Continuous and pulsed epidemiological models for onchocerciasis with implications for eradication strategy.

Onchocerciasis is an endemic disease in parts of sub-Saharan Africa. Complex mathematical models are being used to assess the likely efficacy of efforts to eradicate the disease; however, their predictions have not always been borne out in practice. In this paper, we represent the immunological aspects of the disease with a single empirical parameter in order to reduce the model complexity. Asymptotic approximation allows us to reduce the vector-borne epidemiological model to a model of an infectious disease with nonlinear incidence. We then consider two versions, one with continuous treatment and a more realistic one where treatment occurs only at intervals. Thorough mathematical analysis of these models yields equilibrium solutions for the continuous case, periodic solutions for the pulsed case, and conditions for the existence of endemic disease equilibria in both cases, thereby leading to simple model criteria for eradication. The analytical results and numerical experiments show that the continuous treatment version is an excellent approximation for the pulsed version and that the current onchocerciasis eradication strategy is inadequate for regions where the incidence is highest and unacceptably slow even when the long-term behavior is the disease-free state.

Twelve-month longitudinal parasitological assessment of lymphatic filariasis-positive individuals: impact of a biannual treatment with ivermectin and albendazole.

OBJECTIVE: Mass drug administration (MDA) for the control of lymphatic filariasis (LF), in Ghana, started in the year 2000. While this had great success in many implementation units, there remain areas with persistent transmission, after more than 10 years of treatment. A closer examination of the parasite populations could help understand the reasons for persistent infections and formulate appropriate strategies to control LF in these areas of persistent transmission. MATERIALS AND METHODS: In a longitudinal study, we assessed the prevalence of microfilaraemia (mf) in two communities with 12 years of MDA in Ghana. In baseline surveys 6 months after the National MDA in 2014, 370 consenting individuals were tested for antigenaemia using immunochromatographic test (ICT) cards and had their mf count determined through night blood surveys. 48 ICT positives, of whom, 17 were positive for mf, were treated with 400 µg/kg ivermectin + 400 mg albendazole and subsequently followed for parasitological assessment at 3-month intervals for 1 year. This overlapped with the National MDA in 2015. RESULTS: There was a 68% parasite clearance 3 months after treatment. The pre-treatment mf count differed significantly from the post-treatment mf counts at 3 months (P = 0.0023), 6 months (P = 0.0051), 9 months (P = 0.0113) and 12 months (P = 0.0008). CONCLUSION: In these settings with persistent LF transmission, twice-yearly treatment may help accelerate LF elimination. Further large-scale evaluations are required to ascertain these findings.

Assessment of parasitological findings in heartworm-infected beagles treated with Advantage Multi® for dogs (10% imidacloprid + 2.5% moxidectin) and doxycycline.

BACKGROUND: Anecdotal reports support the position that the adulticidal heartworm treatment utilizing doxycycline and Advantage Multi®/Advocate® for Dogs (10% imidacloprid + 2.5% moxidectin) has successfully converted antigen-positive dogs to antigen-negative. To date, no controlled experimental studies have demonstrated the adulticidal efficacy of this treatment regimen. The aim of this study was to evaluate the parasitological and clinical efficacy of Advantage Multi® for Dogs (IMD + MOX) and doxycycline in heartworm-infected beagles. METHODS: This study utilized 16 dogs, 8 dogs in each of non-treated control and treated groups. A total of 16 adult Dirofilaria immitis (Missouri strain) were surgically transplanted into the jugular vein of each study dog. The treatment regimen of monthly IMD + MOX topically (per labeled dosage and administration) for 10 months and 10 mg/kg doxycycline BID orally for 30 days was initiated 30 days post-surgical transplant. Echocardiograms, radiographs, complete blood counts, clinical chemistry profiles, heartworm antigenemia and microfilaremia were evaluated every 4 weeks. Serum samples were assayed for heartworm antigen using the DiroCHEK® heartworm antigen test. The DiroCHEK® was performed according to the manufacturer's recommendations and read using a spectrophotometer at 490 nm. RESULTS: All dogs tested positive for the presence of heartworm antigen post-surgical transplant and prior to treatment. Heartworm antigen levels began declining in treated dogs 3 months post-treatment. Non-treated control dogs remained antigen-positive. No microfilariae were detected in treated dogs after 21 days post-treatment. At necropsy, adult heartworms were recovered from all non-treated control dogs with a range of 10-12 adult worms/dog for an average recovery of 10.6 adult heartworms/dog. In the IMD + MOX- and doxycycline-treated dogs, the range of adult heartworms recovered was 0-2 adult worms/dog, with five dogs having no adult heartworms present. The average adult heartworm recovery was 0.6/dog in the treated group. This treatment regimen demonstrated a 95.9% efficacy in eliminating adult heartworms (P < 0.0001). CONCLUSIONS: This study demonstrated that this treatment regimen successfully eliminated D. immitis microfilariae by 21 days post-treatment, reduced heartworm antigen concentration over time, and had a 95.9% efficacy in the elimination of mature adult heartworms. Based on this study, we conclude that this treatment regimen is a relatively quick, reliable and safe option to treat canine heartworm infection as compared to other treatment regimens involving macrocyclic lactones, when the approved drug melarsomine dihydrochloride is unavailable, contraindicated or declined by an owner unable to afford the more costly treatment or concerned about the potential side effects.

Progress towards onchocerciasis elimination in the participating countries of the African Programme for Onchocerciasis Control: epidemiological evaluation results.

BACKGROUND: The African Programme for Onchocerciasis Control (APOC) was created in 1995 to establish community-directed treatment with ivermectin (CDTi) in order to control onchocerciasis as a public health problem in 20 African countries that had 80 % of the global disease burden. When research showed that CDTi may ultimately eliminate onchocerciasis infection, APOC was given in 2008 the additional objective to determine when and where treatment can be safely stopped. We report the results of epidemiological evaluations undertaken from 2008 to 2014 to assess progress towards elimination in CDTi areas with ≥6 years treatment. METHODS: Skin snip surveys were undertaken in samples of first-line villages to determine the prevalence of O. volvulus microfilariae. There were two evaluation phases. The decline in prevalence was evaluated in phase 1A. Observed and model-predicted prevalences were compared after correcting for endemicity level and treatment coverage. Bayesian statistics and Monte Carlo simulation were used to classify the decline in prevalence as faster than predicted, on track or delayed. Where the prevalence approached elimination levels, phase 1B was launched to determine if treatment could be safely stopped. Village sampling was extended to the whole CDTi area. Survey data were analysed within a Bayesian framework to determine if stopping criteria (overall prevalence <1.4 % and maximum stratum prevalence <5 %) were met. RESULTS: In phase 1A 127 665 people from 639 villages in 54 areas were examined. The prevalence had fallen dramatically. The decline in prevalence was faster than predicted in 23 areas, on track in another 23 and delayed in eight areas. In phase 1B 108 636 people in 392 villages were examined in 22 areas of which 13 met the epidemiological criteria for stopping treatment. Overall, 32 areas (25.4 million people) had reached or were close to elimination, 18 areas (17.4 million) were on track but required more years treatment, and in eight areas (10.4 million) progress was unsatisfactory. CONCLUSIONS: Onchocerciasis has been largely controlled as a public health problem. Great progress has been made towards elimination which already appears to have been achieved for millions of people. For most APOC countries, nationwide onchocerciasis elimination is within reach.

Extracts of Euphorbia hirta Linn. (Euphorbiaceae) and Rauvolfia vomitoria Afzel (Apocynaceae) demonstrate activities against Onchocerca volvulus microfilariae in vitro.

BACKGROUND: Onchocerciasis transmitted by Onchocerca volvulus is the second major cause of blindness in the world and it impacts negatively on the socio-economic development of the communities affected. Currently, ivermectin, a microfilaricidal drug is the only drug recommended for treating this disease. There have been speculations, of late, concerning O. volvulus resistance to ivermectin. Owing to this, it has become imperative to search for new drugs. World-wide, ethnomedicines including extracts of Euphorbia hirta and Rauvolfia vomitoria are used for treating various diseases, both infectious and non-infectious. METHOD: In this study extracts of the two plants were evaluated in vitro in order to determine their effect against O. volvulus microfilariae. The toxicity of the E. hirta extracts on monkey kidney cell (LLCMK2) lines was also determined. RESULTS: The investigations showed that extracts of both plants immobilised microfilariae at different levels in vitro and, therefore, possess antifilarial properties. It was found that all the E. hirta extracts with the exception of the hexane extracts were more effective than those of R. vomitoria. Among the extracts of E. hirta the ethyl acetate fraction was most effective, and comparable to that of dimethanesulphonate salt but higher than that of Melarsoprol (Mel B). However, the crude ethanolic extract of E. hirta was found to be the least toxic to the LLCMK2 compared to the fractionated forms. CONCLUSIONS: Extracts from both plants possess antifilarial properties; however, the crude extract of E. hirta was found to be least toxic to LLCMK2.

Current practices in the management of lymphatic filariasis.

Lymphatic filariasis is a major cause of acute and chronic morbidity in 81 countries. The availability of safe treatment regimens along with rapid diagnostic tools resulted in a global program to eliminate the disease. The two main objectives of the global elimination program are to interrupt transmission of the parasites and to provide care for those with the disease. The strategy for transmission interruption is preventive chemotherapy through mass drug administration. This article reviews the current treatment regimens for lymphatic filariasis and discusses the challenges posed by co-endemicity with other diseases. The role of integrated vector management as a supplementary strategy for mass drug administration and new strategies for treatment and morbidity control through antibiotic targeting of the Wolbachia endosymbionts are also discussed.

Independent assessment of Mass Drug Administration in filariasis affected Surat city.

The Mass Drug Administration (MDA) done in Surat city (Gujarat) during 2005, revealed good impact on infection and infectivity in mosquitoes and also on microfilaria rate & mean infection density. The overall impact seen was 23% on mf rate, 28% on mean mf density, 65% on infection rate and 50% on infectivity rate in vectors. Indigenous population contribution to microfilaria cases was 9.7%, whereas migratory population contributed 72.2%; predominant 51.9% from Orissa and 20.3% from U.P. Of the total 3640 persons interviewed for MDA compliance in seven zones of the Surat city revealed that actual drug consumption was 76.7% (2792/3640). Another 11.9% although took the drug but did not consume and 11.4% refused. Important reasons for consuming was fear to get the disease (40.7%) and for not consuming; 'will consume after meal' (6.9%), too many tablets (1.7%), seek consent from doctor (1.5%), lack of awareness (1.4%) etc. Refusal was mainly due to the reason as respondents felt apparently healthy. Assessment of IEC activities suggested that main awareness was created by media (local or national TV, banners or handbills, local news papers or mike announcement) alongwith some impact made through NGO's. These observations clearly indicated the utility of effective health education for optimum community participation and shown that it was crucial for successful community based elimination campaign. However some gray areas also suggest the scope for further improvements.

The Leogane, Haiti demonstration project: decreased microfilaremia and program costs after three years of mass drug administration.

To support the global program to eliminate lymphatic filariasis (LF), well-monitored demonstration projects are important for defining the relationship between coverage and reductions in microfilaremia. We are using mass treatment with diethylcarbamazine (DEC) and albendazole in an effort to eliminate LF from Leogane, Haiti. Wuchereria bancrofti microfilaremia prevalence at baseline ranged from 0.8% to 15.9% in four sentinel sites. After three rounds of DEC-albendazole mass drug administration (MDA), both microfilaremia prevalence and intensity decreased dramatically. Mild and moderate adverse reactions after treatment were common, especially after the first MDA, but decreased after subsequent MDAs. Drug coverage for the first year was estimated to be 72%, but concerns about adverse reactions appeared to decrease drug coverage in the second MDA. As a result of community education efforts that focused on providing a greater understanding of adverse reactions, coverage increased dramatically for the third round. Program efficiency increased substantially; the costs per person treated for three rounds of MDA were 2.23 US dollars, 1.96 US dollars, and 1.30 US dollars per person, respectively. The Leogane experience highlights the importance of adapting community education and mobilization campaigns to achieve and maintain good coverage.

Development of in vitro screening system for assessment of antifilarial activity of compounds.

Evaluation of antifilarial activity of new potential agents in vivo is extremely time consuming and uneconomic. In the present study effort has been made to develop an in vitro screening method using Acanthocheilonema viteae, a subcutaneously dwelling rodent filariid with anaerobic metabolic characteristics like human filariids, W. Bancrofti/Brugia malayi as test parasite. Motility test and tetrazolium (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT) based colorimetric assay were used as parameters in in vitro assay. Results showed that 92.3% of compounds (in vivo active) could be picked up in the in vitro assay when both adults and microfilarae (mf) were used simultaneously. Mf and adult stages separately detected, respectively, 84.6 and 69.2% of in vivo active compounds. The adults and mf separately and both the life stages together exhibited, respectively, 80.0, 50.0 and 80.0% false positive results in the in vitro test with in vivo inactive compounds. It is felt that mf stage when used in in vitro test using motility and MTT assays as parameters would be useful in primary screening of new potential filaricides.

Direct assessment of the adulticidal efficacy of a single dose of ivermectin in bancroftian filariasis.

Although the potent microfilaricidal activity of ivermectin is well established, its efficacy against adult Wuchereria bancrofti is unknown. We used longitudinal ultrasound examinations for periods of 3-9 months to assess directly the macrofilaricidal effect of a single 400 micrograms/kg dose of ivermectin in 15 men from Recife, Brazil who were infected with W. bancrofti. Before treatment, microfilarial densities ranged from 3 to 3098 microfilariae per mL of blood, and movements characteristic of the living adult worm (the 'filaria dance sign') were observed by ultrasound examination of the scrotal lymphatic vessels in all 15 men. Following treatment, microfilarial density was markedly reduced in all men, but the filaria dance sign remained unchanged in both location and pattern. Eight months after treatment, a dilated lymphatic vessel was surgically removed from one patient at the site of the filaria dance sign, and 3 intact adult worms were released. When given as a single 400 micrograms/kg dose, ivermectin had no observable effect on adult W. bancrofti. Therefore, prolonged suppression of microfilaraemia following treatment with ivermectin cannot be explained by a macrofilaricidal effect of the drug. Ultrasound is a valuable new tool for directly and rapidly assessing the macrofilaricidal efficacy of antifilarial drugs in lymphatic filariasis.

The chemotherapy of onchocerciasis X. An assessment of four single dose treatment regimes of MK-933 (ivermectin) in human onchocerciasis.

Nineteen patients from an area of vector control in the savanna region of Northern Ghana, all with moderate to heavy infections with Onchocerca volvulus and some with ocular involvement, were treated with 50, 100, 150 or 200 micrograms kg-1 of ivermectin. Detailed monitoring of clinical and ocular reactions and of alterations in skin microfilarial counts and laboratory indices were carried out during the first 28 days. Microfilarial counts in skin snips and detailed ocular examinations were then repeated at intervals over a period of nine months. Ivermectin slowly eliminated microfilariae from the skin and eye without serious adverse clinical or ocular reactions in all treated groups. There was little difference in efficacy between doses of 100, 150 and 200 micrograms kg-1, and these were more effective than the 50 micrograms kg-1 dose. Very low levels of skin microfilariae were maintained for nine months. Microfilariae were not eliminated from the eye for at least three months. The drug was neither macrofilaricidal nor embryotoxic. However, it produced a dose-dependent stimulation of embryogenesis manifest at one month and succeeded by a suppression of embryogenesis at three months after therapy. In areas where transmission of onchocerciasis has been interrupted, ivermectin may need not be given more often than once a year. The efficacy of the drug on single dosage and the mild adverse reactions produced, if confirmed in subsequent controlled studies, would greatly simplify the treatment of onchocerciasis and would reintroduce new concepts of the role of chemotherapy in the control of onchocerciasis.