Single-dose Mass Drug Administration Research Articles

Impacts of ivermectin mass drug administration for onchocerciasis on mosquito populations of Ogun state, Nigeria

BackgroundThe impact of single-dose mass drug administration (MDA) of ivermectin for onchocerciasis on mosquito populations was investigated in Ogun State, Nigeria.MethodsIndoor and outdoor collection of mosquitoes was carried out in two intervention (IC) and two control communities (CC) at three different periods: pre-MDA (baseline), 2–3 days after MDA and 13–14 days after MDA. The density and parity rate of female Anopheles and Culex mosquitoes were determined and compared. Environmental and climatic data of study locations were obtained to perform generalized linear model analysis.ResultsA total of 1399 female mosquitoes were collected, including 1227 Anopheles and 172 Culex mosquitoes. There was a similar magnitude of reduction in the indoor density of Anopheles by 29% in the IC and CC 2–3 days post-MDA but the reduction in indoor parity rate was significantly higher (p = 0.021) in the IC, reducing by more than 50%. In the IC, observation of a significant reduction at 2–3 days post-MDA was consistent for both the indoor density (1.43 to 1.02) and indoor parity rate (95.35% to 44.26%) of Anopheles mosquitoes. The indoor parity rate of Anopheles remained significantly reduced (75.86%) 13–14 post-MDA. On the other hand, the indoor density of Culex increased from 0.07 to 0.10 at 2–3 days post-MDA while the indoor parity rate of Culex did not change. The outdoor density of Anopheles in the IC increased (p = 0.394) from 0.58 to 0.90 at 2–3 days post-MDA; a similar observation was consistent for the outdoor density (2.83 to 3.90) and outdoor parity rate (70.59% to 97.44%) of Culex, while the outdoor parity rate of Anopheles reduced from 85.71 to 66.67% at 2–3 days post-MDA. A generalized linear model showed that ivermectin MDA significantly caused a reduction in both the indoor density (p < 0.001) and indoor parity rate (p = 0.003) of Anopheles in the IC.ConclusionIvermectin MDA resulted in the reduction of both the survival and density of Anopheles mosquitoes. This has strong implications for malaria transmission, which depends strongly on vector survival.Graphical abstract

Bridging the gap in outreach and compliance with mass drug administration for lymphatic filariasis elimination in an endemic district in Kerala, India: an intervention research approach.

Lymphatic filariasis (LF), a neglected tropical disease is targeted for elimination globally by 2020. National Health Policy of India set the goal by 2017 and annual single-dose mass drug administration (MDA) with anti-filarial drugs is in operation in endemic districts since 2004. Performance and effectiveness of MDA was diverse across the nation and prevalence of infection continues above threshold level in 50% of endemic districts which requires alternative strategies. National programme aims at achieving >65% consumption for transmission control. Post 10 rounds of MDA in an endemic district of Kerala state, a three-arm study identified determinants in gap in outreach and consumption, based on which context-dependent intervention using social group work and networking (SGWN) was implemented and impact assessed. A spill over effect with overall increase in coverage and consumption rates irrespective of arms apparently is due to inclusive improvement in MDA programme whereas, significant relative improvement in intervention arm reflects effectiveness of SGWN strategy. Though reduction in microfilaria prevalence in all arms was observed, it was significant between intervention and comparison arm. This study highlights need for context-dependent communication strategy to improve MDA for accelerating LF elimination by the targeted 2020.

Short-term malaria reduction by single-dose azithromycin during mass drug administration for trachoma, Tanzania.

Single-dose mass drug administration of azithromycin (AZT) is underway to eliminate trachoma worldwide. Studies in Ethiopia showed a reduction in all-cause childhood deaths after administration. To examine the effect of single-dose AZ MDA on prevalent malaria infections in a large prospective cohort of children and parents in Dodoma Province, Tanzania, we quantified the temporal prevalence of malaria parasitemia by real-time PCR for 6 months after single-dose AZT. In the first month after treatment but not in subsequent months, Plasmodium falciparum infections were reduced by 73% (95% CI 43%-89%) in treatment versus control villages and differences remained significant (p = 0.00497) in multivariate models with village-level random effects. Genetic sequencing of P. falciparum ribosomal L4 protein showed no mutations associated with AZT resistance. AZT mass drug administration caused a transient, 1-month antimalarial effect without selecting for P. falciparum ribosomal L4 resistance mutations in a region with a 10-year history of treating trachoma with this drug.

Mechanistic and Single-Dose In Vivo Therapeutic Studies of Cry5B Anthelmintic Action against Hookworms

BackgroundHookworm infections are one of the most important parasitic infections of humans worldwide, considered by some second only to malaria in associated disease burden. Single-dose mass drug administration for soil-transmitted helminths, including hookworms, relies primarily on albendazole, which has variable efficacy. New and better hookworm therapies are urgently needed. Bacillus thuringiensis crystal protein Cry5B has potential as a novel anthelmintic and has been extensively studied in the roundworm Caenorhabditis elegans. Here, we ask whether single-dose Cry5B can provide therapy against a hookworm infection and whether C. elegans mechanism-of-action studies are relevant to hookworms.Methodology/Principal FindingsTo test whether the C. elegans invertebrate-specific glycolipid receptor for Cry5B is relevant in hookworms, we fed Ancylostoma ceylanicum hookworm adults Cry5B with and without galactose, an inhibitor of Cry5B-C. elegans glycolipid interactions. As with C. elegans, galactose inhibits Cry5B toxicity in A. ceylanicum. Furthermore, p38 mitogen-activated protein kinase (MAPK), which controls one of the most important Cry5B signal transduction responses in C. elegans, is functionally operational in hookworms. A. ceylanicum hookworms treated with Cry5B up-regulate p38 MAPK and knock down of p38 MAPK activity in hookworms results in hypersensitivity of A. ceylanicum adults to Cry5B attack. Single-dose Cry5B is able to reduce by >90% A. ceylanicum hookworm burdens from infected hamsters, in the process eliminating hookworm egg shedding in feces and protecting infected hamsters from blood loss. Anthelmintic activity is increased about 3-fold, eliminating >97% of the parasites with a single 3 mg dose (∼30 mg/kg), by incorporating a simple formulation to help prevent digestion in the acidic stomach of the host mammal.Conclusions/SignificanceThese studies advance the development of Cry5B protein as a potent, safe single-dose anthelmintic for hookworm therapy and make available the information of how Cry5B functions in C. elegans in order to study and improve Cry5B function against hookworms.

The Global Programme to Eliminate Lymphatic Filariasis: History and achievements with special reference to annual single-dose treatment with diethylcarbamazine in Samoa and Fiji.

Diethylcarbamazine (DEC), first introduced in 1947, was shown to have strong efficacy and safety for treatment of human lymphatic filariasis, which is caused mostly by a species Wuchereria bancrofti. Many studies to optimize the dosage and treatment schedule of DEC followed, and, based on the results, control programs with various regimens were implemented in different endemic areas/countries. By the mid 1970s, with endorsement by the WHO Expert Committee on Filariasis (3rd report, 1974), the standard DEC regimen for W. bancrofti infection in mass treatment had been established in principle: a total dose of 72 mg/kg of body weight given in 12 divided doses, once weekly or monthly, at 6 mg/kg each. Not long after the committee report, the efficacy of annual single-dose treatment at 6 mg/kg, which is only one twelfth of the WHO-recommended dose in a year, was reported effective in French Polynesia (study period: 1973-78), and later in Samoa (study period: 1979-81). These results were published between 1978 and 1985 in the Bulletin of WHO but received little attention. In the mid 1980s, the efficacy of ivermectin, the first-choice drug for onchocerciasis, against lymphatic filariae came to light. Since the effect at a single dose was remarkable, and often better than DEC, it was predicted that the newly introduced drug would replace DEC. Treatment experiments with ivermectin increased quickly in number. Meanwhile, annual single-dose mass drug administration (MDA) with DEC at 6 mg/kg was under scrutiny in Samoa and Fiji. In the early 1990s, the Samoan study, which covered the entire population of 160,000 with 3 annual MDAs, reported a significant reduction in microfilaria (mf) prevalence and mean mf density, while in Fiji, the efficacy of 5 rounds of annual MDA (total dose, 30 mg/kg) was shown to be as effective as 28 multi-dose MDA spread over 2 years (6 weekly plus 22 monthly treatments at 5 mg/kg; total dose, 140 mg/kg). Several additional studies carried out in Samoa in relation to the annual single-dose MDAs revealed that low density mf carriers, who have a very low mf count of 1-20/ml of venous blood, could not play a significant role in filariasis transmission.From around 1990, studies on spaced low-dose DEC treatments and various types of combination chemotherapy with DEC and ivermectin increased. Albendazole, a well-known anti-intestinal helminths agent, was later added to the combination. The main findings of these studies with W. bancrofti are: (i) a single dose of DEC at 6 mg/kg reduced mean mf density by ca. 90% 1 year after treatment; (ii) the same dose could damage/kill adult worms; (iii) a single dose of ivermectin at ca. 400 µg/kg was more effective than DEC in reducing mf density during the first year and was similarly or less effective in the second year; (iv) ivermectin probably could not kill adult worms; (v) a single combined dose of albendazole (400 mg) and DEC (6 mg/kg) was effective to reduce mf density by 85 to nearly 100% 12-24 months after treatment; and (vi) ivermectin or albendazole included in the combination chemotherapy produced “beyond-filariasis” benefits: clearance/reduction of intestinal helminths, and, additionally, in the case of ivermectin, skin-dwelling ectoparasites.The Global Programme to Eliminate Lymphatic Filariasis (GPELF) started its worldwide activities in 2000, with the target of elimination by 2020. The basic strategy is to conduct annual single-dose MDAs for 4-6 years. In 2000-2007, a minimum of 570 million individuals were treated in 48 of 83 endemic countries. The drugs used are DEC 6 mg/kg plus albendazole 400 mg in most countries, or ivermectin 200-400 µg/kg plus albendazole 400 mg particularly in onchocerciasis endemic countries in Africa. (MDAs with DEC alone had been used in India.)The GPELF achieved impressive results in terms of parasitological cure/improvement, clinical benefits, social and economic impacts, etc. However, the most impressive result of all was the programme’s success in mobilizing hundreds of millions of local people, who not only took drugs but many of them actively supported MDAs as drug distributors and volunteers. Beyond filariasis, the role people can play in supplementing rural health services is now a topic of discussion and a source of hope for a new sustainable system.

Global Eradication of Lymphatic Filariasis: The Value of Chronic Disease Control in Parasite Elimination Programmes

The ultimate goal of the global programme against lymphatic filariasis is eradication through irrevocable cessation of transmission using 4 to 6 years of annual single dose mass drug administration. The costs of eradication, managerial impediments to executing national control programmes, and scientific uncertainty about transmission endpoints, are challenges to the success of this effort, especially in areas of high endemicity where financial resources are limited. We used a combined analysis of empirical community data describing the association between infection and chronic disease prevalence, mathematical modelling, and economic analyses to identify and evaluate the feasibility of setting an infection target level at which the chronic pathology attributable to lymphatic filariasis - lymphoedema of the extremities and hydroceles - becomes negligible in the face of continuing transmission as a first stage option in achieving the elimination of this parasitic disease. The results show that microfilaria prevalences below a threshold of 3.55% at a blood sampling volume of 1 ml could constitute readily achievable and sustainable targets to control lymphatic filarial disease. They also show that as a result of the high marginal cost of curing the last few individuals to achieve elimination, maximal benefits can occur at this threshold. Indeed, a key finding from our coupled economic and epidemiological analysis is that when initial uncertainty regarding eradication occurs and prospects for resolving this uncertainty over time exist, it is economically beneficial to adopt a flexible, sequential, eradication strategy based on controlling chronic disease initially.

Global Eradication of Lymphatic Filariasis: The Value Of Chronic Disease Control in Parasite Elimination Programs

AbstractThe ultimate goal of the global programme against lymphatic filariasis is eradication through irrevocable cessation of transmission using 4 to 6 years of annual single dose mass drug administration. The costs of eradication, and logistical and managerial impediments to executing national and regional control programmes, and scientific uncertainty about transmission endpoints, are challenges to the success of this effort, especially in areas of high endemicity where financial resources are limited. We used a combined analysis of empirical community data describing the association between infection and chronic disease prevalence, mathematical modelling, and economic analyses to identify and evaluate the feasibility of setting an infection target level at which the chronic pathology attributable to lymphatic filariasis - lymphoedema of the extremities (elephantiasis) and hydroceles - becomes negligible in the face of continuing transmission as a first stage option in achieving the elimination of this parasitic disease. The results show that microfilaria prevalences below a threshold of 3.55% at a blood sampling volume of 1 ml could constitute readily achievable and sustainable targets to control disease due to lymphatic filariasis. They also show that as a result of the high marginal cost of curing the last few individuals to achieve elimination, maximal benefits can occur at the disease control threshold. Indeed, a key finding from our coupled economic and epidemiological analysis is that when initial uncertainty regarding eradication occurs and prospects for improving information to resolve such uncertainty over time exist, it is economically beneficial to adopt a flexible, sequential, eradication strategy based on controlling chronic disease initially. These results suggest that it may be optimal to set phased targets for the elimination of lymphatic filariasis, starting with disease control followed by intensified efforts to eradicate transmission as better knowledge regarding transmission dynamics and issues of implementation feasibility becomes evident. They also illustrate the importance of taking explicit accounts of uncertainties, multi-staged endpoints, and the value of embedding flexibility in the decision making process when determining optimal parasite eradication strategies.

Impact of single dose of diethylcarbamazine and other antifilarial drug combinations on bancroftian filarial infection variables: Assessment after 2 years

The impact of single dose mass drug administration of diethylcarbamazine (DEC), DEC with albendazole (ALB), and ivermectin (IVR) with albendazole, was examined on the human bancroftian filarial infections in village scale trials in south India, from a follow-up study after 2 years. The treatment arms administered with DEC alone and DEC + ALB demonstrated long-term benefits in reducing microfilaraemia significantly ( P < 0.05), while antigenaemia reduction was negligible. The arm with ALB + IVR did not show such reductions. Among the antigenaemic and microfilaraemic individuals, 87% became amicrofilaraemic in DEC + ALB arm, which were higher than that observed in the other 2 treatment arms. Among amicrofilaraemics (but Ag +), nearly 35% cleared of infection in DEC + ALB, while 26% and 6% in DEC alone and IVR + ALB arms, respectively. The drug combination DEC + ALB was observed to demonstrate a significant impact in reducing filarial infection even after 2 years post treatment.

Effectiveness of two annual, single-dose mass drug administrations of diethylcarbamazine alone or in combination with albendazole on soil-transmitted helminthiasis in filariasis elimination programme.

A longitudinal community-trial on the control of soil-transmitted helminths (STHs), as part of a lymphatic filariasis elimination campaign, was taken up in two revenue blocks of southern India in the years 2001 and 2002 to assess the impact of two annual single-dose mass drug administration (MDA) of diethylcarbamazine (DEC) + albendazole (ALB) with that of DEC alone. The prevalences and intensities of STHs were studied among cross-sectional samples of school children aged 9-10 years by using the Kato-Katz technique at baseline and 11 months after each MDA. The combined drug mass treatment produced a higher reduction in the prevalence (RIP) (51-77%) and the egg reduction rate (ERR) (92-98%) compared with 12-15% RIP and 58-62% ERR of DEC alone mass treatment. The effect of two-drug therapy after two annual treatments was relatively long lasting as shown by RIP and ERR indicating that the reinfection rates were relatively lower in this approach than single-drug therapy. This study demonstrates that mass drug co-administration of DEC + ALB in Global Programme for Elimination of Lymphatic Filariasis (GPELF) targeted at the community had a synergistic and sustainable effect against soil-transmitted helminthiasis and provided considerable 'beyond filariasis' benefits. The additional advantages accrued to the community underscore the importance of scaling-up GPELF to cover the entire population at risk.

Sustainability of soil-transmitted helminth control following a single-dose co-administration of albendazole and diethylcarbamazine

We evaluated the long-term impact of single-dose diethylcarbamazine plus albendazole combination therapy with that of diethylcarbamazine alone on the control of soil-transmitted helminths (STH) in 2 blocks (revenue units) of Villupuram district, south India, as part of an ongoing mass drug administration (MDA) campaign for the elimination of lymphatic filariasis in 2001. The prevalence and intensities of STHs were studied in 287 children, aged 9 and 10 years (136 in the combination therapy cohort and 151 in the diethylcarbamazine alone cohort), using the Kato-Katz technique to examine stool samples at 4 time-points (baseline, and 3 weeks, 6 months and 11 months after MDA). The combination therapy showed long-term efficacy against STHs and the magnitude of control remained at a moderate and significant level for 11 months after MDA compared with the moderate gains of diethylcarbamazine alone. Single-dose MDA with albendazole and diethylcarbamazine combination therapy may prove to be a good strategy in treating multiple parasitic infections in endemic communities.

Long-term population migration: an important aspect to be considered during mass drug administration for elimination of lymphatic filariasis.

Annual 2-drug, single-dose mass drug administration (MDA) to 80-90% of the eligible population for 4-6 years are pre-requisites for the successful elimination of lymphatic filariasis (LF) from endemic communities by interruption of transmission and eventual elimination of new infections. In an experimental intervention project on the control of LF in Villupuram district of Tamil Nadu state, India, migration patterns of the villagers were investigated to determine the appropriate timing to implement MDA in order to attain high coverage in a village-level study. Between January and December 1997, 16 observations took place at 3-week intervals, following MDA with two drugs viz., diethylcarbamazine and ivermectin, in July-August 1996. The migrants from the village constituted 17-27% at different points of time and both short-term and long-term migrating patterns were observed. More villagers were available during the agricultural season (September-January), peaking around mid-January [83%; significantly higher (P < 0.05)] than during most of the remaining months, including a substantial portion of the migrant population. There is an urgent need to reschedule the yearly MDA in this area to take place in January and to plan mopping up operations by involving local self-help groups to include migrants (both short-term and long-term) in the LF elimination efforts.