Efficacy and safety of pyronaridine-artesunate versus artemether-lumefantrine in the treatment of acute uncomplicated malaria in children in South-West Nigeria: an open-labelled randomized controlled trial.

BACKGROUND: In Nigeria, declining responsiveness to artemether-lumefantrine (AL), the artemisinin-based combination therapy (ACT) of choice since 2005, has been reported. Pyronaridine-artesunate (PA) is a newer fixed-dose ACT recently prequalified by the WHO for the treatment of uncomplicated falciparum malaria. However, PA data from the Nigerian pediatric population is scarce. Therefore, the efficacy and safety of PA and AL using the WHO 28-day anti-malarial therapeutic efficacy study protocol in Ibadan, southwest Nigeria, were compared. METHODS: In an open-labelled, randomized, controlled clinical trial, 172 children aged 3-144 months with a history of fever and microscopically confirmed uncomplicated Plasmodium falciparum malaria were enrolled in southwest Nigeria. Enrollees were randomly assigned to receive PA or AL at standard dosages according to body weight for 3 days. Venous blood was obtained for hematology, blood chemistry, and liver function tests on days 0, 3, 7, and 28 as part of the safety evaluation. RESULTS: 165 (95.9%) of the enrolled individuals completed the study. About half (52.3%; 90/172) of enrollees were male. Eighty-seven (50.6%) received AL, while 85 (49.4%) received PA. Day 28, adequate clinical and parasitological response for PA was 92.7% [(76/82) 95% CI 83.1, 95.9] and 71.1% [(59/83) 95% CI 60.4, 79.9] for AL (0.001). Fever and parasite clearance were similar in both groups. Two of six and eight of 24 parasite recurrences were observed among PA- and AL-treated children, respectively. PCR-corrected Day-28 cure rates for PA were 97.4% (76/78) and 88.1% (59/67) for AL (= 0.04) in the per-protocol population after new infections were censored. Hematological recovery at day 28 was significantly better among PA-treated patients (34.9% 2.8) compared to those treated with AL (33.1% 3.0) (0.002). Adverse events in both treatment arms were mild and similar to the symptoms of malaria infection. Blood chemistry and liver function tests were mostly within normal limits, with an occasional marginal rise. CONCLUSION: PA and AL were well-tolerated. PA was significantly more efficacious than AL in both the PCR-uncorrected and PCR-corrected per-protocol populations during this study. The results of this study support the inclusion of PA in the anti-malarial treatment guidelines in Nigeria. RETROSPECTIVE TRIAL REGISTRATION: Clinicaltrials.gov: NCT05192265.

SD-Bioline malaria rapid diagnostic test performance and time to become negative after treatment of malaria infection in Southwest Nigerian Children.

Context and Aim: Given the challenges of microscopy, we compared its performance with SD-Bioline malaria rapid diagnostic test (MRDT) and polymerase chain reaction (PCR) and evaluated the time it took for positive results to become negative after treatment of children with acute uncomplicated malaria. Subjects and Methods: We present the report of 485 participants with complete MRDT, microscopy, and PCR data out of 511 febrile children aged 3-59 months who participated in a cohort study over a 12-month period in rural and urban areas of Ibadan, Nigeria. MRDT-positive children received antimalaria and tested at every visit over 28 days. Speciation was also carried out by PCR. Results: With microscopy as the gold standard, SD-Bioline™ had 95.2% sensitivity, 66.4% specificity, 67.5% positive predictive value (PPV), and 94.9 negative predictive value (NPV), while with PCR the findings were 84.3% sensitivity, 66.5% specificity, 72.7% PPV, and 80.1% NPV. PCR speciation of malaria parasites revealed 91.6% Plasmodium falciparum, 18.9% Plasmodium malariae, and 4.4% Plasmodium ovale. Among the 47 children with P. malariae infections, 66.0% were coinfected with P. falciparum, while 54.6% cases of P. ovale occurred as coinfections with P. falciparum. The median time to a negative MRDT was 23.2 days, while the median time to a negative malaria microscopy was 3.8 days. The two survival curves were significantly different. Conclusions: The SD-BiolineTM MRDT performed well, with remarkable persistence of rapid test-positive for an average of 23 days post treatment. The prevalence of P. malaria is somewhat greater than expected.

Résumé Contexte et objectif: Compte tenu des défis de la microscopie, nous avons comparé le test de diagnostic rapide du paludisme SD-Bioline (MRDT) avec la réaction en chaîne par polymérase (PCR) et évalué le temps qu'il a fallu pour que des résultats positifs deviennent négatifs après le traitement d'enfants atteints de paludisme aigu non compliqué. Sujets et méthodes: Nous présentons le rapport de 485 participants avec des données complètes de MRDT, de microscopie et de PCR sur 511 enfants fébriles âgés de 3 à 59 mois qui ont participé à une étude de cohorte sur une période de 12 mois dans les zones rurales et urbaines d'Ibadan, Nigeria. Les enfants positifs au MRDT ont reçu un antipaludique et ont été testés à chaque visite pendant 28 jours. La spéciation a également été réalisée par PCR. Résultats: Avec la microscopie comme référence, SD-Bioline TM avait une sensibilité de 95,2 %, une spécificité de 66,4 %, une valeur prédictive positive (VPP) de 67,5 % et une valeur prédictive négative (VPN) de 94,9 %, tandis qu'avec la PCR, les résultats étaient de 84,3 % de sensibilité, 66,5 % de spécificité, 72,7 % de VPP et 80,1 % de VPN. La spéciation par PCR des parasites du paludisme a révélé 91,6 % de Plasmodium falciparum, 18,9 % de Plasmodium malariae et 4,4 % de Plasmodium ovale. Parmi les 47 enfants atteints d'infections à P. malariae, 66,0 % étaient co-infectés par P. falciparum, tandis que 54,6 % des cas de P. ovale se sont produits sous forme de co-infections par P. falciparum. Le délai médian jusqu'à un MRDT négatif était de 23,2 jours, tandis que le délai médian jusqu'à une microscopie négative du paludisme était de 3,8 jours. Les deux courbes de survie étaient significativement différentes. Conclusions: Le SD-BiolineTM MRDT a donné de bons résultats, avec une infection à P. malariae un peu plus élevée que attendu dans la population et persistance remarquable des résultats positifs aux tests de diagnostic rapide pendant une moyenne de plus de 23. Mots-clés: Paludisme, microscopie, Nigéria, réaction en chaîne par polymérase, test de diagnostic rapide, spéciationjours après le traitement.

Day and night blood pressure variability among older persons in South-Western Nigeria.

Background: Hypertension is the largest contributor to the global burden of disease. Emerging risk factors for cardiovascular disease include blood pressure variability (BPV), but evidence on BPV is lacking among older Nigerians. We reported BPV in a cohort of older persons at the University College Hospital (UCH), Ibadan. Methods: We conducted a retrospective cohort study of respondents aged >50 years within the Ibadan Ambulatory Blood Pressure Registry at the UCH, Ibadan, Nigeria. Socio-demographic characteristics, lifestyle habits and anthropometric measurements were obtained. Results: Among 639 respondents, 332 (52.0%) were female. The blood pressure (BP) variables were strongly associated with age. Compared with younger age groups, mean diastolic BP (DBP) was less at an older age, whereas mean pulse pressure was greater. During the wake-up and sleep periods, mean DBP and mean arterial BP were less with each increasing age category, whereas mean pulse pressure was larger with each increasing age category. BP dipping, systolic, diastolic and mean arterial BP decreased with age. Overall, timed BPV increased significantly with increasing age. The prevalence of white-coat hypertension was greater among older participants than younger participants. Most respondents in the 50-59 years' age group were non-dippers (55.8%), whereas 33.7% of older respondents were reverse-dippers. Conclusion: Older persons experienced a greater abnormal circadian blood variation and greater BPV than younger people. In Nigeria, follow-up data are needed to determine the prognostic significance of these data in this population.

Non-Malaria Causes of Fever among under-5 Children with Negative Results for Malaria Rapid Diagnostic Test in South-Western Nigeria.

BACKGROUND: Although the global malaria burden is decreasing, there are still concerns about overdiagnosis of malaria and the danger of misdiagnosis of non-malaria causes of fever. Clinicians continue to face the challenge of differentiating between these causes despite the introduction of malaria rapid diagnostic tests (mRDTs). AIM: To determine the prevalence and causes of non-malaria-caused fever in children in South-Western Nigeria. METHODS: Secondary analysis of data obtained to evaluate the effect of restricting antimalarial treatment to positive mRDT children in rural and urban areas of southwest Nigeria. Clinical examinations, laboratory tests for malaria parasites (including thick blood film and mRDT) and bacterial identification were performed on children aged 3-59 months (n = 511). The non-malaria group comprised febrile children who had both negative mRDT and microscopy results, while the malaria group included those who were positive for either mRDT or microscopy. We compared the causes of fever among children with non-malaria fever and those with malaria. RESULTS: The prevalence of non-malaria fever and bacteria-malaria co-infection was 37.2% and 2.0%, respectively. Non-malarial pathogens identified were viral (54.7%) and bacterial (32.1%) infections. The bacterial infections included bacteriaemia (2.7%), urinary tract infections (21.6%), skin infections (11.6%) and otitis media (2.6%). The leading bacterial isolates were Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pneumoniae. CONCLUSION: The high prevalence and wide range of non-malarial infections reinforces the need for point-of-care tests to identify bacterial and viral infections to optimize the treatment of febrile illnesses in malaria-endemic areas.

Rapid HIV Antigen-Antibody Assays and Detection of Acute HIV Infection in Sub-Saharan Africa.

Detection of acute HIV infection is a unique problem that fourth-generation HIV assays were expected to alleviate. In this commentary, we draw attention to the limitations and challenges with use of currently available rapid antigen-antibody (Ag/Ab) combination tests for detection of acute HIV infection in sub-Saharan Africa. Laboratory-based HIV-1 Ag/Ab immunoassays are complex, requiring specialized equipment and handling that are currently not affordable in many settings in Africa. The point-of-care Ag/Ab platform on the other hand is easier to deploy and potentially more accessible in resource-limited settings. However, available fourth-generation HIV-1 rapid diagnostic tests have demonstrated poor performance characteristics in field studies where non-B subtypes of HIV-1 dominate. The potential for point-of-care HIV-1 Ag/Ab diagnostics to significantly improve detection of acute HIV infection remains yet to be realized in sub-Saharan Africa. Assay platforms need to be optimized to identify local circulating subtypes, and optimal algorithms need to be determined.

Therapeutic efficacy of artesunate-amodiaquine combinations and the plasma and saliva concentrations of desethylamodiaquine in children with acute uncomplicated Plasmodium falciparum malaria.

The treatment efficacy of artesunate-amodiaquine (AQ) coformulated or copackaged, and the plasma and saliva concentrations of desethylamodiaquine (DEAQ), the active metabolite of AQ, were evaluated in 120 and 7 children, respectively, with uncomplicated Plasmodium falciparum malaria treated with oral daily doses of the 2 formulations for 3 days. All children recovered clinically. Fever clearance (1.1 ± 0.2 vs 1.0 ± 0 days) and parasite clearance times (21.1 ± 10.2 vs 19.0 ± 7.0 hours) in artesunate-AQ coformulated and artesunate-AQ copackaged treated children, respectively, were similar. All children remained aparasitemic for at least 28 days. Blood and saliva samples were collected over 35 days and DEAQ in plasma and saliva was determined by high-performance liquid chromatography. DEAQ was detectable in plasma and saliva within 40 minutes of oral administration of artesunate-AQ. DEAQ concentrations 7 days after the start of therapy were 247.8 and 125.1 ng/mL in plasma and saliva, respectively. The concentration-time curves of plasma and saliva in declining phases were approximately parallel giving a similar half-life of 169.1 ± 16.4 and 142.8 ± 6.5 hours in plasma and saliva, respectively. Clearance from plasma and saliva was also similar (335.6 and 443.4 mL·h·kg, respectively). Area under concentration-time curves (AUC0-35d) for plasma and saliva were 94,744.9 and 74,004.2 ng·mL·h, respectively. In general, Saliva-plasma concentration ratio was 0.25-0.4. DEAQ concentrations in saliva may be useful for monitoring therapy and for the evaluation of the disposition of AQ in children with falciparum malaria treated with AQ-based combination.

Therapeutic efficacy and effects of artemether-lumefantrine and artesunate-amodiaquine coformulated or copackaged on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in Southwest Nigeria.

The therapeutic efficacy and effects of artemether-lumefantrine (AL) and artesunate-amodiaquine co-formulated (AAcf) or co-packaged (AAcp) on malaria-associated anemia (MAA) were evaluated in 285 children < 12 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive one of the three drug combinations. Fever and parasite clearance times were similar in all treatment groups. Mean drug-attributable fall in hematocrit (DAFH), defined as difference between hematocrit values pre- and 3 d post-initiation of treatment, was low (< 4.5%) and rates of recovery from MAA were similar with all treatments. Mean areas under curve (AUCs) of the plot of deficit in hematocrit levels from 30% versus time in anemic children were similar in all groups. All regimens were well tolerated. AL, AAcf and AAcp cleared fever and parasitemia rapidly and had similar rates of resolution of MAA after treatment in malarious Nigerian children.

Early variations in plasmodium falciparum dynamics in Nigerian children after treatment with two artemisinin-based combinations: implications on delayed parasite clearance.

BACKGROUND: Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Artemether-lumefantrine (AL) and artesunate-amodiaquine (AA) are efficacious regimens that have been widely adopted in sub-Saharan Africa. However, most study designs ignore the effects of these regimens on peripheral parasitaemia in the first 24 hours of therapy. The study protocol was designed to evaluate more closely the early effects and the standard measures of efficacies of these two regimens. METHODS: In an open label, randomized controlled clinical trial, children aged 12 months to 132 months were randomized to receive AL (5-14 kg, one tablet; 15-24 kg, two tablets and 25-34 kg, three tablets twice daily) or artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) for three days. Peripheral blood smears were made hourly in the first 4 hours, 8 h, 16 h, 24 h, and daily on days 2-7, and on days 7, 14, 21, 28, 35, and 42 for microscopic identification and quantification of Plasmodium falciparum. RESULTS: A total of 193 children were randomized to receive either AL (97) or AA (96). In children that received both medications, early response of peripheral parasitaemia showed that 42% of children who received AL and 36.7% of those who received AA had an immediate rise in peripheral parasitaemia (0-4 h after treatment) followed by a rapid fall. The rise in parasitaemia was significant and seems to suggest a mobilization of asexual parasites from the deep tissues to the periphery. Days 3, 7, 14, 28, and 42 cure rates in the per protocol (PP) population were > 90% in both groups of children. Both drug combinations were well tolerated with minimal side effects. CONCLUSION: The study showed the high efficacy of AL and AA in Nigerian children. In addition the study demonstrated the mobilisation of asexual parasites from the deep to the periphery in the early hours of commencing ACT treatment in a subset of patients in both study groups. It is unclear whether the early parasite dynamics discovered in this study play any role in the development of drug resistance and thus it is important to further evaluate this discovery. It may be useful for studies investigating delay in parasite clearance of artemisinin derivatives as a way of monitoring the development of resistance to artemisinin to assess the early effects of the drugs on the parasites.

Factors contributing to delay in parasite clearance in uncomplicated falciparum malaria in children.

BACKGROUND: Drug resistance in Plasmodium falciparum is common in many endemic and other settings but there is no clear recommendation on when to change therapy when there is delay in parasite clearance after initiation of therapy in African children. METHODS: The factors contributing to delay in parasite clearance, defined as a clearance time > 2 d, in falciparum malaria were characterized in 2,752 prospectively studied children treated with anti-malarial drugs between 1996 and 2008. RESULTS: 1,237 of 2,752 children (45%) had delay in parasite clearance. Overall 211 children (17%) with delay in clearance subsequently failed therapy and they constituted 72% of those who had drug failure, i.e., 211 of 291 children. The following were independent risk factors for delay in parasite clearance at enrolment: age less than or equal to 2 years (Adjusted odds ratio [AOR] = 2.13, 95% confidence interval [CI]1.44-3.15, P < 0.0001), presence of fever (AOR = 1.33, 95% CI = 1.04-1.69, P = 0.019), parasitaemia >50,000/ul (AOR = 2.21, 95% CI = 1.77-2.75, P < 0.0001), and enrolment before year 2000 (AOR= 1.55, 95% CI = 1.22-1.96, P < 0.0001). Following treatment, a body temperature >or= 38 degrees C and parasitaemia > 20000/microl a day after treatment began, were independent risk factors for delay in clearance. Non-artemisinin monotherapies were associated with delay in clearance and treatment failures, and in those treated with chloroquine or amodiaquine, with pfmdr 1/pfcrt mutants. Delay in clearance significantly increased gametocyte carriage (P < 0.0001). CONCLUSION: Delay in parasite clearance is multifactorial, is related to drug resistance and treatment failure in uncomplicated malaria and has implications for malaria control efforts in sub-Saharan Africa.