Relationships between Wuchereria bancrofti microfilaria counts in human blood and parasite uptake and maturation in Culex pipiens,with observations on the effects of diethylcarbamazine treatment on these parameters

This study examined relationships between blood microfilaria (MF) counts and parasite uptake and maturation in Culex pipiens fed on Egyptian volunteers with bancroftian filariasis. Uptake of MF and production of infective larvae (L3) were more closely correlated with MF counts in finger prick blood than in venous blood. Only a minority of ingested MF developed into L3. Few MF were ingested, and very few L3 were produced by mosquitoes that fed on infected subjects who were amicrofilaremic by 50 microL thick blood smear; the contribution of such carriers to filariasis transmission in Egypt is probably negligible. These results suggest that filariasis elimination programs should aim to achieve MF smear rates of zero. Single-dose diethylcarbamazine therapy reduced MF counts by 87.9% 6-7 months after treatment; similar reductions were observed for MF uptake, MF/mosquito, infectivity, and L3/mosquito. Thus, single-dose diethylcarbamazine had a major impact on MF ingestion and L3 production by mosquitoes.     

The impact of six rounds of single-dose mass administration of diethylcarbamazine or ivermectin on the transmission of Wuchereria bancrofti by Culex quinquefasciatus and its implications for lymphatic filariasis elimination programmes

Lymphatic filariasis (LF) is targeted for global elimination. Transmission interruption through repeated annual single-dose mass administration of anti-filarial drugs is the mainstay of the LF elimination strategy. This study examined the ability of six rounds of mass administration of diethylcarbamazine (DEC) or ivermectin (IVM) to interrupt transmission of Wuchereria bancrofti by Culex quinquefasciatus, the predominant parasite and vector species, respectively. After six rounds of mass drug administration (MDA), received by 54-75% of the eligible population (> or =15 kg body weight), the resting vector infection and infectivity rates fell by 83% and 79% in the DEC arm, 85% and 84% in the IVM arm and 31% and 45% in the placebo arm, respectively. The landing vector infection and infectivity rates fell by 83% and 94% in the DEC arm, 63% and 75% in the IVM arm and 1% each in the placebo arm, respectively. The filarial larval load per resting mosquito declined by 92% and 93% and per landing mosquito by 83% and 69% in the DEC and IVM arms, respectively. The annual infective biting rate (AIBR) fell from 735 to 93 (87%) in the DEC arm, 422 to 102 (76%) in the IVM arm and 472 to 398 (16%) in the placebo arm. The annual transmission potential (ATP) declined from 2514 to 125 (95%), 1212 to 241 (80%) and 1547 to 1402 (9%) in the DEC, IVM and placebo arms, respectively. However, mosquitoes with infection [microfilaria/larva 1/larva 2 (Mf/L1/L2)] were found in all study villages. Three of five villages in the IVM arm and two of five in the DEC arm recorded no resting mosquitoes with infective-stage (L3) larva. Although the ATP, after six rounds of MDA, fell substantially and remained at 125 and 241 in the DEC and IVM arms, respectively, the cumulative exposure to infective stage larvae (ATP) during the treatment period of 6 years was as high as 2995 in the DEC arm and 1522 in the IVM arm, because of considerable level of transmission during the initial (1-3) rounds of MDA. We conclude that (i) six rounds of MDA, even with 54-75% treatment coverage, can reduce LF transmission very appreciably; (ii) better treatment coverage and a few more rounds of MDA may achieve total interruption of transmission; (iii) high vector densities may partly nullify the reductions achieved in vector infection and infectivity rates by MDA and (iv) achievement of 'true zero' Mf prevalence in communities and 0% infection rate (mosquitoes with Mf/L1/L2) in mosquitoes may be necessary to totally interrupt Culex-transmitted LF.     

A randomized clinical trial comparing single- and multi-dose combination therapy with diethylcarbamazine and albendazole for treatment of bancroftian filariasis

The Global Program for Elimination of Lymphatic Filariasis calls for mass drug administration for endemic populations outside of sub-Saharan Africa with a single dose of diethylcarbamazine (DEC) and albendazole (Alb) annually for 4-6 years. Single-dose DEC/Alb dramatically reduces blood microfilaria (MF) counts, but most treated subjects fail to completely clear MF after a single dose. A more effective regimen might reduce the number of years required for elimination programs. We performed a randomized clinical trial in Egyptian adults with asymptomatic microfilaremia to compare treatment with seven daily doses of oral DEC (6 mg/kg) and Alb (400 mg) with a single dose of the same combination. We also studied the effect of re-treatment with single-dose DEC/Alb 12 months after the first treatment course. Multi-dose DEC/Alb was significantly more effective than single-dose therapy for reducing and clearing microfilaremia (mean reduction in MF/ml relative to pretreatment counts at 12 months, 99.6% versus 85.7%, with complete clearance in 75% versus 23.1%). The two regimens had similar activity against adult filarial worms, as indicated by serial ultrasound assessments. Neither regimen resulted in complete clearance of filarial antigenemia. There was no difference in adverse events, which were mild to moderate. Blood microfilaria and parasite antigen clearance rates increased following re-treatment. Multi-dose DEC/Alb may be a useful option for filariasis elimination programs, especially in the first year (when enthusiasm for mass drug administration and coverage rates are high), to quickly reduce community MF loads and transmission rates.     

Children and adolescents infected with Wuchereria bancrofti in Greater Recife, Brazil: a randomized, year-long clinical trial of single treatments with diethylcarbamazine or diethylcarbamazine-albendazole

In filariasis-endemic areas beyond sub-Saharan Africa, the World Health Organization's recommended strategy for interrupting transmission of the causative parasites is annual, single-dose, mass treatment with a combination of diethylcarbamazine (DEC; given at 6 mg/kg) and albendazole (ALB; given at 400 mg) for 4-6 years (the minimum estimated life-span of the adult parasites). In an open, hospital-based, randomized and controlled trial, with a blinded evaluation of outcome, 82 children and adolescents from Recife, all with Wuchereria bancrofti microfilaraemias, were given either DEC alone (6 mg/kg) or the same dose of DEC combined with ALB (at 400 mg/patient). Every 90 days for 1 year after the single treatment, each patient was checked for microfilaraemia by the filtration of up to 5 ml of venous blood collected at night. One year post-treatment, 16 (39%) of the 41 patients given DEC alone and 20 (49%) of the 41 given DEC-ALB were found microfilaraemic (relative risk=0.8, with a 95% confidence interval of 0.49-1.31) and the corresponding geometric mean levels of microfilaraemia were 2.0% and 1.8% of the levels recorded immediately pre-treatment, respectively (P>0.05). In terms of the prevalences and intensities of microfilaraemia, therefore, the addition of ALB to the DEC appeared to offer no significant benefit.     

The impact of single-dose diethylcarbamazine treatment of bancroftian filariasis in a low-endemicity setting in Egypt

This study was designed to evaluate the effect of a single dose of diethylcarbamazine (DEC, 6 mg/kg) on Wuchereria bancrofti infections in a low-endemicity setting in Egypt (microfilaremia, or MF, 3.7%, median MF 34/mL). Subjects with MF or filarial antigenemia were treated and restudied 1 year later. Treatment with DEC dramatically reduced blood MF counts, with clearance in 69% of subjects. Treatment also reduced filarial antigen levels, but low clearance rates suggest that some adult worms survived treatment in most patients. Mass treatment was administered in one village; 27 months later, MF prevalence had decreased 84% (from 4.9% to 0.8%). These results show that single-dose DEC treatment can have a major effect on MF prevalence rates and levels in low-endemicity settings. Although the World Health Organization advocates repeated multidrug regimens for filariasis elimination, mass treatment with DEC alone may be sufficient to interrupt transmission in areas with low infection intensities and prevalence rates.     

Efficacy of co-administration of albendazole and diethylcarbamazine against geohelminthiases: a study from South India

The efficacy of single-dose combination drug therapy with diethylcarbamazine (DEC) plus albendazole (ALB), and single-drug therapy with DEC alone against geohelminths was compared as part of a mass drug administration (MDA) for elimination of filariasis. This study was conducted in two blocks of Villupuram District of Tamil Nadu State, India, covering a population of 321 000 including about 100 000 children 1-15 years of age. Prevalence and intensity of geohelminth infection were determined by the Kato-Katz technique immediately before and 3 weeks after the MDA. A pre-treatment cross-sectional survey was undertaken in 18 statistically selected villages out of 204 villages, including 646 school children. About 60% were infected with one or more geohelminths. The overall prevalence rates were 53.9%, 12.4% and 5.7% for Ascaris lumbricoides, hookworms and Trichuris trichiura, respectively. Combination therapy (DEC + ALB) produced a cure rate of 74.3% and an egg reduction rate of 97.3% for geohelminths, which were higher than the corresponding rates (30.4% and 79.0%) observed in the single drug therapy arm with DEC alone. The odds of cure with combination therapy were significantly higher for roundworm (5.3 times) and hookworms (3.5 times), then odds of cure with DEC alone. Both therapies were equally effective against trichuriasis, recording cure rates >77% and egg reduction rates >83%. In combination therapy, 53.5% of the children noticed expulsion of worms after MDA, while in single drug therapy only 20.9% did. Our study indicated that MDA of combination therapy was operationally feasible at the community level, and it may secure higher community compliance because of its perceived benefits and enhanced efficacy against geohelminths than single-drug therapy.     

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.     

The effect of six rounds of single dose mass treatment with diethylcarbamazine or ivermectin on Wuchereria bancrofti infection and its implications for lymphatic filariasis elimination

Annual mass treatment with single-dose diethylcarbamazine (DEC) or ivermectin (IVM) in combination with albendazole (ALB) for 4-6 years is the principal tool of lymphatic filariasis (LF) elimination strategy. This placebo-controlled study examined the potential of six rounds of mass treatment with DEC or IVM to eliminate Wuchereria bancrofti infection in humans in rural areas in south India. A percentage of 54-75 of the eligible population (> or =15 kg body weight) received treatment during different rounds of treatment - 27.4% in the DEC arm and 30.7% in the IVM arm received all six treatments, 4.8% and 5.6% received none, and the remainder received one to five treatments. After six cycles of treatment, the microfilaria (Mf) prevalence in treated communities dropped by 86% in the DEC arm (P < 0.01) (n = 5 villages) and by 72% in the IVM arm (P < 0.01) (n = 5 villages), compared with 37% in the placebo arm (P < 0.05) (n = 5 villages). The geometric mean intensity of Mf fell by 91% (t = 8.11, P < 0.05), 84% (t = 6.91, P < 0.05) and 46% (t = 2.98, P < 0.05) in the DEC, IVM and placebo arms, respectively. The proportion of high-count Mf (>50 Mf per 60 mm(3) of blood) carriers was reduced by 94% (P < 0.01) in the DEC arm and by 90% (P < 0.01) in the IVM arm. Among those who received all six treatments, 1.4% in the DEC arm and 2.4% in the IVM arm remained positive for Mf. Two of five villages in the DEC arm and one of five in the IVM arm showed zero Mf prevalence, but continued to have low levels of transmission of infection. The results also indicate that DEC is as effective as or slightly better than IVM against microfilaraemia. Results from this and other recent operational studies proved that single-dose treatment with antifilarials is very effective at community level, feasible, logistically easier and cheap and hence a highly appropriate strategy to control or eliminate LF. Higher treatment coverage than that observed in this study and a few more than six cycles of treatment and more effective treatment tools/strategies may be necessary to reduce microfilaraemia to zero level in all communities, which may lead to elimination of LF.     

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.     

Tolerance and efficacy of combined diethylcarbamazine and albendazole for treatment of Wuchereria bancrofti and intestinal helminth infections in Haitian children

This randomized, placebo-controlled trial investigated the tolerance, efficacy, and nutritional benefit of combining chemotherapeutic treatment of intestinal helminths and lymphatic filariasis. Children were infected with Ascaris (30.7%), Trichuris (53.4%), and hookworm (9.7%) with 69.9% having more than one of these parasites. A total of 15.8% of the children had Wuchereria bancrofti microfilariae. Children were randomly assigned treatment with placebo, albendazole (ALB), diethylcarbamazine (DEC), or combined therapy. The combination of DEC/ALB reduced microfilarial density compared with placebo, ALB, or DEC (P < or = 0.03). Albendazole and DEC/ALB reduced the prevalence of Ascaris, Trichuris, and hookworm more than placebo or DEC (P < or = 0.03). Among Trichuris-infected children, those receiving ALB and DEC/ALB demonstrated greater gains in weight compared with placebo (P < or = 0.05). Albendazole and DEC/ALB were equally efficacious in treating intestinal helminths and for children with W. bancrofti microfilaremia, DEC/ALB was more effective than DEC, with no increase in severity of adverse reactions.     

Community-based study to assess the efficacy of DEC plus ALB against DEC alone on bancroftian filarial infection in endemic areas in Tamil Nadu, south India

As part of the Global Programme for Elimination of Lymphatic Filariasis (GPELF), India is implementing mass drug administration (MDA) with annual single dose of diethylcarbamazine (DEC) with and without albendazole (ALB). The impact of MDAs on filarial infections and soil-transmitted helminth (STH) infections was assessed during a 3-year period in two communities, one with DEC + ALB and the other with DEC alone. Prior to each MDA (during 2001, 2002 and 2003), filarial indices (microfilaraemia and antigenaemia) were assessed from blood samples of 450-650 persons aged 2-25 years and STH infections in stool samples (Kato-Katz method) from 325 to 500 children aged 9-10 years. Mosquitoes resting indoors were collected to determine the filarial infection status. The microfilaraemia prevalence decreased significantly (P < 0.05) in both arms, with the highest decline in the DEC + ALB arm (72%vs. 51%). Decline in micrefilaria intensity was also higher in the DEC + ALB arm (81.4%vs. 48.5%). In this arm alone, the antigenaemia prevalence was reduced significantly (62%; P < 0.001). The reduction in STH prevalence was lower in the DEC alone arm (6.5%; NS) than in the DEC + ALB arm (70.9%; P < 0.001). Also, the egg reduction in DEC alone arm was only half that of DEC + ALB arm (49%vs. 97%). Our community-based follow-up study showed higher and sustained benefits with regard to filarial and STH infections for the two-drug arm over the DEC alone arm. The trends suggest that at least 10 MDAs may be necessary to achieve the goal of elimination.     

Duplex Doppler sonographic assessment of the effects of diethylcarbamazine and albendazole therapy on adult filarial worms and adjacent host tissues in Bancroftian filariasis

We used duplex Doppler sonography to assess effects of diethylcarbamazine and albendazole therapy (DEC/ALB) on adult Wuchereria bancrofti in vivo. The study was performed in clinically normal Egyptian adults with blood microfilaria counts > 80/mL. Motile adult worms were observed before treatment in dilated scrotal lymphatic vessels in 28 of 36 men (78%) and over the proximal extremities in 5 of 22 women (23%). Most worm nests were inactivated in the months following treatment (90% at 12 months). Circulating filarial antigen levels (a marker for living adult worms) also fell dramatically following treatment. Some men had intrascrotal calcifications and/or non-palpable hydroceles detectable by ultrasound before they were treated. New hydroceles and intrascrotal calcifications appeared after treatment in many cases. However, most of these were transient and of no clinical significance. Prevelance rates for hydrocele and intrascrotal calcifications 24 months after treatment were essentially the same as those prior to treatment. These results show that DEC/ALB is highly active against adult W. bancrofti. They also suggest that host responses to dying adult worms are important in the pathogenesis of filarial hydroceles.     

Multiplex bead assay for serum samples from children in Haiti enrolled in a drug study for the treatment of lymphatic filariasis

A multiplex bead assay (MBA) was used to analyze serum samples collected longitudinally from children enrolled in a drug trial for treatment of filariasis in Leogane, Haiti. Recombinant antigens Bm14 and Bm33 from Brugia malayi, third polar tube protein (PTP3) from Encephalitozoon cuniculi, and merozoite surface protein-1(19) (MSP-1(19)) from Plasmodium falciparum were coupled to carboxylated polystyrene microspheres. IgG responses to PTP3 and MSP-1(19) were not affected by albendazole (ALB), diethylcarbamazine (DEC), or combination of diethylcarbamazine and albendazole (DEC/ALB). However, IgG and IgG4 responses to Bm14 and Bm33 were significantly decreased (P < 0.001) by DEC and DEC/ALB treatment. Antibody responses to Bm14 and Bm33 decreased after DEC treatment (but not placebo) among children who were negative for microfilaremia and antigenemia at baseline, suggesting that these children harbored early stages of infection. The MBA is an excellent serologic technique for multiple antigens that offers substantial advantages over single-antigen based enzyme-linked immunosorbent assay in mass drug administration studies for monitoring changes in antibody levels.     

Impact of seven rounds of mass administration of diethylcarbamazine and ivermectin on prevalence of chronic lymphatic filariasis in south India

Objective To evaluate the impact of seven rounds of mass administration of diethylcarbamazine (DEC) and ivermectin on the prevalence of chronic lymphatic filariasis and to compare it with that observed in a placebo arm in a community‐level trial. Methods Cross‐sectional clinical surveys were carried out before and after seven rounds of mass drug administration (MDA). About 54–75% of the target population were treated at each round of MDA. Results After seven rounds, the hydrocele prevalence had declined from the pre‐intervention level of 20.5–5.1% (P < 0.05) in the DEC arm, from 23.9% to 10.4% (P < 0.05) in the ivermectin arm and from 20.4% to 10.9% (P < 0.05) in the placebo arm, equivalent to reductions of 75.3%, 56.6% and 46.6%, respectively. The lymphoedema/elephantiasis prevalence declined only marginally and without statistical significance from 3.7% to 3.2%, 4.6% to 3.9% and 2.9% to 2.3% in the DEC, ivermectin and placebo arm. After the seventh MDA, none of the sampled people in the 0–20 age group was found with hydrocele and there was a statistically significant decline in hydrocele prevalence in all other age groups in the communities treated with DEC, the drug known to have macrofilaricidal effect. The impact was relatively less in ivermectin arm. Conclusion Repeated DEC administration has the potential to prevent incidence of new hydrocele cases and may resolve the manifestation at least in a proportion of affected people. Apart from reducing the microfilaraemia prevalence and transmission of infection, MDA also results in significant public health benefits by reducing the burden of hydrocele in treated communities.     

Comparative assessment of the in vitro sensitivity of Brugia malayi infective larvae to albendazole, diethylcarbamazine and ivermectin alone and in combination

The antifilaricidal drugs ivermectin (IVM), diethylcarbamazine (DEC), and albendazole (ALB), used alone or in combinations against infective third-stage larvae (L3) of nocturnally subperiodic (NSP) Brugia malayi (Narathiwat strain), were tested in vitro for sensitivity, for 7 days. IVM alone reduced larval motility at concentrations of 10(-7), 10(-6), and 10(-5) M on day 3. DEC alone also had this effect at concentrations of 10(-6). 10(-5), and 10(-4) M on day 2. ALB alone did not have this effect throughout the experiment, at various concentrations. However, it had greater effect when used in combination with either DEC or IVM. The result also indicated that DEC or IVM, when used in combination with ALB at concentrations of 10(-6) M/10(-6) M, and 10(-5) M/10(-5) M was effectively better than each drug used alone at those concentrations. When both drug combinations were compared, ALB/DEC seemed to be more effective than ALB/IVM at a concentration of 10(-6) M/10(-6) M on day 3. Although IVM and DEC can reduce larval motility when used alone or in combination with ALB, they cannot kill these larvae in an in vitro cultivation, even at a high concentration (10(-5) M).     

The influence of the mass administration of diethylcarbamazine,alone or with albendazole,on the prevalence of filarial antigenaemia

The current Indian campaign for the elimination of lymphatic filariasis is largely based on mass drug administration (MDA). As part of this campaign, villagers in the Tirukoilur and Mugaiyur 'blocks' (i.e. revenue units) of Villupuram district, in Tamil Nadu, India, were treated with diethylcarbamazine (DEC), either alone (Mugaiyur) or with albendazole (Tirukoilur), in March 2001. The efficacy of treatment, in each of the two treatment arms, was evaluated by determining the percentages of the subjects who were carrying antigen from adult Wuchereria bancrofti before, 6 months and 12 months after the MDA. In a cross-sectional survey at each time-point, commercial, immunochromatographic tests were used to check 1000-1200, randomly selected, young residents (aged 2-25 years) of 18 index villages for the antigen; at least 300 villagers aged 2-9 years and at least 170 aged 10-25 years from each treatment arm were screened in each survey. Before the MDA, 12.7% of the subjects aged 2-9 years and 23.6% of those aged 10-25 years were found to be positive for the filarial antigen. Although only about 50% of villagers aged 2-9 years were successfully treated, MDA (with DEC alone or DEC plus albendazole) led to a significant (28.7%) reduction in the prevalence of antigenaemia in this age-group 6 months later (P<0.05). Although, the prevalences of antigenaemia among those aged 2-9 years were higher 12 months post-treatment than 6 months post-treatment, they were still lower (by 16%-23%) than those observed pre-treatment. The addition of albendazole to the DEC treatment appeared to offer no additional benefit in terms of the prevalence of antigenaemia in children aged <10 years; in fact, the use of DEC alone produced a slightly greater reduction in the prevalence of antigenaemia than the use of both DEC and albendazole. In the block given MDA based on both DEC and albendazole, the prevalences of antigenaemia among the villagers aged 10-25 years were 19.4% and 16.6% lower 6 and 12 months post-treatment, respectively, than observed pre-treatment. Curiously, in the block given DEC alone, the prevalences in this age-group were higher at both post-treatment follow-ups (by 17.4% at 6 months and 35.1% at 12 months) than observed pre-treatment. In concurrent experimental studies, high drug compliance (90%) among young children (aged 2-5 years) led to a pronounced (62.6%) reduction in the prevalence of antigenaemia after one MDA. In follow-up studies of those found antigen-positive, 40% of those aged 2-9 years but only 23% of those aged 10-25 years cleared their antigenaemias after three (annual) MDA. To maximize the benefits of MDA, greater efforts should be made to increase treatment coverage among young children.     

Short-term effects of treatment with 300 mg oral-dose diethylcarbamazine on nocturnally periodic Wuchereria bancrofti microfilaremia and antigenemia

Seven microfilaremic Myanmar patients were treated with a single 300 mg dose of diethylcarbamazine (DEC) orally, as part of a case-finding survey in Ranong Province, Southern Thailand. This was conducted in order to evaluate the short-term effects of single-dose DEC on Wuchereria bancrofti microfilaremia and antigenemia during a 12-week course of treatment. Analysis of microfilarial periodicity on initial treatment revealed the microfilarial peak density (k) was at 52 minutes after midnight (0052). The periodicity index was then 103.26%. Single-dose DEC treatment did not affect the k values. A linear model of W. bancrofti microfilarial density reduction predicts a sharp decrease in the mean microfilarial density 2 weeks after DEC intake (Z = -2.197, p = 0.028). Over a longer period, a non-linear model predicts an increase in the mean microfilarial density to pre-treatment levels, having little or no macrofilaricidal effects. We reconfirmed the existence of nocturnally periodic W. bancrofti infection in Myanmar migrants in Ranong Province, and the short-term microfilaricidal activity of 300 mg single-dose DEC treatment used for biannual mass treatment and the DEC provocative test. Without an adequate DEC treatment dose, recrudescence can occur. A rational approach to the management of introduced nocturnally periodic W. bancrofti in Myanmar migrants, who came for short periods of stay in transmission-prone areas, is needed.     

Significant decrease in the prevalence of Wuchereria bancrofti infection in anopheline mosquitoes following the addition of albendazole to annual, ivermectin-based, mass treatments in Nigeria

A prospective entomological survey was conducted in four sentinel villages in central Nigeria from 1999-2002, to assess the impact of annual, single-dose, mass drug administrations (MDA), with a combination of ivermectin and albendazole, on the transmission of Wuchereria bancrofti. As they were also endemic for human onchocerciasis, the four villages had received annual MDA based on ivermectin alone for 7 years prior to the addition of albendazole. Resting Anophelines gambiae s. l., An. funestus and Culex species were collected from 92 sequentially sampled households and dissected. Mosquitoes harbouring any larval stage of W. bancrofti were classified as 'infected', and those containing the third-stage larvae of the parasite were classified as 'infective'. Over the 41-month observation period, 4407 mosquitoes were captured and dissected, of which 64% were An. gambiae s. l., 34% An. funestus, and 1% Culex species. The baseline data, from dissections performed before the addition of albendazole to the MDA, showed high prevalences of mosquito infection (8.9%) and infectivity (2.9%), despite apparently good treatment coverages during the years of annual ivermectin monotherapy. Only the anopheline mosquitoes were found to harbour W. bancrofti larvae. After the third round of MDA with the ivermectin-albendazole combination, statistically significant decreases in the prevalences of mosquito infection (down to 0.6%) and infectivity (down to 0.4%) were observed (P<0.0001 for each). The combination of albendazole and ivermectin appears to be superior to ivermectin alone for reducing the frequency of W. bancrofti infection in mosquitoes.     

The effect of repeated half-yearly diethylcarbamazine mass treatment on Wuchereria bancrofti infection and transmission in two East African communities with different levels of endemicity

The effect of repeated half-yearly mass treatment with diethylcarbamazine (DEC, 6 mg/kg body weight) on infection and transmission of Wuchereria bancrofti was assessed and compared in communities with high and low endemicity in eastern Africa, with pretreatment microfilaria (mf) and circulating filarial antigen (CFA) prevalences of 29.4% and 53.2% in the high endemicity community and 3.1% and 18.7% in the low endemicity community, respectively. Human infection was monitored by repeated cross-sectional surveys, and transmission by weekly light trap collection of vector mosquitoes in selected houses in each community. Treatments resulted in a progressive decrease in microfilaremia and circulating antigenemia in both communities, with relative reductions being considerably higher for mf than for CFA. Among pretreatment mf-positive individuals, more than 60% were diagnosed as mf negative and mean mf intensities were reduced by 99% in both communities after two treatment rounds. In contrast, only moderate reductions were seen in circulating antigenemia among pretreatment CFA-positive individuals, with mean intensities still being 24-39% of pretreatment values after two treatment rounds. Among the pretreatment mf/CFA-positive individuals, clearance to a CFA-negative status was negligible. Complete CFA clearance was only observed among pretreatment CFA-positive but mf negative individuals who also had much lower initial mean CFA levels than the mf-positive individuals. After treatment, the intensity of transmission decreased in the high-endemicity community, but this appeared mainly to be a consequence of a drought-induced reduction in vector density rather than to reduced mf load in the human population, since the proportion of mosquitoes carrying infective larvae was not reduced. No change in transmission or mosquito infectivity was observed after treatment in the low-endemicity community. Implications of these observations for the control of Bancroftian filariasis are discussed.     

Imported bancroftian filariasis: Diethylcarbamazine response and benzimidazole susceptibility of Wuchereria bancrofti in dynamic cross-border migrant population targeted by the National Program to Eliminate Lymphatic Filariasis in South Thailand

The implementation on the Thailand-Myanmar border of annual mass drug administration (MDA) of a single 6 mg/kg dose of diethylcarbamazine (DEC) plus 400 mg albendazole, part of the National Program to Eliminate Lymphatic Filariasis (PELF), has been challenging. In particular, chain migration of cross-border Myanmar workers at risk for nocturnally periodic Wuchereria bancrofti infection can lead to imported bancroftian filariasis (IBF) in Thailand. IBF is targeted for multiple-dose MDA with 300 mg DEC, in addition to what is recommended by the World Health Organization (WHO). The dynamic Myanmar migrants in Phang-nga, southern Thailand were sampled to test whether the responsible W. bancrofti has a genetic predisposition of benzimidazole exposure, and IBF exhibits DEC susceptibility. The long-term migrants had more access to DEC. IBF in W. bancrofti antigenemic (microfilaremic vs. amicrofilaremic) short-term migrants exhibited susceptibility to a 300-mg single-dose DEC treatment. During the course of a 3-month follow-up, antigenemia was significantly reduced, but microfilaremia was fluctuated. Surprisingly, a newly recognized Mansonella infection co-existing among W. bancrofti-affected Myanmar migrants elicited microfilaremia clearance within a month after treatment. As a result of the presence of genetically stable W. bancrofti β-tubulin (Wbtubb) gene responsible for benzimidazole susceptibility, IBF did not possess a genetic predisposition for benzimidazole exposure. Point mutations at positions Phe167Tyr and Phe200Tyr were not detected by Wbtubb locus-specific nested PCR and sequencing. This study has the potential to help guide not only the Thai/Myanmar PELF surveillance and monitoring of mass treatment impacts on W. bancrofti, but also the other endemic countries allied with the Global Program to Eliminate Lymphatic Filariasis (GPELF).