Safety and Efficacy of Levamisole in Loiasis: A Randomized, Placebo-controlled, Double-blind Clinical Trial.

BACKGROUND: Individuals with high microfilarial densities (MFDs) of Loa loa are at risk of developing serious adverse events (SAEs) after ivermectin treatment. Pretreatment with drugs progressively reducing Loa MFDs below the risk threshold might help prevent these SAEs. We assessed the safety and efficacy of levamisole for this purpose. METHODS: A double-blind, randomized, placebo-controlled, MFD-ascending trial was conducted in the Republic of the Congo. Participants were treated in 3 cohorts defined by pretreatment MFD and levamisole dose (cohort 1: 1.0kg and 1.5mg/kg; cohorts 2 and 3: 2.5mg/kg). Safety outcomes were occurrence of SAE and adverse event frequency during the first week. The efficacy outcomes were MFD reduction from baseline and proportions of individuals with at least 40% and 80% MFD reduction at day 2 (D2), D7, and D30. RESULTS: The 2 lowest doses (1.0mg/kg and 1.5mg/kg) caused no SAEs but were ineffective. Compared with placebo, 2.5mg/kg levamisole caused more mild adverse events (10/85 vs. 3/85, P=.018), a higher median reduction from baseline to D2 (-12.9% vs. +15.5%, P<.001), D7 (-4.9% vs. +18.7%, P<.001), and D30 (-0.5% vs. +13.5%, P=.036) and a higher percentage of participants with >40% MFD reduction at D2 (17.5% vs. 1.2%, P<.001), D7 (11.8% vs. 6.3%, P=.269), and D30 (18.5% vs. 9.6%, P=.107). CONCLUSIONS: A single 2.5mg/kg levamisole dose induces a promising transient reduction in Loa loa MFDs and should encourage testing different regimens.

Adverse reactions with levamisole vary according to its indications and misuse: A systematic pharmacovigilance study.

Levamisole was initially prescribed for the treatment of intestinal worms. Because of immunomodulatory properties, levamisole has been used in inflammatory pathologies and in cancers in association with 5-fluorouracil. Levamisole is misused as a cocaine adulterant. Post-marketing reports have implicated levamisole in the occurrence of adverse drug reactions (ADRs) and its use is now limited in Europe and North America. In contrast, all other parts of the World continue to use single-dose levamisole as an anthelmintic. The aim of this study was to identify ADRs reported after levamisole exposure in VigiBase, the World Health Organisation's pharmacovigilance database, and analyse their frequency compared to other drugs and according to levamisole type of use. METHODS: All levamisole-related ADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate psychiatric, hepatobiliary, renal, vascular, nervous, blood, skin, cardiac, musculoskeletal and general ADRs associated with levamisole and other drugs exposure. In secondary analyses, we compared the frequency of ADRs between levamisole and mebendazole and between levamisole type of use. RESULTS: Among the 1763 levamisole-related ADRs identified, psychiatric disorders (reporting odds ratio with 95% confidence intervals: 1.4 [1.2-2.6]), hepatobiliary disorders (2.4 [1.9-4.3]), vasculitis (6.5 [4.1-10.6]), encephalopathy (22.5 [17.4-39.9]), neuropathy (4.3 [2.9-7.1]), haematological disorders, mild rashes and musculoskeletal disorders were more frequently reported with levamisole than with other drug. The majority of levamisole-related ADRs occurred when the drug was administrated for a non-anti-infectious indication. CONCLUSION: The great majority of the levamisole-related ADRs concerned its immunomodulatory indication and multiple-dose regimen. Our results suggest that single-dose treatments for anthelmintic action have a good safety profile.

Results From 2 Cohort Studies in Central Africa Show That Clearance of Wuchereria bancrofti Infection After Repeated Rounds of Mass Drug Administration With Albendazole Alone Is Closely Linked to Individual Adherence.

BACKGROUND: Two community trials conducted from 2012 to 2018 in the Republic of Congo and the Democratic Republic of the Congo demonstrated the efficacy of semiannual mass drug administration (MDA) with albendazole (ALB) alone on lymphatic filariasis (LF). However, a high interindividual heterogeneity in the clearance of infection was observed. METHODS: We analyzed trial data to assess the effect of individual adherence to ALB MDA on clearance of circulating filarial antigenemia (CFA) and microfilaremia. Community residents were offered a single dose of ALB every 6 months and tested for LF with a rapid test for CFA at baseline and then annually. CFA test results were scored on a semiquantitative scale. At each round, microfilaremia was assessed in CFA-positive individuals. All CFA-positive individuals for whom at least 1 follow-up measure was available were included in the analyses. Parametric survival models were used to assess the influence of treatment adherence on LF infection indicators. RESULTS: Of 2658 individuals enrolled in the trials, 394 and 129 were eligible for analysis of CFA and microfilaremia clearance, respectively. After adjusting for age, sex, and initial CFA score, the predicted mean time for clearing CFA was shorter in persons who had taken 2 doses of ALB per year (3.9 years) than in persons who had taken 1 or 0 dose (4.4 and 5.3 years; P < .001 for both). A similar pattern was observed for microfilaremia clearance. CONCLUSIONS: These results demonstrate a clear dose-response relationship for the effect of ALB on clearance of CFA and microfilaremia.

Evaluation of a novel biplex rapid diagnostic test for antibody responses to Loa loa and Onchocerca volvulus infections.

BACKGROUND: Endemic to Central Africa, loiasis, caused by the vector-borne worm Loa loa, affects approximately 10 million individuals. Clinical manifestations include transient angioedema (Calabar swellings), migration of the adult worm under the eye conjunctiva (eye worm) and less specific general symptoms. Loiasis presents a significant public health challenge because L. loa-infected individuals can develop serious adverse events after taking ivermectin, the drug used to combat onchocerciasis. In this context, alternative interventions and rigorous diagnostic approaches are needed. Diagnosing loiasis is challenging because its main clinical manifestations are sporadic and non-specific. The definitive diagnosis relies on identifying adult worms migrating beneath the conjunctiva, or microfilariae (pre-larvae) in blood smears. However, "occult loiasis" (infection without blood microfilariae) is frequent. Serological rapid antibody diagnostic tests (ARTs) can provide an alternative diagnostic method. We compared a novel ART simultaneously targeting onchocerciasis (IgG4 to Ov-16 and OvOC3261, test line 1) and loiasis (IgG4 to L1-SXP-1, test line 2), called IgG4-SXP-1 biplex test) to the already established Loa-ART (all IgG isotypes to Ll-SXP-1, called pan-IgG-SXP-1 test). METHODOLOGY: Blood samples underwent both ARTs, read qualitatively and semi-quantitatively. Additionally, blood smears, skin snips, Kato-Katz method for soil-transmitted helminthiases identification and eosinophilia measurements were performed. Questionnaires gathered demographic details and loiasis-related signs. ARTs performance was compared using specific loiasis-related signs and microfilaremia as references. Discordances between the two ARTs were investigated using logistic regression models. PRINCIPAL FINDINGS: Out of 971 participants, 35.4% had L. loa microfilaremia, 71.9% had already experienced loiasis-related signs, 85.1% were positive in the pan-IgG-SXP-1 test and 79.4% were positive in the IgG4-SXP-1 biplex test. In the microfilariae-positive population, the sensitivity of the rapid tests was 87.4% for the pan-IgG-SXP-1 test and 88.6% for the prototype IgG4-SXP-1 biplex test. Sensitivity was similar for both ARTs when using eye worm or Calabar swelling as references, but diagnostic performance varied based on microfilaremia levels and occult loiasis. Overall, IgG4-SXP-1 biplex test demonstrated a sensitivity of 84.1% and specificity of 47.6% for loiasis compared to the pan-IgG-SXP-1 test, leading to a Kappa coefficient estimated at 0.27 ± 0.03 for the qualitative results of the 2 ARTs. In the group that tested positive with the Pan-IgG test but negative with the IgG4-specific test, there was a lower prevalence of STH infection (p = 0.008) and elevated eosinophilia (p<0.001) compared to the general tested population. CONCLUSION/SIGNIFICANCE: The sensitivity of each test was good (84-85%) but the diagnostic agreement between the two ARTs was poor, suggesting that IgG and IgG4 antibody responses should be interpreted differently. The assessment of the innovative rapid diagnostic IgG4-SXP-1 biplex test, designed for onchocerciasis and loiasis, shows encouraging sensitivity but underlines the necessity for further in vitro assessment.

Association between arterial stiffness and Loa loa microfilaremia in a rural area of the Republic of Congo: A population-based cross-sectional study (the MorLo project).

BACKGROUND: Loa loa filariasis (loiasis) is still considered a relatively benign disease. However, recent epidemiologic data suggest increased mortality and morbidity in L. loa infected individuals. We aimed to examine whether the density of L. loa microfilariae (mfs) in the blood is associated with cardiovascular disease. METHODOLOGY: Using a point-of-care device (pOpmètre), we conducted a cross-sectional study to assess arterial stiffness and peripheral arterial disease (PAD) in 991 individuals living in a loiasis-endemic rural area in the Republic of the Congo. Microfilaremic individuals were matched for age, sex and village of residence with 2 amicrofilaremic subjects. We analyzed markers of arterial stiffness (Pulse-Wave Velocity, PWV), PAD (Ankle-Brachial Index, ABI) and cardiovascular health (Pulse Pressure, PP). The analysis considered parasitological results (L. loa microfilarial density [MFD], soil-transmitted helminths infection, asymptomatic malaria and onchocerciasis), sociodemographic characteristics and known cardiovascular risk factors (body mass index, smoking status, creatininemia, blood pressure). PRINCIPAL FINDINGS: Among the individuals included in the analysis, 192/982 (19.5%) and 137/976 (14.0%) had a PWV or an ABI considered out of range, respectively. Out of range PWV was associated with younger age, high mean arterial pressure and high L. loa MFD. Compared to amicrofilaremic subjects, those with more than 10,000 mfs/mL were 2.17 times more likely to have an out of range PWV (p = 0.00). Factors significantly associated with PAD were older age, low pulse rate, low body mass index, smoking, and L. loa microfilaremia. Factors significantly associated with an elevation of PP were older age, female sex, high average blood pressure, low pulse rate and L. loa microfilaremia. CONCLUSION: A potential link between high L. loa microfilaremia and cardiovascular health deterioration is suggested. Further studies are required to confirm and explore this association.

Safety and Short-term Efficacy of a Single Dose of 2†mg Moxidectin in Loa loa-Infected Individuals: A Double-Blind, Randomized Ivermectin-Controlled Trial With Ascending Microfilarial Densities.

Background: In 2018, the US Food and Drug Administration approved the macrocylic lactone moxidectin (MOX) at 8 mg dosage for onchocerciasis treatment in individuals aged ≥12 years. Severe adverse reactions have occurred after ivermectin (IVM), also a macrocyclic lactone, in individuals with high Loa microfilarial density (MFD). This study compared the safety and efficacy of a 2 mg MOX dose and the standard 150 µg/kg IVM dose in individuals with low L loa MFD. Methods: A double-blind, randomized, ivermectin-controlled trial of a 2 mg moxidectin dose was conducted in Cameroon between May and July 2022. It enrolled 72 adult men with L loa MFD between 5 and 1000 microfilariae/mL. Outcomes were occurrence of adverse events (AEs) and L loa MFD reduction rate during the first month off treatment. Results: No serious or severe AEs occurred among the 36 MOX- or the 36 IVM-treated individuals. Forty-nine AEs occurred in the MOX arm versus 59 AEs in the IVM arm. Grade 2 AE incidence was higher among IVM- than MOX-treated participants (38.5% and 14.3%, respectively, P = .043). Median MFD reduction rates were significantly higher after IVM than MOX at day 3 (70.2% vs 48.5%), day 7 (76.4% vs 50.0%), and day 30 (79.8% vs 48.1%). Conclusions: A single 2 mg MOX dose is as safe as 150 µg/kg IVM in patients with low L loa MFD. Further studies with higher MOX doses and in patients with higher MFD are warranted. Clinical Trials Registration: NCT04049851.

[Reliability evaluation in rural Congo of the calibrated blood smear technique to assess Loa loa microfilaremia level]. / Évaluation en milieu rural au Congo de la fiabilité de la méthode de la goutte épaisse calibrée pour évaluer le niveau de la microfilarémie à Loa loa.

Background-Rationale: The diagnosis of Loa loa microfilaremia consists in the observation, using a microscope, of microfilariae in a sample of peripheral blood spread on a slide and subsequently stained (the "blood smear technique"). The accurate quantification of Loa loa microfilaremia is important because the choice of the first intention treatment depends on the patient's microfilaremia: severe adverse events can occur in individuals with high microfilarial densities when treated with ivermectin or diethylcarbamazine, the latter drug being the only one which can definitively cure the infection. However, despite the widespread usage of this technique and its role in guiding clinical management of the patient, estimates of its reliability remain scarce. Materials and methods: We evaluated the reliability (reproducibility and repeatability) of blood smear technique using several sets of 10 L. loo-positive slides, randomly selected, and considered the results with regard to regulatory requirements. The slides had been prepared as part of a clinical trial conducted in Sibiti, Republic of Congo, a region where loiasis is endemic. Results: The estimated and acceptable coefficients of repeatability (NB: the lower, the better) were 13.6% and 16.0%, respectively. The estimated and acceptable coefficients of intermediate reliability (reproducibility) were 15.1% and 22.5%, respectively. The poorest coefficient of intermediate reliability was 19.5% when the tested parameter was related to the technician who performed the readings (10.7% when the reading day was changed). The inter-technician coefficient of variation assessed using 1876 L. loo-positive slides was 13.2%. The coefficient of inter-technician variation considered acceptable was estimated at 18.6%. Discussion-Conclusion. All estimated coefficients of variability were lower than the calculated acceptable coefficients suggesting reliability of the technique, although the lack of laboratory references precludes any conclusion on the quality of this diagnosis. It is imperative to implement a quality system and standardization of procedures for the diagnosis of L. loo microfilaremia, both in endemic countries and in the rest of the world, where the demand for diagnosis has been increasing for years.

Temporal variability of Loa loa microfilaraemia.

BACKGROUND: The diurnal periodicity of Loa loa microfilaraemia is well known but few studies have documented the short- and long-term stability of microfilarial density. It seems stable over time at the community level, but significant variations have been observed at the individual level. METHODS: We assessed the temporal variability of L. loa microfilaraemia at 5-day, 1-month and 16-month intervals and analyzed the influence of sex, age, level of microfilaraemia, temperatures and time of sampling on this variability. RESULTS: At the community level, L. loa microfilaraemia is very stable over time at 5-day, 1-month and 16-month intervals (Pearson correlation coefficients of 0.92, 0.91 and 0.78, respectively, all three with P < 0.001). However, some individuals had significant variations of up to ± 50% of their initial microfilaraemia at 5-day (33.0%), 1-month (36.5%) and 16-month (62.6%) intervals, even in individuals with an initial microfilaraemia density > 20,000 mf/ml (7.7, 23.1 and 41.4%, respectively, for 5 days, 1 month and 16 months). We do not highlight any external factors that have a major impact on this variability. CONCLUSION: Although at the community level, microfilaria density is very stable, we highlight some individuals with large variations in both the short and long term, which may have an important impact on onchocerciasis control campaigns and longitudinal studies evaluating the impact of an intervention on L. loa microfilaraemia.

Association between altered cognition and Loa loa microfilaremia: First evidence from a cross-sectional study in a rural area of the Republic of Congo.

BACKGROUND: Individuals with high Loa loa microfilarial densities are at risk of developing severe encephalopathy after administration of antiparasitic drugs. Apart from this finding, loiasis is considered benign with no effect on brain function. However, recent epidemiological data suggest an increased mortality and morbidity in L. loa infected individuals, underscoring the importance of studies on the possible neurological morbidity associated with loiasis. METHODOLOGY: Using MoCA tests and neurological ultrasounds, we conducted a cross-sectional study to assess cognitive alteration in a population living in a rural area endemic for loiasis in the Republic of Congo. Fifty individuals with high microfilarial densities (MFD) were matched on sex, age and residency with 50 individuals with low MFD and 50 amicrofilaremic subjects. Analyses focused on individuals with MoCA scores indicating an altered cognition (i.e. < 23/30) and on the total MoCA score according to Loa loa MFD, sociodemographic characteristics and neurological ultrasound results. PRINCIPAL FINDINGS: MoCA scores were very low in the studied population (mean of 15.6/30). Individuals with more than 15,000 microfilariae per milliliter of blood (mean predicted score:14.0/30) are more than twenty times more likely to have an altered cognition, compared to individuals with no microfilaremia (mean predicted score: 16.3/30). Years of schooling were strongly associated with better MoCA results. Extracranial and intracranial atheroma were not associated with L. loa MFD. CONCLUSION/SIGNIFICANCE: Loaisis microfilaremia is probably involved in cognitive impairment, especially when the MFD are high. These results highlight the urgent need to better understand loaisis-induced morbidity. Further studies investigating neurological morbidity of loiasis are needed.

Loa loa and Mansonella perstans microfilaremia in the department of Lékoumou, Republic of Congo.

BACKGROUND: Loiasis is endemic in the northern and western part of the Republic of Congo. Between 2004 and 2010, surveys were conducted, using the RAPLOA method, in all departments of the Republic of Congo to assess the distribution of loiasis. Prior to 2004, only two parasitological surveys on loiasis had been conducted in Congo and mainly in the Department of Lékoumou, in the southwestern of the country. In 2019, we conducted a parasitological survey in this same department, more than 30 years after the first surveys. METHODS: The study was conducted in 21 villages. Loa loa and Mansonella perstans microfilaremia levels were quantified using 50 µl calibrated blood smears. RESULTS: A total of 2444 individuals were examined. The median age of the screened individuals was 43 (interquartile range: 30-57, range: 18-91) years old. The overall prevalences of L. loa and M. perstans microfilaremia were 20.0% [95% confidence intervals (CI) 18.0-21.6%] and 1.0% (95% CI 0.6-1.4%) respectively. The proportion of individuals with a microfilarial density of L. loa > 8000 mf/ml and > 30,000 mf/ml were 5.1% (95% CI 4.3-6.1%) and 1.1% (95% CI 0.8-1.7%), respectively. The overall community microfilarial load was 3.4 mf/ml. CONCLUSIONS: Prevalences and intensities of L. loa infection remained generally stable between the late 1980s and 2019 in the Lékoumou Department. In contrast, parasitological indicators for M. perstans have declined sharply in the intervening years for an unknown reason.

Excess Mortality Associated With Loiasis: Confirmation by a New Retrospective Cohort Study Conducted in the Republic of Congo.

Background: Loiasis (Loa loa filariasis) is considered a benign disease and is currently not included in the World Health Organization's (WHO's) list of Neglected Tropical Diseases, despite mounting evidence suggesting significant disease burden in endemic areas. We conducted a retrospective cohort study to assess the mortality associated with L. loa microfilaremia in the Southwestern Republic of Congo. Methods: The cohort included 3329 individuals from 53 villages screened for loiasis in 2004. We compared mortality rates in 2021 for individuals initially diagnosed as with or without L. loa microfilariae 17 years earlier. Data were analyzed at the community level to calculate crude mortality rates. Survival models were used to estimate the effect of L. loa microfilaremia on mortality in the population. Results: At baseline, prevalence of microfilaremia was 16.2%. During 17.62 years of cohort follow-up, 751 deaths were recorded, representing a crude mortality rate of 15.36 (95% CI, 14.28-16.50) per 1000 person-years. Median survival time was 58.5 (95% CI, 49.7-67.3) years and 39.2 (95% CI, 32.6-45.8) years for amicrofilaremic and microfilaremic indiviudals, respectively. Conclusions: A significant reduction in life expectancy was associated with L. loa microfilaremia, confirming previous observations from Cameroon. This adds to the evidence that loiasis is not a benign disease and deserves to be included in the WHO's list of Neglected Tropical Diseases.

Association between blood Loa loa microfilarial density and proteinuria levels in a rural area of the Republic of Congo (the MorLo project): a population-based cross-sectional study.

BACKGROUND: Case reports have hypothesised that proteinuria, sometimes with glomerulopathy or nephrotic syndromes, might be associated with loiasis. To our knowledge, no study has been done to assess this association. We aimed to investigate the association between Loa loa microfilariae burden and proteinuria. METHODS: We did a cross-sectional study between May 16, 2022, and June 11, 2022, to assess the relationship between Loa loa microfilaraemia densities and proteinuria in a rural area of the Republic of Congo. We included all consenting adults living in the target area at study commencement who had L loa microfilarial densities greater than 500 microfilariae per mL during previous screening for a clinical trial in 2019. This study is part of the MorLo project, and used the project's study population of individuals aged 18 years or older who were living near Sibiti. For each microfilaraemic individual, two individuals without L loa microfilarial densities matched on age, sex, and place of residence were included. The association between proteinuria (assessed by dipstick) and L loa microfilarial densities, age, and sex was assessed using an unconstrained ordinal regression model since the parallel-lines assumption was violated for microfilarial densities. FINDINGS: 991 participants were included, of whom 342 (35%) were L loa microfilaraemic. The prevalence of microfilaraemia was 38% (122 of 325) among individuals with trace proteinuria (<300 mg/24 h), 51% (45 of 89) among individuals with light proteinuria (300 mg to 1 g/24 h), and 71% (15 of 21) among individuals with high proteinuria (>1 g/24 h). Individuals with high proteinuria had significantly higher L loa microfilarial densities (p<0·0001): mean microfilariae per mL were 1595 (SD 4960) among individuals with no proteinuria, 2691 (7982) for those with trace proteinuria, 3833 (9878) for those with light proteinuria, and 13 541 (20 118) for those with high proteinuria. Individuals with 5000-14 999 microfilariae per mL and individuals with 15 000 microfilariae per mL or greater were, respectively, 5·39 and 20·49 times more likely to have a high proteinuria than individuals with no microfilaraemia. INTERPRETATION: The risk of proteinuria increases with L loa microfilaraemia. Further studies are needed to identify renal disorders (eg, tubulopathies, glomerulopathies, or nephrotic syndromes) responsible for loiasis-related proteinuria. FUNDING: European Research Council, MorLo project. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Factors associated with the periodicity of Loa loa microfilaremia in the Republic of the Congo.

BACKGROUND: Loa loa microfilariae circulate in the peripheral blood of human hosts following a diurnal periodicity, with maximal microfilaremia levels generally observed between 10:00 am and 3:00 pm. Few studies have assessed factors potentially associated with this periodicity. METHODS: Microfilaremia data were collected repeatedly between 9:00 am and 8:00 pm from 13 individuals in the Republic of the Congo. Using local polynomial regression (LOESS), we determined the best models representing the dynamics of microfilaremia over this period. In a second step, using cosinor models, we evaluated the influence of sex, age, and body temperature on the periodicity of L. loa microfilaremia in blood. RESULTS: All subjects reached their maximum microfilaremia between 10:00 am and 4:00 pm. Individual microfilaremia showed different patterns between individuals, and some clearly showed multiple peaks within a day. LOESS provided a good fit to the observed data. Without adjustment, the maximum microfilarial density was reached around 11:00 am. Adjustment revealed three distinct modes of microfilaremia, occurring around 10:00 am, 1:00 pm, and 4:00 pm. Cosinor models also provided good fit to our data. After adjustment on body temperature, the L. loa microfilaremia fluctuation amplitude decreased significantly from 1684.8 to 310.6 microfilariae(mf)/ml and the predicted peak was estimated at 12:02 pm. CONCLUSIONS: We characterized the periodicity of L. loa microfilaremia mathematically with two different approaches: cosinor models and LOESS regression. Both models suggest that body temperature plays a role in the variation in microfilaremia within a day. Further studies are needed to identify individual co-factors affecting microfilaremia.

Serious adverse reactions associated with ivermectin: A systematic pharmacovigilance study in sub-Saharan Africa and in the rest of the World.

BACKGROUND: Ivermectin is known to cause severe encephalopathies in subjects infected with loiasis, an endemic parasite in Sub-Saharan Africa (SSA). In addition, case reports have described ivermectin-related serious adverse drug reactions (sADRs) such as toxidermias, hepatic and renal disorders. The aim of this study was to identify suspected sADRs reported after ivermectin administration in VigiBase, the World Health Organization's global individual case safety reports database and analyze their frequency relative to the frequency of these events after other antinematodal drugs reported in SSA and other areas of the world (ROW). METHODS: All antinematodal-related sADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate nervous, cutaneous, psychiatric, respiratory, renal, hepatic and cardiac suspected sADRs reported after ivermectin and benzimidazole drug administration across the world, in SSA and RoW. PRINCIPAL FINDINGS: 2041 post-ivermectin or post-benzimidazole suspected sADRs were identified including 667 after ivermectin exposure (208 in SSA and 459 in the RoW). We found an increased reporting for toxidermias, encephalopathies, confusional disorders after ivermectin compared to benzimidazole drug administration. Encephalopathies were not only reported from SSA but also from the RoW (adjusted reporting odds ratios [aROR] 6.30, 95% confidence interval: 2.68-14.8), highlighting the fact these types of sADR occur outside loiasis endemic regions. CONCLUSION: We described for the first time suspected sADRs associated with ivermectin exposure according to geographical origin. While our results do not put in question ivermectin's excellent safety profile, they show that as for all drugs, appropriate pharmacovigilance for adverse reactions is indicated.

A strong effect of individual compliance with mass drug administration for lymphatic filariasis on sustained clearance of soil-transmitted helminth infections.

BACKGROUND: The impact of semiannual mass drug administration (MDA) with albendazole (ALB; 400 mg) alone on lymphatic filariasis (LF) and soil-transmitted helminth (STH) infections was assessed during two trials conducted from 2012 to 2018 in the Republic of Congo and the Democratic Republic of Congo. The collected data were analyzed to evaluate the effect of compliance with ALB treatment on STH infections. METHODS: STH infections were diagnosed with duplicate Kato-Katz thick smears and the results are reported as eggs per gram of stool. All subjects with at least two STH infection assessments were included in the analyses. We used parametric survival models to assess the influence of compliance with ALB treatment on the probability of (i) achieving sustained clearance of an STH infection, and (ii) acquiring an STH infection during the follow-up. RESULTS: Out of 2658 subjects included in the trials, data on 202 participants (701 person-years; PY) with hookworm infection, 211 (651 PY) with Ascaris lumbricoides infection and 270 (1013 PY) with Trichuris trichiura infection were available to calculate the probability of achieving sustained clearance of infection. The effect of ALB was dose related for all three STH. For hookworm, the time required for sustained clearance was longer (4.3 years, P < 0.001) for participants who took zero doses per year and shorter (3.4 years, P = 0.112) for participants who took two doses per year compared to those who took one dose per year (3.7 years). For Ascaris, the time required to obtain sustained clearance followed the same pattern: 6.1 years (P < 0.001) and 3.2 years (P = 0.004) vs 3.6 years for, zero, two and one dose per year, respectively. For Trichuris, less time was required for sustained clearance (4.2 years, P < 0.001) for fully compliant participants, i.e. those who took two doses per year, than for those who only took one dose per year (5.0 years). ALB was more effective in achieving sustained clearance of STH infection in subjects with light baseline infection intensities compared to those with higher egg counts. CONCLUSION: Our results illustrate the importance of MDA compliance at the level of the individual with respect to the STH benefit provided by semiannual ALB MDA, which is used for the elimination of LF in Central Africa.

Effect of Lymphatic Filariasis and Hookworm Infection on Pregnancy Course and Outcome in Women Living in the Democratic Republic of the Congo.

Little is known about the effect of helminth infections on the natural gynecological and pregnancy course. Our goal was to assess the relationship between Wuchereria bancrofti and hookworm (HW) infections with pregnancy course and outcome in a group of 82 women living in a rural area of the Democratic Republic of the Congo. Demographics and information on gynecological and obstetrical histories were collected retrospectively with standardized questionnaires. Wuchereria bancrofti and HW infections were diagnosed using a filarial antigen-detection test and the Kato-Katz method, respectively. Analyses consisted of multivariable logistic regressions adjusting for age, number of deliveries, and history of anthelmintic treatment (HAHT). The median age of study participants was 35 (interquartile range [IQR]: 30-44) years, and the median number of deliveries was five (IQR: 3-7). Wuchereria bancrofti and HW infection rates were 44.5% and 43.3%, respectively. Filarial antigenemia and HW infection were not significantly associated with the number of deliveries. The proportions of women with a history of pregnancy resulting in neonatal death, miscarriage, premature birth, and postpartum hemorrhage were 56%, 44%, 23%, and 36%, respectively. History of pregnancy associated with neonatal death was less frequent in women with HAHT, tended to be more frequent in women with filarial antigenemia, and was not associated with HW infection. None of the three other pregnancy events studied (miscarriage, premature birth, and postpartum hemorrhage) were associated with filarial antigenemia or HW infection. The positive association found between HAHT and lower risk of neonatal death warrants investigation in larger groups of women.

Individuals living in an onchocerciasis focus and treated three-monthly with ivermectin develop fewer new onchocercal nodules than individuals treated annually.

BACKGROUND: Little information is available on the effect of ivermectin on the third- and fourth-stage larvae of Onchocerca volvulus. To assess a possible prophylactic effect of ivermectin on this parasite, we compared the effects of different ivermectin regimens on the acquisition of onchocercal nodules. METHODS: We analyzed data from a controlled randomized clinical trial of ivermectin conducted in the Mbam Valley (Cameroon) between 1994 and 1998 in a cohort of onchocerciasis infected individuals. The number of nodules that appeared between the start and the end of the clinical trial was analyzed, using ANOVA and multivariable Poisson regressions, between four treatment arms: 150 µg/kg annually, 800 µg/kg annually, 150 µg/kg 3-monthly, and 800 µg/kg 3-monthly. RESULTS: The mean number of nodules that appeared during the trial was reduced by 17.7% in subjects treated 3-monthly compared to those treated annually (regardless of the dose). Poisson regression model, adjusting on subject's age and weight, initial number of nodules and intensity of O. volvulus infection in his village of residence, confirmed that the incidence of new nodules was reduced in 3-monthly treatment arms compared to annually treatment arms, and that the dosage of ivermectin does not seem to influence this effect. Furthermore, the number of newly acquired nodules was positively associated with the initial number of nodules. Analysis of disappearance of nodules did not show any significant difference between the treatment groups. CONCLUSIONS: To our knowledge, these results suggest for the first time in humans, that ivermectin has a partial prophylactic effect on O. volvulus. Three-monthly treatment seems more effective than annual treatment to prevent the appearance of nodules.

A Second Population-Based Cohort Study in Cameroon Confirms the Temporal Relationship Between Onchocerciasis and Epilepsy.

To confirm our earlier evidence of a temporal and dose-response relationship between onchocerciasis and epilepsy, we conducted another cohort study in a different setting in Cameroon. Individuals whose Onchocerca volvulus microfilarial density (Ov-MFD) was measured in 1992-1994 when they were children were revisited in 2019 to determine if they acquired epilepsy. With reference to individuals with no microfilariae in 1992-1994, the relative risks of acquiring epilepsy were 0.96, 2.76, 3.67, and 11.87 in subjects with initial Ov-MFD of 1-7, 8-70, 71-200, and > 200 microfilariae per skin snip, respectively. This study further demonstrates reproducibility using the Bradford Hill's criteria for causality.