• View in gallery

    Individual estimates of the fraction of Mf killed and the reduction in overall Mf production due to treatment with ivermectin (A) or DEC (B). The histograms along the upper and right axes of the graphs show the corresponding frequency distributions of the efficacy estimates.

  • View in gallery

    Observed and predicted trends in arithmetic mean Mf density. Symbols indicate the mean of the observed individual Mf counts; the lines show the average of the individual predicted Mf densities (○ and dashed line for DEC; • and solid line for ivermectin).

  • View in gallery

    Observed and predicted trend in Mf density for 6 individuals with typical patterns for ivermectin (A–C) or DEC (D–F). Corresponding values of both efficacy parameters are given above each graph.

  • View in gallery

    Flow-chart of the model, showing the dynamics of immature worms (L), adult worms (W), and microfilariae (M) in the human host.

  • 1

    McCarthy JS, Guinea A, Weil GJ, Ottesen EA, 1995. Clearance of circulating filarial antigen as a measure of the macrofilaricidal activity of diethylcarbamazine in Wuchereria bancrofti infection. J Infect Dis 172 :521–526.

    • Search Google Scholar
    • Export Citation
  • 2

    Weil GJ, Lammie PJ, Richards FO Jr, Eberhard ML, 1991. Changes in circulating parasite antigen levels after treatment of Bancroftian filariasis with diethylcarbamazine and ivermectin. J Infect Dis 164 :814–816.

    • Search Google Scholar
    • Export Citation
  • 3

    Dreyer G, Amaral F, Norões J, Medeiros Z, Addiss D, 1995. A new tool to assess the adulticidal efficacy in vivo of antifilarial drugs for Bancroftian filariasis. Trans R Soc Trop Med Hyg 89 :225–226.

    • Search Google Scholar
    • Export Citation
  • 4

    Norões J, Dreyer G, Santos A, Mendes VG, Medeiros Z, Addiss D, 1997. Assessment of the efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo.Trans R Soc Trop Med Hyg 91 :78–81.

    • Search Google Scholar
    • Export Citation
  • 5

    Melrose WD, 2002. Lymphatic filariasis: new insights into an old disease. Int J Parasitol 32 :947–960.

  • 6

    Brown KR, Ricci FM, Ottesen EA, 2000. Ivermectin: effectiveness in lymphatic filariasis. Parasitology 121 :S133–S146.

  • 7

    Ottesen EA, Ismail MM, Horton J, 1999. The role of albendazole in programmes to eliminate lymphatic filariasis. Parasitol Today 15 :382–386.

    • Search Google Scholar
    • Export Citation
  • 8

    International Filariasis Review Group, (David Addiss, Julia Critchley, Henry Ejere, Paul Garner, Hellen Gelband, Carroll Gamble), 2004. Albendazole for lymphatic filariasis (Cochrane Review). The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd.

  • 9

    Plaisier AP, Cao WC, van Oortmarssen GJ, Habbema JD, 1999. Efficacy of ivermectin in the treatment of Wuchereria bancrofti infection: a model-based analysis of trial results. Parasitology 119 :385–394.

    • Search Google Scholar
    • Export Citation
  • 10

    Stolk WA, Subramanian S, Oortmarssen GJ, Das PK, Habbema JD, 2003. Prospects for elimination of Bancroftian filariasis by mass drug treatment in Pondicherry, India: a simulation study. J Infect Dis 188 :1371–1381.

    • Search Google Scholar
    • Export Citation
  • 11

    Subramanyam Reddy G, Vengatesvarlou N, Das PK, Vanamail P, Vijayan AP, Kala S, Pani SP, 2000. Tolerability and efficacy of single-dose diethyl carbamazine (DEC) or ivermectin in the clearance of Wuchereria bancrofti microfilaraemia in Pondicherry, south India. Trop Med Int Health 5 :779–785.

    • Search Google Scholar
    • Export Citation
  • 12

    World Health Organization, 1992. Lymphatic filariasis: the disease and its control. Fifth report of the WHO Expert Committee on Filariasis. World Health Organ Tech Rep Ser 821 :1–71.

    • Search Google Scholar
    • Export Citation
  • 13

    Vanamail P, Ramaiah KD, Pani SP, Das PK, Grenfell BT, Bundy DA, 1996. Estimation of the fecund life span of Wuchereria bancrofti in an endemic area. Trans R Soc Trop Med Hyg 90 :119–121.

    • Search Google Scholar
    • Export Citation
  • 14

    Subramanian S, Stolk WA, Ramaiah KD, Plaisier AP, Krishnamoorthy K, Van Oortmarssen GJ, Dominic Amalraj D, Habbema JD, Das PK, 2004. The dynamics of Wuchereria bancrofti infection: a model-based analysis of longitudinal data from Pondicherry, India. Parasitology 128 :467–482.

    • Search Google Scholar
    • Export Citation
  • 15

    Figueredo-Silva J, Jungmann P, Norões J, Piessens WF, Coutinho A, Brito C, Rocha A, Dreyer G, 1996. Histological evidence for adulticidal effect of low doses of diethylcarbamazine in Bancroftian filariasis. Trans R Soc Trop Med Hyg 90 :192–194.

    • Search Google Scholar
    • Export Citation
  • 16

    Dreyer G, Norões J, Amaral F, Nen A, Medeiros Z, Coutinho A, Addiss D, 1995. Direct assessment of the adulticidal efficacy of a single dose of ivermectin in Bancroftian filariasis. Trans R Soc Trop Med Hyg 89 :441–443.

    • Search Google Scholar
    • Export Citation
  • 17

    Dreyer G, Addiss D, Norões J, Amaral F, Rocha A, Coutinho A, 1996. Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in Bancroftian filariasis. Trop Med Int Health 1 :427–432.

    • Search Google Scholar
    • Export Citation
  • 18

    Ismail MM, Jayakody RL, Weil GJ, Fernando D, De Silva MS, De Silva GA, Balasooriya WK, 2001. Long-term efficacy of single-dose combinations of albendazole, ivermectin and diethylcarbamazine for the treatment of Bancroftian filariasis. Trans R Soc Trop Med Hyg 95 :332–335.

    • Search Google Scholar
    • Export Citation
  • 19

    Freedman DO, Plier DA, De Almeida AB, De Oliveira AL, Miranda J, Braga C, 2001. Effect of aggressive prolonged diethylcarbamazine therapy on circulating antigen levels in Bancroftian filariasis. Trop Med Int Health 6 :37–41.

    • Search Google Scholar
    • Export Citation
  • 20

    El Setouhy M, Ramzy RMR, Ahmed ES, Kandil AM, Hussain O, Farid HA, Helmy H, Weil GJ, 2004. A randomized clinical trial comparing single- and multi-dose combination therapy with diethylcarbamazine and albendazole for treatment of Bancroftian filariasis. Am J Trop Med Hyg 70 :191–196.

    • Search Google Scholar
    • Export Citation
  • 21

    Kshirsagar NA, Gogtay NJ, Garg BS, Deshmukh PR, Rajgor DD, Kadam VS, Kirodian BG, Ingole NS, Mehendale AM, Fleckenstein L, Karbwang J, Lazdins-Helds JK, 2004. Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India. Trans R Soc Trop Med Hyg 98 :205–217.

    • Search Google Scholar
    • Export Citation
  • 22

    Kazura J, Greenberg J, Perry R, Weil G, Day K, Alpers M, 1993. Comparison of single-dose diethylcarbamazine and ivermectin for treatment of Bancroftian filariasis in Papua New Guinea. Am J Trop Med Hyg 49 :804–811.

    • Search Google Scholar
    • Export Citation
  • 23

    Addiss DG, Eberhard ML, Lammie PJ, McNeeley MB, Lee SH, McNeeley DF, Spencer HC, 1993. Comparative efficacy of clearing-dose and single high-dose ivermectin and diethylcarbamazine against Wuchereria bancrofti microfilaremia. Am J Trop Med Hyg 48 :178–185.

    • Search Google Scholar
    • Export Citation
  • 24

    Moulia-Pelat JP, Glaziou P, Nguyen LN, Chanteau S, Martin PM, Cartel JL, 1993. Long-term efficacy of single-dose treatment with 400 micrograms.kg-1 of ivermectin in Bancroftian filariasis: results at one year. Trop Med Parasitol 44 :333–334.

    • Search Google Scholar
    • Export Citation
  • 25

    Moulia-Pelat JP, Nguyen LN, Hascoet H, Nicolas L, 1996. Associations de l’ivermectine et de la diethylcarbamazine pour obtenir un meilleur controle de l’infection en filariose lymphatique. Parasite 3 :45–48.

    • Search Google Scholar
    • Export Citation
  • 26

    Nicolas L, Plichart C, Nguyen LN, Moulia-Pelat JP, 1997. Reduction of Wuchereria bancrofti adult worm circulating antigen after annual treatments of diethylcarbamazine combined with ivermectin in French Polynesia. J Infect Dis 175 :489–492.

    • Search Google Scholar
    • Export Citation
  • 27

    Dreyer G, Coutinho A, Miranda D, Norões J, Rizzo JA, Galdino E, Rocha A, Medeiros Z, Andrade LD, Santos A, Figueredo-Silva J, Ottesen EA, 1995. Treatment of Bancroftian filariasis in Recife, Brazil: a two-year comparative study of the efficacy of single treatments with ivermectin or diethylcarbamazine. Trans R Soc Trop Med Hyg 89 :98–102.

    • Search Google Scholar
    • Export Citation
  • 28

    Kimura E, Penaia L, Spears GF, 1985. The efficacy of annual single-dose treatment with diethylcarbamazine citrate against diurnally subperiodic Bancroftian filariasis in Samoa. Bull World Health Organ 63 :1097–1106.

    • Search Google Scholar
    • Export Citation
  • 29

    Andrade LD, Medeiros Z, Pires ML, Pimentel A, Rocha A, Figueredo-Silva J, Coutinho A, Dreyer G, 1995. Comparative efficacy of three different diethylcarbamazine regimens in lymphatic filariasis. Trans R Soc Trop Med Hyg 89 :319–321.

    • Search Google Scholar
    • Export Citation
  • 30

    Pani S, Subramanyam Reddy G, Das L, Vanamail P, Hoti S, Ramesh J, Das P, 2002. Tolerability and efficacy of single dose albendazole, diethylcarbamazine citrate (DEC) or co-administration of albendazole with DEC in the clearance of Wuchereria bancrofti in asymptomatic microfilaraemic volunteers in Pondicherry, South India: a hospital-based study. Filaria J 1 :1.

    • Search Google Scholar
    • Export Citation
  • 31

    Cao WC, Van der Ploeg CP, Plaisier AP, van der Sluijs IJ, Habbema JD, 1997. Ivermectin for the chemotherapy of Bancroftian filariasis: a meta-analysis of the effect of single treatment. Trop Med Int Health 2 :393–403.

    • Search Google Scholar
    • Export Citation
  • 32

    Ottesen EA, Duke BOL, Karam M, Behbehani K, 1997. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ 75 :491–503.

    • Search Google Scholar
    • Export Citation

 

 

 

 

EFFECTS OF IVERMECTIN AND DIETHYLCARBAMAZINE ON MICROFILARIAE AND OVERALL MICROFILARIA PRODUCTION IN BANCROFTIAN FILARIASIS

View More View Less
  • 1 Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Vector Control Research Centre (Indian Council of Medical Research), Pondicherry, India

Ivermectin and diethylcarbamazine (DEC) are used in mass treatment programs for the elimination of lymphatic filariasis because of their strong effects on microfilaremia. However, the effects of treatment on adult worms and the degree of individual variation in efficacy are unclear. We analyzed series of microfilaria (Mf) counts from individuals treated with a single dose of 400 μg/kg ivermectin or 6 mg/kg DEC (N = 23 in each group; 1 year follow-up). For each individual, we estimated the microfilaricidal effect and the reduction in overall Mf production (e.g., caused by death or sterilization of worms, or inhibited Mf release from the female worm uterus). Ivermectin on average killed 96% of Mf and reduced Mf production by 82%. DEC killed 57% of Mf and reduced Mf production by 67%, with some individuals responding very poorly. The strong reduction in overall Mf production is good news for control of lymphatic filariasis, but the prospects of elimination will be diminished if part of the population systematically responds poorly to treatment.

INTRODUCTION

Programs are being initiated worldwide to eliminate lymphatic filariasis by yearly mass treatment with ivermectin or diethylcarbamazine (DEC), given alone or in combination with albendazole. It is unclear, though, how many treatment rounds will be required to achieve the goal of elimination. A major problem is our incomplete understanding of the effects of treatment on the adult worm. Control needs to be continued for many years if overall microfilaria (Mf) production by adult worms is largely unaffected by treatment. Antigen tests have been used to demonstrate macrofilaricidal effects,1,2 but it is unclear how the reduction in antigen level relates to the proportion of worms killed. Ultrasound has been used to assess the macrofilaricidal effects of treatment directly3,4; however, its application is limited to the scrotal area and superficial lymphatics. Neither of these tools can assess an effect on fecundity.

Most commonly, the effects of treatment have been assessed by measuring the change in Mf density over time. Many clinical trials and community-based interventions showed that treatment with ivermectin or DEC, given alone or in combination with albendazole, leads to a strong and sustained reduction in Mf density (reviewed in Refs. 58). Mathematical models that describe the development of parasites in the human body can be used to analyze such trends in Mf density for indirect quantification of the effects of treatment. In this way, it was estimated from published data that a single dose treatment with 200 or 400 μg /kg ivermectin not only results in immediate killing of all Mf but also in a reduction in the overall Mf production in the follow-up period of respectively 35% or 65% at least.9 The reduction in Mf production indicates that adult worms are affected, but the nature of this effect (e.g., death or sterilization of worms, reduced Mf release from female worm uterus) cannot be determined. However, there was no indication that the reduction in Mf production was only temporary. Similar estimates for the efficacy of a single dose of DEC are not available yet.

Another aspect of interest is the variation in treatment efficacy that occurs between individuals. This has received little attention in literature. However, the impact of mass treatment may be undermined when there is a number of individuals who respond poorly to treatment and who continue to transmit infection in the population.10

Here, we present the results of a double-blind, randomized, hospital-based trial that was carried out to investigate the efficacy of a single dose of ivermectin (400 μg/kg body weight) or DEC (6 mg/kg body weight) for treatment of bancroftian filariasis.11 We analyzed the one-year follow-up trends in Mf density at the individual level to quantify the effects of treatment and the individual variation in these effects.

MATERIALS AND METHODS

Data.

A double-blind, randomized, hospital-based trial was carried out in Pondicherry, India, to compare the safety and efficacy of a single dose of ivermectin (400 μg/kg body weight) or DEC (6 mg/kg body weight) for treatment of bancroftian filariasis.11 In each treatment group, 30 Mf carriers with pretreatment Mf counts ≥ 100 Mf/mL were included. Mf density in the blood was determined by membrane filtration of 1 mL venous night blood, and all blood samples were taken between 8:30 pm and 9:30 pm (not always on the exact same time for an individual). Mf counts were taken with monthly intervals during the first year after treatment. Available observations for part of the individuals made 24 months after treatment were not included in our analysis. This was because these observations are not only determined by the effects of treatment, but to a large extent also by trends in transmission intensity or other external factors that are not accounted for in our model. One-year follow-up is long enough to measure the effects of treatment, but distortion of the trends due to reinfection will be minimal because of the long immature period of the worms. Only individuals with complete follow-up were included in the analysis (23 individuals in each group).

The two treatment groups were comparable with respect to age and gender: the mean age was 20 years in the ivermectin group and 22 years in the DEC group, and the male:female ratio was 14:9 and 12:11, respectively. The mean pretreatment Mf load was higher in the ivermectin group than in the DEC group (538 Mf/mL versus 338 Mf/mL), but this difference was not significant (t test on log-transformed values, P = 0.118).

Statistical analysis.

We used a mathematical model, which describes the course of Wuchereria bancrofti infection in individuals over time and the impact of treatment on the different parasite stages (see Appendix). We assumed that the pretreatment Mf density represents an equilibrium situation where the acquisition of worms and Mf is balanced by the loss. This equilibrium is disturbed by two immediate and irreversible effects of treatment: a fraction of Mf is killed (resulting in an immediate drop in Mf density) and the overall Mf production is reduced by a certain fraction (resulting in a lower rate of Mf recurrence in the blood than expected if Mf production had not been affected). The cause of the reduced Mf production (e.g., death or sterilization of adult worms or any other mechanism that inhibits the release of Mf from the female worm uterus) cannot be determined from the data on Mf density.

The rate of recurrence of Mf after treatment (relative to an individual’s pretreatment level) depends not only on the effects of treatment, but also on assumptions on the duration of the immature period of worms and the adult worm and Mf life span. Based on literature, we assumed these durations to be, respectively, 8 months,12 8 years,13,14 and 12 months9 on average. As argued above, new infections acquired during the first year after treatment will have little impact on trends in Mf density and were ignored in this analysis. Under these assumptions, Mf density 1 year after treatment is 61% of the pretreatment level if treatment kills all Mf but has no effect on adult worms. The behavior of the model is further explained elsewhere.9

Individual trends in Mf density are described by the pre-treatment force-of-infection (β), the fraction Mf killed due to treatment (δ), and the effect of treatment on overall Mf production (λ). The values of these parameters are estimated by fitting the model to the individual data using nonlinear regression and assuming extra-Poisson variation. A more detailed description of the model and the estimation procedure is given in the Appendix.

In a sensitivity analysis, we assessed how the estimates of the efficacy parameters depend on assumptions on the immature period and the worm and Mf life span by halving and doubling their values. We also checked how the results change if we take account of new infections acquired during follow-up with the rate of acquisition being equal to the pre-treatment rate. Spearman’s rank correlation was used to test for correlations between efficacy estimates (δ or λ) and the predicted pretreatment Mf intensities (reflected by β).

RESULTS

The results of the analysis are summarized in Figure 1 and Table 1. On average, the efficacy of ivermectin was higher than that of DEC. The fraction of Mf killed (δ) was high in all ivermectin-treated individuals; in 87% of the individuals, even more than 90% of the Mf was killed. Usually there was also a strong reduction in overall Mf production (λ). The effects of DEC treatment were somewhat lower on average and varied strongly between individuals. In both groups, there was no significant correlation between the individual estimates of δ or λ and the pretreatment Mf intensity β, indicating that the effects of treatment do not depend on the pre-treatment level of infection.

Figure 2 shows the average trend in observed and predicted Mf intensities. Figure 3 gives some typical examples of individual trends in Mf density after treatment. Ivermectin led to a strong initial reduction of Mf density in all individuals, and usually the density remained low during follow-up (Figures 3A and 3B), indicating that the treatment killed nearly all Mf and almost completely interrupted Mf production. Three individuals even had zero Mf counts at all measurements post-treatment, suggesting complete effectiveness of treatment. In several individuals, the strong immediate reduction was followed by a gradual increase, which indicates that Mf production was not completely interrupted (Figure 3C). In the DEC-group, only few individuals showed the nearly ideal pattern of Figures 3A or 3B and there were no individuals who had zero Mf counts during the entire follow-up period. Often, a limited immediate reduction in Mf density after treatment was followed by gradual decline during the follow-up period (Figure 3D). This pattern reflects little direct effect on Mf and a strong effect on Mf production. Sometimes there was no immediate effect on microfilaremia (Figure 3E). In several DEC-treated individuals, Mf counts during follow-up remained high. Due to the high variability in Mf counts, such trends were difficult to interpret, but anyway the effects are poor (Figure 3F). In one individual treated with DEC, treatment did not have any effect on Mf or Mf production.

The sensitivity analysis showed that our results did not depend on the assumed duration of immature period and worm life span. Only the assumptions on Mf life span influenced the individual efficacy estimates, although the change was not always in the same direction. Assuming a Mf life span of 6 or 24 months, the average reduction in overall Mf production was 0.63 or 0.69, respectively, in the DEC group and 0.86 or 0.75, respectively, in the ivermectin group. Allowing for acquisition of new infections during the post-treatment period, we found slightly (around 0–3%) higher estimates for the reduction in overall Mf production; the estimated fraction of Mf killed hardly changed at all.

DISCUSSION

Our analysis of individual-level trends in Mf density after treatment showed that a single dose of ivermectin (400 μg/kg) in all treated individuals resulted in death of a large fraction of Mf and in most instances also in a strong reduction in overall Mf production. The effects of DEC were somewhat lower on average and more variable. In some individuals treated with DEC, almost all Mf were killed and Mf production was nearly completely interrupted; in others, the drug had little effect. The data provide no information about the cause of the reduction in overall Mf production. For DEC it is probably explained by a macrofilaricidal effect.2,4,15 Ivermectin probably does not kill adult worms.16,17 Possibly, ivermectin causes damage to the reproductive system of female worms, so that embryogenesis, maturation, or release of Mf from the uterus is inhibited.

Based on ultrasound examination of the male scrotum, it was previously estimated that a single dose of DEC kills about half of the adult worms.4 The estimated reduction in overall Mf production in our study was only slightly higher. Care is required in this comparison: the reduction in Mf production may be higher than the proportion of adult worms affected, because unmated worms may have survived and retained their ability to produce Mf. Any effect of ivermectin on the fertility of adult worms cannot directly be measured. However, the current estimates are in agreement with the results of a previous model-based analysis.9 This analysis of 2-year follow-up data provided no indication that the effect on Mf production was only temporal, but studies with longer follow-up are required to be more certain on this aspect. Analysis of combined data on Mf and antigen density and on the presence of motile worms1821 may enhance our qualitative and quantitative understanding of the effects of treatment on adult worms.

The validity of our efficacy estimates depends on the validity of the model that was used to describe the average trends. We do not know exactly how the filarial worm develops in the human body. However, assumptions about the immature period or worm life span proved to have little impact on our efficacy estimates and did not change the main conclusions. The results were more sensitive to assumptions about the Mf life span. The effect of changing the assumed Mf life span depends on the observed trend. Assuming a shorter Mf life span results in higher estimates of the reduction in overall Mf production, if a strong initial decline in Mf density is followed by a gradual increase. However, it results in lower estimates, if a gradual decline in Mf density is observed over time. Assuming a longer Mf life span results in changes in the other direction. Although individual estimates were influenced by assumptions on the Mf life span, the impact on the average efficacy estimate was rather limited and strong variability remained.

Assumptions on the acquisition of new infections during follow-up had little impact on the outcomes. Because of the long immature period of the worm (8 months), the contribution of newly acquired infection on the Mf density 1 year after treatment is very limited. Indeed, when we allowed for the acquisition of new infections, assuming that transmission in the post-treatment continues at the same rate as before treatment, we found only slightly higher estimates for the reduction in overall Mf production, and the estimated fraction Mf killed hardly changed.

To assess the generalizability of our efficacy estimates, we compared our data with that from other trials. Higher effectiveness of ivermectin (400 μg/kg) compared with DEC (6 mg/kg) was reported in several studies,2224 but other studies revealed only small differences between both treatment regimens,25,26 and one study found that DEC was even more effective than ivermectin.27 For DEC, the geometric mean Mf density 1 year after treatment varied widely in published studies from 4.5% to 33.4% (average 12%) of the pretreatment level.2330 In our data, it was reduced to about 17% of the pretreatment level, which is within the range of other studies. For ivermectin, too, trends in Mf density varied between studies.31 Analysis of data from other studies may therefore yield somewhat different efficacy estimates.

For part of the individuals in our study one additional observation made 2 years after treatment was available, but these observations were not used. These observations were usually low relative to the observed trend during the first year after treatment.31 Explorative attempts to fit the model to all data (including the 2-year follow-up data) resulted in somewhat higher estimates of the reduction in overall Mf production, but a poorer fit. This suggests that these observations were probably influenced by (external) factors that are not accounted for by our model.

A problem in the analysis of individual level data is the large variability in Mf counts, so that sometimes trends were difficult to interpret. The pretreatment Mf density was based on only one measurement. In some individuals, the pretreatment Mf count by chance will have been lower than the true density. This was probably seen in some DEC-treated individuals, who had higher Mf counts during follow-up than before treatment (e.g., Figures 3E and 3F). In other individuals, the observed Mf count will by chance have been higher than the true Mf density. With our approach, however, we cannot identify when this occurs. This might have led to a small overestimation of the average effects of treatment. The selection of Mf positives for our study population may have added to the overestimation. In the whole population, therefore, the average efficacy may be somewhat lower than we estimated.

Our study provides important information for the ongoing elimination programs for lymphatic filariasis, which are based on mass treatment with DEC and ivermectin in combination with albendazole. The average effects of DEC and ivermectin treatment are high, which triggers optimism about the potential impact of mass treatment. However, ivermectin is usually given in lower dosages (150–200 μg/kg instead of the 400 μg/kg given in this study), which is less effective in reducing the overall Mf production.9 It is unknown to what extent the impact of treatment is improved by giving the drugs in combination with albendazole.8

Especially in the DEC group, there was much variation in treatment efficacy, and in several individuals the effects were poor. A remaining question is whether the observed variation is random or systematic. More information is needed about the impact of a second treatment in individuals who had a poor response. The presence of systematic nonresponders in a population will considerably reduce the probability of elimination, or at least necessitate a longer duration of treatment programs (until most adult worms have died naturally). It would be interesting to study whether the average efficacy of treatment increases and whether the number of people with poor response to treatment is reduced when ivermectin or DEC are given in combination with albendazole, as is recommended for the ongoing elimination programs.32

APPENDIX
 MATHEMATICAL DESCRIPTION OF THE MODEL

The structure of the model is schematically presented in Figure A1. The dynamics of parasite development and Mf production are described by the following set of differential equations:

dL(t)dt=βi(γ+μ1)L(t)dW(t)dt=γL(t)μ1W(t)dM(t)dt=ρW(t)μ2M(t)}

The rate of acquisition of new worms depends on the force-of-infection βi, which is defined as the average number of successfully inoculated new parasites per year. The rate of maturation, γ, is defined by the duration of the immature period (immature period = 1/γ). Similarly, the death rate of larvae and worms, μ1, is defined by the average life span of the parasites (parasite life span = 1/μ1). Mature adult worms start producing Mf (M) at a constant per capita rate ρ. Parameter ρ is defined as the rate of Mf production per mature worm per unit of blood taken for diagnosis. The death rate of larvae and worms, μ2 is defined by the average Mf life span (Mf life span = 1/μ2).

We assume that the force-of-infection has been constant over time, so that the worm and Mf density are in equilibrium prior to treatment, meaning that death of worms is balanced by new infections. The force-of-infection varies between individuals, reflected in different pretreatment counts. Because of the long immature period of worms, new infections acquired during the first year after treatment will have little impact on trends in Mf density, and we ignore these in our analysis. In other words, βi = 0 in the post-treatment period for all individuals.

At the moment of treatment (t = 0), a fraction δi of the Mf (M) is being killed instantaneously and a fraction λi of all worms present in the body (L and W) stop producing Mf or, in the case of immature worms, lose their ability to produce Mf.

SOLUTION OF THE DIFFERENTIAL EQUATIONS

For estimating the effects of treatment, we are interested in the relationship between the Mf density M and time t. By solving the set of differential equations A1 for dL(t)/dt = dW(t)/dt = dM(t)/dt = 0, we derived the following relationship for the equilibrium Mf density pretreatment M*:

M*=ρβiγμ1μ2(γ+μ1)

From the moment of treatment onwards, the relationship is given by a nonlinear function:

M(t)=ρβiμ1μ2(γ+μ1)[γ(1δi)eμ2tμ2(γ+μ1)μ2μ1(λi1)(eμ1teμ2t)+μ1μ2μ2γμ1(λi1)(e(γ+μ1)teμ2t)]

with βi reflecting the pre-treatment individual force-of-infection. For t = 0 (i.e., directly after treatment), this becomes:

M(0)=ρβiγ(1δi)μ1μ2(γ+μ1)

ESTIMATION OF MODEL PARAMETERS

Equations (A2) and (A3) were fitted to the data. Because we have no sound knowledge of the worm load of a person or the Mf production per worm, and because mathematically one of the parameters βi and ρ is redundant, we put ρ = 1 and only estimated βi. Further, we estimated the individual values of δi and λi. These parameters were estimated by nonlinear regression, using SAS (v. 8.2). In doing so, we assumed that Mf counts follow a Poisson distribution with overdispersion (i.e., extra-Poisson variation, the variance being a factor 𝛉 larger than the mean Mf density). The value of 𝛉 was estimated at 30.9, indicating a high variation in Mf counts. Assuming a negative binomial distribution of Mf counts resulted in a worse fit of the data.

Explorative analyses showed that the individual level parameters did not follow a normal distribution and that efficacy estimates were frequently on the boundaries of the possible range of values (implying full or no effect on Mf or Mf production). Including these parameters as random effects in the model was not useful, and we therefore estimated all parameters as fixed effects.

Table 1

Variation in the estimated fraction of microfilaria (Mf) killed and the reduction in overall Mf production between individuals who were treated with ivermectin or diethylcarbamazine (DEC)

Ivermectin (N = 23)DEC (N = 23)
Impact on Mf
    Fraction of Mf killed (δ)
        Average (SD)0.96 (0.05)0.57 (0.39)
        Median (25th to 75th percentile)0.98 (0.95–1.00)0.77 (0.00–0.87)
    Number (%) of individuals with all Mf killed (δ > 0.999)7 (30%)0 (0%)
    Number (%) of individuals with no Mf killed (δ < 0.001)0 (0%)6 (26%)
Impact on Mf production
    Reduction in overall Mf production (λ)
        Average (SD)0.82 (0.27)0.67 (0.36)
        Median (25th and 75th percentiles)0.96 (0.78–1.00)0.87 (0.38–0.96)
    Number (%) of individuals with complete cessation of Mf production (λ > 0.999)7 (30%)5 (22%)
    Number (%) of individuals with no change in Mf production (λ < 0.001)1 (4%)2 (9%)
Figure 1.
Figure 1.

Individual estimates of the fraction of Mf killed and the reduction in overall Mf production due to treatment with ivermectin (A) or DEC (B). The histograms along the upper and right axes of the graphs show the corresponding frequency distributions of the efficacy estimates.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 73, 5; 10.4269/ajtmh.2005.73.881

Figure 2.
Figure 2.

Observed and predicted trends in arithmetic mean Mf density. Symbols indicate the mean of the observed individual Mf counts; the lines show the average of the individual predicted Mf densities (○ and dashed line for DEC; • and solid line for ivermectin).

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 73, 5; 10.4269/ajtmh.2005.73.881

Figure 3.
Figure 3.

Observed and predicted trend in Mf density for 6 individuals with typical patterns for ivermectin (A–C) or DEC (D–F). Corresponding values of both efficacy parameters are given above each graph.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 73, 5; 10.4269/ajtmh.2005.73.881

Figure A1.
Figure A1.

Flow-chart of the model, showing the dynamics of immature worms (L), adult worms (W), and microfilariae (M) in the human host.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 73, 5; 10.4269/ajtmh.2005.73.881

*

Address correspondence to Wilma A. Stolk, Department of Public Health, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: w.stolk@erasmusmc.nl

Authors’ addresses: Wilma A. Stolk, Gerrit J. van Oortmarssen, Sake J. de Vlas, and J. Dik F. Habbema, Department of Public Health, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands, Telephone: +31 10 4087714, Fax: +31 10 4089449. S. P. Pani, S. Subramanian, and P. K. Das, Vector Control Research Centre, Indian Council of Medical Research, Indira Nagar, Medical Complex, Pondicherry 605 006, India, Telephone: +91 413 2272396/2272397, Fax: +91 413 2272041.

Acknowledgments: The authors thank Paul Simonsen (DBL), Dan Meyrowitsch (DBL), and Anton Plaisier for their contribution to this work in earlier stages of the project. The authors thank Theo Stijnen for his statistical advice.

Financial support: This investigation received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.

REFERENCES

  • 1

    McCarthy JS, Guinea A, Weil GJ, Ottesen EA, 1995. Clearance of circulating filarial antigen as a measure of the macrofilaricidal activity of diethylcarbamazine in Wuchereria bancrofti infection. J Infect Dis 172 :521–526.

    • Search Google Scholar
    • Export Citation
  • 2

    Weil GJ, Lammie PJ, Richards FO Jr, Eberhard ML, 1991. Changes in circulating parasite antigen levels after treatment of Bancroftian filariasis with diethylcarbamazine and ivermectin. J Infect Dis 164 :814–816.

    • Search Google Scholar
    • Export Citation
  • 3

    Dreyer G, Amaral F, Norões J, Medeiros Z, Addiss D, 1995. A new tool to assess the adulticidal efficacy in vivo of antifilarial drugs for Bancroftian filariasis. Trans R Soc Trop Med Hyg 89 :225–226.

    • Search Google Scholar
    • Export Citation
  • 4

    Norões J, Dreyer G, Santos A, Mendes VG, Medeiros Z, Addiss D, 1997. Assessment of the efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo.Trans R Soc Trop Med Hyg 91 :78–81.

    • Search Google Scholar
    • Export Citation
  • 5

    Melrose WD, 2002. Lymphatic filariasis: new insights into an old disease. Int J Parasitol 32 :947–960.

  • 6

    Brown KR, Ricci FM, Ottesen EA, 2000. Ivermectin: effectiveness in lymphatic filariasis. Parasitology 121 :S133–S146.

  • 7

    Ottesen EA, Ismail MM, Horton J, 1999. The role of albendazole in programmes to eliminate lymphatic filariasis. Parasitol Today 15 :382–386.

    • Search Google Scholar
    • Export Citation
  • 8

    International Filariasis Review Group, (David Addiss, Julia Critchley, Henry Ejere, Paul Garner, Hellen Gelband, Carroll Gamble), 2004. Albendazole for lymphatic filariasis (Cochrane Review). The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd.

  • 9

    Plaisier AP, Cao WC, van Oortmarssen GJ, Habbema JD, 1999. Efficacy of ivermectin in the treatment of Wuchereria bancrofti infection: a model-based analysis of trial results. Parasitology 119 :385–394.

    • Search Google Scholar
    • Export Citation
  • 10

    Stolk WA, Subramanian S, Oortmarssen GJ, Das PK, Habbema JD, 2003. Prospects for elimination of Bancroftian filariasis by mass drug treatment in Pondicherry, India: a simulation study. J Infect Dis 188 :1371–1381.

    • Search Google Scholar
    • Export Citation
  • 11

    Subramanyam Reddy G, Vengatesvarlou N, Das PK, Vanamail P, Vijayan AP, Kala S, Pani SP, 2000. Tolerability and efficacy of single-dose diethyl carbamazine (DEC) or ivermectin in the clearance of Wuchereria bancrofti microfilaraemia in Pondicherry, south India. Trop Med Int Health 5 :779–785.

    • Search Google Scholar
    • Export Citation
  • 12

    World Health Organization, 1992. Lymphatic filariasis: the disease and its control. Fifth report of the WHO Expert Committee on Filariasis. World Health Organ Tech Rep Ser 821 :1–71.

    • Search Google Scholar
    • Export Citation
  • 13

    Vanamail P, Ramaiah KD, Pani SP, Das PK, Grenfell BT, Bundy DA, 1996. Estimation of the fecund life span of Wuchereria bancrofti in an endemic area. Trans R Soc Trop Med Hyg 90 :119–121.

    • Search Google Scholar
    • Export Citation
  • 14

    Subramanian S, Stolk WA, Ramaiah KD, Plaisier AP, Krishnamoorthy K, Van Oortmarssen GJ, Dominic Amalraj D, Habbema JD, Das PK, 2004. The dynamics of Wuchereria bancrofti infection: a model-based analysis of longitudinal data from Pondicherry, India. Parasitology 128 :467–482.

    • Search Google Scholar
    • Export Citation
  • 15

    Figueredo-Silva J, Jungmann P, Norões J, Piessens WF, Coutinho A, Brito C, Rocha A, Dreyer G, 1996. Histological evidence for adulticidal effect of low doses of diethylcarbamazine in Bancroftian filariasis. Trans R Soc Trop Med Hyg 90 :192–194.

    • Search Google Scholar
    • Export Citation
  • 16

    Dreyer G, Norões J, Amaral F, Nen A, Medeiros Z, Coutinho A, Addiss D, 1995. Direct assessment of the adulticidal efficacy of a single dose of ivermectin in Bancroftian filariasis. Trans R Soc Trop Med Hyg 89 :441–443.

    • Search Google Scholar
    • Export Citation
  • 17

    Dreyer G, Addiss D, Norões J, Amaral F, Rocha A, Coutinho A, 1996. Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in Bancroftian filariasis. Trop Med Int Health 1 :427–432.

    • Search Google Scholar
    • Export Citation
  • 18

    Ismail MM, Jayakody RL, Weil GJ, Fernando D, De Silva MS, De Silva GA, Balasooriya WK, 2001. Long-term efficacy of single-dose combinations of albendazole, ivermectin and diethylcarbamazine for the treatment of Bancroftian filariasis. Trans R Soc Trop Med Hyg 95 :332–335.

    • Search Google Scholar
    • Export Citation
  • 19

    Freedman DO, Plier DA, De Almeida AB, De Oliveira AL, Miranda J, Braga C, 2001. Effect of aggressive prolonged diethylcarbamazine therapy on circulating antigen levels in Bancroftian filariasis. Trop Med Int Health 6 :37–41.

    • Search Google Scholar
    • Export Citation
  • 20

    El Setouhy M, Ramzy RMR, Ahmed ES, Kandil AM, Hussain O, Farid HA, Helmy H, Weil GJ, 2004. A randomized clinical trial comparing single- and multi-dose combination therapy with diethylcarbamazine and albendazole for treatment of Bancroftian filariasis. Am J Trop Med Hyg 70 :191–196.

    • Search Google Scholar
    • Export Citation
  • 21

    Kshirsagar NA, Gogtay NJ, Garg BS, Deshmukh PR, Rajgor DD, Kadam VS, Kirodian BG, Ingole NS, Mehendale AM, Fleckenstein L, Karbwang J, Lazdins-Helds JK, 2004. Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India. Trans R Soc Trop Med Hyg 98 :205–217.

    • Search Google Scholar
    • Export Citation
  • 22

    Kazura J, Greenberg J, Perry R, Weil G, Day K, Alpers M, 1993. Comparison of single-dose diethylcarbamazine and ivermectin for treatment of Bancroftian filariasis in Papua New Guinea. Am J Trop Med Hyg 49 :804–811.

    • Search Google Scholar
    • Export Citation
  • 23

    Addiss DG, Eberhard ML, Lammie PJ, McNeeley MB, Lee SH, McNeeley DF, Spencer HC, 1993. Comparative efficacy of clearing-dose and single high-dose ivermectin and diethylcarbamazine against Wuchereria bancrofti microfilaremia. Am J Trop Med Hyg 48 :178–185.

    • Search Google Scholar
    • Export Citation
  • 24

    Moulia-Pelat JP, Glaziou P, Nguyen LN, Chanteau S, Martin PM, Cartel JL, 1993. Long-term efficacy of single-dose treatment with 400 micrograms.kg-1 of ivermectin in Bancroftian filariasis: results at one year. Trop Med Parasitol 44 :333–334.

    • Search Google Scholar
    • Export Citation
  • 25

    Moulia-Pelat JP, Nguyen LN, Hascoet H, Nicolas L, 1996. Associations de l’ivermectine et de la diethylcarbamazine pour obtenir un meilleur controle de l’infection en filariose lymphatique. Parasite 3 :45–48.

    • Search Google Scholar
    • Export Citation
  • 26

    Nicolas L, Plichart C, Nguyen LN, Moulia-Pelat JP, 1997. Reduction of Wuchereria bancrofti adult worm circulating antigen after annual treatments of diethylcarbamazine combined with ivermectin in French Polynesia. J Infect Dis 175 :489–492.

    • Search Google Scholar
    • Export Citation
  • 27

    Dreyer G, Coutinho A, Miranda D, Norões J, Rizzo JA, Galdino E, Rocha A, Medeiros Z, Andrade LD, Santos A, Figueredo-Silva J, Ottesen EA, 1995. Treatment of Bancroftian filariasis in Recife, Brazil: a two-year comparative study of the efficacy of single treatments with ivermectin or diethylcarbamazine. Trans R Soc Trop Med Hyg 89 :98–102.

    • Search Google Scholar
    • Export Citation
  • 28

    Kimura E, Penaia L, Spears GF, 1985. The efficacy of annual single-dose treatment with diethylcarbamazine citrate against diurnally subperiodic Bancroftian filariasis in Samoa. Bull World Health Organ 63 :1097–1106.

    • Search Google Scholar
    • Export Citation
  • 29

    Andrade LD, Medeiros Z, Pires ML, Pimentel A, Rocha A, Figueredo-Silva J, Coutinho A, Dreyer G, 1995. Comparative efficacy of three different diethylcarbamazine regimens in lymphatic filariasis. Trans R Soc Trop Med Hyg 89 :319–321.

    • Search Google Scholar
    • Export Citation
  • 30

    Pani S, Subramanyam Reddy G, Das L, Vanamail P, Hoti S, Ramesh J, Das P, 2002. Tolerability and efficacy of single dose albendazole, diethylcarbamazine citrate (DEC) or co-administration of albendazole with DEC in the clearance of Wuchereria bancrofti in asymptomatic microfilaraemic volunteers in Pondicherry, South India: a hospital-based study. Filaria J 1 :1.

    • Search Google Scholar
    • Export Citation
  • 31

    Cao WC, Van der Ploeg CP, Plaisier AP, van der Sluijs IJ, Habbema JD, 1997. Ivermectin for the chemotherapy of Bancroftian filariasis: a meta-analysis of the effect of single treatment. Trop Med Int Health 2 :393–403.

    • Search Google Scholar
    • Export Citation
  • 32

    Ottesen EA, Duke BOL, Karam M, Behbehani K, 1997. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ 75 :491–503.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Wilma A. Stolk, Department of Public Health, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands, Telephone: +31 10 4087714, Fax: +31 10 4089449, E-mail: w.stolk@erasmusmc.nl.
Save