Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg ...used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment.
We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18–50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m2; women: <23 vs ≥23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353.
Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio RR 2·26, 95% CI 1·93–2·65, p<0·0001; hazard ratio HR 6·32, 4·61–8·67, p<0·0001; ivermectin 300 μg/kg per day RR 2·18, 1·86–2·57, p<0·0001; HR 4·21, 3·06–5·79, p<0·0001). Mosquito mortality remained significantly increased 28 days post treatment (ivermectin 600 μg/kg per day RR 1·23, 1·01–1·50, p=0·0374; and ivermectin 300 μg/kg per day 1·21, 1·01–1·44, p=0·0337). Five (11%) of 45 patients receiving ivermectin 600 μg/kg per day, two (4%) of 48 patients receiving ivermectin 300 μg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events.
Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days after treatment. Ivermectin 300 μg/kg per day for 3 days provided a good balance between efficacy and tolerability, and this drug shows promise as a potential new tool for malaria elimination.
Malaria Eradication Scientific Alliance (MESA) and US Centers for Disease Control and Prevention (CDC).
In this randomized, placebo-controlled trial in children younger than 5 years of age with severe anemia in an area in which malaria is endemic, dihydroartemisinin–piperaquine administered after ...hospital discharge resulted in a lower incidence of readmission or death in the 3 months after discharge than placebo.
Global gains toward malaria elimination have been heterogeneous and have recently stalled. Interventions targeting afebrile malaria infections may be needed to address residual transmission. We ...studied the efficacy of repeated rounds of community-based mass testing and treatment (MTaT) on malaria infection prevalence in western Kenya.
Twenty clusters were randomly assigned to 3 rounds of MTaT per year for 2 years or control (standard of care for testing and treatment at public health facilities along with government-sponsored mass long-lasting insecticidal net LLIN distributions). During rounds, community health volunteers visited all households in intervention clusters and tested all consenting individuals with a rapid diagnostic test. Those positive were treated with dihydroartemisinin-piperaquine. Cross-sectional community infection prevalence surveys were performed in both study arms at baseline and each year after 3 rounds of MTaT. The primary outcome was the effect size of MTaT on parasite prevalence by microscopy between arms by year, adjusted for age, reported LLIN use, enhanced vegetative index, and socioeconomic status.
Demographic and behavioral characteristics, including LLIN usage, were similar between arms at each survey. MTaT coverage across the 3 annual rounds ranged between 75.0% and 77.5% in year 1, and between 81.9% and 94.3% in year 2. The adjusted effect size of MTaT on the prevalence of parasitemia between arms was 0.93 (95% confidence interval CI, .79-1.08) and 0.92 (95% CI, .76-1.10) after year 1 and year 2, respectively.
MTaT performed 3 times per year over 2 years did not reduce malaria parasite prevalence in this high-transmission area.
NCT02987270.
Progress with malaria control in western Kenya has stagnated since 2007. Additional interventions to reduce the high burden of malaria in this region are urgently needed. We conducted a two-arm, ...community-based, cluster-randomized, controlled trial of active case detection and treatment of malaria infections in all residents mass testing and treatment (MTaT) of 10 village clusters (intervention clusters) for two consecutive years to measure differences in the incidence of clinical malaria disease and malaria infections compared with 20 control clusters where MTaT was not implemented. All residents of intervention clusters, irrespective of history of fever or other malaria-related symptoms, were tested three times per year before the peak malaria season using malaria rapid diagnostic tests. All positive cases were treated with dihydroartemisinin-piperaquine. The incidence of clinical malaria was measured through passive surveillance, whereas the cumulative incidence of malaria infection was measured using active surveillance in a cohort comprising randomly selected residents. The incidence of clinical malaria was 0.19 cases/person-year (p-y, 95% CI: 0.13-0.28) in the intervention arm and 0.24 cases/p-y (95% CI: 0.15-0.39) in the control arm (incidence rate ratio IRR 0.79, 95% CI: 0.61-1.02). The cumulative incidence of malaria infections was similar between the intervention (2.08 infections/p-y, 95% CI: 1.93-2.26) and control arms (2.19 infections/p-y, 95% CI: 2.02-2.37) with a crude IRR of 0.95 (95% CI: 0.87-1.04). Six rounds of MTaT over 2 years did not have a significant impact on the incidence of clinical malaria or the cumulative incidence of malaria infection in this area of high malaria transmission.
High‐dose ivermectin, co‐administered for 3 days with dihydroartemisinin‐piperaquine (DP), killed mosquitoes feeding on individuals for at least 28 days posttreatment in a recent trial (IVERMAL), ...whereas 7 days was predicted pretrial. The current study assessed the relationship between ivermectin blood concentrations and the observed mosquitocidal effects against Anopheles gambiae s.s. Three days of ivermectin 0, 300, or 600 mcg/kg/day plus DP was randomly assigned to 141 adults with uncomplicated malaria in Kenya. During 28 days of follow‐up, 1,393 venous and 335 paired capillary plasma samples, 850 mosquito‐cluster mortality rates, and 524 QTcF‐intervals were collected. Using pharmacokinetic/pharmacodynamic (PK/PD) modeling, we show a consistent correlation between predicted ivermectin concentrations and observed mosquitocidal‐effects throughout the 28‐day study duration, without invoking an unidentified mosquitocidal metabolite or drug‐drug interaction. Ivermectin had no effect on piperaquine's PKs or QTcF‐prolongation. The PK/PD model can be used to design new treatment regimens with predicted mosquitocidal effect. This methodology could be used to evaluate effectiveness of other endectocides.
Ivermectin is being considered for mass drug administration for malaria, due to its ability to kill mosquitoes feeding on recently treated individuals. In a recent trial, 3-day courses of 300 and 600 ...mcg/kg/day were shown to kill Anopheles mosquitoes for at least 28 days post-treatment when fed patients' venous blood using membrane feeding assays. Direct skin feeding on humans may lead to higher mosquito mortality, as ivermectin capillary concentrations are higher. We compared mosquito mortality following direct skin and membrane feeding.
We conducted a mosquito feeding study, nested within a randomized, double-blind, placebo-controlled trial of 141 adults with uncomplicated malaria in Kenya, comparing 3 days of ivermectin 300 mcg/kg/day, ivermectin 600 mcg/kg/day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. On post-treatment day 7, direct skin and membrane feeding assays were conducted using laboratory-reared Anopheles gambiae sensu stricto. Mosquito survival was assessed daily for 28 days post-feeding.
Between July 20, 2015, and May 7, 2016, 69 of 141 patients participated in both direct skin and membrane feeding (placebo, n = 23; 300 mcg/kg/day, n = 24; 600 mcg/kg/day, n = 22). The 14-day post-feeding mortality for mosquitoes fed 7 days post-treatment on blood from pooled patients in both ivermectin arms was similar with direct skin feeding (mosquitoes observed, n = 2941) versus membrane feeding (mosquitoes observed, n = 7380): cumulative mortality (risk ratio 0.99, 95% confidence interval CI 0.95-1.03, P = .69) and survival time (hazard ratio 0.96, 95% CI 0.91-1.02, P = .19). Results were consistent by sex, by body mass index, and across the range of ivermectin capillary concentrations studied (0.72-73.9 ng/mL).
Direct skin feeding and membrane feeding on day 7 resulted in similar mosquitocidal effects of ivermectin across a wide range of drug concentrations, suggesting that the mosquitocidal effects seen with membrane feeding accurately reflect those of natural biting. Membrane feeding, which is more patient friendly and ethically acceptable, can likely reliably be used to assess ivermectin's mosquitocidal efficacy.
NCT02511353.
BACKGROUND Primary mediastinal non-seminomatous germ cell tumors (NSGCTs) are aggressive and carry a poor five-year disease free survival rate even with aggressive treatment. We describe a young ...adult male with primary mediastinal NSGCT presenting with airway obstruction and superior vena cava syndrome (SVCS). CASE REPORT The patient presented with four weeks of nonproductive cough, weight loss, and right-sided pleuritic chest pain. Chest computed topography (CT) imaging demonstrated a right-sided mediastinal mass determined as a yolk sac tumor on biopsy. The patient underwent induction chemotherapy with etoposide and cisplatin for stage III NSGCT. In the interim, he developed SVCS warranting a second cycle of chemotherapy along with intravenous steroids, with notable improvement in symptoms. However, serial alpha-fetoprotein (AFP) measurements showed progressively increasing levels up to a maximum of 18,781 ng/mL indicating treatment failure. He is currently on salvage chemotherapy. CONCLUSIONS Obstruction of the SVC by external compression is often a manifestation of a malignant process in the thorax. SVCS is a medical emergency and occurs in 6% of patients with mediastinal GCTs. Historically, irradiation was initiated without a histologic diagnosis to relieve the life-threatening obstruction. However, newer data suggest that it is acceptable to defer therapy until a full diagnostic workup is completed. This case highlights the malignant nature of primary mediastinal NSGCTs. In addition, inasmuch as SVCS is dramatic in presentation, it is important to recognize that symptomatic obstruction often develops over weeks or longer. In a hemodynamically stable patient, an accurate histologic diagnosis prior to starting treatment is essential in guiding therapy.
A randomized, placebo-controlled treatment trial was conducted among 546 anemic (hemoglobin concentration, 7–11 g/dL) children aged 2–36 months in an area with intense malaria transmission in western ...Kenya. All children used bednets and received a single dose of sulfadoxine-pyrimethamine (SP) on enrollment, followed by either intermittent preventive treatment (IPT) with SP at 4 and 8 weeks and daily iron for 12 weeks, daily iron and IPT with SP placebo, IPT and daily iron placebo, or daily iron placebo and IPT with SP placebo (double placebo). The mean hemoglobin concentration at 12 weeks, compared with that for the double-placebo group, was 1.14 g/dL (95% confidence interval CI, 0.82–1.47 g/dL) greater for the IPT+iron group, 0.79 g/dL (95% CI, 0.46–1.10 g/dL) greater for the iron group, and 0.17 g/dL (95% CI, −0.15–0.49 g/dL) greater for the IPT group. IPT reduced the incidence of malaria parasitemia and clinic visits, but iron did not. The combination of IPT and iron supplementation was most effective in the treatment of mild anemia. Although IPT prevented malaria, the hematological benefit it added to that of a single dose of SP and bednet use was modest
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Background: Cardiotoxicity is a known side effect of anthracyclines & trastuzumab. Dilated cardiomyopathy is the most common form of cardiotoxicity associated with this ...treatment. Cardiovascular disease & cancer are common conditions in the geriatric populations. These comorbidities complicate the treatment of geriatric breast cancer patients. The purpose of this study was to determine the cardiotoxic effects of chemotherapy & trastuzumab in a geriatric population of breast cancer patients. Methods: An institutional database of a total of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 years or older at the time of diagnosis was reviewed in an IRB approved fashion. Patients were divided in groups depending on the therapy (AC/TAC, CMF, TC and Trastuzumab) they received. Fisher’s exact test was used to calculate overall survival (OS). Results: Of the 269 patients, 72 (26.8%) were offered chemotherapy & 197 (73.2%) were not. Of the patients offered chemotherapy, 58 (21.6%) accepted treatment & 14 (5.2%) declined. 17 (6.7%) had an early termination, AC n = 11,( 4.1%), TAC n = 13, (4.8%), CMF n = 0, (0%), Trastuzumab n = 12, (4.5%), TC n = 11, (4.1%). Cardiovascular risk factors taken into consideration were, CAD n = 30, (13.8%), HLD n = 23, (10.6%), HTN n = 98, (45.2%), HTN/HLD n = 66, (30.4%), DM (N = 45, (16.7%), Smoking n = 121, (46.4%) & BMI > 30, n = 116,( 48.1%). Patients completing chemotherapy had higher OS than patients who had early termination (P = 0.017). Of the 24 patients who received Anthracycline containing regimen, 1 experienced cardiotoxicity. There was no statistically significant difference in OS between AC, TAC & Trastuzumab (P = 0.570, P = 0.547, P = 0.614). A decrease in OS was seen for patient who received TC (P = 0.002). Of the 12 who received trastuzumab, 1 experienced cardiotoxicity. There was a significant association between patients with a high BMI ( > 30) & increased cardiovascular comorbidities (P = 0.0009) but had no impact early on termination of chemotherapy or OS, NS (P = 0.7). Conclusions: The cardiotoxic effect of anthracyclines and trastuzumab are well known, however in our study, only 2 elderly breast cancer patients who received chemotherapy experienced cardiotoxicity. As would be expected, those who completed chemotherapy had improved OS. There were no difference in OS between AC, TAC and Trastuzumab, however TC treatment was associated with a decrease in OS.BMI had an impact on cardiovascular comorbidities but not on early termination of chemotherapy or OS.
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