Background: Drugs that kill or inhibit sexual stages of Plasmodium such as Primaqiune (PQ) could potentially amplify or synergize the impact of first line antimalarials by blocking transmission to mosquitoes. This stu...Background: Drugs that kill or inhibit sexual stages of Plasmodium such as Primaqiune (PQ) could potentially amplify or synergize the impact of first line antimalarials by blocking transmission to mosquitoes. This study examined the effect of Primaquine on gametocyte carriage in the case management of uncomplicated falciparum malaria with artemisinin-based combination therapy (ACT) with the overall purpose of possibly recommending it as an adjunct drug for malaria control. Methods: A total of 181 patients with uncomplicated falciparum malaria, normal glucose-6-phosphate dehydrogenase (G6PD) enzyme levels, and haemoglobin levels ≥ 8 g/dL completed this two-arm randomized blinded clinical trial to test the efficacy of a single dose PQ (0.75 mg/kg) on falciparum gametocytaemia. 88 subjects were assigned to a standard 3-day course of Dihydroartemisinin-Piperaquine (DHP) alone (n = 88) while 93 others had DHP combined with a single dose of PQ on day 3 (n = 93). A 28-day follow-up schedule carried out in the outpatient clinic of a Primary health facility in Vom, Plateau State Nigeria where study participants were seen on days 1, 3, 7 and then weekly to assess the presence of asexual parasites and gametocytes by microscopy. A Kaplan-Meier analysis was employed to determine the survival function of gametocytes on day 3. The data was analyzed using Epi info version 7.1.5. Results: With a gametocyte prevalence of 27.1%, gametocyte carriage rate was lower in the PQ group due to higher probability of clearing gametocytes (Breslow test χ2 = 8.306, df = 1, p = 0.004) and significantly less likely to harbor gametocytes by day 7 when compared to the DHP-alone group (χ2 = 6.218, df = 1, p = 0.013). Conclusion: Addition of single-dose 0.75 mg/kg PQ was associated with reduced gametocyte carriage as a result of faster gametocyte clearance and lower incidence of gametocyte development in DHP-treated patients. PQ as gametocytocidal drug may be useful in combination with artemisinin-based combination therapy (ACT) regimen to clear gametocytes and thereby interrupt malaria transmission to mosquito vector more effectively than ACT alone.展开更多
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-as...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.展开更多
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 arte...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.展开更多
文摘Background: Drugs that kill or inhibit sexual stages of Plasmodium such as Primaqiune (PQ) could potentially amplify or synergize the impact of first line antimalarials by blocking transmission to mosquitoes. This study examined the effect of Primaquine on gametocyte carriage in the case management of uncomplicated falciparum malaria with artemisinin-based combination therapy (ACT) with the overall purpose of possibly recommending it as an adjunct drug for malaria control. Methods: A total of 181 patients with uncomplicated falciparum malaria, normal glucose-6-phosphate dehydrogenase (G6PD) enzyme levels, and haemoglobin levels ≥ 8 g/dL completed this two-arm randomized blinded clinical trial to test the efficacy of a single dose PQ (0.75 mg/kg) on falciparum gametocytaemia. 88 subjects were assigned to a standard 3-day course of Dihydroartemisinin-Piperaquine (DHP) alone (n = 88) while 93 others had DHP combined with a single dose of PQ on day 3 (n = 93). A 28-day follow-up schedule carried out in the outpatient clinic of a Primary health facility in Vom, Plateau State Nigeria where study participants were seen on days 1, 3, 7 and then weekly to assess the presence of asexual parasites and gametocytes by microscopy. A Kaplan-Meier analysis was employed to determine the survival function of gametocytes on day 3. The data was analyzed using Epi info version 7.1.5. Results: With a gametocyte prevalence of 27.1%, gametocyte carriage rate was lower in the PQ group due to higher probability of clearing gametocytes (Breslow test χ2 = 8.306, df = 1, p = 0.004) and significantly less likely to harbor gametocytes by day 7 when compared to the DHP-alone group (χ2 = 6.218, df = 1, p = 0.013). Conclusion: Addition of single-dose 0.75 mg/kg PQ was associated with reduced gametocyte carriage as a result of faster gametocyte clearance and lower incidence of gametocyte development in DHP-treated patients. PQ as gametocytocidal drug may be useful in combination with artemisinin-based combination therapy (ACT) regimen to clear gametocytes and thereby interrupt malaria transmission to mosquito vector more effectively than ACT alone.
基金supported by a Swiss Pharma Nigeria PLC Grant given to AS,and by World Bank Malaria Booster Project and the Global Fund for Malaria to Federal Ministry of Health,Abuja,Nigeria through Drug Therapeutic Efficacy Testing in Nigeria.
文摘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.
基金The efficacy study from which the data were derived received financial support from The Global Fund to Fights AIDS,Tuberculosis and Malariathe United States President’s Malaria Initiative(PMI)Malaria Consortium Grants to The Federal Ministry of Health,Abuja,through Drug Therapeutic Efficacy Testing in Nigeria.Logistic support was provided by the governments of the study states.
文摘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.
