Therapeutic efficacy and effects of artemisinin-based combination treatments on uncomplicated Plasmodium falciparum malaria-associated anaemia in Nigerian children during seven years of adoption as first-line treatments

Background:Artemisinin-based combination treatments(ACTs)are the first-line treatments of uncomplicated Plasmodium falciparum malaria in many endemic areas but there are few evaluation of their efficacy in anaemic malarious children.Methods:Therapeutic efficacy of 3-day regimens of artesunate-amodiaquine and artemether-lumefantrine was evaluated in 437 anaemic and 909 non-anaemic malarious children following treatment during a seven-year period(2008-2014).Patterns of temporal changes in haematocrit were classified based on haematocrit values<30%and≥30%.Kinetics of the disposition of the deficit in haematocrit from 30%following treatment were evaluated using a non-compartment model.Results:PCR-corrected parasitological efficacy 28 days after start of treatment was significantly higher in artesunateamodiaquine-compared to artemether-lumefantrine-treated children[97%(95%CI:92.8-100)versus 96.4%(95%CI:91.3-99.4),P=0.02],but it was similar in non-anaemic and anaemic children.Fall in haematocrit/1000 asexual parasites cleared from peripheral blood was significantly greater at lower compared to higher parasitaemias(P<0.0001),and in non-anaemic compared to anaemic children(P=0.007).In anaemic children at presentation,mean anaemia recovery time(AnRT)was 15.4 days(95%CI:13.3-17.4)and it did not change over the years.Declines in haematocrit deficits from 30%were monoexponential with mean estimated half-time of 1.4 days(95%CI:1.2-1.6).Anaemia half-time(t_(1/2anaemia))correlated positively with AnRT in the same patients(r=0.69,P<0.0001).Bland-Altman analysis of 10 multiples of t_(1/2anaemia) and AnRT showed narrow limit of agreement with insignificant bias(P=0.07)suggesting both can be used interchangeably in the same patients.Conclusions:Artesunate-amodiaquine and artemether-lumefantrine remain efficacious treatments of uncomplicated P.falciparum infections in non-anaemic and anaemic Nigerian children in the last 7 years of adoption as first-line treatments.These ACTs may also conserve haematocrit at high parasitaemias and in anaemic children.Trials registration:Pan African Clinical Trial Registry PACTR201508001188143,3 July 2015;PACTR201510001189370,3 July 2015;PACTR201508001191898,7 July 2015 and PACTR201508001193368,8 July 2015.

Therapeutic efficacy and effects of artesunate-amodiaquine and artemetherlumefantrine on malaria-associated anaemia in Nigerian children aged two years and under

Background:Artemisinin-based combination therapies are recommended as first-line treatments for uncomplicated falciparum malaria,but there is little evaluation of their efficacy and effects on uncomplicated malaria-associated anaemia in children aged 2 years and under.Methods:Parasitological efficacy and effects on malaria-associated anaemia were evaluated in 250 malarious children aged 2 years and under,and efficacy was evaluated in 603 malarious children older than two but younger than 5 years of age following treatment with artesunate-amodiaquine(AA)or artemether-lumefantrine(AL).Kinetics of the disposition of parasitaemia following treatment were evaluated using a non-compartment model.Late-appearing anaemia(LAA)was diagnosed using the following criteria:clearance of parasitaemia,fever and other symptoms occurring within 7 days of starting treatment,adequate clinical and parasitological response on days 28–42,haematocrit(HCT)≥30%at 1 and/or 2 weeks,a fall in HCT to<30%occurring at 3–6 weeks,absence of concomitant illness at 1–6 weeks,and absence of asexual parasitaemia detected using both microscopy and polymerase chain reaction(PCR)at 1–6 weeks.Results:Overall,in children aged 2 years and under,the PCR-corrected parasitological efficacy was 97.2%(95%CI 92.8–101.6),which was similar for both treatments.In children older than 2 years,parasitological efficacy was also similar for both treatments,but parasite prevalence 1 day after treatment began was significantly higher,and fever and parasite clearance times were significantly faster in the AA-treated children compared with the AL-treated children.Declines in parasitaemia were monoexponential with an estimated elimination half-time of 1 h.Elimination half-times were similar for both treatments.In children aged 2 years and under who were anaemic at presentation,the mean anaemia recovery time was 12.1 days(95%CI 10.6–13.6,n=127),which was similar for both treatments.Relatively asymptomatic LAA occurred in 11 children(4.4%)aged 2 years and under,the recovery from which was uneventful.Conclusion:This study showed that AA and AL are efficacious treatments for uncomplicated falciparum malaria in Nigerian children aged 2 years and under,and that AA clears parasitaemia and fever significantly faster than AL in children older than 2 years.Both treatments may cause a relatively asymptomatic LAA with uneventful recovery in a small proportion of children aged 2 years and under.Trials registration:Pan African Clinical Trial Registry PACTR201508001188143,3 July 2015;PACTR201510001189370,3 July 2015;PACTR201508001191898,7 July 2015 and PACTR201508001193368,8 July 2015 http://www.pactr.org.

Parasite reduction ratio one day after initiation of artemisinin-based combination therapies and its relationship with parasite clearance time in acutely malarious children

Background:In acute falciparum malaria,asexual parasite reduction ratio two days post-treatment initiation(PRRD2)≥10000 per cycle has been used as a measure of the rapid clearance of parasitaemia and efficacy of artemisinin derivatives.However,there is little evaluation of alternative measures;for example,parasite reduction ratio one day after treatment initiation(PRRD1)and its relationship with parasite clearance time(PCT)or PRRD2.This study evaluated the use of PRRD1 as a measure of responsiveness to antimalarial drugs.Methods:In acutely malarious children treated with artesunate-amodiaquine(AA),artemether-lumefantrine(AL)or dihydroartemisinin-piperaquine(DHP),the relationships between PRRD1 or PRRD2 and PCT,and between PRRD1 and PRRD2 were evaluated using linear regression.Agreement between estimates of PCT using PRRD1 and PRRD2 linear regression equations was evaluated using the Bland-Altman analysis.Predictors of PRRD1>5000 per half cycle and PRRD2≥10000 per cycle were evaluated using stepwise multiple logistic regression models.Using the linear regression equation of the relationship between PRRD1 and PCT previously generated in half of the DHP-treated children during the early study phase,PCT estimates were compared in a prospective blinded manner with PCTs determined by microscopy during the later study phase in the remaining half.Results:In 919 malarious children,PRRD1 was significantly higher in DHP-and AA-treated compared with AL-treated children(P<0.0001).PRRD1 or PRRD2 values correlated significantly negatively with PCT values(P<0.0001 for each)and significantly positively with each other(P<0.0001).PCT estimates from linear regression equations for PRRD1 and PRRD2 showed insignificant bias on the Bland-Altman plot(P=0.7)indicating the estimates can be used interchangeably.At presentation,age>15months,parasitaemia>10000/μl and DHP treatment independently predicted PRRD1>5000 per half cycle,while age>30months,haematocrit≥31%,body temperature>37.4°C,parasitaemia>100000/μl,PRRD1 value>1000 and no gametocytaemia independently predicted PRRD2≥10000 per cycle.Using the linear regression equation generated during the early phase in 166 DHP-treated children,PCT estimates and PCTs determined by microscopy in the 155 children in the later phase were similar in the same patients.Conclusions:PRRD1 and estimates of PCT using PRRD1 linear regression equation of PRRD1 and PCT can be used in therapeutic efficacy studies.Trial registration:Pan African Clinical Trial Registration PACTR201709002064150,1 March 2017,http://www.pactr.org.

Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria

Background:The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies(ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria.Methods: At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009-2010 and 2014-2015 and at 2-year interval in 2009-2010 and 2012-2015, respectively after deployment in 2005.Results: Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009-2010 to 2014-2015(P=0.002 and P<0.0001, respectively).Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55-1.64) to 1.9 days (95% C,1.9-2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P< 00001 for each). Enrolment parasitaemia > 75 000 μl^-1, haematocrit > 27% 1 day post-treatment initiatiortreatment with artemether-lumefantrine and enrolment in 2014-2015 independently predicted APPD1. In paralle , Kaplan-Meier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P=0005) and from 9 to 15%(P=0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3h within 2 years (P<0.0001).Conclusions:These data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children.