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The Global Programme to Eliminate Lymphatic Filariasis (LF) is using mass drug administration (MDA) of antifilarial medications to treat filarial infections, prevent disease and interrupt transmission. Almost 500 million people receive these medications each year. Clinical trials have recently shown that a single dose of a triple-drug combination comprised of ivermectin, diethylcarbamazine and albendazole (IDA) is dramatically superior to widely used two-drug combinations for clearing larval filarial parasites from the blood of infected persons. A large multicenter community study showed that IDA was well-tolerated when it was provided as MDA. IDA was rapidly advanced from clinical trial to policy and implementation; it has the potential to accelerate LF elimination in many endemic countries. [ABSTRACT FROM AUTHOR]

Background: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings.Methods and Findings: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites.Conclusions: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA.Trial Registration: Clinicaltrials.gov registration number: NCT02899936. [ABSTRACT FROM AUTHOR]

The article discusses the therapeutic effects of the triple drug therapy in the treatment program for lymphatic filariasis and onchocerciasis in Africa. It mentions the benefits and challenges of the use of ivermectin, diethylcarbamazine, and albendazole. It also mentions the apprehension on the use of diethylcarbamazine due to adverse effects of ocular diseases.

Abstract: Genetic characterization of field isolates and clinical specimens of filarial nematodes is often limited by a shortage of DNA; therefore, we evaluated a multiple displacement amplification (MDA) based whole genome amplification method. The quality of amplified DNA was examined by conventional PCR, real-time PCR, and DNA hybridization. MDA of 5.0ng of adult Brugia malayi DNA and one-fifteenth of the DNA isolated from a single microfilaria resulted in 6.3 and 4.2μg of amplified DNA, respectively. Amplified DNA was equivalent to native genomic DNA for hybridization to B. malayi BAC library clones or to an oligonucleotide microarray with approximately 18,000 filarial DNA sequences. MDA is useful for whole genome amplification of filarial DNA from very small amounts of starting material. This technology will permit detailed studies of genetic diversity that were not previously feasible. [Copyright &y& Elsevier]

The ambitious and exciting Global Programme to Eliminate Lymphatic Filariasis (GPELF) is largely based on a strategy of mass drug administration (MDA) of repeated rounds of antifilarial medications to endemic populations around the world. Diagnostic tools are important to GPELF because they affect decisions regarding where to distribute MDA, how to measure its effects, how to define targets and endpoints for stopping MDA, and how to monitor populations for possible resurgence of filariasis transmission following suspension of MDA. This article reviews available diagnostic tests for filariasis and their potential use as tools for different phases of filariasis elimination programs. [Copyright &y& Elsevier]

The article offers information on the single-dose triple-drug therapy for Wuchereria bancrofti. It discusses the limitation of treatment with ivermectindiethylcarbamazine-albendazole. It mentions the need for different surveillance strategy to assess the effect of the three-drug regimen on lymphatic filariasis populations.

Human IgG antibody responses to Wuchereria bancrofti third stage infective larvae (L3) surface and somatic antigens were studied by indirect immunofluorescence (IFA) and immunoblot with endemic Egyptian sera (n = 115) with the aim of identifying targets of protective immunity. Human sera variably recognized 14 major bands in L3 by immunoblot. The statistical significance of group differences in antibody prevalence was assessed by the chi-squared test. Children and young adults (aged 10–20 years) tended to have antibodies to more L3 somatic antigens than older adults, with significant differences for bands at 66, 60 and 5 kDa. Infected subjects had more consistent antibody responses to antigens at 55, 50 and 6 kDa than endemic normal subjects with negative serum filarial antigen tests, who are presumed to be uninfected. A 5 kDa antigen was preferentially recognized by the latter group. Antibodies to L3surface antigens were equally prevalent in uninfected children (75%) and adults (90%) but less prevalent in people with microfilaremia (38%) than in amicrofilaremic subjects with or without filarial antigenemia (81%) (P < 0.001). IFA-positive sera showed significantly enhanced recognition of antigens at 66, 40 and 14 kDa in immunoblots relative to IFA-negative sera. Additional studies are needed to further characterize antigens identified in this study and to establish whether they are indeed targets of protective immunity in humans. [ABSTRACT FROM AUTHOR]

Background: Loiasis is a disease caused by the nematode Loa loa. Serious adverse events sometimes occur in people with heavy L. loa microfilaremia after ivermectin treatment. In regions of Central Africa where loiasis is endemic, this significantly impedes global elimination programs for lymphatic filariasis and onchocerciasis that use mass distribution of ivermectin. Improved diagnostic tests to identify individuals at increased risk of serious adverse events could facilitate efforts to eliminate lymphatic filariasis and onchocerciasis in this region. Methods and findings: We previously identified the L. loa protein Ll-Bhp-1 in loiasis patient sera. Here, we further characterize Ll-Bhp-1 and report development of an antigen capture ELISA to detect this antigen. This assay detected Ll-Bhp-1 in 74 of 116 (63.8%) loiasis patient sera. Ll-Bhp-1 levels were significantly correlated with L. loa microfilarial counts, and the sensitivity of the assay was highest for samples from people with high counts, (94% and 100% in people with ≥20,000 and ≥50,000 microfilaria per milliliter of blood, respectively). The antigen was not detected in 112 sera from people with other filarial infections, or in 34 control sera from the USA. Conclusions: This Ll-Bhp-1 antigen assay is specific for loiasis, and highly sensitive for identifying people with high L. loa microfilarial counts who are at increased risk for serious adverse events after ivermectin treatment. L. loa antigen detection has the potential to facilitate loiasis mapping efforts and programs to eliminate lymphatic filariasis and onchocerciasis in Central Africa. Author summary: Lymphatic filariasis and onchocerciasis are major neglected tropical diseases that have been targeted for elimination by the World Health Organization. Elimination campaigns for these infections using mass drug administration have had a huge impact in Africa. However, they face a major challenge in 11 countries in Central Africa where there is co-endemic loiasis, another filarial infection caused by the parasite Loa loa. The anti-filarial medication ivermectin that is used in elimination programs can cause serious and fatal adverse drug events in people with heavy loiasis infections, or high blood microfilarial counts. These programs would benefit from practical and affordable screening tests to detect people at high risk of adverse events from ivermectin. Furthermore, loiasis itself causes a variety of negative health outcomes and improved diagnostic tests would help control this infection. Here, we report the development of a sandwich immunoassay that detects the L. loa protein Ll-Bhp-1 in human serum samples. This assay is specific for L. loa infection and is highly sensitive in people with high microfilarial counts. Further work is needed to refine this prototype test and to determine whether antigen testing for loiasis can facilitate filarial eliminations efforts in Central Africa. [ABSTRACT FROM AUTHOR]

Filarial nematode infections cause a substantial global disease burden. Genomic studies of filarial worms can improve our understanding of their biology and epidemiology. However, genomic information from field isolates is limited and available reference genomes are often discontinuous. Single molecule sequencing technologies can reduce the cost of genome sequencing and long reads produced from these devices can improve the contiguity and completeness of genome assemblies. In addition, these new technologies can make generation and analysis of large numbers of field isolates feasible. In this study, we assessed the performance of the Oxford Nanopore Technologies MinION for sequencing and assembling the genome of Brugia malayi, a human parasite widely used in filariasis research. Using data from a single MinION flowcell, a 90.3 Mb nuclear genome was assembled into 202 contigs with an N50 of 2.4 Mb. This assembly covered 96.9% of the well-defined B. malayi reference genome with 99.2% identity. The complete mitochondrial genome was obtained with individual reads and the nearly complete genome of the endosymbiotic bacteria Wolbachia was assembled alongside the nuclear genome. Long-read data from the MinION produced an assembly that approached the quality of a well-established reference genome using comparably fewer resources. [ABSTRACT FROM AUTHOR]

Comments on a study conducted by S.P. Pani et al. (2000) which evaluated the effectiveness of the immunochromatographic filarial test kit for detection of circulating Wuchereria bancrofti antigen. Finite sensitivity for filarial antigen in human blood of the test kit; Technical factors that affect test sensitivity; Problem related to the low microfilariae count by filter subjects with negative antigen tests.

Paragonimiasis is a zoonotic, food-borne trematode infection that affects 21 million people globally. Trematodes interact with their hosts via extracellular vesicles (EV) that carry protein and RNA cargo. We analyzed EV in excretory-secretory products (ESP) released by Paragonimus kellicotti adult worms cultured in vitro (EV ESP) and EV isolated from lung cyst fluid (EV CFP) recovered from infected gerbils. The majority of EV were approximately 30–50 nm in diameter. We identified 548 P. kellicotti-derived proteins in EV ESP by mass spectrometry and 8 proteins in EV CFP of which 7 were also present in EV ESP. No parasite-derived proteins were reliably detected in EV isolated from plasma samples. A cysteine protease (MK050848, CP-6) was the most abundant protein found in EV CFP in all technical and biological replicates. Immunolocalization of CP-6 showed strong labeling in the tegument of P. kellicotti and in the adjacent cyst and lung tissue that contained worm eggs. It is likely that CP-6 present in EV is involved in parasite-host interactions. These results provide new insights into interactions between Paragonimus and their mammalian hosts, and they provide potential clues for development of novel diagnostic tools and treatments. [ABSTRACT FROM AUTHOR]

Background: Moxidectin is a macrocyclic lactone registered for the treatment of human onchocerciasis. The drug has a good safety profile, large volume of distribution and a long elimination half-life. This paper reports tolerability data from the first use of moxidectin in persons with Wuchereria bancrofti infection. Methods: In this randomized, open-label, masked-observer superiority trial, adults with Wuchereria bancrofti microfilaremia in Côte d'Ivoire were randomized to 1 of 4 treatment arms: ivermectin + albendazole (IA), moxidectin + albendazole (MoxA), ivermectin + diethylcarbamazine (DEC) + albendazole (IDA), or moxidectin + DEC + albendazole (MoxDA). As part of a larger efficacy trial, all participants were closely monitored for 7 days after treatment. Results: One hundred sixty-four individuals were treated, and monitored for treatment emergent adverse events (TEAE). Eighty-seven participants (53%) experienced one or more mild (grade 1) or moderate (grade 2) TEAE. Four participants had transient Grade 3 hematuria after treatment (3 after IDA and 1 after IA). There were no serious adverse events. There were no significant differences in frequency or types of TEAE between treatment groups (IA = 22/41 (53%), MoxA = 24/40 (60%), IDA = 18/41 (44%), MoxDA = 15/42 (36%), p = 0.530). Fifty-nine participants (36%) had multiple TEAE, and 8.5% had a one or more grade 2 (moderate) TEAE. Grade 2 TEAE were more frequent after triple drug treatments (IDA, 14.6%; MoxDA, 9.5%) than after two-drug treatments (IA, 7.3%; MoxA, 2.5%). There was no difference in TEAEs based on baseline Mf counts (OR 0.69 (0.33, 1.43), p-value 0.319). Conclusion: All treatment regimens were well tolerated. We observed no difference in safety parameters between regimens that contained ivermectin or moxidectin. Trial registration: Clinicaltrials.gov, NCT04410406. Author summary: Lymphatic Filariasis (LF) is a mosquito-borne parasitic infection caused predominantly by Wuchereria bancrofti. Infection can lead to significant lymphatic dysfunction, including hydroceles and lymphedema, which can progress to elephantiasis. The World Health Organization's Global Programme to Eliminate LF (GPELF) recommends mass drug administration (MDA) in endemic populations to eliminate the disease. GPELF recommendations for MDA include ivermectin (IVM) plus albendazole (IA) in sub-Saharan Africa where onchocerciasis is present. In 2018 the US Food and Drug Administration approved use of moxidectin for treatment of onchocerciasis. Moxidectin is a macrocytic lactone, similar to IVM, but more lipophilic, with a larger volume of distribution and longer half-life. Onchocerciasis studies found moxidectin to be superior to IVM for clearance of microfiladermia in people with onchocerciasis, with a treatment emergent adverse event (TEAE) profile similar to that of ivermectin. Moxidectin has not yet been studied, alone or in combination with other antihelminthic drugs. This is a safety evaluation of the first trial of moxidectin combination therapy for LF, which shows that moxidectin combination regimens are well tolerated in Wuchereria bancrofti-infected patients, with a TEAE profile comparable to standard ivermectin containing regimens. [ABSTRACT FROM AUTHOR]

Background Lymphatic filariasis (LF) and malaria are important vector-borne diseases that are co-endemic throughout Nigeria. These infections are transmitted by the same mosquito vector species in Nigeria and their transmission is similarly influenced by climate and sociodemographic factors. The goal of this study was to assess the relationship between the geospatial distribution of both infections in Nigeria to better coordinate interventions. Methods We used national survey data for malaria from the Demographic and Health Survey dataset and site-level LF mapping data from the Nigeria Lymphatic Filariasis Control Programme together with a suite of predictive climate and sociodemographic factors to build geospatial machine learning models. These models were then used to produce continuous gridded maps of both infections throughout Nigeria. Results The R2 values for the LF and malaria models were 0.68 and 0.59, respectively. Also, the correlation between pairs of observed and predicted values for LF and malaria models were 0.69 (95% confidence interval [CI] 0.61 to 0.79; p<0.001) and 0.61 (95% CI 0.52 to 0.71; p<0.001), respectively. However, we observed a very weak positive correlation between overall overlap of LF and malaria distribution in Nigeria. Conclusions The reasons for this counterintuitive relationship are unclear. Differences in transmission dynamics of these parasites and vector competence may contribute to differences in the distribution of these co-endemic diseases. [ABSTRACT FROM AUTHOR]

We examined human stool samples from Liberia for soil-transmitted helminth ova by Kato-Katz smear and by quantitative PCR. Twenty-five samples were positive for Trichuris trichiura by smear but negative by quantitative PCR. Reexamination of samples showed that they contained Capillaria eggs that resemble T. trichiura in Kato-Katz smears. [ABSTRACT FROM AUTHOR]

Moxidectin (MOX) is a milbemycin endectocide recently approved by the U.S. FDA for the treatment of onchocerciasis in persons at least 12 years of age. MOX has been shown to have a good safety profile in recent clinical trials. The efficacy of MOX for the treatment of lymphatic filariasis (LF) and its potential use in mass drug administration protocols for the elimination of LF is currently under evaluation. In the context of a clinical trial, we investigated the pharmacokinetics and drug interactions of a combination of MOX plus albendazole (ALB) with or without diethylcarbamazine (DEC) compared to ivermectin (IVM) plus ALB with or without DEC in the following four different treatment arms: (I) IVM (0.2mg/kg) plus DEC (6 mg/kg) and ALB (400mg); (II) IVM plus ALB; (III) MOX (8 mg) plus DEC and ALB; and (IV) MOX plus ALB. Drug concentrations were determined using validated liquid chromatography-mass spectrometric methods. Pharmacokinetic parameters were determined using standard non-compartmental analysis methods. Statistical analysis was performed using JMP software. Fifty-eight of 164 study participants (53 men and five women) were included with ages ranging from 18 to 63 yrs (mean = 37). MOX apparent oral clearance (Cl/F) ranged from 0.7 to 10.8 L/hr with Cmax values ranging from 20.8 to 314.5 ng/mL. The mean (range) area under the curve (AUC)0-∞ for MOX, 3405 ng*hr/mL (742–11376), and IVM 1906 ng*hr/mL (692–5900), varied over a ~15.3 and ~8.5-fold range, respectively. The geometric mean ratio for Cmax, AUC0–t, and AUC0–∞ were within the no-drug interaction range of 80–125% for all drugs. This indicates that the addition of MOX to ALB alone or ALB plus DEC for LF therapy did not alter the drug exposure of co-administered drugs compared to IVM combinations. Clinical Trial Registration: NCT04410406, https://clinicaltrials.gov/. Author summary: Mass Drug administration (MDA) with multiple drugs is common for the treatment and control of lymphatic filariasis (LF). This study aimed to determine whether the incorporation of moxidectin (MOX) into MDA regimens for LF will alter the pharmacokinetics (PK) of co-administered drugs. In the context of a clinical trial, we investigated the PK and drug interactions of a combination of moxidectin (MOX) plus albendazole (ALB) with or without diethylcarbamazine (DEC) compared to ivermectin (IVM) plus ALB with or without DEC. The study was conducted in adult patients located in Côte d'Ivoire. The addition of MOX did not alter the exposure (AUC0-t) or maximum concentration (Cmax) of co-administered drugs. These results suggest the incorporation of MOX into current MDA LF treatment programs will not result in clinically significant alterations in drug exposure. [ABSTRACT FROM AUTHOR]

Paragonimiasis is a zoonotic, food-borne trematode infection that affects 21 million people globally. Trematodes interact with their hosts via extracellular vesicles (EV) that carry protein and RNA cargo. We analyzed EV in excretory-secretory products (ESP) released by Paragonimus kellicotti adult worms cultured in vitro (EV ESP) and EV isolated from lung cyst fluid (EV CFP) recovered from infected gerbils. The majority of EV were approximately 30–50 nm in diameter. We identified 548 P. kellicotti-derived proteins in EV ESP by mass spectrometry and 8 proteins in EV CFP of which 7 were also present in EV ESP. No parasite-derived proteins were reliably detected in EV isolated from plasma samples. A cysteine protease (MK050848, CP-6) was the most abundant protein found in EV CFP in all technical and biological replicates. Immunolocalization of CP-6 showed strong labeling in the tegument of P. kellicotti and in the adjacent cyst and lung tissue that contained worm eggs. It is likely that CP-6 present in EV is involved in parasite-host interactions. These results provide new insights into interactions between Paragonimus and their mammalian hosts, and they provide potential clues for development of novel diagnostic tools and treatments. [ABSTRACT FROM AUTHOR]

Background: Lymphatic filariasis (LF) is a neglected tropical disease and a major cause of chronic disability. Improved diagnostic tests are needed because of long-term persistence of anti-filarial antibodies or circulating filarial antigenemia after treatments that clear microfilaremia. Here, we assess changes in levels of antibodies to the recombinant filarial antigens Wb-Bhp-1, Wb123, and Bm14 after anti-filarial treatment. Methodology/principal findings: IgG4 antibodies to recombinant filarial antigens were assessed by ELISA. We tested serial plasma samples from a clinical trial in Papua New Guinea. Before treatment, 90%, 71% and 99% of participants had antibodies to Wb-Bhp-1, Wb123, and Bm14, respectively. Antibodies to Wb-Bhp-1 and Wb123, but not Bm14, were significantly higher in participants with persistent microfilaremia 24 months after treatment. Antibodies to all three antigens declined significantly by 60 months after treatment with ivermectin, diethylcarbamazine and albendazole despite circulating filarial antigen in 76% of participants. By 60 months follow up, antibodies to Wb-Bhp-1, Wb123, and Bm14 were detected in 17%, 7% and 90% of participants, respectively. Antibodies to Wb-Bhp-1 also declined more rapidly after treatment than antibodies to Bm14 in samples from a clinical trial conducted in Sri Lanka. We also tested archived serum samples from people living in filariasis-endemic communities in Egypt with different infection profiles. Antibodies to Wb-Bhp-1 were detected in 73% of microfilaremic people, 53% of amicrofilaremic people with circulating filarial antigen, and 17.5% of endemic individuals without microfilaria or circulating filarial antigen. Tests performed with legacy samples from India showed that few people with filarial lymphedema had antibodies to these recombinant antigens. Conclusions: Antibodies to Wb-Bhp-1 and Wb123 are more closely correlated with persistent microfilaremia than circulating filarial antigenemia or antibodies to Bm14, and they clear more rapidly after anti-filarial treatment. Additional studies are needed to assess the value of Wb-Bhp-1 serology as a tool for determining the success of LF elimination efforts. Author summary: Lymphatic filariasis (LF) is a neglected tropical disease targeted for elimination by the World Health Organization. Public health programs aim to eliminate the infection with repeated rounds of mass distribution of anti-filarial medicines in areas with LF. These mass drug administration campaigns have been highly successful. Improved diagnostic tests are needed to monitor and verify the success of infection elimination efforts. We have previously shown that detection of antibodies to the recombinant parasite protein Wb-Bhp-1 are sensitive and specific for diagnosis of active filarial infections. Here, we show that antibodies to Wb-Bhp-1 are correlated with the persistence of filarial parasites in the blood after treatment, and that they decrease after effective anti-filarial treatment. Importantly, antibodies to Wb-Bhp-1 decrease after treatment more rapidly than other diagnostic markers such as circulating filarial antigenemia or antibodies to Bm14. Thus, this antibody test may be useful as a tool for monitoring the success of filariasis elimination programs. [ABSTRACT FROM AUTHOR]

Background: The standard treatment strategy of mass drug administration with ivermectin plus albendazole for lymphatic filariasis cannot be applied in central Africa, because of the risk of serious adverse events in people with high Loa loa microfilaraemia. Thus, alternative strategies are needed. We investigated one such alternative strategy for mass drug administration for elimination of lymphatic filariasis and soil-transmitted helminth infections in Republic of the Congo.Methods: In 2012, we started a 3 year community trial of biannual mass administration of albendazole in a village in Republic of the Congo. All volunteering inhabitants aged 2 years or older were offered albendazole (400 mg) every 6 months. Infection with Wuchereria bancrofti was diagnosed with a rapid card immunochromatographic test for antigenaemia. People with antigenaemia were tested for microfilaraemia by night blood smears. Individuals were also tested for soil-transmitted helminth infections (ie, hookworm, Ascaris lumbricoides, Trichuris trichiura) with the Kato-Katz method. Assessment surveys were done at 12, 24, and 36 months. The main outcome measure was change in infection rates from baseline to year 3.Findings: Therapeutic coverage was more than 80% in all six rounds of mass administration of albendazole. Between 2012 and 2015, W bancrofti antigenaemia and microfilaraemia rates in the community fell significantly, from 17·3% (95% CI 14·7-20·0) to 4·7% (3·3-6·6; p<0·0001) and from 5·3% (3·9-7·1) to 0·3% (0·1-1·2; p<0·0001), respectively. The geometric mean microfilaria count in microfilaraemic people fell from 199·4 (120·4-330·5) per mL in 2012 to 39·1 (95% CIs not computed) per mL in 2015 (p=0·0095). Hookworm infection was undetectable after 1 year. Between 2012 and 2015, the number of A lumbricoides eggs expelled per g of faeces fell from 9844·6 (8209·0-11 480·0) to 724·4 (340·7-1114·2; p<0·0001), and of T trichiura eggs from 1107·4 (878·5-1336·3) to 366·0 (255·7-476·2; p<0·0001).Interpretation: Our findings strongly support WHO's provisional strategy of biannual mass administration of albendazole to eliminate lymphatic filariasis in areas where loiasis is co-endemic and ivermectin cannot be safely mass administered.Funding: Bill & Melinda Gates Foundation. [ABSTRACT FROM AUTHOR]

Background: Onchocerciasis ("river blindness") has been targeted for elimination. New treatments that kill or permanently sterilize female worms could accelerate this process. Prior studies have shown that triple drug treatment with ivermectin plus diethylcarbamazine and albendazole (IDA) leads to prolonged clearance of microfilaremia in persons with lymphatic filariasis. We now report results from a randomized clinical trial that compared the tolerability and efficacy of IDA vs. a comparator treatment (ivermectin plus albendazole, IA) in persons with onchocerciasis. Methods and findings: The study was performed in the Volta region of Ghana. Persons with microfiladermia and palpable subcutaneous nodules were pre-treated with two oral doses of ivermectin (150 μg/kg) separated by at least 6 months prior to treatment with either a single oral dose of ivermectin 150 μg/kg plus albendazole 400 mg (IA), a single oral dose of IDA (IDA1, IA plus diethylcarbamazine (DEC. 6 mg/kg) or three consecutive daily doses of IDA (IDA3). These treatments were tolerated equally well. While adverse events were common (approximately 30% overall), no severe or serious treatment-emergent adverse events were observed. Skin microfilariae were absent or present with very low densities after all three treatments through 18 months, at which time nodules were excised for histological assessment. Nodule histology was evaluated by two independent assessors who were masked regarding participant infection status or treatment assignment. Significantly lower percentages of female worms were alive and fertile in nodules recovered from study participants after IDA1 (40/261, 15.3%) and IDA3 (34/281, 12.1%) than after IA (41/180, 22.8%). This corresponds to a 40% reduction in the percentage of female worms that were alive and fertile after IDA treatments relative to results observed after the IA comparator treatment (P = 0.004). Percentages of female worms that were alive (a secondary outcome of the study) were also lower after IDA treatments (301/574, 52.4%) than after IA (127/198, 64.1%) (P = 0.004). Importantly, some comparisons (including the reduced % of fertile female worms after IDA1 vs IA treatment, which was the primary endpoint for the study) were not statistically significant when results were adjusted for intraclass correlation of worm fertility and viability for worms recovered from individual study participants. Conclusions: Results from this pilot study suggest that IDA was well tolerated after ivermectin pretreatment. They also suggest that IDA was more effective than the comparator treatment IA for killing or sterilizing female O. volvulus worms. No other short-course oral treatment for onchocerciasis has been demonstrated to have macrofilaricidal activity. However, this first study was too small to provide conclusive results. Therefore, additional studies will be needed to confirm these promising findings. Trial registration: The study is registered at Cinicaltrials.gov under the number NCT04188301. Author summary: Why was this study done?: Onchocerciasis is a neglected tropical disease caused by parasitic round worms. The infective worm larvae are transmitted by black flies that breed near rivers in sub-Saharan Africa. The parasites cause severe skin disease with itching and ocular disease; the common name for the infection is "river blindness". WHO has targeted onchocerciasis for elimination and mass drug administration is the key intervention strategy. There is an urgent need for improved treatments to kill or permanently sterilize the adult parasites. This study tested a combination drug treatment that is quite effective for treating other related worm infections. What did the researchers do and find?: We performed a randomized clinical trial that compared a triple drug combination with a standard of care two-drug treatment that is widely used in Africa. We found that the new treatment was as safe as the standard treatment. More importantly, analysis of adult female worms surgically removed from study participants suggested that the new treatment might be more effective than the standard treatment for killing or permanently sterilizing the parasites. However, this first study was too small to provide conclusive results. What do these findings mean?: An improved treatment could improve chances for eliminating onchocerciasis in Africa. Results from this study can be used to better plan follow-up studies to explore the value of this and other new combination treatments for onchocerciasis. [ABSTRACT FROM AUTHOR]

Abstract: Antibody tests are useful for mapping the distribution of lymphatic filariasis (LF) in countries and regions and for monitoring progress in elimination programs based on mass drug administration (MDA). Prior antibody tests have suffered from poor sensitivity and/or specificity or from a lack of standardization. We conducted a multicenter evaluation of a new commercial ELISA that detects IgG4 antibodies to the recombinant filarial antigen Bm14. Four laboratories tested a shared panel of coded serum or plasma samples that included 55 samples from people with microfilaremic Wuchereria bancrofti or Brugia infections and 26 control samples. Qualitative results were identical in all four test sites. In addition, each laboratory tested samples from their own serum banks. The test detected antibodies in 32 of 36 samples (91%) from people with Brugian filariasis and in 96 of 98 samples (98%) from people with Bancroftian filariasis. Specificity testing showed that many serum or plasma samples from patients with other filarial infections such as onchocerciasis had positive antibody tests. Specificity was otherwise excellent, although 3 of 30 samples from patients with ascariasis and 4 of 51 with strongyloidiasis had positive antibody tests; it is likely that some or all of these people had previously lived in filariasis-endemic areas. Antibody test results obtained with eluates from blood dried on filter paper were similar to those obtained with plasma tested at the same dilution. This test may be helpful for diagnosing LF in patients with clinical signs of filariasis. It may also be a useful tool for use in LF endemic countries to monitor the progress of filariasis elimination programs and for post-MDA surveillance. [Copyright &y& Elsevier]

Improved methods are needed for field diagnosis of onchocerciasis, to support efforts aimed at elimination of the disease. A rapid-format card test was evaluated that detects IgG4 antibodies to recombinant Onchocerca volvulus antigen Ov16 with serum samples from patients with oncho-cerciasis and with various types of control serum samples. The sensitivity of the test with serum samples from 106 microfilariae-positive subjects was 90.6%. The test was equally sensitive with serum samples obtained from patients in Africa and Latin America. Specificity was excellent; positive tests were observed for 2 of 38 serum samples from patients with other filarial infections and for 1 of 23 serum samples from patients with nonfilarial helminth infections. The 3 "false-positive" serum samples were from West Africans who could have been coinfected with oncho-cerciasis. No positive tests were observed with nonendemic serum samples from normal adults, patients with autoimmune disorders, or patients with the hyper-IgE syndrome. This new test holds great promise as a simple tool for diagnosis of onchocerciasis. [ABSTRACT FROM AUTHOR]

Background: Mass drug administration (MDA) is the main strategy towards lymphatic filariasis (LF) elimination. Progress is monitored by assessing microfilaraemia (Mf) or circulating filarial antigenaemia (CFA) prevalence, the latter being more practical for field surveys. The current criterion for stopping MDA requires <2% CFA prevalence in 6- to 7-year olds, but this criterion is not evidence-based. We used mathematical modelling to investigate the validity of different thresholds regarding testing method and age group for African MDA programmes using ivermectin plus albendazole. Methodolgy/Principal findings: We verified that our model captures observed patterns in Mf and CFA prevalence during annual MDA, assuming that CFA tests are positive if at least one adult worm is present. We then assessed how well elimination can be predicted from CFA prevalence in 6-7-year-old children or from Mf or CFA prevalence in the 5+ or 15+ population, and determined safe (>95% positive predictive value) thresholds for stopping MDA. The model captured trends in Mf and CFA prevalences reasonably well. Elimination cannot be predicted with sufficient certainty from CFA prevalence in 6-7-year olds. Resurgence may still occur if all children are antigen-negative, irrespective of the number tested. Mf-based criteria also show unfavourable results (PPV <95% or unpractically low threshold). CFA prevalences in the 5+ or 15+ population are the best predictors, and post-MDA threshold values for stopping MDA can be as high as 10% for 15+. These thresholds are robust for various alternative assumptions regarding baseline endemicity, biological parameters and sampling strategies. Conclusions/Significance: For African areas with moderate to high pre-treatment Mf prevalence that have had 6 or more rounds of annual ivermectin/albendazole MDA with adequate coverage, we recommend to adopt a CFA threshold prevalence of 10% in adults (15+) for stopping MDA. This could be combined with Mf testing of CFA positives to ensure absence of a significant Mf reservoir for transmission. Author summary: Mass drug administration (MDA) of antifilarial drugs is the main strategy towards the elimination of lymphatic filariasis (LF), but defining when MDA can safely be stopped is challenging. Current stopping guidelines require that the prevalence of microfilaraemia (Mf) in the population falls below 1% or the prevalence of circulating filarial antigenaemia (CFA) in 6-and-7-year-old children falls below 2%. The evidence base underlying this threshold is limited. The accuracy of this threshold is hard to assess in field studies due to the long timespan between stopping MDA and the occurrence of either elimination or resurgence. We used mathematical modelling to assess how well elimination can be predicted at community-level from the Mf or CFA prevalence observed 1-year after the last MDA round and we determined safe stopping thresholds (>95% certainty that elimination is achieved). We found that the currently used CFA prevalence in 6–7 year-old children is a poor indicator for stopping decisions in LF elimination programmes implementing MDA with ivermectin plus albendazole, and that CFA prevalence among people aged 5 or 15 years and older is a much more reliable and practical indicator of elimination outcomes. Lymphatic filariasis elimination programmes should reconsider guidelines for stopping MDA. [ABSTRACT FROM AUTHOR]

Background: Onchocerciasis is endemic in most local government areas (LGAs) in Enugu and Ogun states. Most meso- and hyper-endemic LGAs have received many rounds of ivermectin mass drug administration (MDA). This study aimed to determine the current prevalence of onchocerciasis in villages in Enugu and Ogun states that were formerly highly endemic and to assess progress toward elimination of the infection in areas believed to be at high risk for persistence.Methods: Cross-sectional community surveys were conducted 8 to 12 months after the last round of MDA in 16 villages (6 in Enugu state and 10 in Ogun state) in individuals aged ≥ 18 years. Study participants were examined for the presence of palpable subcutaneous nodules. Skin snips from the posterior iliac crests were used to assess microfiladermia (Mf) prevalence and density.Results: 643 subjects were palpated for nodules and 627 individuals (225 in Enugu state; 402 in Ogun state) provided skin snips. Nodule prevalence in the study villages ranged from 42 to 66.7% in Enugu state and from 0 to 25.0% in Ogun state. Mf prevalence in the Enugu and Ogun study villages ranged from 32 to 51.1% and 0 to 28.6%, respectively. Geometric mean skin Mf density in surveyed Enugu state villages ranged between 1 and 3.1 Mf/mg; these values were < 1 Mf/mg in all but one community in Ogun state villages.Conclusion: Results from this study show that onchocerciasis persists in adults in many villages in Enugu and Ogun states despite many prior rounds of ivermectin MDA. Prevalence was higher in villages surveyed in Enugu than in Ogun. Low Mf densities suggest the MDA program is working well to reduce disease, but more time will be required to reach the elimination goal. [ABSTRACT FROM AUTHOR]

Onchocerciasis (river blindness) is a major public health problem in sub-Saharan Africa. Major disease-control programs have greatly reduced both disease and infection prevalence by mass distribution of donated ivermectin. Recent studies have shown that local elimination was achieved in some areas following many years of ivermectin. The global health community has recently decided to build on these successes with a new program that aims to eliminate onchocerciasis. Diagnostic tests that were useful for identifying priority areas for disease prevention may not be adequate tools for elimination programs. This paper reviews available and emerging diagnostic tests for onchocerciasis and considers how they might be best employed during different stages of onchocerciasis elimination programs. [ABSTRACT FROM AUTHOR]

Paragonimus kellicotti is a zoonotic lung fluke infection, the agent of North American paragonimiasis, and an excellent model for other Paragonimus infections. The excretory/secretory proteins (ESP) released by parasites and presented at the parasite-host interface are frequently proposed to be useful targets for drugs and/or vaccines In vitro culture conditions may alter ESP compared to those produced in vivo. In order to investigate ESPs produced in vivo we took advantage of the fact that adult P. kellicotti reproduce in the lungs of experimentally infected gerbils in tissue cysts. We performed a mass-spectrometric analysis of adult P. kellicotti soluble somatic protein (SSPs) extracts, excreted/secreted proteins (ESPs) produced by adult worms during in vitro culture, and lung cyst fluid proteins (CFPs) from experimentally infected gerbils. We identified 2,137 P. kellicotti proteins that were present in at least two of three biological replicates and supported by at least two peptides. Among those were 1,914 proteins found in SSP, 947 in ESP and 37 in CFP. In silico analysis predicted that only 141 of the total 2,137 proteins were secreted via classical or non-classical pathways. The most abundant functional categories in SSP were storage and oxidative metabolism. The most abundant categories in ESP were proteins related to metabolism and signal transduction. The 37 parasite-related proteins in CFP belonged to 11 functional categories. The largest groups were proteins with unknown function, cytoskeletal proteins and proteasome machinery. 29 of these 37 proteins were shared among all three sample types. To our knowledge, this is the first study that compares in vitro and in vivo ESP for any Paragonimus species. This study has provided new insights into ESPs of food-borne trematodes that are produced and released in vivo. Proteins released at the host-parasite interface may help the parasite evade host immunity and may represent new targets for novel treatments or diagnostic tests for paragonimiasis. Author summary: Neglected tropical diseases include food-borne trematode infections such as paragonimiasis that causes severe illness with important social and economic consequences. In this study, we compared excretory/secretory products (ESPs) produced by the North American lung fluke Paragonimus kellicotti that are released during in vitro culture with those that are released in vivo inside the lungs of experimentally infected animals. We identified a total of 2,137 P. kellicotti proteins. These included 1,914 proteins in soluble extracts of whole flukes, 947 proteins identified in ESPs released during in vitro culture, and 37 proteins identified in fluid recovered from lung cysts that surround adult flukes in experimentally infected gerbils. The most abundant functional protein categories varied by sample type. To our knowledge, this is the first study that has compared proteins released in vitro and in vivo by adult Paragonimus flukes. Proteins released in vivo may help the parasite evade host immunity. They may have practical value as novel drug targets or lead to improved diagnostic tests for paragonimiasis. [ABSTRACT FROM AUTHOR]

Background: A single co-administered dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to be safe and more efficacious for clearing Wuchereria bancrofti microfilariae than the standard two-drug regimen of diethylcarbamazine plus albendazole in clinical trials. However, the effectiveness of mass drug administration with the triple-drug regimen compared with the two-drug regimen is unknown. We compared the effectiveness of mass drug administration with the triple-drug and two-drug regimens for reducing microfilariae prevalence to less than 1% and circulating filarial antigen prevalence to less than 2%, levels that are unlikely to sustain transmission of lymphatic filariasis, in Papua New Guinea.Methods: This open-label, cluster-randomised study was done in 24 villages in a district endemic for lymphatic filariasis in Papua New Guinea. Villages paired by population size were randomly assigned to receive mass drug administration with a single dose of the triple-drug oral regimen of ivermectin (200 μg per kg of bodyweight) plus diethylcarbamazine (6 mg per kg of bodyweight) plus albendazole (400 mg) or a single dose of the two-drug oral regimen of diethylcarbamazine (6 mg per kg of bodyweight) plus albendazole (400 mg). This is a follow-on study of a previously reported safety study (ClinicalTrials.govNCT02899936). All residents aged 5 years or older and non-pregnant women were asked to participate. After cross-sectional night blood microfilariae and circulating filarial antigen surveys, mass drug administration was provided at baseline and repeated 12 months later. The primary outcomes were mean prevalence of microfilariae and circulating filarial antigen at 12 months and 24 months, assessed in all residents willing to participate at each timepoint. This study is registered with ClinicalTrials.gov, NCT03352206.Findings: Between Nov 18, 2016, and May 26, 2017, 4563 individuals were enrolled in 24 clusters; 12 clusters (2382 participants) were assigned to the triple-drug regimen and 12 clusters (2181 participants) to the two-drug regimen. Mean drug ingestion rates (of residents aged ≥5 years) were 66·1% at baseline and 63·2% at 12 months in communities assigned to the triple-drug regimen and 65·9% at baseline and 54·9% at 12 months in communities assigned to the two-drug regimen. Microfilariae prevalence in the triple-drug regimen group decreased from 105 (4·4%) of 2382 participants (95% CI 3·6-5·3) at baseline to nine (0·4%) of 2319 (0·1-0·7) at 12 months and four (0·2%) of 2086 (0·1-0·5) at 24 months. In the two-drug regimen group, microfilariae prevalence decreased from 93 (4·3%) of 2181 participants (95% CI 3·5-5·2) at baseline to 29 (1·5%) of 1963 (1·0-2·1) at 12 months and eight (0·4%) of 1844 (0·2-0·9) at 24 months (adjusted estimated risk ratio 4·5, 95% CI 1·4-13·8, p=0·0087, at 12 months; 2·9, 95% CI 1·0-8·8, p=0·058, at 24 months). The prevalence of circulating filarial antigen decreased from 523 (22·0%) of 2382 participants (95% CI 20·3-23·6) at baseline to 378 (16·3%) of 2319 (14·9-17·9) at 12 months and 156 (7·5%) of 2086 (6·4-8·7) at 24 months in the triple-drug regimen group and from 489 (22·6%) of 2168 participants (20·7-24·2) at baseline to 358 (18·2%) of 1963 (16·7-20·1) at 12 months and 184 (10·0%) of 1840 (8·7-11·5) at 24 months in the two-drug regimen group; after adjustment, differences between groups were not significant.Interpretation: Mass administration of the triple-drug regimen was more effective than the two-drug regimen in reducing microfilariae prevalence in communities to less than the target level of 1%, but did not reduce circulating filarial antigen prevalence to less than 2%. These results support the use of mass drug administration with the triple-drug regimen to accelerate elimination of lymphatic filariasis.Funding: Bill & Melinda Gates Foundation. [ABSTRACT FROM AUTHOR]

Background Ivermectin (IVM) plus albendazole (ALB), or IA, is widely used in mass drug administration (MDA) programs that aim to eliminate lymphatic filariasis (LF) in Africa. However, IVM can cause severe adverse events in persons with heavy Loa loa infections that are common in Central Africa. ALB is safe in loiasis, but more information is needed on its efficacy for LF. This study compared the efficacy and safety of 3 years of semiannual treatment with ALB to annual IA in persons with bancroftian filariasis. Methods Adults with Wuchereria bancrofti microfilaremia (Mf) were randomized to receive either 3 annual doses of IA (N = 52), 6 semiannual doses of ALB 400 mg (N = 45), or 6 semiannual doses of ALB 800 mg (N = 47). The primary outcome is amicrofilaremia at 36 months. Results IA was more effective for completely clearing Mf than ALB 400mg or ALB 800mg (79%, 95% confidence interval [CI]: 67–91; vs 48%, 95% CI: 32–66 and 57%, 95% CI: 41–73, respectively). Mean percentage reductions in Mf counts at 36 months relative to baseline tended to be greater after IA (98%, 95% CI: 88–100) than after ALB 400 mg (88%, 95% CI: 78–98) and ALB 800 mg (89%, 95% CI: 79–99) (P  = .07 and P  = .06, respectively). Adult worm nest numbers (assessed by ultrasound) were reduced in all treatment groups. Treatments were well tolerated. Conclusions Repeated semiannual treatment with ALB is macrofilaricidal for W. bancrofti and leads to sustained reductions in Mf counts. This is a safe and effective regimen that could be used as MDA to eliminate LF in areas where ivermectin cannot be used. Clinical Trials Registration NCT02974049 [ABSTRACT FROM AUTHOR]

Background: Wolbachia α-proteobacteria are essential for growth, reproduction and survival for many filarial nematode parasites of medical and veterinary importance. Endobacteria were discovered in filarial parasites by transmission electron microscopy in the 1970’s using chemically fixed specimens. Despite improvements of fixation and electron microscopy techniques during the last decades, methods to study the Wolbachia/filaria interaction on the ultrastructural level remained unchanged and the mechanisms for exchange of materials and for motility of endobacteria are not known. Methodology/Principal Finding: We used high pressure freezing/freeze substitution to improve fixation of Brugia malayi and its endosymbiont, and this led to improved visualization of different morphological forms of Wolbachia. The three concentric, bilayer membranes that surround the endobacterial cytoplasm were well preserved. Vesicles with identical membrane structures were identified close to the endobacteria, and multiple bacteria were sometimes enclosed within a single outer membrane. Immunogold electron microscopy using a monoclonal antibody directed against Wolbachia surface protein-1 labeled the membranes that enclose Wolbachia and Wolbachia-associated vesicles. High densities of Wolbachia were observed in the lateral chords of L4 larvae, immature, and mature adult worms. Extracellular Wolbachia were sometimes present in the pseudocoelomic cavity near the developing female reproductive organs. Wolbachia-associated actin tails were not observed. Wolbachia motility may be explained by their residence within vacuoles, as they may co-opt the host cell’s secretory pathway to move within and between cells. Conclusions/Significance: High pressure freezing/freeze substitution significantly improved the preservation of filarial tissues for electron microscopy to reveal membranes and sub cellular structures that could be crucial for exchange of materials between Wolbachia and its host. [ABSTRACT FROM AUTHOR]

Background: Lymphatic filariasis (LF) is a neglected tropical disease caused by the filarial nematodes Wuchereria bancrofti, Brugia malayi and Brugia timori. The Global Program to Eliminate LF uses mass drug administration (MDA) of anti-filarial drugs that clear microfilariae (Mf) from blood to interrupt transmission by mosquitos. New diagnostic tools are needed to assess the impact of MDA on bancroftian filariasis, because available serologic tests can remain positive after successful treatment. Methodology/Principal findings: We identified Wb-bhp-1, which encodes a W. bancrofti homologue of BmR1, the B. malayi protein used in the Brugia Rapid antibody test for brugian filariasis. Wb-bhp-1 has a single exon that encodes a 16.3 kD protein (Wb-Bhp-1) with 45% amino acid identity to BmR1. Immunohistology shows that anti-Wb-Bhp-1 antibodies primarily bind to Mf. Plasma from 124 of 224 (55%) microfilaremic individuals had IgG4 antibodies to Wb-Bhp-1 by ELISA. Serologic reactivity to Wb-Bhp-1 varied widely with samples from different regions (sensitivity range 32–92%), with 77% sensitivity for 116 samples collected from microfilaremic individuals outside of sub-Saharan Africa. This variable sensitivity highlights the importance of validating new diagnostic tests for parasitic diseases with samples from different geographical regions. Individuals with higher Mf counts were more likely to have anti-Wb-Bhp-1 antibodies. Cross-reactivity was observed with a minority of plasma samples from people with onchocerciasis (17%) or loiasis (10%). We also identified, cloned and characterized BmR1 homologues from O. volvulus and L. loa that have 41% and 38% identity to BmR1, respectively. However, antibody assays with these antigens were not sensitive for onchocerciasis or loiasis. Conclusions: Wb-Bhp-1 is a novel antigen that is useful for serologic diagnosis of bancroftian filariasis. Additional studies are needed to assess the value of this antigen for monitoring the success of filariasis elimination programs. Author summary: Lymphatic filariasis (LF) is a highly disabling and stigmatizing disease caused by parasitic worms that are transmitted by mosquitoes. There is a coordinated global effort to eliminate LF based on mass drug administration (MDA) of donated anti-filarial medications. Improved methods are needed to determine when transmission of the infection has been interrupted in previously endemic areas so that MDA can be safely stopped. This paper reports the discovery and characterization of a novel W. bancrofti antigen, Wb-Bhp-1, which is a homologue of the Brugia malayi protein used in antibody tests to monitor filariasis elimination in areas of Asia where LF is caused by Brugia species. We show that a test for IgG4 antibodies to Wb-Bhp-1 was fairly specific for W. bancrofti infection. However, the sensitivity of this test varied by the geographic origin of the samples. Sensitivity was highest for samples collected in the Indo-Pacific region and lowest for samples collected in Côte d'Ivoire. Geographic differences in the parasite or the human immune responses to infection may account for this variability. This range in sensitivity highlights the importance of validating new diagnostic tests for parasitic diseases with samples from different geographical regions. [ABSTRACT FROM AUTHOR]

Background: The success of programs to eliminate lymphatic filariasis (LF) depends in large part on their ability to achieve and sustain high levels of compliance with mass drug administration (MDA). This paper reports results from a comprehensive review of factors that affect compliance with MDA. Methodology/Principal Findings: Papers published between 2000 and 2012 were considered, and 79 publications were included in the final dataset for analysis after two rounds of selection. While results varied in different settings, some common features were associated with successful programs and with compliance by individuals. Training and motivation of drug distributors is critically important, because these people directly interact with target populations, and their actions can affect MDA compliance decisions by families and individuals. Other important programmatic issues include thorough preparation of personnel, supplies, and logistics for implementation and preparation of the population for MDA. Demographic factors (age, sex, income level, and area of residence) are often associated with compliance by individuals, but compliance decisions are also affected by perceptions of the potential benefits of participation versus the risk of adverse events. Trust and information can sometimes offset fear of the unknown. While no single formula can ensure success MDA in all settings, five key ingredients were identified: engender trust, tailor programs to local conditions, take actions to minimize the impact of adverse events, promote the broader benefits of the MDA program, and directly address the issue of systematic non-compliance, which harms communities by prolonging their exposure to LF. Conclusions/Significance: This review has identified factors that promote coverage and compliance with MDA for LF elimination across countries. This information may be helpful for explaining results that do not meet expectations and for developing remedies for ailing MDA programs. Our review has also identified gaps in understanding and suggested priority areas for further research. Author Summary: Lymphatic filariasis (LF, also known as "elephantiasis") is a deforming and disabling disease that is caused by roundworm parasites that are transmitted by mosquitoes. The Global Programme to Eliminate Lymphatic Filariasis is the largest public health intervention program attempted to date based on mass drug administration (MDA). MDA does not cure filarial infections, but it can reduce or interrupt transmission of new infections by clearing larval parasites from human blood so that they are not available for mosquitoes. High levels of participation are required for this strategy to work; guidelines from the World Health Organization call for at least 65% of the eligible population to take the medications annually for four to six years. MDA presents logistical challenges that require cooperation between donors, health ministries, and communities. The success of MDA depends on coverage (drug delivery) and compliance (people ingesting antifilarial drugs), which depends on individual interactions between drug distributors and the people who live in LF-endemic areas. This paper focuses on this last step of implementation with a comprehensive review of published and unpublished information on factors that affect compliance with MDA at the level of the individual. We have also provided an outline of current gaps in understanding and recommendations for further research. [ABSTRACT FROM AUTHOR]

Background: The success of programs to eliminate lymphatic filariasis (LF) depends in large part on their ability to achieve and sustain high levels of compliance with mass drug administration (MDA). This paper reports results from a comprehensive review of factors that affect compliance with MDA. Methodology/Principal Findings: Papers published between 2000 and 2012 were considered, and 79 publications were included in the final dataset for analysis after two rounds of selection. While results varied in different settings, some common features were associated with successful programs and with compliance by individuals. Training and motivation of drug distributors is critically important, because these people directly interact with target populations, and their actions can affect MDA compliance decisions by families and individuals. Other important programmatic issues include thorough preparation of personnel, supplies, and logistics for implementation and preparation of the population for MDA. Demographic factors (age, sex, income level, and area of residence) are often associated with compliance by individuals, but compliance decisions are also affected by perceptions of the potential benefits of participation versus the risk of adverse events. Trust and information can sometimes offset fear of the unknown. While no single formula can ensure success MDA in all settings, five key ingredients were identified: engender trust, tailor programs to local conditions, take actions to minimize the impact of adverse events, promote the broader benefits of the MDA program, and directly address the issue of systematic non-compliance, which harms communities by prolonging their exposure to LF. Conclusions/Significance: This review has identified factors that promote coverage and compliance with MDA for LF elimination across countries. This information may be helpful for explaining results that do not meet expectations and for developing remedies for ailing MDA programs. Our review has also identified gaps in understanding and suggested priority areas for further research. [ABSTRACT FROM AUTHOR]

Abstract: Lymphatic filariasis is caused by three closely related nematode parasites: Wuchereria bancrofti, Brugia malayi and Brugia timori. These species have many ecological variants that differ in several aspects of their biology such as mosquito vector species, host range, periodicity, and morphology. Although the genome of B. malayi (the first genome sequenced from a parasitic nematode) has been available for more than five years, very little is known about genetic variability among the lymphatic dwelling filariae. The genetic diversity among these worms is not only interesting from a biological perspective, but it may have important practical implications for the Global Program to Eliminate Lymphatic Filariasis, as the parasites may respond differently to diagnostic tests and/or medical interventions. Therefore, better information on their genetic variability is urgently needed. With improved methods for nucleic acid extraction and recent advances in sequencing chemistry and instrumentation, this gap can be filled relatively inexpensively. Improved information on filarial genetic diversity may increase the chances of success for lymphatic filariasis elimination programs. [Copyright &y& Elsevier]

Abstract: Third-stage infective larvae (L3i) of Brugia malayi are developmentally arrested in mosquitoes but must quickly adapt to a new environment when they enter mammalian hosts to initiate infections. These changes can be studied by in vitro culture of L3 (L3c) under conditions that permit molting of L3–L4. Irradiated L3 (L3ir) have stunted growth and limited lifespan in mammalian hosts, and they induce high levels of immunity to challenge infections in animal models. This study explored differences in gene expression in L3i, L3c and L3ir by expressed sequence tag EST generation and qRT-PCR. 2506 ESTs generated from cDNA libraries constructed from L3i, L3c and L3ir were grouped into 1309 gene clusters. Despite extensive prior sampling from B. malayi (>22,000 ESTs in dbEST), 73% of the L3 clusters described here are novel. Sixty-three percentage of the clusters have homology to proteins from other species including 187 specific to nematodes and 141 that have to date only been described in non-nematode species. The transcript levels of 62 candidates for up- or down-regulation in L3i, L3c and L3ir based on EST frequencies were evaluated by qRT-PCR. Twenty-eight were confirmed to have ≥3-fold differences in expression. Genes coding for proteins believed to be involved in establishment of infection, host adaptation and targets of protective immunity were confirmed to have higher expression in L3i than in L3c. Some of the genes that were down-regulated in L3c were highly expressed in L3ir. This study provides an improved description of the adaptations that accompany the transition from L3i to L3c and the special ability of L3ir to induce protective immunity. [Copyright &y& Elsevier]

Background: Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG. Methodology: All consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an additional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy. Principal findings: Of the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treatment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treatment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p<0.001) and in Mf-positive participants treated with IDA (39%), compared to those treated with DA (24%, p = 0.023). One year after treatment, 64% (645/1013) of participants who were antigen-positive at baseline were re-screened and 74% of these participants (475/645) remained antigen positive. Clearance of Mf was achieved in 97% (52/54) of infected individuals in the IDA arm versus 84% (56/67) of infected individuals in the DA arm (relative risk (RR) 1.15; 95% CI, 1.02 to 1.30; p = 0.019). Participants receiving DA treatment had a 4-fold higher likelihood of failing to clear Mf (RR 4.67 (95% CI: 1.05 to 20.67; p = 0.043). In the DA arm, a significant predictor of failure to clear was baseline Mf density (RR 1.54; 95% CI, 1.09 to 2.88; p = 0.007). Conclusion: IDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG. Trial registration: Registration number NCT02899936; https://clinicaltrials.gov/ct2/show/NCT02899936. Author summary: Lymphatic filariasis (LF) is a mosquito-transmitted parasitic nematode that can live in human hosts for up to 6–8 years, disrupting the normal functions of the lymphatic system leading to the abnormal enlargement of body parts, causing pain, severe disability, and social stigma. Lymphatic filariasis can be eliminated by stopping the spread of infection through preventive chemotherapy with safe medicine combinations repeated annually. Several small-scale trials demonstrated that a single dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole or IDA) was more effective at clearing infection than the standard two-drug regimen (diethylcarbamazine and albendazole or DA). This study was conducted to investigate the safety and efficacy of IDA in a large community-randomised trial in a moderate transmission setting. IDA was shown to be as safe as the standard two-drug DA treatment and more effective for clearing microfilariae compared to DA. These results show that IDA is well tolerated in PNG and has the potential to accelerate LF elimination. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that intracellular Wolbachia bacteria are necessary for reproduction and survival of adult filarial worms. We now report results of in vitro studies of effects of antibacterial antibiotics (tetracycline, rifampicin, chloramphenicol, azithromycin, and doxycycline) on Brugia malayi infective larvae (L3) motility and molting. All of the antibiotics tested except chloramphenicol decreased L3 motility by 50% or more at 10 days, with minimal effective concentrations (MECs) of 20–100 μg/ml. Tetracyclines, rifampicin, and chloramphenicol inhibited L3 to L4 molting by 12 days in a concentration- and time-dependent manner, with MECs in the range of 1–20 μg/ml. These studies show that antibiotics active against Rickettsiaceae inhibit B. malayi L3 molting at low concentrations in vitro; higher concentrations kill the larvae. While it is possible that antibiotics directly affect filarial L3, we believe it is more likely that the effects seen are indirect effects related to bacterial killing. Index Descriptors and Abbreviations: Brugia malayi; Filarioidea; Rickettsiaceae; Wolbachia; antibiotics; NI-medium; NCTC-135 and IMDM, Iscove’s Modified Dulbecco’s Medium; FCS, fetal calf serum; Tet, tetracycline; Rif, rifampicin; Chlor, chloramphenicol; Azith, azithromycin; Doxy, doxycycline; IM, incomplete molting larvae; MEC, minimum effective concentration; PCR, polymerase chain reaction. [Copyright &y& Elsevier]

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs and use-case analyses to be used by product developers. Here, we describe the development of two priority TPPs for LF diagnostics needed for making decisions for stopping mass drug administration (MDA) of a triple drug regimen and surveillance. Utilizing the WHO core TPP development process as the framework, the LF subgroup convened to discuss and determine attributes required for each use case. TPPs considered the following parameters: product use, design, performance, product configuration and cost, and access and equity. Version 1.0 TPPs for two use cases were published by WHO on 12 March 2021 within the WHO Global Observatory on Health Research and Development. A common TPP characteristic that emerged in both use cases was the need to identify new biomarkers that would allow for greater precision in program delivery. As LF diagnostic tests are rarely used for individual clinical diagnosis, it became apparent that reliance on population-based surveys for decision making requires consideration of test performance in the context of such surveys. In low prevalence settings, the number of false positive test results may lead to unnecessary continuation or resumption of MDA, thus wasting valuable resources and time. Therefore, highly specific diagnostic tools are paramount when used to measure low thresholds. The TPP process brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools. Author summary: High quality diagnostic tools are an essential component of lymphatic filariasis (LF) programs. Currently, diagnostic tools are used by national programs to establish baseline endemicity, monitor progress of program interventions, determine when interventions can be stopped, and surveillance. For years, LF programs have relied on diagnostic tools that have been central to informing key program decisions but were not necessarily designed to undertake the roles for which they are used. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. Target product profiles (TPP) provide product requirements to guide developers and manufacturers in their efforts to design tools fit for purpose. However, development of diagnostic tools used in public health programs requires consideration of aspects beyond those considered when developing diagnostic tools used for clinical diagnosis. The TPP process for two LF use cases brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Scabies is a neglected tropical disease hyperendemic to many low- and middle-income countries. Scabies can be successfully controlled using mass drug administration (MDA) using 2 doses of ivermectin-based treatment. If effective, a strategy of 1-dose ivermectin-based MDA would have substantial advantages for implementing MDA for scabies at large scale.Methods and Findings: We did a cluster randomised, noninferiority, open-label, 3-group unblinded study comparing the effectiveness of control strategies on community prevalence of scabies at 12 months. All residents from 35 villages on 2 Fijian islands were eligible to participate. Villages were randomised 1:1:1 to 2-dose ivermectin-based MDA (IVM-2), 1-dose ivermectin-based MDA (IVM-1), or screen and treat with topical permethrin 5% for individuals with scabies and their household contacts (SAT). All groups also received diethylcarbamazine and albendazole for lymphatic filariasis control. For IVM-2 and IVM-1, oral ivermectin was dosed at 200 μg/kg and when contraindicated substituted with permethrin. We designated a noninferiority margin of 5%. We enrolled 3,812 participants at baseline (July to November 2017) from the 35 villages with median village size of 108 (range 18 to 298). Age and sex of participants were representative of the population with 51.6% male and median age of 25 years (interquartile range 10 to 47). We enrolled 3,898 at 12 months (July to November 2018). At baseline, scabies prevalence was similar in all groups: IVM-2: 11.7% (95% confidence interval (CI) 8.5 to 16.0); IVM-1: 15.2% (95% CI 9.4 to 23.8); SAT: 13.6% (95% CI 7.9 to 22.4). At 12 months, scabies decreased substantially in all groups: IVM-2: 1.3% (95% CI 0.6 to 2.5); IVM-1: 2.7% (95% CI 1.1 to 6.5); SAT: 1.1% (95% CI 0.6 to 2.0). The risk difference in scabies prevalence at 12 months between the IVM-1 and IVM-2 groups was 1.2% (95% CI -0.2 to 2.7, p = 0.10). Limitations of the study included the method of scabies diagnosis by nonexperts, a lower baseline prevalence than anticipated, and the addition of diethylcarbamazine and albendazole to scabies treatment.Conclusions: All 3 strategies substantially reduced prevalence. One-dose was noninferior to 2-dose ivermectin-based MDA, as was a screen and treat approach, for community control of scabies. Further trials comparing these approaches in varied settings are warranted to inform global scabies control strategies.Trial Registration: Clinitrials.gov NCT03177993 and ANZCTR N12617000738325. [ABSTRACT FROM AUTHOR]

Background Bancroftian filariasis remains endemic in Fiji despite >10 years of mass drug administration (MDA) using diethylcarbamazine and albendazole (DA). The addition of ivermectin to this combination (IDA) has improved efficacy of microfilarial clearance at 12 months in individually randomized trials in nocturnal transmission settings, but impact in a setting of diurnally subperiodic filarial transmission has not been evaluated. Methods This cluster randomized study compared the individual efficacy and community impact of IDA vs DA as MDA for lymphatic filariasis in 35 villages on 2 islands of Fiji. Participants were tested at enrollment for circulating filarial antigen and, if positive, for microfilariae. Weight-dosed treatment was offered according to village randomization. Communities were visited at 12 months and retested for lymphatic filariasis. Infected individuals from Rotuma were retested at 24 months. Results A total of 3816 participants were enrolled and 3616 were treated. At 12 months, microfilariae clearance was achieved in 72 of 111 participants detected with infection at baseline, with no difference in efficacy between treatment groups: DA, 69.2% (95% confidence interval [CI], 57.2%–79.1%) vs IDA, 62.5% (95% CI, 43.6%–78.2%); risk difference, 11.3 % (95% CI, –10% to 32.7%); P =.30. There was no difference between treatment groups in community prevalence of microfilariae at 12 months or individual clearance at 24 months. Conclusions We found no difference between IDA and DA in individual clearance or community prevalence of lymphatic filariasis at 12 months, and no improved efficacy following a second annual round of IDA. Possible explanations for the apparent lack of benefit of IDA compared to DA include drug and parasite factors affecting clearance, and higher than expected reinfection rates. Clinical Trials Registration : NCT03177993 and Australian New Zealand Clinical Trial Registry: N12617000738325. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Improved treatments for lymphatic filariasis (LF) could accelerate the global elimination program for this disease. A triple drug combination of the anti-filarial drugs ivermectin, diethylcarbamazine (DEC) and albendazole (IDA) has been shown to be safe and effective for achieving sustained clearance of microfilariae (Mf) of the filarial parasite Wuchereria bancrofti from human blood. However, the triple drug combination has not been previously been evaluated for treatment of brugian filariasis, which accounts for about 10% of the global LF burden. This hospital-based clinical trial compared the safety and efficacy of IDA with that of the standard treatment (DEC plus albendazole, DA) in persons with Brugia timori infections on Sumba island, Indonesia. Fifty-five asymptomatic persons with B. timori Mf were treated with either a single oral dose of IDA (28 subjects) or with DEC plus albendazole (DA, 27 subjects). Participants were actively monitored for adverse events (AE) for two days after treatment by nurses and physicians who were masked regarding treatment assignments. Passive monitoring was performed by clinical teams that visited participant's home villages for an additional five days. Microfilaremia was assessed by membrane filtration of 1 ml night blood at baseline, at 24h and one year after treatment. IDA was more effective than DA for completely clearing Mf at 24 hours (25/28, 89% vs. 11/27, 41%, P < 0.001). By 12 months after treatment, only one of 28 IDA recipients had Mf in their blood (4%) vs. 10 of 27 (37%) in persons treated with DA (P = 0.002). Approximately 90% of participants had antibodies to recombinant filarial antigen BmR1 at baseline. Antibody prevalence decreased to approximately 30% in both treatment groups at 12 months. About 45% of persons in both treatment groups experienced AE such as fever, muscle aches, lower back, joint and abdominal pain. These were mostly mild and most common during the first two days after treatment. No participant experienced a severe or serious AE. This study showed that IDA was well-tolerated and significantly more effective for clearing B. timori Mf from the blood than DA. Larger studies should be performed to further assess the safety and efficacy of IDA as a mass drug administration regimen to eliminate brugian filariasis. Trial Registration:NCT02899936. Author summary: Improved treatments for lymphatic filariasis (LF) could accelerate the global elimination program for this disease. A triple drug combination of the anti-filarial drugs ivermectin, diethylcarbamazine (DEC) and albendazole (IDA) has been shown to be safe and effective for achieving sustained clearance of microfilariae (Mf) of the filarial parasite Wuchereria bancrofti from human blood. However, the triple drug combination has not been previously been evaluated for treatment of brugian filariasis, which accounts for about 10% of the global LF burden. This hospital-based clinical trial compared the safety and efficacy of IDA with that of the standard treatment (DEC plus albendazole, DA) in persons with Brugia timori infections on Sumba island, Indonesia. Fifty-five asymptomatic persons with B. timori Mf were treated with either a single oral dose of IDA (28 subjects) or with DA (27 subjects). Adverse events (AE) were assessed in the hospital for two days after treatment and for another five days in participants' home villages. IDA was much more effective than DA for clearing Mf from the blood at 24 hr. Only 1 person (4% of those treated) had Mf in their blood one year after IDA, while 10 persons (37%) treated with DA were Mf positive at that time. About 45% of persons in both treatment groups experienced mostly mild AE as fever, muscle aches, lower back, joint and abdominal pain (mostly during the first two days after treatment). This study showed that IDA was well-tolerated and significantly more effective than DA for clearing B. timori Mf from the blood. Larger studies should be performed to further assess the safety and efficacy of IDA as a mass drug administration regimen to eliminate brugian filariasis. [ABSTRACT FROM AUTHOR]

Background: Better drug regimens for mass drug administration (MDA) could accelerate the Global Programme to Eliminate Lymphatic Filariasis (LF). This community study was designed to compare the safety and efficacy of MDA with IDA (ivermectin, diethylcarbamazine and albendazole) or DA (diethylcarbamazine and albendazole) in India. Methodology/Principal findings: This two-armed, open-labelled, block randomised, community study was conducted in LF endemic villages in Yadgir district, Karnataka, India. Consenting participants ≥5 years of age were tested for circulating filarial antigenemia (CFA) and microfilaremia (Mf) before treatment with a single oral dose of IDA or DA. Adverse events (AEs) were monitored actively for two days and passively for five more days. Persons with positive CFA or Mf tests at baseline were retested 12-months post-treatment to assess treatment efficacy. Baseline CFA and Mf—rates were 26.4% and 6.9% in IDA and 24.5% and 6.4% in DA villages respectively. 4758 and 4160 participants received IDA and DA. Most AEs were mild after both treatments; fewer than 0.1% of participants experienced AEs with severity > grade 1. No serious AEs were observed. Fever, headache and dizziness were the most common AEs. AE rates were slightly higher after IDA than DA (8.3% vs. 6.4%, P<0.01). AEs were more frequent in females and Mf-positives after either treatment, but significantly more frequent after IDA (40.5% vs 20.2%, P < 0.001). IDA was more effective for clearing Mf than DA (84% vs. 61.8%, P < 0.001). Geometric mean Mf counts per 60μl in retested Mf-positives decreased by 96.4% from 11.8 after IDA and by 90.0% from 9.5 after DA. Neither treatment was effective for clearing CFA. Conclusions/Significance: IDA had an acceptable safety profile and was more effective for clearing Mf than DA. With adequate compliance and medical support to manage AEs, IDA has the potential to accelerate LF elimination in India. Trial registration: Clinical Trial Registry of India (CTRI No/2016/10/007399) Author summary: Lymphatic filariasis (LF) is a major neglected tropical disease that is caused by filarial nematode worms. The strategies of the Global Programme to Eliminate Lymphatic Filariasis, launched in 2000, are mass drug administration (MDA) of antifilarial medications to kill the parasites and reduce transmission and morbidity management and disability prevention for those who are already affected by the disease. Recent clinical trials have shown that a single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) is more effective for clearing microfilariae (Mf) from the blood than the traditional two-drug regimen (DA). That is important, because blood Mf are essential for mosquitoes to transmit the parasite. As part of a large multicenter study, we assessed the safety of IDA and compared the efficacy of IDA and DA for clearing parasites from the blood. We treated almost 9,000 people in Wuchereria bancrofti endemic villages with either IDA or DA. Adverse events (AE) were monitored actively for two days and passively for another five days. AE rates were slightly higher after IDA than DA, but AEs were mild and self-limited. Infected persons, adults and females had higher AE rates in both treatment areas. We retested infected persons one year after treatment. IDA was significantly more effective for clearing Mf and reducing blood Mf counts than DA. Neither treatment was effective for clearing circulating filarial antigenemia. Our large study showed that IDA was well tolerated and more effective than DA. This new treatment has the potential to hasten LF elimination in India and many other countries. [ABSTRACT FROM AUTHOR]

Background: Côte d'Ivoire has had 45 years of intervention for onchocerciasis by vector control (from 1975 to 1991), ivermectin mass drug administration (MDA) (from 1992 to 1994) and community directed treatment with ivermectin (CDTi) from 1995 to the present. We modeled onchocerciasis endemicity during two time periods that correspond to the scale up of vector control and ivermectin distribution, respectively. This analysis illustrates progress towards elimination during these periods, and it has identified potential hotspots areas that are at risk for ongoing transmission. Methods and findings: The analysis used Ministry of Health skin snip microfilaria (MF) prevalence and intensity data collected between 1975 and 2016. Socio-demographic and environmental factors were incorporated into a predictive, machine learning algorithm to create continuous maps of onchocerciasis endemicity. Overall predicted mean MF prevalence decreased from 51.8% circa 1991 to 3.9% circa 2016. The model predicted infection foci with higher prevalence in the southern region of the country. Predicted mean community MF load (CMFL) decreased from 10.1MF/snip circa 1991 to 0.1MF/snip circa 2016. Again, the model predicts foci with higher Mf densities in the southern region. For assessing model performance, the root mean squared error and R2 values were 1.14 and 0.62 respectively for a model trained with data collected prior to 1991, and 1.28 and 0.57 for the model trained with infection survey data collected later, after the introduction of ivermectin. Finally, our models show that proximity to permanent inland bodies of water and altitude were the most informative variables that correlated with onchocerciasis endemicity. Conclusion/Significance: This study further documents the significant reduction of onchocerciasis infection following widespread use of ivermectin for onchocerciasis control in Côte d'Ivoire. Maps produced predict areas at risk for ongoing infection and transmission. Onchocerciasis might be eliminated in Côte d'Ivoire in the future with a combination of sustained CDTi with high coverage, active surveillance, and close monitoring for persistent infection in previously hyper-endemic areas. Author summary: Côte d'Ivoire is endemic for onchocerciasis (also known as "river blindness"). This neglected tropical disease is transmitted by biting black flies that breed in fast flowing rivers. From 1975 to 1991, onchocerciasis control was based on weekly aerial spraying of the insecticide temephos, on black fly breeding sites. Vector control, however, was mostly focused on the northern and central parts of the country. From 1992 to present, mass treatment with ivermectin was implemented in all endemic areas, including forested regions in the south. Here we present the first geospatial estimates of onchocerciasis endemicity over time. Using the machine learning algorithm quantile regression forest, we implemented models to: identify important socio-demographic and environmental factors that correlate with onchocerciasis infection; predict the prevalence and density of infection in areas without ground-truth data; delineate remaining infection hotspots. Our results show that Côte d'Ivoire has made very significant progress in reducing infection parameters over time, and they may help to inform future interventions to achieve the goal of onchocerciasis elimination in Côte d'Ivoire. [ABSTRACT FROM AUTHOR]

Paragonimiasis is a foodborne trematode infection that affects 23 million people, mainly in Asia. Lung fluke infections lead frequently to chronic cough with fever and hemoptysis, and are often confused with lung cancer or tuberculosis. Paragonimiasis can be efficiently treated with praziquantel, but diagnosis is often delayed, and patients are frequently treated for other conditions. To improve diagnosis, we selected five Paragonimus kellicotti proteins based on transcriptional abundance, recognition by patient sera, and conservation among trematodes and expressed them as His-fusion proteins in Escherichia coli. Sequences for these proteins have 76–99% identity with amino acid sequences for orthologs in the genomes of Paragonimus westermani, Paragonimus heterotremus, and Paragonimus miyazakii. Immunohistology studies showed that antibodies raised to four recombinant proteins bound to the tegument of adult P. kellicotti worms, at the parasite host interface. Only a known egg antigen was absent from the tegument but present in developing and mature eggs. We evaluated the diagnostic potential of these antigens by Western blot with sera from patients with paragonimiasis (from MO and the Philippines), fascioliasis, and schistosomiasis, and with sera from healthy North American controls. Two recombinant proteins (a cysteine protease and a myoglobin) showed the highest sensitivity and specificity as diagnostic antigens, and they detected antibodies in sera from paragonimiasis patients with early or mature infections. In contrast, antibodies to egg yolk ferritin appeared to be specific marker for patients with adult fluke infections that produce eggs. Our study has identified and localized antigens that are promising for serodiagnosis of human paragonimiasis. [ABSTRACT FROM AUTHOR]

Background. Improved drug regimens are needed to accelerate elimination of lymphatic filariasis in Africa. This study determined whether a single co-administered dose of ivermectin plus diethylcarbamazine plus albendazole [IDA] is noninferior to standard 3 annual doses of ivermectin plus albendazole (IA) used in many LF-endemic areas of Africa. Methods. Treatment-naive adults with Wuchereria bancrofti microfilaremia in Côte d’Ivoire were randomized to receive a single dose of IDA (n = 43) or 3 annual doses of IA (n = 52) in an open-label, single-blinded trial. The primary endpoint was the proportion of participants who were microfilaria (Mf) negative at 36 months. Secondary endpoints were Mf clearance at 6, 12, and 24 months; inactivation of adult worm nests; and safety. Results. At 36 months posttreatment with IDA, 18/33 (55%; 95% CI, 38–72%) cleared Mf versus 33/42 (79%; 67–91%) with IA (P = .045). At 6 and 12 months IDA was superior to IA in clearing Mf (89% [77–99%] and 71% [56–85%]), respectively, versus 34% (20–48%) and 26% (14–42%) (P < .001). IDA was equivalent to IA at 24 months (61% [45–77%] vs 54% [38–72%]; P = .53). IDA was superior to IA for inactivating adult worms at all time points. Both treatments were well tolerated, and there were no serious adverse events. Conclusions. A single dose of IDA was superior to 2 doses of IA in reducing the overall Mf burden by 24 months. Reinfection may have contributed to the lack of sustained clearance of Mf with IDA. [ABSTRACT FROM AUTHOR]

Mass Drug Administration (MDA) programs to eliminate Lymphatic Filariasis (LF) in western Africa use the anthelminthics ivermectin plus albendazole. These drugs have the potential to impact also Soil-Transmitted Helminth (STH) infections, since the drugs have a broad range of anthelminthic activity. Integration of preventive chemotherapy efforts for LF, onchocerciasis and STH is recommended by the World Health Organization (WHO) in order to avoid duplication of MDA and to reduce costs. The objective of the current study was to determine whether five semi-annual rounds of community-wide MDA to eliminate LF and onchocerciasis have a greater impact on STH than three annual rounds of MDA with similar compliance. The effects of MDA using ivermectin (IVM, 0.2 mg/kg) combined with albendazole (ALB, 400 mg) on the prevalence and intensity of hookworm infection were evaluated in the Abengourou (annual MDA) and Akoupé (semi-annual MDA) health Districts in eastern Côte d'Ivoire from 2014 to 2017. A cross-sectional approach was used together with mixed logistic regression, and mixed linear models. Subjects were tested for STH using the Kato-Katz technique before the first round of MDA and 12, 24, and 36 months after the first round of MDA. The mean self-reported MDA compliance assessed during the survey was 65%, and no difference was observed between treatment areas. These results were confirmed by an independent coverage survey as recommended by WHO. Hookworm was the most prevalent STH species in both areas (23.9% vs 12.4%) and the prevalence of other STH species was less than 1%. The crude prevalence of hookworm dropped significantly, from 23.9% to 5.5% (p <0.001, 77% reduction) in the annual MDA treatment area and from 12.4% to 1.9% (p <0.001, 85% reduction) in the semi-annual treatment area. The average intensity of hookworm infection decreased in the annual MDA area (406.2 epg to 118.3 epg), but not in the semi-annual MDA area (804.9 epg to 875.0 epg). Moderate and heavy infections (1% and 1.3% at baseline) were reduced to 0% and 0.4% in the annual and semi-annual treatment areas, respectively. Using a mixed logistic regression model, and after adjusting for baseline prevalence, only the year 2 re-examination showed a difference in prevalence between treatments (OR: 2.26 [95% CI: 1.03, 4.98], p = 0.043). Analysis of intensity of hookworm infection indicated also that treatment differences varied by follow-up visit. In conclusion twelve months after the last treatment cycle, three annual and five semi-annual rounds of community-wide MDA with the combination of IVM and ALB showed strong, but similar impact on hookworm prevalence and intensity in eastern Côte d'Ivoire. Therefore, an annual MDA regimen seems to be an efficient strategy to control hookworm infection in endemic areas with low and moderate infection prevalence. Trial registration: The study was registered at ClinicalTrial.gov under the number NTC02032043. Author summary: Community-wide MDA to eliminate LF and onchocerciasis has the beneficial effect to reduce also STH infections. The objective of the current study was to determine whether five semi-annual rounds of MDA have a greater impact on STH than three annual rounds of MDA using ivermectin combined with albendazole. In Abengourou and Akoupé health Districts in eastern Côte d'Ivoire the prevalence and intensity of hookworm infection were evaluated before and after MDA. Prior to MDA and after each annual treatment cycle, study participants were tested for STH using the Kato-Katz technique. The mean MDA compliance assessed during the survey was 65%, and no difference was observed between treatment areas. Compliance results were confirmed by an independent coverage survey as recommended by WHO. Hookworm was the most prevalent STH species in both areas and the prevalence of other STH species was less than 1%. The crude prevalence of hookworm dropped significantly, from 23.9% to 5.5% in the annual and from 12.4% to 1.9% in the semi-annual treatment areas. The intensity of hookworm infection in infected persons decreased significantly in the annual MDA area (406.2 epg to 118.3 epg, p = 0.017), but not in the semi-annual MDA area (804.9 epg to 875.0 epg, p = 0.216). Moderate and heavy infections were reduced to less than 1% in both treatment areas. Three annual and five semi-annual rounds of community-wide MDA with the combination of IVM and ALB showed strong, but similar effects on hookworm prevalence and intensity in eastern Côte d'Ivoire. Therefore, an annual MDA regimen seems to be an efficient strategy for controlling hookworm infection in endemic areas with low and moderate infection prevalence. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization now recommends semiannual mass drug administration (MDA) of albendazole with integrated vector management as an option for eliminating lymphatic filariasis (LF) in areas of loiasis-endemic countries where it may not be safe to use diethylcarbamazine or ivermectin in MDA programs. However, the published evidence base to support this policy is thin, and uptake by national programs has been slow. Methodology/Principal findings: We conducted a community trial to assess the impact of semiannual MDA on lymphatic filariasis and soil-transmitted helminth infections (STH) in two villages in the Bandundu province of the Democratic Republic of the Congo with moderately high prevalences for LF and hookworm infections. MDA with albendazole was provided every six months from June 2014 to December 2017 with treatment coverages of the eligible population (all ≥ 2 year of age) that ranged between 56% and 88%. No adverse effects were reported during the trial. Evaluation at 48 months, (i.e. 6 months after the 8th round of MDA), showed that W. bancrofti microfilaremia (Mf) prevalence in the study communities had decreased between 2014 to 2018 from 12% to 0.9% (p<0.001). The prevalence of W. bancrofti antigenemia was also significantly reduced from 31.6% to 8.5% (p<0.001). MDA with albendazole also reduced hookworm, Ascaris lumbricoides and Trichuris trichiura infection prevalences in the community from 58.6% to 21.2% (p<0.001), from 14.0% to 1.6% and 4.1% to 2.9%, respectively. Hookworm and Ascaris infection intensities were reduced by 93% (p = 0.02) and 57% (p = 0.03), respectively. In contrast, Trichuris infection intensity was not significantly reduced by MDA (p = 0.61) over this time period. Conclusion/Significance: These results provide strong evidence that semiannual MDA with albendazole alone is a safe and effective strategy for LF elimination in Central Africa. Community MDA also had a major impact on STH infections. Author summary: In low-income rural settings of Africa, populations are commonly affected by multiple parasitic diseases. Some of these diseases have been targeted for elimination through dedicated national or international programs. In 2012, the World Health Organization (WHO) defined a specific strategy to eliminate lymphatic filariasis, the disease responsible for elephantiasis, in central Africa. This strategy consists in treating the whole population living in endemic areas every six months with a single donated drug—albendazole. Together with the use of the night bed nets distributed as part of malaria programs, it was expected that this strategy could interrupt the transmission and eliminate lymphatic filariasis locally within period of 4 to 7 years. Here, we evaluated this strategy in two endemic communities near Bandundu in the Democratic Republic of the Congo. We also assessed the impact of the semiannual community treatments on three species of gastrointestinal parasitic worms. Our results suggest that semiannual MDA with albendazole is effective for LF elimination in Central Africa, but they also indicate that drug-based only intervention is not enough to eliminate gastrointestinal worm infections in areas with high transmission. [ABSTRACT FROM AUTHOR]

In Haiti, 22 communes still require mass drug administration (MDA) to eliminate lymphatic filariasis (LF) as a public health problem. Several clinical trials have shown that a single oral dose of ivermectin (IVM), diethylcarbamazine (DEC) and albendazole (ALB) (IDA) is more effective than DEC plus ALB (DA) for clearing Wuchereria bancrofti microfilariae (Mf). We performed a cluster-randomized community study to compare the safety and efficacy of IDA and DA in an LF-endemic area in northern Haiti. Ten localities were randomized to receive either DA or IDA. Participants were monitored for adverse events (AE), parasite antigenemia, and microfilaremia. Antigen-positive participants were retested one year after MDA to assess treatment efficacy. Fewer participants (11.0%, 321/2917) experienced at least one AE after IDA compared to DA (17.3%, 491/2844, P<0.001). Most AEs were mild, and the three most common AEs reported were headaches, dizziness and abdominal pain. Serious AEs developed in three participants who received DA. Baseline prevalence for filarial antigenemia was 8.0% (239/3004) in IDA localities and 11.5% (344/2994) in DA localities (<0.001). Of those with positive antigenemia, 17.6% (42/239) in IDA localities and 20.9% (72/344, P = 0.25) in DA localities were microfilaremic. One year after treatment, 84% percent of persons with positive filarial antigen tests at baseline could be retested. Clearance rates for filarial antigenemia were 20.5% (41/200) after IDA versus 25.4% (74/289) after DA (P = 0.3). However, 94.4% (34/36) of IDA recipients and 75.9% (44/58) of DA recipients with baseline microfilaremia were Mf negative at the time of retest (P = 0.02). Thus, MDA with IDA was at least as well tolerated and significantly more effective for clearing Mf compared to the standard DA regimen in this study. Effective MDA coverage with IDA could accelerate the elimination of LF as a public health problem in the 22 communes that still require MDA in Haiti. Author summary: Lymphatic filariasis (LF) also known as "elephantiasis" is caused by infection with filarial worms that are transmitted by mosquitoes. The Global Programme to Eliminate LF (GPELF) aims to interrupt disease transmission through annual rounds of mass drug administration (MDA). Several studies have shown that a single dose of a triple-drug therapy (ivermectin, diethylcarbamazine and albendazole or IDA) was superior to a single dose of the standard double-drug therapy (diethylcarbamazine and albendazole or DA) and might accelerate LF elimination. In Northern Haiti, we performed a large community treatment study to compare the safety and efficacy of three-drug and two-drug therapies. Almost 6,000 participants were treated with IDA or DA and tested for LF. Each participant was assessed for adverse events (AE) and participants who tested positive for LF at enrollment were retested one year after treatment. Less participants who received IDA (11.0%) experienced AEs compared to participants who received DA (17.3%). IDA was also more effective to eliminate microfilariae (adult worm offspring) from the blood compare to DA. Results from this study showed that IDA was well tolerated in Haiti and has the potential to accelerate LF elimination in countries that currently use DA if high MDA coverage can be achieved. [ABSTRACT FROM AUTHOR]

Lymphatic filariasis has remained endemic in Fiji despite repeated mass drug administration using the well-established and safe combination of diethylcarbamazine and albendazole (DA) since 2002. In certain settings the addition of ivermectin to this combination (IDA) remains a safe strategy and is more efficacious. However, the safety has yet to be described in scabies and soil-transmitted helminth endemic settings like Fiji. Villages of Rotuma and Gau islands were randomised to either DA or IDA. Residents received weight-based treatment unblinded with standard exclusions. Participants were actively found and asked by a nurse about their health daily for the first two days and then asked to seek review for the next five days if unwell. Anyone with severe symptoms were reviewed by a doctor and any serious adverse event was reported to the Medical Monitor and Data Safety Monitoring Board. Of 3612 enrolled and eligible participants, 1216 were randomised to DA and 2396 to IDA. Age and sex in both groups were representative of the population. Over 99% (3598) of participants completed 7 days follow-up. Adverse events were reported by 600 participants (16.7%), distributed equally between treatment groups, with most graded as mild (93.2%). There were three serious adverse events, all judged not attributable to treatment by an independent medical monitor. Fatigue was the most common symptom reported by 8.5%, with headache, dizziness, nausea and arthralgia being the next four most common symptoms. Adverse events were more likely in participants with microfilaremia (43.2% versus 15.7%), but adverse event frequency was not related to the presence of scabies or soil-transmitted helminth infection. IDA has comparable safety to DA with the same frequency of adverse events experienced following community mass drug administration. The presence of co-endemic infections did not increase adverse events. IDA can be used in community programs where preventative chemotherapy is needed for control of lymphatic filariasis and other neglected tropical diseases. Author summary: Lymphatic filariasis is a parasitic infection that is spread between humans by mosquitos. The adult worms can live up to 6 years in humans causing chronic irreversible damage to lymphatic vessels resulting in permanent limb swelling known as elephantiasis. The filariasis worm is susceptible to three different drugs: ivermectin, diethylcarbamazine and albendazole. They have been used in two drug combinations globally in communities at risk of filariasis infection, including Fiji, for over a decade. In an attempt to improve efficacy of the treatment with the ultimate goal of eliminating the infection, the three drugs are now being used in the one administration. In this study, the safety of the triple combination in Fiji was proven to be as safe as the standard two drug treatment. Two other common infections that will be affected by the new treatment, scabies and intestinal worms, did not impact on the frequency of adverse events. The use of the triple combination in Fiji has the potential to improve the control of common neglected diseases without excess side effects. [ABSTRACT FROM AUTHOR]