (SMC) with sulfadoxine pyrimethamine plus amodiaquine (SPAQ) as a new strategy for malaria control in children in areas of highly seasonal transmission (4, 5), defined as areas where at least 60% of malaria cases occur during 4 months of the year and where SP and AQ retain good efficacy. Most parts of Burkina Faso fit these criteria, and implementation of SMC in Burkina Faso started in 2014 in seven districts.Resistance to both SP and AQ is common in much of Africa, but in most areas of seasonal transmission in the Sahel these drugs retain their antimalarial efficacy (5). However, alternative drug regimens may be needed in these areas in the future, and they are needed now if SMC is to be deployed in areas of eastern or southern Africa where antifolate resistance makes SP an unsuitable drug for SMC. Dihydroartemisinin-piperaquine (DHAPQ) is a potential alternative. Piperaquine (PQ) is a long-acting antimalarial; administration dail...

“…Although ASϩMQ and AL treatment failures have previously been reported from Battambang and Pursat (2,13), the clinical efficacy of these regimens in the setting of DHA-PPQ resistance is not known. However, studies have suggested a lack of cross-resistance between PPQ and MQ in vitro; for example, pfmdr1 amplification is associated with decreased susceptibility to MQ but increased susceptibility to PPQ (14).…”

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Decreasing pfmdr1 Copy Number Suggests that Plasmodium falciparum in Western Cambodia Is Regaining In Vitro Susceptibility to Mefloquine

Lim

Dek

Try

et al. 2015

b Dihydroartemisinin-piperaquine is the current frontline artemisinin combination therapy (ACT) for Plasmodium falciparum malaria in Cambodia but is now failing in several western provinces. To investigate artesunate plus mefloquine (AS؉MQ) as a replacement ACT, we measured the prevalence of multiple pfmdr1 copies-a molecular marker for MQ resistance-in 844 P. falciparum clinical isolates collected in 2008 to 2013. The pfmdr1 copy number is decreasing in Western Cambodia, suggesting that P. falciparum is regaining in vitro susceptibility to MQ.A rtemisinin-based combination therapy (ACT) is used worldwide to treat uncomplicated Plasmodium falciparum malaria. Artesunate plus mefloquine (ASϩMQ) was adopted as Cambodia's first-line treatment in 2000. ASϩMQ treatment failures were first observed in 10 to 20% of patients in Pailin and Battambang Provinces, Western Cambodia, in 2003 to 2004 (1, 2). The presence of multiple (i.e., Ն2) pfmdr1 copies-a genetic marker of MQ resistance-was associated with ASϩMQ failures and reduced parasite in vitro susceptibility to MQ not only in Pailin and Battambang but in neighboring Pursat and Kampot Provinces as well (3)(4)(5). This development, along with emerging evidence of reduced in vitro susceptibility to MQ in other provinces (6), prompted Cambodia's National Malaria Control Program to adopt dihydroartemisinin-piperaquine (DHA-PPQ) as the firstline ACT in Western Cambodia in 2008 and in the entire country in 2010. Unfortunately, recent clinical studies suggest that the efficacy of DHA-PPQ is rapidly declining in five Western Cambodian provinces: Pursat, Battambang, Pailin, Oddar Meancheay, and Preah Vihear. For example, DHA-PPQ treatment failures were observed in 25% and 11% of patients in Pailin and Pursat in 2010 (7) and in 36% of patients in Oddar Meancheay in 2013 (8). The rapidly increasing prevalence of DHA-PPQ failures in these provinces, likely due to entrenched artemisinin resistance (9, 10) and suspected PPQ resistance (7, 8), demands additional evaluations of newer antimalarial drugs (11, 12), as well as reevaluation of previously used ACTs.Only a few ACTs, including ASϩMQ and artemether-lumefantrine (AL), are presently available for widespread use in Cambodia to replace DHA-PPQ as it fails. Although ASϩMQ and AL treatment failures have previously been reported from Battambang and Pursat (2, 13), the clinical efficacy of these regimens in the setting of DHA-PPQ resistance is not known. However, studies have suggested a lack of cross-resistance between PPQ and MQ in vitro; for example, pfmdr1 amplification is associated with decreased susceptibility to MQ but increased susceptibility to PPQ (14). Given these and related findings (15), and the fact that earlier use of DHA-PPQ was associated with decreasing prevalence of multiple pfmdr1 copies in Pailin (from 33% in 2005 to 5% in 2007) (16), we hypothesized that the recent substantially reduced use of ASϩMQ in Pursat and Preah Vihear would select for parasites that have regained sensitivity to MQ. To explore this hyp...