Journal Article > ResearchFull Text
Malar J. 2012 April 30; Volume 11; 139.; DOI:10.1186/1475-2875-11-139
Van Malderen C, Van Geertruyden JP, Machevo S, Gonzalez R, Bassat Q, et al.
Malar J. 2012 April 30; Volume 11; 139.; DOI:10.1186/1475-2875-11-139
BACKGROUND
Malaria is a leading cause of mortality, particularly in sub-Saharan African children. Prompt and efficacious treatment is important as patients may progress within a few hours to severe and possibly fatal disease. Chlorproguanil-dapsone-artesunate (CDA) was a promising artemisinin-based combination therapy (ACT), but its development was prematurely stopped because of safety concerns secondary to its associated risk of haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The objective of the study was to assess whether CDA treatment and G6PD deficiency are risk factors for a post-treatment haemoglobin drop in African children <5 years of age with uncomplicated malaria.
METHODS
This case–control study was performed in the context of a larger multicentre randomized clinical trial comparing safety and efficacy of four different ACT in children with uncomplicated malaria. Children, who after treatment experienced a haemoglobin drop ≥2 g/dl (cases) within the first four days (days 0, 1, 2, and 3), were compared with those without an Hb drop (controls). Cases and controls were matched for study site, sex, age and baseline haemoglobin measurements. Data were analysed using a conditional logistic regression model.
RESULTS
G6PD deficiency prevalence, homo- or hemizygous, was 8.5% (10/117) in cases and 6.8% (16/234) in controls (p = 0.56). The risk of a Hb drop ≥2 g/dl was not associated with either G6PD deficiency (adjusted odds ratio (AOR): 0.81; p = 0.76) or CDA treatment (AOR: 1.28; p = 0.37) alone. However, patients having both risk factors tended to have higher odds (AOR: 11.13; p = 0.25) of experiencing a Hb drop ≥2 g/dl within the first four days after treatment, however this finding was not statistically significant, mainly because G6PD deficient patients treated with CDA were very few. In non-G6PD deficient individuals, the proportion of cases was similar between treatment groups while in G6PD-deficient individuals, haemolytic anaemia occurred more frequently in children treated with CDA (56%) than in those treated with other ACT (29%), though the difference was not significant (p = 0.49).
CONCLUSION
The use of CDA for treating uncomplicated malaria may increase the risk of haemolytic anaemia in G6PD-deficient children.
Malaria is a leading cause of mortality, particularly in sub-Saharan African children. Prompt and efficacious treatment is important as patients may progress within a few hours to severe and possibly fatal disease. Chlorproguanil-dapsone-artesunate (CDA) was a promising artemisinin-based combination therapy (ACT), but its development was prematurely stopped because of safety concerns secondary to its associated risk of haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The objective of the study was to assess whether CDA treatment and G6PD deficiency are risk factors for a post-treatment haemoglobin drop in African children <5 years of age with uncomplicated malaria.
METHODS
This case–control study was performed in the context of a larger multicentre randomized clinical trial comparing safety and efficacy of four different ACT in children with uncomplicated malaria. Children, who after treatment experienced a haemoglobin drop ≥2 g/dl (cases) within the first four days (days 0, 1, 2, and 3), were compared with those without an Hb drop (controls). Cases and controls were matched for study site, sex, age and baseline haemoglobin measurements. Data were analysed using a conditional logistic regression model.
RESULTS
G6PD deficiency prevalence, homo- or hemizygous, was 8.5% (10/117) in cases and 6.8% (16/234) in controls (p = 0.56). The risk of a Hb drop ≥2 g/dl was not associated with either G6PD deficiency (adjusted odds ratio (AOR): 0.81; p = 0.76) or CDA treatment (AOR: 1.28; p = 0.37) alone. However, patients having both risk factors tended to have higher odds (AOR: 11.13; p = 0.25) of experiencing a Hb drop ≥2 g/dl within the first four days after treatment, however this finding was not statistically significant, mainly because G6PD deficient patients treated with CDA were very few. In non-G6PD deficient individuals, the proportion of cases was similar between treatment groups while in G6PD-deficient individuals, haemolytic anaemia occurred more frequently in children treated with CDA (56%) than in those treated with other ACT (29%), though the difference was not significant (p = 0.49).
CONCLUSION
The use of CDA for treating uncomplicated malaria may increase the risk of haemolytic anaemia in G6PD-deficient children.
Journal Article > ResearchFull Text
PLOS One. 2014 May 1; Volume 9 (Issue 5); DOI:10.1371/journal.pone.0096388
Kajungu DK, Erhart A, Talisuna AO, Bassat Q, Karema C, et al.
PLOS One. 2014 May 1; Volume 9 (Issue 5); DOI:10.1371/journal.pone.0096388
Pharmacovigilance programmes monitor and help ensuring the safe use of medicines which is critical to the success of public health programmes. The commonest method used for discovering previously unknown safety risks is spontaneous notifications. In this study we examine the use of data mining algorithms to identify signals from adverse events reported in a phase IIIb/IV clinical trial evaluating the efficacy and safety of several Artemisinin-based combination therapies (ACTs) for treatment of uncomplicated malaria in African children.
Journal Article > Meta-AnalysisFull Text
Malar J. 2019 July 5; Volume 18 (Issue 1); 225.; DOI:10.1186/s12936-019-2837-4.
WorldWide Antimalarial Resistance Network Methodology Study Group, Dahal P, Simpson JA, Abdulla S, Achan J, et al.
Malar J. 2019 July 5; Volume 18 (Issue 1); 225.; DOI:10.1186/s12936-019-2837-4.
BACKGROUND
Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.
METHODS
Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.
RESULTS
Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (ρ): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [ρ: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.
CONCLUSIONS
The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.
METHODS
Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.
RESULTS
Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (ρ): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [ρ: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.
CONCLUSIONS
The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
Journal Article > ResearchFull Text
PLOS One. 2009 November 17; Volume 4 (Issue 11); DOI:10.1371/journal.pone.0007871
Bassat Q, Mulenga M, Tinto H, Piola P, Borrmann S, et al.
PLOS One. 2009 November 17; Volume 4 (Issue 11); DOI:10.1371/journal.pone.0007871
BACKGROUND: Artemisinin combination therapies (ACTs) are currently the preferred option for treating uncomplicated malaria. Dihydroartemisinin-piperaquine (DHA-PQP) is a promising fixed-dose ACT with limited information on its safety and efficacy in African children. METHODOLOGY/PRINCIPAL FINDINGS: The non-inferiority of DHA-PQP versus artemether-lumefantrine (AL) in children 6-59 months old with uncomplicated P. falciparum malaria was tested in five African countries (Burkina Faso, Kenya, Mozambique, Uganda and Zambia). Patients were randomised (2:1) to receive either DHA-PQP or AL. Non-inferiority was assessed using a margin of -5% for the lower limit of the one-sided 97.5% confidence interval on the treatment difference (DHA-PQP vs. AL) of the day 28 polymerase chain reaction (PCR) corrected cure rate. Efficacy analysis was performed in several populations, and two of them are presented here: intention-to-treat (ITT) and enlarged per-protocol (ePP). 1553 children were randomised, 1039 receiving DHA-PQP and 514 AL. The PCR-corrected day 28 cure rate was 90.4% (ITT) and 94.7% (ePP) in the DHA-PQP group, and 90.0% (ITT) and 95.3% (ePP) in the AL group. The lower limits of the one-sided 97.5% CI of the difference between the two treatments were -2.80% and -2.96%, in the ITT and ePP populations, respectively. In the ITT population, the Kaplan-Meier estimate of the proportion of new infections up to Day 42 was 13.55% (95% CI: 11.35%-15.76%) for DHA-PQP vs 24.00% (95% CI: 20.11%-27.88%) for AL (p<0.0001). CONCLUSIONS/SIGNIFICANCE: DHA-PQP is as efficacious as AL in treating uncomplicated malaria in African children from different endemicity settings, and shows a comparable safety profile. The occurrence of new infections within the 42-day follow up was significantly lower in the DHA-PQP group, indicating a longer post-treatment prophylactic effect. TRIAL REGISTRATION: Controlled-trials.com ISRCTN16263443.