DIHYDROARTEMISININ- PIPERAQUINE COMBINATION THERAPY IN UNCOMPLICATED FALCIPARUM MALARIA IN ADULTS; ARE THERE ANY ECG CHANGES? Khin Phyu Pyar, Zar Ni Htet Aung, Lay Mg Mg, Nyan Lin Mg, Chan Aye Aung, Soe Win Hlaing, Win Win Myint, Sai Aik Hla & MarlarThan
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DIHYDROARTEMISININ-PIPERAQUINE COMBINATION THERAPY IN UNCOMPLICATED
FALCIPARUM MALARIA IN ADULTS; ARE THERE ANY ECG CHANGES?
Khin Phyu Pyar, Zar Ni Htet Aung, Lay Mg Mg, Nyan Lin Mg, Chan Aye Aung, Soe Win Hlaing, Win Win Myint, Sai Aik Hla &
MarlarThan
Introduction
Malaria - serious global health challange
MDR drug resistance in SEA WHO & National anti-malarial drug policy
recommended ACT in co-formulated tab (ACT – AS/M, AM/L, AS/AM and DHA/P) DHA/P - Artekin /
Artepip/Duocotexin/Piperamisinin/Artequin
• It was reported to have ECG changes especially ventricular arrhythmia and long QT interval in some studies.
Objectives
• To find out the
– therapeutic efficacy,
– safety and tolerability of
Dihydroartemisinin/ Piperaquine compound tablet
• (to detect ECG changes before and after treatment)
Study design
• a hospital based descriptive study
Patients & methods
Inclusion criteria
• Age above 18 year
• mono-infection with P. falciparum detected by microscopy (parasitaemia of 300-100,000/µl asexual forms) presence of axillary ≥ 37.5 °C or history of fever during the past 24 h;
• ability to swallow oral medication.
Exclusion criteria
• signs of severe falciparum malaria • mixed malaria detected by microscopy; • severe malnutrition • febrile conditions other than malaria (e.g. measles, acute
lower respiratory tract infection, severe diarrhoea with dehydration)
• chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS);
• regular medication, which may interfere with anti-malarial pharmacokinetics
• history of hypersensitivity reactions • a positive pregnancy test or breastfeeding;
Withdrawal Criteria
• patient's request
• any serious adverse effects to drugs
• serious or repeated non-compliance with protocol specifications
Procedure
• The patients who fulfilled the inclusion criteria were keep in hospital for 28- 42 days. ( 28 days hospital stay till 2010 and 42 days after 2010).
Materials
• Supervised treatment with Dihydroartemisinin and piperaquine phosphate co-formulated tablets (Dihydroartemesinin 40 mg and Piperaquine 375 mg) was given for 3 days.
Procedure
• Clinical, parasitological and biochemical monitoring (full blood count, blood sugar, serum creatinine, liver function test) were done in hospital under the supervision of the physician.
28-days follow-up
Efficacy
Safety
CLINICAL ASSESSMENT
Safety
• Physical examination
• Blood chemistry
• Hematology
• 12-lead ECG
• Serial ECG recordings were done on (Day 0, Day3, Day 7, Day 14, Day 21and Day 28) ( Day 35 and Day 42).
• Interpretations on changes like heart rate, rhythm, PR interval, QRS complexes, QT interval, T wave changes and U waves.
• reviewed by senior physicians.
• Corrected QT interval was calculated.
Correcting the QT interval
• is affected by heart rate
(heart rate increases, the QT interval decreases)
Thus QT interval based on a standard heart rate of 60.
QTc.
( women < 0.46 second , men < 0.45 sec )
(When the QTc is longer than 0.50 sec, torsades de pointes is more likely to
• Each tab contains 50mg dihydroartemisinin and 350 mg piperaquine phosphate
Ethical consideration
• The protocol was approved by the Ethical Committee (Research & Development Committee) - Ministry of Defence.
• Written informed consent was obtained from all the patients.
Statistical Evaluation
• EPI-INFO software.
• Categorical data were compared by calculation the chi-square value with Yate's correction. Normally distributed continuous data were compared by the Student's t-test and analysis of variance
Results
• A total of 200 patients were obtained for the study. Follow up was completed for 28-42 days in all patients.
Table 1–Base line characteristic of patients (n=200)
Dihydroartemisinin / Piperaquine combination
therapy
Age [years]
Mean + S.D 29 + 10.77
Body weight [Kg]
Mean+S.D 58 + 4.9
Height [ins]
Mean +S.D 163 + 7.6
Initial Temp. <C
Mean± S.D 37.6 + 0.6
Initial parasitaemia/ul
[range] ( 390 – 187590 )
Table 2.Outcome/cure rate (n=200)
Outcome Number Percent
ETF 0 0
LTF 0 0
ACPR 200 100
Withdrawal 0 0
Loss to follow up 0 0
Total 200 100
Table (3 ) Study drugs, sites & year (n=200)
SR Name of drug Country of
origin
Study site Number of patients Study year
1 Artekin China
Holleykin
Ygn, POL 30 2006
2 Artepip China Ygn, POL, Lashio 30 2007
3 Piperamisinin Myanmar Ygn, POL, Lashio,
Myitkyina, NPT
30 2008- 2010
4 Duocotexin Ygn, Kyaington,
Bokpyin, Ann,
Homalin
95 2010- 2015
5 Artequine Ygn, Bokpyin,
Ann, Homalin
15 2016- 2018
200
Table (4) Cardiovascular side effects (symptoms) (n=200)
symptoms Number Percent
giddiness 10 5
vomiting 5 2.5
palpitation 2 1
Fainting attack 0 0
Chest pain 0 0
Total 200 100
Table (5) Cardiovascular side effects (signs) (n=200)
Parameter Number Percent
Significant BP changes 0 0
Undue tachycardia 0 0
Undue bradycardia 0 0
arrhythmia 0 0
Prolonged corrected QT
interval
0 0
Total 200 100
Table ( 6) QT interval (corrected ) (n=200)
Mean QT interval (corrected)
(sec) SD
Normal QT interval
(sec)
Gender Patients Reference
male 0.45 <0.46
female 0.44 <0.45
Total 200
Discussion
• Multidrug resistant falciparum malaria is an increasing problem in Southeast Asia including Myanmar.
• According to WHO 2010 guideline, artemisinin combination therapy such as Dihydroartemisinin / Piperaquine or Artemether / Lumefantrine or Artesunate / Mefloquine or Artesunate / Amodiaquine is a recommended therapy for treatment of uncomplicated falciparum malaria.
• Artemisinine derivatives are very potent against falciparum malaria leading to rapid decrease of parasitaemia and faster defervescence than other antimalarials.
• The combination of piperaquine with dihydroartemisinin has been used in treatment of falciparum malaria in China, Vietnam, Cambodia and Thailand. The 28-day cure rate is about 95% in the regimen of 8 tablets for 2 to 3 days . (1,2,3,4,5,6)
• The cardiotoxicity of various antimalarial drugs have been problems for long term.(7) There were few reports that the use of quinine, quinidine and halofantrine in treatment of falciparum malaria produced prolong QT interval .( 7,8,9)
• Regarding the newer drug- dihydroartemisinin/ - piperaquine , the data were conflicting. In vitro study done by Franco & group did not show cardiovascular signal They did not display an in vitro signal for a significant pro-arrhythmic risk. They did not appear to induce potential torsadogenic effects in vitro . .(11 )
• Cambodia study revealed cardiac adverse effects. They divided the patients into two groups – two day treatment regimen and three days treatment regimen. They found significant prolongation of QT interval in those receiving two day treatment regimen. Thus, they recommended dihydroartemisinin/ - piperaquine three days treatment regimen. (10 )
• the study done by Boje showed QT prolongation in patients taking piperaquine . (12)
• In this study none of our patients had QT prolongation in serial ECG done on Day 0, Day 3, Day 7, Day 14 and Day 28. No unexplained sudden death.
One report mentioned the cardiac untoward effect was related with meals. They prescribed piperaquine in 3 situations ; • high fat & low calorie meal, • high fat & high calorie meal • and lastly fasting state. They found that QT prolongation was seen in those taking piperaquine on empty stomach.(14) In our study, we did not give particular advice on diet. None of them had severe cardiac side effects.
• According to WHO, there were several precipitating factors for fatal arrhythmia and QT prolongation. They were Risk factors for drug-induced QT/QTc prolongation- female gender, structural heart disease, genetic defects of cardiac ion channels, electrolyte disturbances, bradycardia, hepatic impairment, and concomitant use of medications that prolong the QT/QTc interval or increase drug levels. (6 )
• The concomitant use of medications that prolong the QT/QTc interval was challenging in this study. The patients having nausea or vomiting were prescribed either metoclopramide or odensetron. Even though their ECG did not have long QT interval.
• There were reports on sudden cardiac arrest due to Torsade de pointe. (16)
This study included only 200 patients – supervised treatment by physician.
• QTc was not prolong. • None of them had syncope or sudden death. • Moreover, there were more than 2,000
uncomplicated falciparum malaria patients receiving DHA/P three days treatment regimen in various military hospitals over one decade. There, they did ECG on requirement and no significant changes.
• They did not see syncope or sudden death. • The cure rate was excellent (100%).
• Thus, dihydroartemisinin/ - piperaquine three days treatment regimen was safe and effective
• still the first line pocket therapy for treatment of uncomplicated falciparum malaria in adults in military population.
Conclusion
• Dihydroartemisinin / Piperaquine combination therapy was effective in treatment of uncomplicated falciparum malaria in adults.
• Dihydroartemisinin / Piperaquine combination therapy did not cause prolongation of QT interval or sudden death.
• The adverse effects were tolerable.
Acknowledgement
1)all patients, commanding officer, medical specialists, medical officers, nursing staff, microscopists and medical assistants for their active cooperation in the study.
2) Director, Directorate of Medical Services, Ministry of Defence
References
• 1.WHO 2009. Malaria in the Greater Mekong Subregion: Regional and Country Profiles. http://www.whothailand.org/en/Section3/Section113_269.htm
• 2.WHO 2010. Treatment guidelines for malaria. 2nd edition. World Health Organization, Geneva. ISBN 978 92 4 154792 5. http://www.who.int/malaria/publications/atoz/978924547925/en/index.html.
• 3.WHO 2010. Global Report on Antimalarial Drug Efficacy and Drug Resistance: 2000-2010.ISBN978 92 4 1500470. http://www.who.int/malaria/marketing_of_oral_artemisinin_monotherapies/en/index.html
• 4.WHO 2010. Report of the workshop to review and plan therapeutic efficacy studies to monitor P. falciparum and P. vivax resistance to anti-malarial drugs in the Greater Mekong Sub-region. Mandalay, Myanmar, 30 Sept – 2 Oct 2009. SEA-MAL-263.
• 5.WHO 2012. Minutes of the The Mekong Malaria in vivo Therapeutic Efficacy Study Network*,China, Draft V4_31 July 2012
• 6. WHO/HTM/GMP/MPAC/2017.2. The cardiotoxicity of antimalarials .Report of WHO Evidence Review Group Meeting, 13–14 October 2016 Varembé Conference Centre, Geneva, Switzerland
• 7. K Atsushi , Y Harumi , K Hajime & K Mikio. Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system . Malaria Journal ; 2010, 9:318
• 8. Ye Thwe, Win Win Myint, Yin Yin Htun & Khin Phyu Pyar. QT interval and quinidine in uncomplicated falciparum malaria. 10 Myanmar Military Medical Conference, 1998
• 9.Pe Than Myint , Tin Shwe & et al. QT changes in quinine therapy • 10.V Pattaraporn , L Chanthap, S Michele , S Sommethy , T Winita, K Chanikarn, P Sut-Thang & et al.
Piperaquine population pharmacokinetics and cardiac safety in Cambodia. Antimicrob. Agents Chemother. doi:10.1128/AAC.02000-16 • 11. B Franco, C William, P Silvia, U David, W Barb, Y Gan-Xin & F-B Christian. In vitro cardiovascular
effects of dihydroartemisinin piperaquine combinations : Comparisons with other antimalarials. Antimicrob. Agents Chemother. doi:10.1128/AAC.05688-11
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a combination of piperaquine and a novel antimalarial drug candidate OZ439 for the treatment of uncomplicated malaria. Br J Clin Pharmacol; (2015) 80:4; 706–715
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http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-Product_Information/human/001199/WC500118113.pdf (last accessed 8 June 2015).
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human/001199/WC500118116.pdf (last accessed 8 June 2015). • 15.Keating GM. Dihydroartemisinin/Piperaquine: a review of its use
in the treatment of uncomplicated Plasmodium falciparum malaria. Drugs 2012; 72: 937–61.
• 16. Xin Hui S Chan, Yan Naung Win, Laura J Mawer, Jireh Y Tan, Josep Brugada, Nicholas J White . Risk of sudden unexplained death after use of dihydroartemisinin–piperaquine for malaria: a systematic review and Bayesian meta-analysis; Lancet Infect Dis 2018;18: 913–23