Failure of dihydroartemisinin-piperaquine treatment of uncomplicated Plasmodium falciparum malaria in a traveller coming from Ethiopia
© The Author(s) 2016
Received: 15 July 2016
Accepted: 16 October 2016
Published: 3 November 2016
Artemisinin combination therapy (ACT) is used worldwide as the first-line treatment against uncomplicated Plasmodium falciparum malaria. Despite the success of ACT in reducing the global burden of malaria, the emerging of resistance to artemisinin threatens its use.
This report describes the first case of failure of dihydroartemisinin-piperaquine (DHA-PPQ) for the treatment of P. falciparum malaria diagnosed in Europe. It occurred in an Italian tourist returned from Ethiopia. She completely recovered after the DHA-PPQ treatment but 32 days after the end of therapy she had a recrudescence. The retrospective analysis indicated a correct DHA-PPQ absorption and genotyping demonstrated that the same P. falciparum strain was responsible for the both episodes.
In consideration of the growing number of cases of resistance to ACT, it is important to consider a possible recrudescence, that can manifest also several weeks after treatment.
Artemisinin combination therapy (ACT) is used worldwide as the first-line treatment against uncomplicated falciparum malaria . Dihydroartemisinin-piperaquine (DHA-PPQ) is characterized by a post-treatment prophylactic effect against re-infections that is longer than artemether-lumefantrine . Despite the success of ACT in reducing the global burden of malaria, the emergence of resistance to artemisinin threatens its use. In Cambodia, failure of ACT is now frequently observed [3, 4]. The increase of treatment failures and parasite clearance times observed soon after the widespread introduction of DHA-PPQ suggests a rapid emergence of resistance to both artemisinin and piperaquine components. In Asia, treatment failures have been reported in Myanmar . In South America, data on (good) efficacy of DHA-PPQ is based on only one trial, conducted in Peru between 2003 and 2005 . In Africa, trials conducted in Burkina Faso , Kenya  and Angola  showed that DHA-PPQ was highly effective, with very rare cases of recrudescence invariably within 28 days.
A 72-year-old Italian woman was admitted on 26 November, 2014 to the Centre for Tropical Diseases (CTD) of Negrar (Verona), for myalgias and arthralgias since 2 days, fever (up to 40 °C) and nausea since one day. She had visited Ethiopia (Omo River Valley) from 6 to 18 November 2014. She was vaccinated against yellow fever, hepatitis A and B, but had not taken any malaria chemoprophylaxis. Her travel history included Ethiopia, Niger, India, and Nambia, not South East Asia. Upon admission, her temperature was 38.3 °C, her weight 67.5 kg. Physical examination was unremarkable. The blood tests showed white blood cells (WBCs) 3.85 × 109/L (normal range 5.2–12.4 × 109/L), haemoglobin (Hb) 12.5 g/dL (normal range 14–18 × g/dL), platelets 46 × 109/L (normal range 130–400 × 109/L), C-reactive protein 135 mg/L (normal range 0–5 mg/L), procalcitonin 14 μg/L (normal range 0–0.5 μg/L). The quantitative buffy coat (QBC) test, antigen malarial test and blood smears resulted positive for Plasmodium falciparum, with a parasitaemia of 0.3% (14,600/μL). The patient was treated with DHA-PPQ 320/40 mg, three tablets/day for 3 days. The first day after treatment the parasitaemia dropped to 0.0023% (96/μL). After two days, the blood films and the QBC test resulted negative. Also, iv ceftriaxone 2 g/day was administrated for a left basal bronchopneumonia. The patient was discharged on 5 December, 2014.
At a follow-up visit on 23 December, the QBC test and blood smears were still negative. The blood tests showed WBC 7.98 × 109/L, Hb 11.8 g/dL, platelets 233 × 109/L.
She was re-admitted on 7 January, 2015 complaining of fever, nausea and vomiting that had started 7 days before (more than 4 weeks after anti-malaria treatment). The QBC test, antigen malarial test and blood smears all resulted positive again for falciparum malaria, with a parasitaemia of 0.4% (12,100/μL). WBCs were 5.5 × 109/L, Hb 9.5 g/dL, platelets 96 × 109/L. The patient was treated this time with atovaquone-proguanil 250/100 mg, four tablets/day for 3 days. The parasitaemia decreased to 0.36% (10,930/μL) 24 h after first dose of treatment, 0.16% (5017/μL) the second day, 0.0016% (46/μL) the third day. After 4 days, blood films resulted negative. The patient was discharged on 12 January, 2015.
At follow-up visits 28 and 56 days after the second malaria episode, QBC and blood smears resulted negative and the main laboratory findings were normal.
Serum concentrations of dihydroartemisinin-piperaquine
Hours since last administration
Day 7 (calculated)
This is the first case of failure of DHA-PPQ reported in Europe. The patient returned from Ethiopia, a country where DHA-PPQ failures have not been reported before. In this case, the rapid response to DHA-PPQ and the lack of mutations in the PfK13 gene suggest the involvement of an artemisinin-sensitive strain. Although it was not possible to analyse a specific molecular marker of resistance to PPQ (a newly identified gene, PFE1085w is presumably associated to resistance to this drug) , the combination of results obtained from molecular and pharmacokinetic analyses and the clinical characteristics support that the strain was resistant to the PPQ component.
In the last 2 years (July 2014 to June 2016) DHA-P was administered to 36 patients attended at the CTD for falciparum malaria, observing no other failure. These data are in agreement with the literature. The efficacy of DHA-PPQ has been found very high, particularly in the African continent. There was a relevant delay between the onset of symptoms and the second diagnosis because the index of suspicion was low due to the negative laboratory tests performed at the 28-day follow-up visit. In consideration of the growing number of cases of resistance to ACT, it is important to consider a possible recrudescence, which can manifest several weeks after treatment.
FG, DB and ZB drafted the manuscript. FG, DB and AA collected clinical and laboratory data. MM and CS performed the molecular tests. GL and SG were responsible for the pharmacokinetic analysis. All authors commented and agreed upon the final manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent for the publication of the present case was obtained from the patient.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Nguyen TD, Olliaro P, Dondorp AM, Baird JK, Lam HM, Farrar J, et al. Optimum population-level use of artemisinin combination therapies: a modelling study. Lancet Glob Health. 2015;3:e758–66.View ArticlePubMedPubMed CentralGoogle Scholar
- Pfeil J, Borrmann S, Bassat Q, Mulenga M, Talisuna A, Tozan Y. An economic evaluation of the posttreatment prophylactic effect of dihydroartemisinin-piperaquine versus artemether-lumefantrine for first-line treatment of Plasmodium falciparum malaria across different transmission settings in Africa. Am J Trop Med Hyg. 2015;93:961–6.View ArticlePubMedGoogle Scholar
- Saunders DL, Vanachayangkul P, Lon C. Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med. 2014;371:484–5.View ArticlePubMedGoogle Scholar
- Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, et al. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis. 2016;16:357–65.View ArticlePubMedGoogle Scholar
- Tun KM, Jeeyapant A, Imwong M, Thein M, Aung SS, Hlaing TM, et al. Parasite clearance rates in Upper Myanmar indicate a distinctive artemisinin resistance phenotype: a therapeutic efficacy study. Malar J. 2016;15:185.View ArticlePubMedPubMed CentralGoogle Scholar
- Grande T, Bernasconi A, Erhart A, Gamboa D, Casapia M, Delgado C, et al. A randomised controlled trial to assess the efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Peru. PLoS ONE. 2007;2:e1101.View ArticlePubMedPubMed CentralGoogle Scholar
- Zongo I, Somé FA, Somda SA, Parikh S, Rouamba N, Rosenthal PJ, et al. Efficacy and day 7 plasma piperaquine concentrations in African children treated for uncomplicated malaria with dihydroartemisinin-piperaquine. PLoS ONE. 2014;9:e103200.View ArticlePubMedPubMed CentralGoogle Scholar
- Agarwal A, McMorrow M, Onyango P, Otieno K, Odero C, Williamson J, et al. A randomized trial of artemether-lumefantrine and dihydroartemisinin-piperaquine in the treatment of uncomplicated malaria among children in western Kenya. Malar J. 2013;12:254.View ArticlePubMedPubMed CentralGoogle Scholar
- Plucinski MM, Talundzic E, Morton L, Dimbu PR, Macaia AP, Fortes F, et al. Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for treatment of uncomplicated malaria in children in Zaire and Uíge provinces, Angola. Antimicrob Agents Chemother. 2015;59:437–43.View ArticlePubMedGoogle Scholar
- Nguyen DV, Nguyen QP, Nguyen ND, Le TT, Nguyen TD, Dinh DN, et al. Pharmacokinetics and ex vivo pharmacodynamics antimalarial activity of dihydroartemisinin-piperaquine in patients with uncomplicated falciparum malaria in Vietnam. Antimicrob Agents Chemother. 2009;53:3534–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Price RN, Hasugian AR, Ratcliff A, Siswantoro H, Purba HL, Kenangalem E, et al. Clinical and pharmacological determinants of the therapeutic response to dihydroartemisinin-piperaquine for drug-resistant malaria. Antimicrob Agents Chemother. 2007;51:4090–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Wooden J, Kyes S, Sibley CH. PCR and strain identification in Plasmodium falciparum. Parasitol Today. 1993;9:303–5.View ArticlePubMedGoogle Scholar
- Viriyakosol S, Siripoon N, Petcharapirat C, Petcharapirat P, Jarra W, Thaithong S, et al. Genotyping of Plasmodium falciparum isolates by the polymerase chain reaction and potential uses in epidemiological studies. Bull World Health Organ. 1995;73:85–95.PubMedPubMed CentralGoogle Scholar
- Taylor SM, Parobek CM, DeConti DK, Kayentao K, Coulibaly SO, Greenwood BM, et al. Absence of putative artemisinin resistance mutations among Plasmodium falciparum in sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis. 2015;211:680–8.View ArticlePubMedGoogle Scholar
- Menegon M, Pearce RJ, Inojosa WO, Pisani V, Abel PM, Matondo A, et al. Monitoring for multidrug-resistant Plasmodium falciparum isolates and analysis of pyrimethamine resistance evolution in Uige province, Angola. Trop Med Int Health. 2009;14:1251–7.View ArticlePubMedGoogle Scholar
- Duraisingh MT, Jones P, Sambou I, von Seidlein L, Pinder M, Warhurst DC. The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Mol Biochem Parasitol. 2000;108:13–23.View ArticlePubMedGoogle Scholar
- Palmieri F, Petrosillo N, Paglia MG, Conte A, Goletti D, Pucillo LP, et al. Genetic confirmation of quinine-resistant Plasmodium falciparum malaria followed by postmalaria neurological syndrome in a traveler from Mozambique. J Clin Microbiol. 2004;42:5424–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Korsinczky M, Chen N, Kotecka B, Saul A, Rieckmann K, Cheng Q. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother. 2000;44:2100–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Duru V, Khim N, Leang R, Kim S, Domergue A, Kloeung N, et al. Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations. BMC Med. 2015;13:305.View ArticlePubMedPubMed CentralGoogle Scholar