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ORIGINAL ARTICLE
Year : 2017  |  Volume : 19  |  Issue : 1  |  Page : 60-64

Gametocytocidal clearance by artemether–lumefantrine versus artesunate–amodiaquine in North-Central Nigeria


1 Department of Paediatrics, Faculty of Medical Sciences University of Jos/Jos University Teaching Hospital, Jos, Nigeria
2 Department of Family Medicine, Jos University Teaching Hospital, Jos, Nigeria
3 APIN/Harvard/PEPFAR, Jos University Teaching Hospital, Jos, Nigeria
4 Department of Medical Microbiology, Faculty of Medical Sciences University of Jos/Jos University Teaching Hospital, Jos, Nigeria

Date of Web Publication7-Jun-2017

Correspondence Address:
David D Shwe
Department of Paediatrics, Faculty of Medical Sciences University of Jos/Jos University Teaching Hospital, Jos
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jomt.jomt_48_16

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  Abstract 


Background: The deployed artemether–lumefantrine (AL) and artesunate–amodiaquine (AA) medicines are known to be gametocytocidal. Continuous monitoring of their efficacies is imperative for malaria elimination interventions. To compare gametocytocidal clearance by AL versus AA.
Materials and Methods: Data on demographics, anthropometry measures and gametocytes densities of 111 of 114 Human Immunodeficiency Virus (HIV) sero-negative children aged 6–59 months with uncomplicated Plasmodium falciparum malaria mono-infection, who participated in a drug therapeutic efficacy testing, were extracted. Patients who had severe malnutrition, other causes of common childhood fevers and use of antimalarial medicines in the preceding 1 week were excluded from the study. Study participants who met the enrolment criteria and gave written informed parental consent were randomized to receive AL or AA according to the manufacturer’s instructions. Clinical and parasitological evaluations were performed on D0, D1, D2, D3, D7, D14, D21 and D28. Analysis was restricted to 111 participants who completed the study.
Results: Twelve (10.8%) patients had gametocytes on D0. Six (5.4%) study participants were in the AL treatment arm and 6 (5.4%) participants were in the AA treatment arm (P = 0.32). Gametocyte clearance time (GCT)AL was 104 h and (GCT)AA was 152 h (P = 0.44).
Conclusion: AL and AA demonstrated comparable gametocytocidal activity in North-Central Nigeria. There is a need for continuous monitoring of the efficacies of these artemisinin-based combination therapies to keep track with the emergence of resistant Plasmodium gametocyte isolates in Nigeria.

Keywords: Artemether–lumefantrine, artesunate–amodiaquine, gametocytes, gametocytocidal clearance


How to cite this article:
Shwe DD, Pitmang SL, Abba JO, Akindigh MT, Egah DZ, Oguche S. Gametocytocidal clearance by artemether–lumefantrine versus artesunate–amodiaquine in North-Central Nigeria. J Med Trop 2017;19:60-4

How to cite this URL:
Shwe DD, Pitmang SL, Abba JO, Akindigh MT, Egah DZ, Oguche S. Gametocytocidal clearance by artemether–lumefantrine versus artesunate–amodiaquine in North-Central Nigeria. J Med Trop [serial online] 2017 [cited 2020 Aug 14];19:60-4. Available from: http://www.jmedtropics.org/text.asp?2017/19/1/60/207597




  Introduction Top


Plasmodium falciparum gametocytaemia suggests that the asexual forms of the parasite have survived long enough in its host to have developed into the matured sexual forms. Although these gametocytes are not infective and do not cause clinical malaria, it has crucial epidemiological potentials in the natural disease transmission through the female Anopheles mosquito vector.[1] Antimalarials with gametocytocidal activity are very important in the reduction of parasite transmission in the community.[2] Thus, such antimalarials will substantially contribute to the reduction of malaria attributable morbidity and mortality.[2],[3]

To improve treatment efficacy, the World Health Organization (WHO) recommended and deployed the artemisinin-based combination therapy (ACT) for the clinical cure of uncomplicated malaria partly because the artemisinins’ derivatives inhibit the development of matured (stages 1–3) falciparum gametocytes.[4],[5]

Recent works indicate that targeting the gametocytes, either alone or as part of integrated malaria control programme, is essential for the global malaria elimination efforts.[6],[7]

We hypothesized that artemether–lumefantrine (AL) and artesunate–amodiaquine (AA) have comparable gametocytocidal activity.


  Materials and methods Top


Study site and participants

This study was conducted at the General Hospital of Barki-Ladi Local Government Area of Plateau State, North-Central Nigeria during September to December, 2010.

Study design

An open-label randomized treatment of AL versus AA using a 28-day study protocol was followed.

Enrolment criteria

Demographic data, other clinical variables and gametocyte density were obtained on 114 eligible children treated for uncomplicated P. falciparum malaria were extracted from a drug therapeutic efficacy testing, safety and tolerability study. Clinical variables included children aged 6 months to 59 months, history of fever in the last 24 h and/or measured axillary temperature ≥37.5°C. Laboratory variables included: P. falciparum mono-infection with P. falciparum gametocytes, Human Immunodeficiency Virus (HIV) sero-negative status, written informed consent and parental or guardian readiness to comply with follow-up visits. Children with packed cell volume (PCV) <15%, severe malnutrition (z score <−3) or bilateral oedema, signs of severe malaria, ‘danger sign’ (inability to drink or breast feed, vomiting everything, recent history of convulsion, lethargy or unconsciousness and inability to sit or stand up), other common causes of childhood fever such as otitis media, tonsillitis and history of allergy to the study drugs were also excluded from the study.

Urinary tract infection was excluded by the use of Combi-11 urinalysis strip test kits for the presence of nitrite and leucocyte esterase in clean mid-stream urine sample. Following pre-test counselling, HIV-infection was excluded by Abbot Determine HIV-1 and 2 Whole Blood Assay Kit (Abbott Laboratory, USA).

P. falciparum gametocytes count was performed against 8000 leucocytes (WHO/MAL/82.988).

Gametocyte density was then calculated with the following formula:



Parasite genotyping

Blood spot on Whatman’s filtered paper for parasite genotyping was obtained using Chelex® extraction method on D0 for all study participants, and then on any subsequent day, the study participants were found to be parasitaemic. Malaria parasite polymorphic markers, merozoite surface protein-1 (MSP-1), MSP-2 and glutamine-rich protein in P. falciparum isolates were used to examine the complexity of parasite populations and discriminate between recrudescent and re-infections in the enrolees.

Enrolees were randomized into two treatment arms to receive either AL (20/120 mg) or AA (25/67.5 mg or 50/135 mg) according to manufacturer’s instructions.

Antimalarial treatment administration

Study drugs were initially dissolved in water, and then those were administered and the participants supervised by the study nurse. Participants were observed for 30 min after drug administration for vomiting. If vomiting occurred within this period, the drug was repeated once. If vomiting occurred the second time within 30 min of second dosing in any participant, then that participant was excluded from the study but would be managed on alternate antimalarial regimen and followed up for safety. Administered study medications were recorded in the case record form (CRF).

Clinical and parasitological evaluations were performed on D0 to D3, thereafter, on D7, D14, D21 and D28. Parents/guardians, who failed to return to the clinic, were visited in their homes. In addition, GSM mobile telephone was used to remind the parents/guardians of their clinic visit.

Ethical statement and confidentiality

Ethical approval was obtained from the Jos University Teaching Hospital Ethics Committee. A written informed consent was obtained from each parent/legal guardian of the eligible study participant prior to the enrolment. All participants’ medical information was kept confidential. Only investigators had access to the participants’ data.

Data management and analysis

The primary analysis was restricted to 111 study participants who completed the study on D28. Data generated were recorded in a CRF; thereafter, those were transferred to electronic format using the Statistical Package for Social Sciences (SPSS) Version 17.0 software (SPSS Inc., Chicago, Illinois, United States of America). Frequency tables and percentages were used to calculate gametocyte density. They were also used to determine the means of all the variables used. Means were used to get the difference in averages between the two drugs (AL and AA) according to all parameters used. Student’s t-test was used to calculate the significant difference between the two drugs. Standard deviation and standard error were also calculated. Levene’s test for equality of variances was used to get the F- and P-values. Line graphs were used to examine the profile for all gametocyte clearance rates. All the tests of significance were two-tailed. P-value <0.05 was taken to indicate significant difference.


  Results Top


Baseline characteristics

One hundred and eleven participants (97.4%) out of 114 enrollees completed the study. One of the three participants who did not complete the study was relocated from the study area to his home state for reasons not connected to the study and was followed-up for safety using mobile telephone. One of the participants developed severe malaria, and one other participant was excluded from analysis owing to missing PCV and parasite count data. All these three patients were excluded from data analysis. The participant with severe malaria was successfully treated with rate-controlled intravenous infusion of quinine.

The demographic characteristics of study participants in the two study arms were comparable at enrolment [Table 1].
Table 1: Baseline presenting symptoms of patients studied

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Gametocytocidal activity of artemether–lumefantrine versus artesunate–amodiaquine measured in terms of gametocyte clearance rate and gametocyte clearance time

Gametocyte carriage rate

Twelve (10.8%) patients had gametocytes on D0. Six (5.4%) study participants were in the AL treatment arm and 6 (5.4%) participants in the AA treatment arm (P = 0.32). The mean gametocyte densities on D0 were 38.9 ± 157.05 μL−1 and 24.0 ± 74.25 μL−1 for the AL and AA treatment arms, respectively. The gametocyte density gradually dropped to 8.4 ± 52.99 μL−1 in AL and 1.42 ± 7.37 μL−1 in AA treatment arm on D3 and completely cleared by D7 in the AA treatment arm but persisted up to D21 in the AL treatment arm [Figure 1].
Figure 1: Gametocyte clearance profile over time.

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Gametocyte clearance time

In the AL treatment arm, four study participants were completely cleared of gametocytes within 72 h, while two participants were cleared in 168 h. Therefore,



In the AA treatment arm, two study participants completely cleared gametocytes within 48 h, another two participants within 72 h, whereas one participant cleared in 168 h. The last participant completely cleared gametocytes in 504 h. Therefore,




  Discussion Top


Gametocyte carriage rate (GCR) in this study was high and similar in both AL and AA treatment arms. This rate compares favourably with the 10% reported from an efficacy, safety and tolerability testing of AA among children 6 months to 6 years treated for uncomplicated P. falciparum malaria in Maiduguri, Borno State, North-Eastern Nigeria.[8] The current GCR, however, rose higher than 0.07%[9] as reported from a comparative multicentre therapeutic efficacy testing of dihydroartemisinine–piperaquine–trimethoprim and AL in Central Cameroon, Ivory Coast and in Sahel regions of Senegal, respectively. Similarly, the finding in the present study fell almost fourfolds and threefolds lower than 46.4 and 27.3%, respectively, as reported in Chocó North-Western Colombia in 2007 among patients treated for uncomplicated P. falciparum malaria with artesunate/placebo treatment group and the comparator artesunate/amodiaquine antimalarial medications group in the same clinical trial.[10] The gametocyte clearance rate (GCR) from the studies cited above also included almost a quarter (26.3%) among hospitalized severely-ill children in North-Eastern Nigeria and a half (41.5%)[11] and in Bangkok Hospital for Tropical Diseases, Thailand in 2008 respectively.[12] The reasons for such sharp differences between the two studies cited above were not immediately apparent. It may be due to the fact that the trials were conducted in settings of lower malaria parasite transmission intensity and larger sample sizes compared to that of the current study.

Gametocyte clearance times for AL and AA were similar. Fortunately, apart from the rapid clearance of asexual forms of P. falciparum, AL and AA are both gametocytocidal. They caused significant clearance of gametocytes from the peripheral blood in less than 1 week of initiation of treatment. However, AL appeared to have a slightly better gametocytocidal activity than AA. This finding is similar to reports from Maiduguri, North-Eastern Nigeria.[8] Following a radical cure of malaria infection, the normal mean circulation time of gametocyte has been estimated at 4.6–6.5 days using light microscopy detection methods. However, estimates are as high as 3–6 weeks when molecular gametocyte detection methods are used.[6],[7] Once ingested by a mosquito taking a blood meal, gametocytes develop through different mosquito-specific stages that ultimately render the mosquito infectious to humans.[13]Recent works indicate that targeting the gametocytes, either alone or as part of integrated malaria control programmes, is essential for malaria control and elimination efforts.[6],[7],[12] The gametocytocidal activity of ACTs would contribute to reduction of risk of malaria transmission. It would also reduce the morbidity and mortality attributable to malaria infection.[6],[7],[12]

The findings of this study have substantial public health significance. Gametocytaemia is a potential source of P. falciparum malarial infectivity to the community, since transmission of malaria depends on the presence of mature sexual stage of parasites, the gametocyte, in the human peripheral blood.[6],[7],[12] It suggests, therefore, that 175,267 inhabitants of the study area (2006 National Census) were potentially exposed to malaria infection. To mitigate these threats, there are urgent needs to scale-up and sustain the health educational and health promotional efforts by primary health care providers. There is also a need for parents/care-givers to use insecticide-treated bed nets in our setting to reduce children’s exposure to Anopheles mosquito vector. It also underscores the need for improved environmental sanitation in our setting.


  Conclusions Top


AL and AA demonstrated comparable gametocytocidal clearance in North-Central Nigeria. There is a need to continuously monitor the efficacies of these ACTs to keep tract with emergence of resistant gametocyte isolates in North-Central Nigeria.

Acknowledgements

We are thankful to all study participants and their parents who consented to the study. Microscopy expertise was provided for by Mr. Adeniji BO, National Institute for Medical Research, Lagos. We were equally grateful to the Federal Ministry of Health, Abuja, Nigeria for providing molecular diagnostics and the study medications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Firtz HK, Kurt AB, Johannes E, Rolf MZ. Keyser Medical Microbiology. 9th ed. New York: Thieme; 2005.  Back to cited text no. 1
    
2.
World Health Organization. Antimalarial Drug Combination Therapy: Report of a WHO Technical Consultation. Geneva: World Health Organization 2001.  Back to cited text no. 2
    
3.
Breman JG, Alilio MS, White NJ, editors. Defining and Defeating the Intolerable Burden of Malaria III: Progress and Perspectives. Supplement to Volume 77(6) of American Journal of Tropical Medicine and Hygiene. Northbrook (IL): American Society of Tropical Medicine and Hygiene 2007.  Back to cited text no. 3
    
4.
Price RN, Nosten F, Luxemburger C, ter Kuile F, Paiphun L, Chongsuphajaisiddhi T et al. The effects of artemisinin derivatives on malaria transmissability. Lancet 1996;347:1654-8. [PubMed: 8642959].  Back to cited text no. 4
    
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Targett G, Drakeley C, Jawara M, von Seidlein L, Coleman R, Deen J et al. Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae. J Infect Dis 2001;183:1254-9. [PubMed: 11262208].  Back to cited text no. 5
    
6.
Smalley ME, Sinden RE. Plasmodium falciparum gametocytes: Their longevity and infectivity. Parasitology 1977;74:1-8.  Back to cited text no. 6
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Eichner M, Diebner HH, Molineaux L, Collins WE, Jeffery GM, Dietz K. Genesis, sequestration and survival of Plasmodium falciparum gametocytes: Parameter estimates from fitting a model to malaria therapy data. Trans R Soc Trop Med Hyg 2001;95:497-501.  Back to cited text no. 7
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Watila IM, Oguche SO, Sha’a KA, Shandi IS, Molta NB. A study of efficacy, safety and tolerability of prepackage amodiaquine/artesunate for treatment of uncomplicated Plasmodium falciparum malaria in children age 6 month to 6 years, North-Eastern Nigeria. Hosp Digest 2006;212.  Back to cited text no. 8
    
9.
Hervi M, Ouma F, Albert SE, Agbeya SS, Babacar F, Christian PK et al. Comparative study of the efficacy and tolerability of dihydroartemisisne-piperaquine-trimethoprime versus artemether-lumefantrine in the treatment of uncomplicated P. falciparum malaria in Cameroon, Ivory Coast and Senegal. Malar J 2011;10:185.  Back to cited text no. 9
    
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Osorio L, Gonzalez I, Olliaro P, Taylor WR. Artemisinine-based combination therapy for uncomplicated Plasmodium falciparum in Colombia. Malar J 2007;6:25.  Back to cited text no. 10
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Samdi LM, Oguche S, Molta NB, Agomo PU, Watila IM. Gametocytaemia in severely-ill children: Implications for malaria vector infectivity and transmission in North-Eastern Nigeria. Niger J Exp Appl Biol 2005;6:87-93.  Back to cited text no. 11
    
12.
Tangpukdee N, Krudsood S, Srivilairit S, Phophak N, Chonsawat P, Yanpanich W et al. Gametocyte clearance in uncomplicated and severe Plasmodium falciparum malaria after artesunate-mefloquine treatment in Thailand. Korean J Parasitol 2008;46:65-70.  Back to cited text no. 12
    
13.
Tuen B, Lucy O, Seif S, Jamie TG, Sabah O, Patrick S et al. Revisiting the circulation time of P. falciparum gametocytes: Molecular detection method to estimate the duration of gametocyte carriage and the effects of gametocidal drugs. Malar J 2010;9:136.  Back to cited text no. 13
    


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