Comparing changes in haematologic parameters occurring in patients included in randomized controlled trials of artesunate-amodiaquine vs single and combination treatments of uncomplicated falciparum in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>Artesunate-amodiaquine (AS&AQ) is a widely used artemisinin combination therapy (ACT) for falciparum malaria. A comprehensive appreciation of its effects on haematology <it>vs </it>other anti-malarials is needed in view of potential safety liabilities.</p> <p>Methods</p> <p>Individual-patient data analysis conducted on a database from seven randomized controlled trials conducted in sub-Saharan African comparing AS&AQ to reference treatments in uncomplicated falciparum malaria patients of all ages. Haematologic values (white cells total and neutrophil counts, haemoglobin/haematocrit, platelets) were analysed as both continuous and categorical variables for their occurrence, (severity grade 1-4) and changes during follow-up. Risks and trends were calculated using multivariate logistic random effect models.</p> <p>Results</p> <p>4,502 patients (72% < 5 years old), from 13 sites in nine countries with 28-day follow-up were treated with AS&AQ (45%) or a comparator (other forms of ACT accounted for 27%, other combination 12%, mono-therapies 16%). Pre-treatment leucopaenia (3%) and neutropaenia (6%) were infrequent; anaemia was common (39%). The treatment-emergent adverse events incidence (TEAE = condition not present or less severe pre-treatment) was 11% for neutropaenia, 6% for thrombocytopaenia with AS&AQ and not different from treatment groups; anaemia was higher with AS&AQ (20%) or other forms of ACT (22%) than in non-artemisinin groups (4%, <it>p </it>= 0.001). Multivariate analysis showed that the risk of anaemia, thrombocytopaenia, and leucopaenia decreased with follow-up time, while neutropaenia increased; the risk of anaemia and thrombocytopaenia increased with higher baseline parasitaemia and parasitological reappearance. White cells total count was not a good surrogate for neutropaenia. No systematic significant difference between treatments was detected. Older patients were at lower risks.</p> <p>Conclusion</p> <p>The effects of AS&AQ on haematologic parameters were not different from those of other anti-malarial treatments used in sub-Saharan Africa. This analysis provides the basis for a broader evaluation of haematology following anti-malarial treatment. Continuing monitoring of haematologic safety on larger databases is required.</p

Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis

BACKGROUND: Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. METHODS: An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. RESULTS: A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6-77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2-94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. CONCLUSION: AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required

Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial.

Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce

An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours) versus artesunate/amodiaquine (fixed dose over 48 hours)

<p>Abstract</p> <p>Background</p> <p>Several studies have demonstrated the efficacy of artemisinin-combination therapy (ACT) across malaria zones of the world. Fixed dose ACT with shorter courses and fewer tablets may be key determinants to ease of administration and compliance.</p> <p>Methods</p> <p>Children aged one year to 13 years presenting with uncomplicated <it>Plasmodium falciparum </it>malaria were recruited in Ibadan, south-western Nigeria. A total of 250 children each were randomly assigned to receive three doses of artesunate/sulphamethoxypyrazine/pyrimethamine (AS + SMP) (12 hourly doses over 24 hours) or three doses of artesunate/amodiaquine (AS + AQ) (daily doses over 48 hours). Efficacy and safety of the two drugs were assessed using a 28-day follow-up and the primary outcome was PCR- corrected parasitological cure rate and clinical response.</p> <p>Results</p> <p>There were two (0.4%) early treatment failures, one in each treatment arm. The PCR corrected cure rates for day 28 was 97.9% in the AS + AQ arm and 95.6% in the AS + SMP arm (p = 0.15). The re-infection rate was 1.7% in the AS + AQ arm and 5.7% in the AS + SMP arm (p = 0.021). The fever clearance time was similar in the two treatment groups: 1 - 2 days for both AS + SMP and AS + AQ (p = 0.271). The parasite clearance time was also similar in the two treatment groups with 1 - 7 days for AS + SMP and 1 - 4 days for AS + AQ (p = 0.941). The proportion of children with gametocytes over the follow-up period was similar in both treatment groups. Serious Adverse Events were not reported in any of the patients and in all children, laboratory values (packed cell volume, liver enzymes, bilirubin) remained within normal levels during the follow-up period but the packed cell volume was significantly lower in the AS + SMP group.</p> <p>Conclusions</p> <p>This study demonstrates that AS + SMP FDC given as three doses over 24 hours (12-hour intervals) has similar efficacy as AS + AQ FDC given as three doses over 48 hours (24-hour interval) for the treatment of uncomplicated <it>Plasmodium falciparum </it>malaria in children in Nigeria. Both drugs also proved to be safe. Therefore, AS + SMP could be an alternative to currently recommended first-line ACT with continuous resistance surveillance.</p

The Origin and Evolutionary History of HIV-1 Subtype C in Senegal

Background: The classification of HIV-1 strains in subtypes and Circulating Recombinant Forms (CRFs) has helped in tracking the course of the HIV pandemic. In Senegal, which is located at the tip of West Africa, CRF02_AG predominates in the general population and Female Sex Workers (FSWs). In contrast, 40% of Men having Sex with Men (MSM) in Senegal are infected with subtype C. In this study we analyzed the geographical origins and introduction dates of HIV-1 C in Senegal in order to better understand the evolutionary history of this subtype, which predominates today in the MSM population Methodology/Principal Findings: We used a combination of phylogenetic analyses and a Bayesian coalescent-based approach, to study the phylogenetic relationships in pol of 56 subtype C isolates from Senegal with 3,025 subtype C strains that were sampled worldwide. Our analysis shows a significantly well supported cluster which contains all subtype C strains that circulate among MSM in Senegal. The MSM cluster and other strains from Senegal are widely dispersed among the different subclusters of African HIV-1 C strains, suggesting multiple introductions of subtype C in Senegal from many different southern and east African countries. More detailed analyses show that HIV-1 C strains from MSM are more closely related to those from southern Africa. The estimated date of the MRCA of subtype C in the MSM population in Senegal is estimated to be in the early 80's. Conclusions/Significance: Our evolutionary reconstructions suggest that multiple subtype C viruses with a common ancestor originating in the early 1970s entered Senegal. There was only one efficient spread in the MSM population, which most likely resulted from a single introduction, underlining the importance of high-risk behavior in spread of viruses

Enhanced Pro-Inflammatory Cytokine Responses following Toll-Like-Receptor Ligation in Schistosoma haematobium-Infected Schoolchildren from Rural Gabon

BACKGROUND: Schistosoma infection is thought to lead to down-regulation of the host's immune response. This has been shown for adaptive immune responses, but the effect on innate immunity, that initiates and shapes the adaptive response, has not been extensively studied. In a first study to characterize these responses, we investigated the effect of Schistosoma haematobium infection on cytokine responses of Gabonese schoolchildren to a number of Toll-like receptor (TLR) ligands. METHODOLOGY: Peripheral blood mononuclear cells (PBMCs) were collected from S. haematobium-infected and uninfected schoolchildren from the rural area of Zile in Gabon. PBMCs were incubated for 24 h and 72 h with various TLR ligands, as well as schistosomal egg antigen (SEA) and adult worm antigen (AWA). Pro-inflammatory TNF-alpha and anti-inflammatory/regulatory IL-10 cytokine concentrations were determined in culture supernatants. PRINCIPAL FINDINGS: Infected children produced higher adaptive IL-10 responses than uninfected children against schistosomal antigens (72 h incubation). On the other hand, infected children had higher TNF-alpha responses than uninfected children and significantly higher TNF-alpha to IL-10 ratios in response to FSL-1 and Pam3, ligands of TLR2/6 and TLR2/1 respectively. A similar trend was observed for the TLR4 ligand LPS while Poly(I:C) (Mda5/TLR3 ligand) did not induce substantial cytokine responses (24 h incubation). CONCLUSIONS: This pilot study shows that Schistosoma-infected children develop a more pro-inflammatory TLR2-mediated response in the face of a more anti-inflammatory adaptive immune response. This suggests that S. haematobium infection does not suppress the host's innate immune system in the context of single TLR ligation