Clinical picture and outcome of Serious Adverse Events in the treatment of Onchocerciasis

Ivermectin (Mectizan®) is the only drug currently recommended for the treatment and control of onchocerciasis. Serious adverse events rarely occur during treatment, except in subjects heavily infected with Loa Loa. This review of drug-related serious adverse events in the treatment of onchocerciasis therefore revisited the pre-Mectizan® reference drugs, DEC and suramin, and other candidate drugs studied extensively for the treatment of human onchocerciasis. The benzimidazole carbamate derivatives and the antibiotic doxycycline were excluded, since no serious adverse events have been reported regarding their use. Using recommended definitions, serious adverse events reported or observed after the use of each drug were summarised, the level of attribution determined, and the results tabulated. Prominence was given to treatment-related deaths. The clinical picture of severe symptomatic postural hypotension is described and used to illustrate the difference between the severity and the seriousness of an adverse event. The epidemiology, management and outcome of serious adverse events are presented. The role of future research is discussed

Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus

Onchocerciasis, commonly known as river blindness, is caused by the filarial nematode Onchocerca volvulus and is transmitted by a blackfly vector. Over 37 million people are thought to be infected, with over 90 million at risk. Infection predominantly occurs in sub-Saharan Africa. Foci also exist in the Arabian Peninsula and Central and South America. Ivermectin, the sole pharmaceutical available for mass chemotherapy, has been used on a community basis for annual or semi-annual treatment since 1987. Multiple treatments with ivermectin kill the microfilariae that are responsible for the pathology of onchocerciasis. More importantly, ivermectin suppresses the reproductive activity of the adult female worms, thus delaying or preventing the repopulation of the skin with new microfilariae and thereby reducing transmission. This study extends earlier reports of sub-optimal responses to ivermectin by examining repopulation levels of microfilaria one year after treatment, worm burdens per nodule, the age structure of adult female worms recovered from nodules, and the reproductive status of adult female worms 90 days after ivermectin treatment. In some communities which have shown a pattern of sub-optimal response to treatment, the data is consistent with an emergence of ivermectin non response or resistance manifested by a loss of the effect of ivermectin on the suppression of parasite reproduction

A Research Agenda for Helminth Diseases of Humans: Towards Control and Elimination

Human helminthiases are of considerable public health importance in sub-Saharan Africa, Asia, and Latin America. The acknowledgement of the disease burden due to helminth infections, the availability of donated or affordable drugs that are mostly safe and moderately efficacious, and the implementation of viable mass drug administration (MDA) interventions have prompted the establishment of various large-scale control and elimination programmes. These programmes have benefited from improved epidemiological mapping of the infections, better understanding of the scope and limitations of currently available diagnostics and of the relationship between infection and morbidity, feasibility of community-directed or school-based interventions, and advances in the design of monitoring and evaluation (M&E) protocols. Considerable success has been achieved in reducing morbidity or suppressing transmission in a number of settings, whilst challenges remain in many others. Some of the obstacles include the lack of diagnostic tools appropriate to the changing requirements of ongoing interventions and elimination settings; the reliance on a handful of drugs about which not enough is known regarding modes of action, modes of resistance, and optimal dosage singly or in combination; the difficulties in sustaining adequate coverage and compliance in prolonged and/or integrated programmes; an incomplete understanding of the social, behavioural, and environmental determinants of infection; and last, but not least, very little investment in research and development (R&D). The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to undertake a comprehensive review of recent advances in helminthiases research, identify research gaps, and rank priorities for an R&D agenda for the control and elimination of these infections. This review presents the processes undertaken to identify and rank ten top research priorities; discusses the implications of realising these priorities in terms of their potential for improving global health and achieving the Millennium Development Goals (MDGs); outlines salient research funding needs; and introduces the series of reviews that follow in this PLoS Neglected Tropical Diseases collection, “A Research Agenda for Helminth Diseases of Humans.

Overview of assessment of treatment effects.

<p>D: Day, M: Month. X indicates examination at each time point indicated in the top row, numbers indicate the day or alternative days for performing the examination.</p>1<p>PE: Physical examination including neurological examination and subcutaneous nodule palpation.</p>2<p>VS: Vital signs including temperature, respiratory rate, pulse rate (PR) and blood pressure (BP) after at least 5 minutes supine.</p><p>PR and BP were repeated after 2 minutes standing following ≥5 minutes supine.</p><p>Day 1: once before and 3 times after drug administration PR and BP after ≥5 minutes supine and subsequent 2 minutes standing still, Days 2–8: 5 times, PR and BP after ≥5 minutes supine and subsequent 2 minutes standing still, Days 9–17: twice, supine only, M1–M18: once, supine only.</p>3<p>12 lead ECG on day 1 approximately 4 hours after drug administration.</p>4<p>OE: Ocular Examination included visual acuity, visual fields (calibrated Goldman perimeter), colour vision, intraocular pressure, examination of the fundus, slit lamp examination of anterior segment, counting of microfilariae in anterior chamber, living and dead microfilariae in cornea and punctate opacities.</p><p>Colour fundus photography and fluorescein angiography to month 3, thereafter as per protocol only in participants with lesions or visual defects on OE (which was not applicable).</p>5<p>LE: Laboratory evaluations included: serum biochemistry (Na⁺, K⁺, Cl⁻, bicarbonate, glucose, total protein, albumin, urea, creatinine, alkaline phosphatase, lactic dehydrogenase, total bilirubin, gamma-glutamyl transpeptidase, aspartate aminotransferase, and alanine aminotransferase), hematology (prothrombin time, a complete blood cell count, hematocrit, hemoglobin, 5-part differential white blood cell count, platelet count), dipstick semiquantitative urinalysis microscopic urine evaluation, urine and blood microfilariae quantitation after nucleopore membrane filtration and Giemsa staining.</p>6<p>Minimum of 1 mg from each iliac crest and calf with a 2 mm corneoscleral punch.</p>7<p>Aseptical excision of all palpable nodules under 2% xylocaine anaesthesia.</p>8<p>Blood sampling time points for pharmacokinetics (PK) on day 1–4: within 2 hours of drug administration, 1, 2, 4, 8, 24, and 72 hours after treatment.</p

Number of participants by cohort screened, randomized, treated and analyzed.

<p>1. Cohorts were screened for and eligible participants randomized and treated in sequential order. 2. In each dose group, subjects were randomized 3∶1 to the dose of moxidectin (Moxi) specified and ivermectin (IVM). 3. Mild: <10 microfilaria/mg skin, no ocular involvement, Moderate: 10–20 mf/mg skin, ocular involvement with sum of microfilariae in both eyes ≤10, Severe: >20 mf/mg skin without or with any level of ocular involvement. 4. Screen failure reasons: not meeting criteria for intensity of infection of the cohort for which screening was conducted (56%), laboratory values outside the protocol specified range (26%), ocular disease inconsistent with the eligibility criteria of the cohort for which screening was performed (7%), hypertension (6%) and others (5%, including age outside protocol specified range, orthostatic hypotension, pregnancy, weight below the limit specified in the eligibility criteria, history of neurologic/neuropsychiatric disorder/epilepsy). 5. All participants received the treatment they had been randomized to and completed the intervention (single dose study). 6. mITT modified intent to treat population including all treated participants. Safety analysis population. 7. e-mITT efficacy modified intent to treat population, including all participants who completed the study. Efficacy analysis was conducted for the e-mITT and the mITT population. 6 participants did not complete the study: 1 who died due to a snake bite, 1 who decided to withdraw from the study and 4 who were lost to follow up, i.e. could not be located despite several attempts.</p

Skin microfilariae density in individual participants pre-treatment (0) and at the different times post-treatment (e-mITT population) in the four treatment groups.

<p>A Ivermectin. The data for the three participants treated with ivermectin whose decrease in skin microfilariae levels did not meet the criteria of ‘adequate response’ are indicated by markers at the evaluation time points. B 2 mg moxidectin, C 4 mg moxidectin, D 8 mg moxidectin.</p