The performance of different malaria rapid diagnostic tests (RDT) may be influenced by transmission intensity and by the length of time each test requires to become negative after treatment and ...patient's recovery.
Results of three RDTs (two HRP2 and one pLDH antigen-based tests) were compared to blood smear microscopy (the gold standard method) in children under 5 years of age living in a high versus low malaria intensity setting in southwestern Uganda. In each setting, 212 children, who tested positive by at least one RDT and by microscopy, were treated with artemether-lumefantrine. RDTs and microscopy were then repeated at fixed intervals to estimate each test's time to negativity after treatment and patient recovery.
In the two settings, sensitivities ranged from 98.4 to 99.2 % for the HRP2 tests and 94.7 to 96.1 % for the pLDH test. Specificities were 98.9 and 98.8 % for the HRP2 tests and 99.7 % for the pLDH test in the low-transmission setting and 79.7, 80.7 and 93.9 %, respectively, in the high-transmission setting. Median time to become negative was 35-42 or more days for the HRP2 tests and 2 days for the pLDH test.
High transmission contexts and a long time to become negative resulted in considerably reduced specificities for the HRP2 tests. Choice of RDT for low- versus high-transmission settings should balance risks and benefits of over-treatment versus missing malaria cases.
Registry number at ClinicalTrial.gov: NCT01325974.
The emergence of resistance against artemisinin combination treatment is a major concern for malaria control. ACTs are recommended as the rescue treatment, however, there is limited evidence as to ...whether treatment and re-treatment with ACTs select for drug-resistant P. falciparum parasites. Thus, the purpose of the present study is to investigate the impact of (re-)treatment using artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) on the selection of P. falciparum multidrug resistance-1 (Pfmdr1) alleles in clinical settings.
P. falciparum positive samples were collected from children aged 12-59 months in a clinical trial in DR Congo and Uganda. Pfmdr1 single nucleotide polymorphisms (SNPs) analysis at codons N86Y, Y184F, and D1246Y were performed at baseline and post-treatment with either AL or ASAQ as a rescue treatment using nested PCR followed by restriction fragment length polymorphism (RFLP) assays.
The pre-treatment prevalence of Pfmdr1 N86 and D1246Y varied significantly between the sites, (p>0.001) and (p = 0.013), respectively. There was borderline significant directional selection for Pfmdr1 184F in recurrent malaria infections after treatment with AL in Uganda site (p = 0.05). Pfmdr1 NFD haplotype did not significantly change in post-treatment infections after re-treatment with either AL or ASAQ. Comparison between pre-treatment and post-treatment recurrences did not indicate directional selection of Pfmdr1 N86, D1246 alleles in the pre-RCT, RCT and post-RCT phases in both AL and ASAQ treatment arms. Pfmdr1 86Y was significantly associated with reduced risk of AL treatment failure (RR = 0.34, 95% CI:0.11-1.05, p = 0.04) while no evidence for D1246 allele (RR = 1.02; 95% CI: 0.42-2.47, p = 1.0). Survival estimates showed that the Pfmdr1 alleles had comparable mean-time to PCR-corrected recrudescence and new infections in both AL and ASAQ treatment arms.
We found limited impact of (re-)treatment with AL or ASAQ on selection for Pfmdr1 variants and haplotypes associated with resistance to partner drugs. These findings further supplement the evidence use of same or alternative ACTs as a rescue therapy for recurrent P.falciparum infections. Continued monitoring of genetic signatures of resistance is warranted to timely inform malaria (re-)treatment policies and guidelines.
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.
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).
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.
Controlled-trials.com ISRCTN16263443.
Malaria is a major public health problem, especially for children. However, recent reports suggest a decline in the malaria burden. The aim of this study was to assess the change in the prevalence of ...malaria infection among children below five years of age between 2004 and 2010 in a mesoendemic area of Uganda and to analyse the risk factors of malaria infection.
Two cross-sectional surveys were conducted in 2004 and in 2010 at the end of the rainy and dry seasons to measure the prevalence of P. falciparum infection among children less than five years of age. Rapid diagnostic tests and blood smears were used to diagnose malaria infection. In 2010, sampling was stratified by urban and rural areas. In each selected household, knowledge of malaria and bed nets, and bed net ownership and use, were assessed.
In 2004 and 2010, respectively, a total of 527 and 2,320 (999 in the urban area and 1,321 in rural areas) children less than five years old were enrolled. Prevalence of malaria infection declined from 43% (95% CI: 34-52) in 2004, to 23% (95% CI: 17-30) in rural areas in 2010 and 3% (95% CI: 2-5) in the urban area in 2010. From the rainy to dry season in 2010, prevalence decreased from 23% to 10% (95% CI: 6-14) in rural areas (P = 0.001) and remained stable from 3% to 4% (95% CI: 1-7) in the urban area (P = 0.9). The proportion of households reporting ownership and use of at least one bed net increased from 22.9% in 2004 to 64.7% in the urban area and 44.5% in rural areas in 2010 (P < 0.001). In 2010, the risk of malaria infection was consistently associated with child age and household wealth. In rural areas, malaria infection was also associated with geographic factors.
This study reports a significant drop in the prevalence of malaria infection among children below five years of age, paralleled by an uptake in bed-net use. However, prevalence remains unacceptably high in rural areas and is strongly associated with poverty.
Summary Background Malaria in pregnancy is associated with maternal and fetal morbidity and mortality. In 2006, WHO recommended use of artemisinin-based combination treatments during the second or ...third trimesters, but data on efficacy and safety in Africa were scarce. We aimed to assess whether artemether–lumefantrine was at least as efficacious as oral quinine for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy in Mbarara, Uganda. Methods We did an open-label, randomised, non-inferiority trial between October, 2006, and May, 2009, at the antenatal clinics of the Mbarara University of Science and Technology Hospital in Uganda. Pregnant women were randomly assigned (1:1) by computer generated sequence to receive either quinine hydrochloride or artemether–lumefantrine, and were followed up weekly until delivery. Our primary endpoint was cure rate at day 42, confirmed by PCR. The non-inferiority margin was a difference in cure rate of 5%. Analysis of efficacy was for all randomised patients without study deviations that could have affected the efficacy outcome. This study was registered with ClinicalTrials.gov , number NCT00495508. Findings 304 women were randomly assigned, 152 to each treatment group. By day 42, 16 patients were lost to follow-up and 25 were excluded from the analysis. At day 42, 137 (99·3%) of 138 patients taking artemether–lumefantrine and 122 (97·6%) of 125 taking quinine were cured—difference 1·7% (lower limit of 95% CI −0·9). There were 290 adverse events in the quinine group and 141 in the artemether–lumefantrine group. Interpretation Artemisinin derivatives are not inferior to oral quinine for the treatment of uncomplicated malaria in pregnancy and might be preferable on the basis of safety and efficacy. Funding Médecins Sans Frontières and the European Commission.
Summary Background Quinine or alternative artemisinin-based combination treatment (ACT) is the recommended rescue treatment for uncomplicated malaria. However, patients are often re-treated with the ...same ACT though it is unclear whether this is the most suitable approach. We assessed the efficacy and safety of re-treating malaria patients with uncomplicated failures with the same ACT used for the primary episode, compared with other rescue treatments. Methods This was a bicentre, open-label, randomised, three-arm phase 3 trial done in Lisungi health centre in DR Congo, and Kazo health centre in Uganda in 2012–14. Children aged 12–60 months with recurrent malaria infection after treatment with the first-line ACT were randomly assigned to either re-treatment with the same first-line ACT, an alternative ACT, which were given for 3 days, or quinine-clindamycin (QnC), which was given for 5–7 days, following a 2:2:1 ratio. Randomisation was done by computer-generated randomisation list in a block design by country. The three treatment groups were assumed to have equivalent efficacy above 90%. Both the research team and parents or guardians were aware of treatment allocation. The primary outcome was the proportion of patients with an adequate clinical and parasitological response (ACPR) at day 28, in the per-protocol population. This trial was registered under the numbers NCT01374581 in ClinicalTrials.gov and PACTR201203000351114 in the Pan African Clinical Trials Registry. Findings From May 22, 2012, to Jan 31, 2014, 571 children were included in the trial. 240 children were randomly assigned to the re-treatment ACT group, 233 to the alternative ACT group, and 98 to the QnC group. 500 children were assessed for the primary outcome. 71 others were not included because they did not complete the follow-up or PCR genotyping result was not conclusive. The ACPR response was similar in the three groups: 91·4% (95% CI 87·5–95·2) for the re-treatment ACT, 91·3% (95% CI 87·4–95·1) for the alternative ACT, and 89·5% (95% CI 83·0–96·0) for QnC. The estimates for rates of malaria recrudescence in the three treatment groups were similar (log-rank test: χ2 =0·22, p=0·894). Artemether-lumefantrine was better tolerated than QnC (p=0·0005) and artesunate-amodiaquine (p<0·0001) in the modified intention-to-treat analysis. No serious adverse events were observed. The most common adverse events reported in the re-treatment ACT group were anorexia (31 13% of 240 patients), asthenia (20 8%), coughing (16 7%), abnormal behaviour (13 5%), and diarrhoea (12 5%). Anorexia (13 6% of 233 patients) was the most frequently reported adverse event in the alternative ACT group. The most commonly reported adverse events in the QnC group were anorexia (12 12% of 98 patients), abnormal behaviour (6 6%), asthenia (6 6%), and pruritus (5 5%). Interpretation Re-treatment with the same ACT shows similar efficacy as recommended rescue treatments and could be considered for rescue treatment for Plasmodium falciparum malaria. However, the effect of this approach on the selection of resistant strains should be monitored to ensure that re-treatment with the same ACT does not contribute to P falciparum resistance. Funding Fonds Wetenschappelijk Onderzoek, Vlaamse Interuniversitaire Raad-Universitaire Ontwikkelings Samenwerking, European and Developing Countries Clinical Trials Partnership, and the Belgian Technical Cooperation-Programme d'Etudes et d'Expertises-in the Democratic Republic of Congo.
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.
We used paediatric safety data from a multi-site, multi-country clinical study conducted in seven African countries (Burkina Faso, Gabon, Nigeria, Rwanda, Uganda, Zambia, and Mozambique). Each site compared three out of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) or chlorproguanil/dapsone and artesunate (CD+A). We examine two pharmacovigilance signal detection methods, namely proportional reporting ratio and Bayesian Confidence Propagation Neural Network on the clinical safety dataset.
Among the 4,116 children (6-59 months old) enrolled and followed up for 28 days post treatment, a total of 6,238 adverse events were reported resulting into 346 drug-event combinations. Nine signals were generated both by proportional reporting ratio and Bayesian Confidence Propagation Neural Network. A review of the manufacturer package leaflets, an online Multi-Drug Symptom/Interaction Checker (DoubleCheckMD) and further by therapeutic area experts reduced the number of signals to five. The ranking of some drug-adverse reaction pairs on the basis of their signal index differed between the two methods.
Our two data mining methods were equally able to generate suspected signals using the pooled safety data from a phase IIIb/IV clinical trial. This analysis demonstrated the possibility of utilising clinical studies safety data for key pharmacovigilance activities like signal detection and evaluation. This approach can be applied to complement the spontaneous reporting systems which are limited by under reporting.
Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in ...Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance.
Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data.
Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria.
Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy.
http://clinicaltrials.gov/ct2/show/NCT00495508.
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.
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.
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).
The use of CDA for treating uncomplicated malaria may increase the risk of haemolytic anaemia in G6PD-deficient children.
Neisseria meningitidis serogroup A is the main causative pathogen of meningitis epidemics in sub-Saharan Africa. In recent years, serogroup W135 has also been the cause of epidemics. Mass vaccination ...campaigns with polysaccharide vaccines are key elements in controlling these epidemics. Facing global vaccine shortage, we explored the use of fractional doses of a licensed A/C/Y/W135 polysaccharide meningococcal vaccine.
We conducted a randomized, non-inferiority trial in 750 healthy volunteers 2-19 years old in Mbarara, Uganda, to compare the immune response of the full dose of the vaccine versus fractional doses (1/5 or 1/10). Safety and tolerability data were collected for all subjects during the 4 weeks following the injection. Pre- and post-vaccination sera were analyzed by measuring serum bactericidal activity (SBA) with baby rabbit complement. A responder was defined as a subject with a > or =4-fold increase in SBA against a target strain from each serogroup and SBA titer > or =128. For serogroup W135, 94% and 97% of the vaccinees in the 1/5- and 1/10-dose arms, respectively, were responders, versus 94% in the full-dose arm; for serogroup A, 92% and 88% were responders, respectively, versus 95%. Non-inferiority was demonstrated between the full dose and both fractional doses in SBA seroresponse against serogroups W135 and Y, in total population analysis. Non-inferiority was shown between the full and 1/5 doses for serogroup A in the population non-immune prior to vaccination. Non-inferiority was not shown for any of the fractionate doses for serogroup C. Safety and tolerability data were favourable, as observed in other studies.
While the advent of conjugate A vaccine is anticipated to largely contribute to control serogroup A outbreaks in Africa, the scale-up of its production will not cover the entire "Meningitis Belt" target population for at least the next 3 to 5 years. In view of the current shortage of meningococcal vaccines for Africa, the use of 1/5 fractional doses should be considered as an alternative in mass vaccination campaigns.
ClinicalTrials.gov NCT00271479.
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