Cost-effectiveness of triple drug administration (TDA) with praziquantel, ivermectin and albendazole for the prevention of neglected tropical diseases in Nigeria.

Onchocerciasis, lymphatic filariasis (LF), schistosomiasis and soil transmitted, helminthiasis (STH) are all co-endemic in Nigeria. Annual mass drug administration (MDA) with ivermectin (for onchocerciasis), albendazole (for STH and with ivermectin for LF) and praziquantel (for schistosomiasis) is the WHO-recommended treatment strategy for preventive chemotherapy. Separate delivery rounds for distribution of these drugs have been the usual approach to MDA. All three drugs, however, have now been shown to be clinically and programmatically safe for co-administration with what has come to be known as triple drug administration (TDA). We examined the cost savings of converting from separate delivery rounds to TDA in two states in Nigeria. In 2008, eight local government areas received a single round of ivermectin with albendazole followed at least 1 week later by a single round of praziquantel to school-aged children. The following year, a single round was administered with TDA. The number of treated individuals was essentially unchanged during both years (1,301,864 in 2008 and 1,297,509 in 2009) and no change in adverse events was reported. The total programmatic costs for the MDA, not including drug and overhead costs, reduced by 41% from $123,624 to $72,870. Cost savings were limited in larger populations due to economies of scale. TDA is recommended for mature MDA.

The presumptive treatment of all school-aged children is the least costly strategy for schistosomiasis control in Plateau and Nasarawa states, Nigeria.

The results of previous studies in Nigeria indicate that 81% of the villages in Plateau and Nasarawa states probably qualify for the mass administration of praziquantel (PZQ) because of Schistosoma haematobium (SH) and/or S. mansoni (SM) infection. To determine the best strategy, relative costs were modelled for four different programmatic approaches to mass drug administration (MDA) at village level. The approaches considered were (1) village-by-village screening for SH (using dipsticks to test for haematuria), with MDA confined to those villages where at least 20% of school-aged children were found infected; (2) screening for both SM (using Kato-Katz smears) and SH, with MDA confined to those villages where at least 20% of school-aged children were found infected with SH or at least 10% of such children were found SM-positive; (3) the presumptive annual treatment of all school-aged children with PZQ (without village-by-village screening); and (4) the presumptive annual treatment of all eligible adults and children with PZQ. In the MDA in models 1 and 2, treatment is only given to children unless the prevalence of schistosome infection is >or=50%, when adults are also treated. As first-year 'assessment' costs were particularly high for the models that included screening, costs were projected over 5 years for all four models. The total 5-year costs, to cover a population of 30,000, were U.S.$18,673 for the model with screening only for SH, U.S.$36,816 for the model with screening for both SH and SM, U.S. $15,510 for the treatment of all school-aged children, and U.S.$68,610 for the treatment of the entire population. Although the presumptive treatment of school-aged children appeared to be the cheapest approach, it would exclude the community-wide treatment of highly endemic communities, the importance of which needs further study.

Molecular cloning and characterization of recombinant parasite antigens for immunodiagnosis of onchocerciasis.

Immunological cross-reactivity among nematodes has hampered the development of specific serodiagnostic assays for onchocerciasis. In the present study, an Onchocerca volvulus adult worm complementary DNA expression library was differentially screened with human sera from patients infected with O. volvulus and with an omnibus anti-nematode serum pool comprised of sera from patients infected with Brugia malayi, Loa loa, Wuchereria bancrofti, Mansonella perstans, Strongyloides stercoralis, Ancylostoma duodenale, Ascaris lumbricoides, and Dracunculus medinensis. Seven Onchocerca-specific clones were identified and screened with individual onchocerciasis patient sera. Additional studies were performed to characterize the most immunoreactive clones, OC 3.6 and OC 9.3. OC 3.6 produced a 152-kD beta-galactosidase fusion protein that was recognized in dot-immunoblots by 54 of 55 sera from onchocerciasis patients (98%). The OC 3.6 DNA insert is 996 bp long with an open reading frame of 627 bp and a 369-bp untranslated 3' end. OC 3.6 is closely related to a previously reported clone (OV 33-3), but it differs from that clone at both the 5' and 3' ends. OC 9.3 contained a novel 565-bp insert and produced a 138-kD fusion protein that was recognized by 46 of 55 sera from onchocerciasis patients (83%). Additional studies are in progress to develop and evaluate immunodiagnostic tests for onchocerciasis based on measurement of antibodies to these promising recombinant antigens.

Mass ivermectin treatment for onchocerciasis: lack of evidence for collateral impact on transmission of Wuchereria bancrofti in areas of co-endemicity.

There has long been interest in determining if mass ivermectin administration for onchocerciasis has 'unknowingly' interrupted lymphatic filariasis (LF) transmission where the endemicity of the two diseases' overlaps. We studied 11 communities in central Nigeria entomologically for LF by performing mosquito dissections on Anopheline LF vectors. Six of the communities studied were located within an onchocerciasis treatment zone, and five were located outside of that zone. Communities inside the treatment zone had been offered ivermectin treatment for two-five years, with a mean coverage of 81% of the eligible population (range 58-95%). We found 4.9% of mosquitoes were infected with any larval stage of W. bancrofti in the head or thorax in 362 dissections in the untreated villages compared to 4.7% infected in 549 dissections in the ivermectin treated villages (Mantel-Haenszel ChiSquare 0.02, P = 0.9). We concluded that ivermectin annual therapy for onchocerciasis has not interrupted transmission of Wuchereria bancrofti (the causative agent of LF in Nigeria).

Knowledge, beliefs, and practices in relation to malaria transmission and vector control in Guatemala.

As part of an effort to involve community members in malaria control activities, we studied knowledge, beliefs, and practices of residents of both the Pacific coastal plain and northeastern Guatemala related to malaria transmission and Anopheles albimanus control. Most residents recognized the role of mosquitoes in malaria transmission, but few knew how mosquitoes acquired their infections or understood the risk of having an untreated person in their midst. If this were more widely known, residents might put greater pressure on infected patients to seek timely and appropriate antimalarial treatment. Seventy-three percent of families owned one or more bed nets; however, even though most informants believed that bed nets help protect against malaria, the major reason for using them was to prevent nuisance mosquito bites. It is concluded that efforts should be made to promote bed net use by seeking ways to make them more affordable and by emphasizing their effectiveness as a barrier to nuisance mosquitoes. Although residents have a very positive opinion of the National Malaria Service spray teams, it is proposed that cooperation might be improved if malaria workers would emphasize the fact that house spraying reduces the numbers of nuisance mosquitoes and other pest insects, rather than focusing solely on malaria prevention, which most informants believed was less important. This study emphasizes the importance of understanding community beliefs and practices when planning or evaluating vector control activities.

Cysticercosis surveillance: locally acquired and travel-related infections and detection of intestinal tapeworm carriers in Los Angeles County.

A surveillance system for cysticercosis was initiated in January 1988 in Los Angeles County to measure the incidence of the disease, to more accurately assess the level of locally acquired and travel-related infection, and to evaluate household contacts for intestinal tapeworm infection. In three years of surveillance (1988-1990), 138 incident cases were reported for an average crude annual incidence rate of 0.6 per 100,000 population. The highest rates were among Hispanics (1.6/100,000), most of whom were Mexican immigrants. Eight (5.8%) cases were fatal. Nine (6.5%) probable travel-associated cases occurred among persons born in the United States who had traveled to Mexico. Ten (7.2%) autochthonous cases of cysticercosis were documented. Taenia eggs were recovered more commonly in specimens from contacts with cysticercosis cases (1.1%) than in specimens from noncontact patients (0.2%). At least one Taenia tapeworm carrier was found among contacts of five (6.9%) of 72 cysticercosis patients. Carriers were more likely to be found among contacts of patients born in the United States (22.2%) than among those of foreign-born (4.8%) patients (odds ratio = 5.4) Cysticercosis causes appreciable morbidity and mortality in Los Angeles County, principally among Hispanic immigrants. However, these results indicate that both travel-acquired and locally acquired cysticercosis may be more common than previously recognized. Public health followup of cysticercosis cases, including screening of household contacts, can identify tapeworm carriers, who can be treated and removed as potential sources of further infection.

An evaluation of quantitative techniques for Schistosoma haematobium eggs in urine preserved with carbolfuchsin.

The objective of this study was to determine a suitable method for quantitating Schistosoma haematobium eggs in urine specimens preserved in carbolfuchsin. Using a 0.002% carbolfuchsin-phenol-alcohol solution as a stain/preservative for urine obtained from 30 patients infected with S. haematobium, we compared egg counts obtained with four quantitative techniques: Nytrel filtration, Nuclepore filtration, suction filtration and centrifugation. Centrifugation gave statistically higher values than all other techniques for absolute number of eggs recovered in the preserved urine. We also measure a statistical difference between the counts obtained from Nuclepore filtration of fresh urine and those established on an equivalent volume of preserved urine by Nuclepore and Nytrel filtration. The preserved urine frequently caused obstruction of both Nuclepore filters and Whatman No. 1 filters (used in suction filtration), rendering them technically difficult to use and less satisfactory than other methods. From the techniques we examined, we conclude that in field studies where preservation of urine is necessary, preparation of Nuclepore filters with fresh urine, or centrifugation of a carbolfuchsin-preserved urine, are the methods of choice for quantitation of specimens.

Permethrin-impregnated bed nets for malaria control in northern Guatemala: epidemiologic impact and community acceptance.

Permethrin-impregnated bed nets were evaluated as a control measure for malaria in northern Guatemala. Twelve hundred forty participants were allocated to one of three experimental groups (impregnated bed nets [IBN], untreated bed nets [UBN], and controls) and followed up for a period of 13 months. The incidence density of malaria was significantly lower in both IBN (86 cases/1,000 person-years) and UBN groups (106/1,000) compared with that in controls (200/1,000). No difference in malaria incidence was noted between the IBN and UBN groups. Complaints of fever and chills were less frequent in the IBN group compared with controls. The participants were enthusiastic about the nets, which they saw as a means for avoiding nuisance insects more than for preventing malaria. Most (85%) wanted to wash their nets every 4-12 weeks, a practice known to shorten the duration of residual insecticide action. Larger studies are needed to determine whether or not impregnated bed nets offer an advantage over untreated nets in this setting.

Recent trends in the prevalence and distribution of schistosomiasis in the Nile delta region.

In 1983, a survey of 71 villages in the Nile delta demonstrated that the overall prevalence of Schistosoma mansoni and S. haematobium infections was 39% and 5%, respectively. Recent increased availability of praziquantel, combined with Egyptian Ministry of Health-sponsored media efforts to educate the public about schistosomiasis, prompted us to determine the current status of S. mansoni and S. haematobium infections in the delta and evaluate any changes that may have occurred since the previous survey. The same villages that participated in the 1983 survey were resampled in 1990. Stool and urine samples were requested from all occupants over the age of two years in a 5% sample of houses within each village. Stool (Kato) thick smears and urine sediments were read qualitatively at the rural health station. Field-prepared Kato smears and a 20% sample of urine specimens were forwarded to the Ministry of Health Laboratory, where quantitative readings were also performed. Analysis of samples obtained from 17,310 persons revealed that S. mansoni prevalence had decreased to 23% and that S. haematobium prevalence had decreased to 3% (P < 0.001). The highest levels of schistosome infection were found in governates located in the eastern section of the delta. The observed changes in the prevalence of S. mansoni and S. haematobium suggest that control measures are having a favorable impact on schistosomiasis transmission in this region.

1983 Nile Delta schistosomiasis survey: 48 years after Scott.

To determine whether the sharply declining Schistosoma haematobium infection rates in parts of the Nile Delta could be generalized to the entire region, and to update the status of S. mansoni infection rates, a large scale survey was undertaken in 1983 in 70 of the 71 districts of the Nile Delta. In a house-to-house survey, greater than 91% of the sample population of 16,675 participated by providing stool and/or urine specimens which were examined qualitatively by Kato thick smear and sedimentation techniques, respectively. After the 1935 survey by Scott, the prevalence of S. mansoni appeared to change little, from 33% in 1935 to 39% in 1983, but a more sensitive diagnostic technique in 1983 strongly suggested that the actual prevalence had decreased between the 2 surveys. In contrast, the prevalence of S. haematobium infection decreased from 56% to 5%, with a similar decline in all 8 governorates. The dramatic decline in S. haematobium prevalence has been accompanied temporally with a sharp decrease in the population density of Bulinus truncatus. S. mansoni has become the predominant human schistosome species in the Nile Delta.

Alterations in filarial antigen-specific immunologic reactivity following treatment with ivermectin and diethylcarbamazine.

The presence of circulating microfilariae has been associated with alterations in B and T cell functions. In this study, we compared the influence of diethylcarbamazine (DEC) and ivermectin on filarial antigen-specific immune responses in a Haitian population. Both drugs were effective at reducing microfilaremia levels to less than 10% of pretreatment levels for up to one year. This reduction in microfilaremia was associated with two phases of altered cellular responsiveness monitored with in vitro assays. Five days post-treatment, cellular proliferation in response to both filarial and nonfilarial antigens was significantly increased, as was the background response in the absence of any antigen. At both nine months and one year post-treatment, the filarial antigen-specific reactivity of both DEC- and ivermectin-treated patients was significantly increased over baseline levels. No differences were observed between the two treatment groups in terms of humoral or cellular reactivity to filarial antigens, despite evidence suggesting a role for DEC in adult worm killing. These results provide additional evidence that microfilariae modulate antifilarial immune reactivity.

Ivermectin: reduction in prevalence and infection intensity of Onchocerca volvulus following biannual treatments in five Guatemalan communities.

Residents of five hyperendemic communities located in the central focus of onchocerciasis in Guatemala were treated with ivermectin (Mectizan) or placebo every six months for 30 months. The effects of treatment on prevalence and the intensity of skin infection (microfilarial skin density [MFD]) were evaluated. Significant and persistent reductions in both of these indices were achieved by coverage of 80.7% of the eligible populations. The highest proportionate reductions in both indicators of infection occurred after the first treatment, followed by more gradual decreases through the fourth treatment. In one community in which the mean coverage was 92.7%, prevalence decreased from 74.0% at pretreatment to 34.9% after four treatments, while the MFD decreased from 7.8 to 2.0; reductions of 52.8% and 74.3% from pretreatment values, respectively. In every ivermectin-treated community except one, in which drug acceptance was low, the mean community MFD values were reduced to the level associated with low infectiousness for the vector, Simulium ochraceum. Moreover, the category of MFD associated with high vector infectiousness was reduced at least ten-fold over the pretreatment level. One community had low participation during the first two treatments (32.8% and 22.7% of those eligible). This increased to 55.2% at the third treatment because of implementation of an educational program describing both the disease and the beneficial effects of ivermectin and because skin biopsies and nodulectomies were not performed. Secondary reaction rates for all communities were 29.5%, 9.9%, 10.3%, 8.2%, and 7.1% for the first through fifth treatments, respectively. Pruritus was the most common (34.0%) secondary reaction, followed by facial edema (31.8%). All reactions were classified as mild to moderate. Recommendations for mass distribution of ivermectin in Guatemala are given.

Experimental Onchocerca volvulus infections in mangabey monkeys (Cercocebus atys) compared to infections in humans and chimpanzees (Pan troglodytes).

Three chimpanzees, three mangabey monkeys (Cercocebus atys), and 14 patas monkeys (Erythrocebus patas) were inoculated with L3 Onchocerca volvulus of Guatemalan origin. One chimpanzee and two mangabey monkeys developed antibody activity to at least three different antigens. Both mangabey monkeys recognized a 20 kDa antigen 3.5-5 months post-inoculation, and the monkeys and the chimpanzee developed antibody activity to 14 and 22 kDa antigens 7.5-13 months post-inoculation. One mangabey monkey and the chimpanzee became microfilaria-positive in skin snips at 16 and 21 months post-inoculation, respectively. Antibody activity to the 20 kDa antigen in the mangabey monkeys is noteworthy because of the prominence of this antigen among putatively immune persons living in onchocerciasis-endemic areas. The two mangabey monkeys responded parasitologically in a manner comparable to immune humans. No microfilariae were detected in one monkey and only scant numbers of microfilariae were observed in the second. The mangabey monkey may be a good animal model for the study of onchocerciasis.

Comparison of high dose ivermectin and diethylcarbamazine for activity against bancroftian filariasis in Haiti.

This three-phase study was designed to compare high dose ivermectin with a standard diethylcarbamazine (DEC) regimen for patient tolerability, potential to kill adult filaria, and duration of microfilarial suppression in 30 Haitian subjects with Wuchereria bancrofti microfilaremia. All were first given a 1-mg oral dose of ivermectin (phase 1) to reduce microfilaria densities. Participants were randomized into three groups: Group 1 received DEC (6mg/kg per day for 12 days), Group 2 received 200 mcg/kg of ivermectin, and Group 3 received 400 mcg/kg of ivermectin (200 mcg/kg per day for 2 days). All drug regimens were well tolerated with few adverse reactions. Most reactions occurred during phase I and consisted primarily of headache, fever, and myalgia. At the end of phase 1, 27 of 30 (90%) patients were microfilaria negative. During phase 2, four of the six men receiving DEC developed scrotal reactions suggesting killing adult worms; no such reactions were noted in 10 men receiving ivermectin (p less than 0.05). At one-year follow up (phase 3), all treatment groups had less than 10% return to pretreatment microfilaria levels. The mean percent of baseline microfilaria counts were for Group 1, 0.9% (range 0-5%); Group 2, 8.2% (range 0-31%); and Group 3, 3.8% (range 0-25%). Seven individuals in Group 1 were microfilaria-negative, while only one and three individuals were microfilaria-negative in Groups 2 and 3, respectively. These results suggest that DEC causes more damage to the adult worms and greater reduction in microfilaria densities than ivermectin, but that high doses of ivermectin may suppress microfilaremia in lymphatic filariasis for periods much longer than previously reported.

The Carter Center's assistance to river blindness control programs: establishing treatment objectives and goals for monitoring ivermectin delivery systems on two continents.

Periodic mass treatment with ivermectin in endemic communities prevents eye and dermal disease due to onchocerciasis. As part of an international global partnership to control onchocerciasis, The Carter Center's Global 2000 River Blindness Program (GRBP) assists the ministries of health in ten countries to distribute ivermectin (Mectizan, donated by Merck & Co.). The GRBP priorities are to maximize ivermectin treatment coverage and related health education and training efforts, and to monitor progress through regular reporting of ivermectin treatments measured against annual treatment objectives and ultimate treatment goals (e.g., full coverage, which is defined as reaching all persons residing in at risk villages who are eligible for treatment). Since the GRBP began in 1996, more than 21.2 million ivermectin treatment encounters have been reported by assisted programs. In 1999, more than 6.6 million eligible persons at risk for onchocerciasis received treatment, which represented 96% of the 1999 annual treatment objective of 6.9 million, and 78% of the ultimate treatment goal in assisted areas.

Adverse reactions after community treatment of onchocerciasis with ivermectin in Guatemala.

Male and female residents on a Guatemalan coffee plantation where Onchocerca volvulus infections were hyperendemic were offered oral ivermectin (100-200 micrograms/kg) as part of a community-wide treatment programme for onchocerciasis. Forty-five persons were treated and then questioned daily for 28 d about changes in their health. Those with complaints were monitored until all signs and symptoms had resolved. Sixty-seven percent complained of some adverse event after treatment; 60% developed observable adverse reactions attributed clinically to ivermectin. No reaction was life-threatening; the most common were oedema (53%) and fever (47%). Expulsion of intestinal helminths was reported by 38%. Almost all reactions began 24-48 h after treatment; their mean duration was 5 d, despite treatment with acetaminophen and antihistamines. Three patients had oedematous changes lasting over 2 weeks. Incidence, but not severity, of reactions was related to the pretreatment density of microfilariae in skin.