Tansy Edwards

Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea

BACKGROUND In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Unions Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Active convulsive epilepsy in a rural district of Kenya: a study of prevalence and possible risk factors

BACKGROUND Few large-scale studies of epilepsy have been done in sub-Saharan Africa. We aimed to estimate the prevalence of, treatment gap in, and possible risk factors for active convulsive epilepsy in Kenyan people aged 6 years or older living in a rural area. METHODS We undertook a three-phase screening survey of 151,408 individuals followed by a nested community case-control study. Treatment gap was defined as the proportion of cases of active convulsive epilepsy without detectable amounts of antiepileptic drugs in blood. FINDINGS Overall prevalence of active convulsive epilepsy was 2.9 per 1000 (95% CI 2.6-3.2); after adjustment for non-response and sensitivity, prevalence was 4.5 per 1000 (4.1-4.9). Substantial heterogeneity was noted in prevalence, with evidence of clustering. Treatment gap was 70.3% (65.9-74.5), with weak evidence of a difference by sex and area. Adjusted odds of active convulsive epilepsy for all individuals were increased with a family history of non-febrile convulsions (odds ratio 3.3, 95% CI 2.4-4.7; p<0.0001), family history of febrile convulsions (14.6, 6.3-34.1; p<0.0001), history of both seizure types (7.3, 3.3-16.4; p<0.0001), and previous head injury (4.1, 2.1-8.1; p<0.0001). Findings of multivariable analyses in children showed that adverse perinatal events (5.7, 2.6-12.7; p<0.0001) and the childs mother being a widow (5.1, 2.4-11.0; p<0.0001) raised the odds of active convulsive epilepsy. INTERPRETATION Substantial heterogeneity exists in prevalence of active convulsive epilepsy in this rural area in Kenya. Assessment of prevalence, treatment use, and demographic variation in screening response helped to identify groups for targeted interventions. Adverse perinatal events, febrile illness, and head injury are potentially preventable associated factors for epilepsy in this region.

Incidence and outcome of convulsive status epilepticus in Kenyan children: a cohort study.

Summary Background Convulsive status epilepticus (CSE) is the most common neurological emergency in childhood and is often associated with fever. In sub-Saharan Africa, the high incidence of febrile illnesses might influence the incidence and outcome of CSE. We aimed to provide data on the incidence, causes, and outcomes of childhood CSE in this region. Methods Between March, 2006, and June, 2006, we studied all children who had been admitted with CSE to a Kenyan rural district hospital in 2002 and 2003. Confirmed CSE had been observed directly; probable CSE was inferred from convulsions on arrival, requirement for phenobarbital or phenytoin, or coma with a recent history of seizures. We estimated the incidence with linked demographic surveillance, and risk factors for death and neurological sequelae were analysed by multivariable analysis. Findings Of 388 episodes of CSE, 155 (40%) were confirmed CSE and 274 (71%) were caused by an infection. The incidence of confirmed CSE was 35 (95% CI 27–46) per 100 000 children per year overall, and was 52 (21–107) and 85 (62–114) per 100 000 per year in children aged 1–11 months and 12–59 months, respectively. The incidence of all CSE was 268 (188–371) and 227 (189–272) per 100 000 per year in these age-groups. 59 (15%) children died in hospital, 81 (21%) died during long-term follow-up, and 46 (12%) developed neurological sequelae. Mortality of children with confirmed CSE while in hospital was associated with bacterial meningitis (adjusted relative risk [RR]=2·6; 95% CI 1·4–4·9) and focal onset seizures (adjusted RR=2·4; 1·1–5·4), whereas neurological sequelae were associated with hypoglycaemia (adjusted RR=3·5; 1·8–7·1) and age less than 12 months (adjusted RR=2·5; 1·2–5·1). Interpretation Prevention of infections and appropriate early management of seizures might reduce the incidence and improve the outcome of CSE in children in sub-Saharan Africa.

Geographical Variation in the Response of Visceral Leishmaniasis to Paromomycin in East Africa: A Multicentre, Open-Label, Randomized Trial

Background Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India. Methods This was a 3-arm multicentre, open-label, randomized, controlled clinical trial to compare three treatment regimens for VL in East Africa: paromomycin sulphate (PM) at 15 mg/kg/day for 21 days versus sodium stibogluconate (SSG) at 20 mg/kg/day for 30 days; and the combination of both dose regimens for 17 days. The primary efficacy endpoint was cure based on parasite-free tissue aspirates taken 6 months after treatment. Findings Overall, 135 patients per arm were enrolled at five centres in Sudan (2 sites), Kenya (1) and Ethiopia (2), when the PM arm had to be discontinued due to poor efficacy. The trial has continued with the higher dose of PM as well as the combination of PM and SSG arms. These results will be reported later. Baseline patient characteristics were similar among treatment arms. The overall cure with PM was significantly inferior to that with SSG (63.8% versus 92.2%; difference 28.5%, 95%CI 18.8% to 38.8%, p<0.001). The efficacy of PM varied among centres and was significantly lower in Sudan (14.3% and 46.7%) than in Kenya (80.0%) and Ethiopia (75.0% and 96.6%). No major safety issues with PM were identified. Conclusion The efficacy of PM at 15 mg/kg/day for 21 days was inadequate, particularly in Sudan. The efficacy of higher doses and the combination treatment warrant further studies.

Gametocytaemia after Drug Treatment of Asymptomatic Plasmodium falciparum

Objectives: Treatment of Plasmodium falciparum malaria with sulfadoxine-pyrimethamine (SP) is followed by a sharp rise in the prevalence and density of gametocytes. We did a randomized trial to determine the effect of treatment of asymptomatic infections with SP or SP plus one dose of artesunate (SP+AS) on gametocyte carriage. Design: The study was a three-arm open-label randomized trial. We randomized asymptomatic carriers of P. falciparum to receive antimalarial treatment or placebo, and recorded the prevalence and density of gametocytes over the next 2 mo. Setting: The trial was conducted during the dry (low malaria transmission) season in four rural villages in Gambia. Participants: Participants were adults and children aged over 6 mo with asexual P. falciparum infection and confirmed free of clinical symptoms of malaria over a 2-d screening period. Interventions: Participants were randomized to receive a single dose of SP or SP+AS or placebo. Outcome Measures: The outcome measures were the presence of gametocytes 7 and 56 d after treatment, and the duration and density of gametocytaemia over 2 mo. Results: In total, 372 asymptomatic carriers were randomized. Gametocyte prevalence on day 7 was 10.5% in the placebo group, 11.2% in the SP group (risk difference to placebo 0.7%, 95% confidence interval −7.4% to 8.7%, p = 0.87), and 7.1% in the SP+AS group (risk difference to placebo 4.1%, 95% confidence interval −3.3% to 12%, p = 0.28). By day 56, gametocyte prevalence was 13% in the placebo group and 2% in both drug-treated groups. Gametocyte carriage (the area under the curve of gametocyte density versus time), was reduced by 71% in the SP group, and by 74% in the SP+AS group, compared to placebo. Gametocyte carriage varied with age and was greater among children under 15 than among adults. Conclusions: Treatment of asymptomatic carriers of P. falciparum with SP does not increase gametocyte carriage or density. Effective treatment of asexual parasitaemia in the dry season reduces gametocyte carriage to very low levels after 4 wk.

Sodium Stibogluconate (SSG) & Paromomycin Combination Compared to SSG for Visceral Leishmaniasis in East Africa: A Randomised Controlled Trial

Background Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India. Methods A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4–60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data. Findings The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: −1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens. Conclusion The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa. Clinical Trials Registration www.clinicaltrials.gov NCT00255567

Risk factors associated with the epilepsy treatment gap in Kilifi, Kenya: a cross-sectional study

Summary Background Many people with epilepsy in low-income countries do not receive appropriate biomedical treatment. This epilepsy treatment gap might be caused by patients not seeking biomedical treatment or not adhering to prescribed antiepileptic drugs (AEDs). We measured the prevalence of and investigated risk factors for the epilepsy treatment gap in rural Kenya. Methods All people with active convulsive epilepsy identified during a cross-sectional survey of 232 176 people in Kilifi were approached. The epilepsy treatment gap was defined as the percentage of people with active epilepsy who had not accessed biomedical services or who were not on treatment or were on inadequate treatment. Information about risk factors was obtained through a questionnaire-based interview of sociodemographic characteristics, socioeconomic status, access to health facilities, seizures, stigma, and beliefs and attitudes about epilepsy. The factors associated with people not seeking biomedical treatment and not adhering to AEDs were investigated separately, adjusted for age. Findings 673 people with epilepsy were interviewed, of whom 499 (74%) reported seeking treatment from a health facility. Blood samples were taken from 502 (75%) people, of whom 132 (26%) reported taking AEDs, but 189 (38%) had AEDs detectable in the blood. The sensitivity and specificity of self-reported adherence compared with AEDs detected in blood were 38·1% (95% CI 31·1–45·4) and 80·8% (76·0–85·0). The epilepsy treatment gap was 62·4% (58·1–66·6). In multivariable analysis, failure to seek biomedical treatment was associated with a patient holding traditional animistic religious beliefs (adjusted odds ratio 1·85, 95% CI 1·11–2·71), reporting negative attitudes about biomedical treatment (0·86, 0·78–0·95), living more than 30 km from health facilities (3·89, 1·77–8·51), paying for AEDs (2·99, 1·82–4·92), having learning difficulties (2·30, 1·29–4·11), having had epilepsy for longer than 10 years (4·60, 2·07–10·23), and having focal seizures (2·28, 1·50–3·47). Reduced adherence was associated with negative attitudes about epilepsy (1·10, 1·03–1·18) and taking of AEDs for longer than 5 years (3·78, 1·79–7·98). Interpretation The sensitivity and specificity of self-reported adherence is poor, but on the basis of AED detection in blood almost two-thirds of patients with epilepsy were not on treatment. Education about epilepsy and making AEDs freely available in health facilities near people with epilepsy should be investigated as potential ways to reduce the epilepsy treatment gap. Funding Wellcome Trust.

Prevalence, incidence and risk factors of epilepsy in older children in rural Kenya

BACKGROUND There is little data on the burden or causes of epilepsy in developing countries, particularly in children living in sub-Saharan Africa. METHODS We conducted two surveys to estimate the prevalence, incidence and risk factors of epilepsy in children in a rural district of Kenya. All children born between 1991 and 1995 were screened with a questionnaire in 2001 and 2003, and those with a positive response were then assessed for epilepsy by a clinician. Active epilepsy was defined as two or more unprovoked seizures with one in the last year. RESULTS In the first survey 10,218 children were identified from a census, of whom 110 had epilepsy. The adjusted prevalence estimates of lifetime and active epilepsy were 41/1000 (95% CI: 31-51) and 11/1000 (95% CI: 5-15), respectively. Overall two-thirds of children had either generalized tonic-clonic and/or secondary generalized seizures. A positive history of febrile seizures (OR=3.01; 95% CI: 1.50-6.01) and family history of epilepsy (OR=2.55; 95% CI: 1.19-5.46) were important risk factors for active epilepsy. After the second survey, 39 children from the same birth cohort with previously undiagnosed epilepsy were identified, thus the incidence rate of active epilepsy is 187 per 100,000 per year (95% CI: 133-256) in children aged 6-12 years. CONCLUSIONS There is a considerable burden of epilepsy in older children living in this area of rural Kenya, with a family history of seizures and a history of febrile seizures identified as risk factors for developing epilepsy.

A Diagnostics Platform for the Integrated Mapping, Monitoring, and Surveillance of Neglected Tropical Diseases: Rationale and Target Product Profiles

JX; Chen, JH; Churcher, TS; Drakeley, CJ; Edwards, T; Fenwick, A; French, M; Gabrielli, AF; Grassly, NC; Harding-Esch, EM; Holland, MJ; Koukounari, A; Lammie, PJ; Leslie, J; Mabey, DC; Rhajaoui, M; Secor, WE; Stothard, JR; Wei, H; Willingham, AL; Zhou, XN; Peeling, RW (2012) A diagnostics platform for the integrated mapping, monitoring, and surveillance of neglected tropical diseases: rationale and target product profiles. PLoS neglected tropical diseases, 6 (7). e1746. ISSN 1935-2727

Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study.

Background A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days. Methods This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg. Findings 42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively). Conclusion Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa. Trial Registration ClinicalTrials.gov NCT00255567