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Objectives The Global Programme to Eliminate Lymphatic Filariasis recommends albendazole in combination with other antifilarial drugs. This systematic review examines albendazole in treatment and control of lymphatic filariasis.
Datasources The Cochrane Controlled Trials Register, MEDLINE and EMBASE to April 2005; contacting experts, international organisations and drug manufacturers.
Methods Randomised or quasi-randomised controlled trials included; two reviewers independently assessed eligibility, quality, and extracted data. We calculated the relative risk of microfilaraemia (mf) prevalence using fixed effect, or random effects model in case of heterogeneity.
Results Six trials met inclusion criteria. Three trials compared albendazole with placebo: no effect was demonstrated on mf prevalence, but density was lower in one of the three studies at 6 months. Three trials added albendazole to ivermectin, with no demonstrable effect; prevalence tended to be lower at 4–6 months but not at 12 months (4–6 months; RR 0.49, 95% CI 0.18 to 1.39, n = 255, 2 trials; 12 months: RR 1.00, 95% CI 0.88 to 1.13, n = 348, 2 trials). Mf density was significantly lower in two of the three trials; one of two trials measuring density at 12 months showed a difference. Three trials added albendazole to diethylcarbamazine; two were small trials with no difference demonstrated; the third study tended to favour combination at 6 months (RR = 0.62, 95% CI 0.32 to 1.21, n = 491), with a significant difference for density.
Conclusions The effect of albendazole against adult and larval filarial parasites, alone and in combination with other antifilarial drugs, deserves further rigorous research.
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Lymphatic filariasis affects about 120 million people in more than 80 countries. Adult worms live in the lymphatic system and produce larvae (microfilariae, mf), which migrate to the blood and are ingested by the mosquito vector. In the absence of a safe and effective drug to kill adult Wuchereria bancrofti or Brugia malayi, the current strategy is to interrupt transmission by reducing mf.
In the 1990s, research suggested enhanced suppression of mf with albendazole (Jayakody et al. 1993; Ismail 1998; Ottesen et al. 1999). In 1998, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) recommended annual mass treatment (treating all community members where the disease is endemic) with two-drug regimens: albendazole plus either ivermectin or DEC (GPELF, 2005). Although albendazole has secondary benefits against intestinal helminths (Ottesen et al. 1999; Dickson et al. 2003), we were asked by the GPELF to assess the effects of albendazole alone or in combination with DEC or ivermectin on mf.
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Table 1. Description of studies
|Studies & Refs.||Losses to follow-up||Participants||(all)||n (Mf +ve)|| Alb#|| DEC*|| Iver$|| A + D|| A + I||Placebo||Time of reporting|
|Haiti 1999 (Addiss et al. 1997; Beach et al. 1999)||Inadequate: 585 analysed (61%)||Children (5–11 years) with or without W. bancrofti microfilaremia|| 965||113||Y|| ||Y|| ||Y||Y||Mf positive at 4 months|
|Ghana 2000 (Dunyo et al. 2000)||Inadequate: 273 (80%) of microfilarial-positive participants analysed||Adults and children with or without W. bancrofti filariasis||1425||340||Y|| ||Y|| ||Y||Y||Mf positive at 12 months|
|Tanzania 2004 (Simonsen et al. 2004)||Inadequate: 1221 (67%) analysed||School children (6–18 years) with or without W. bancrofti microfilaraemia||1829||203||N|| ||Y|| ||Y||N||Mf positive at 6 and 12 months|
|India 2002 (Pani et al. 2002)||Adequate: implies no losses to follow up (54 analysed out of 54 randomised)||Asymptomatic volunteers (aged 10–57), all mf +ve|| 54|| 54||Y||Y|| ||Y|| ||N||Mf positive at 12 months|
|Haiti 2005 (Fox et al. 2005)||Inadequate: 990 (76%) analysed||Children (5–11 years) with or without W. bancrofti microfilaraemia||1292||183||Y||Y|| ||Y|| ||Y||Mf positive at 3, 6 and 12 months|
|India 2004 (Kshirisagar et al. 2004)||No losses, but only 103 of 1403 patients initially enrolled in a safety study were assessed for efficacy||Adults and children over 5 years for safety study; males aged 18–50 for efficacy study|| 103|| 73||N||Y|| ||Y|| ||N||Mf positive at 3, 6 and 12 months|
Reported trial inclusion criteria and outcomes varied. One small trial from India was conducted only in individuals who were mf positive at baseline (Pani et al. 2002); one trial from Ghana reported changes in mf prevalence only on those who were positive at baseline (Dunyo et al. 2000); one trial from Haiti 2005 reported mf prevalence in the whole study population, regardless of mf status at baseline (Fox et al. 2005), and one trial, again from Haiti 1999, reported results both for the whole population, and for those mf positive at baseline only (Addiss et al. 1997; Beach et al. 1999).
Figure 1 shows results for trials reporting only those mf positive at baseline; Figure 2 displays trials that reported mf prevalence for the whole community, including persons who were mf negative at baseline. One trial reported on mf at two time points; 3 and 6 months (Fox et al. 2005), and another trial reported results at three time points (3, 6, and 12 months) (Kshirisagar et al. 2004). Data for each time point are included on the figures.
Figure 1. Albendazole and albendazole combinations compared with placebo or the single agents: relative risks of mf prevalence for participants mf positive at baseline.
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Figure 2. Albendazole and albendazole combinations compared with placebo or the single agents: relative risks of mf prevalence for albendazole compared with other antifilarial drugs or placebo in participants mf positive or negative at baseline.
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Albendazole compared with placebo
Table 2. Microfilarial density for albendazole vs. placebo, vs. ivermectin, and in combination with ivermectin (months of follow-up)
| ||Unit|| ||Placebo||Albendazole||Ivermectin||Albendazole + ivermectin|
|Haiti 1999 (Addiss et al. 1997; Beach et al. 1999)||Mf/20 μl||n||29||29||28||24|
|Ghana 2000 (Dunyo et al. 2000)||Mf/100 μl||n||66||71||70||75|
|Tanzania 2004 (Simonsen et al. 2004)||Mf/100 μl||n|| || ||98||105|
|Baseline|| || ||763.5||812.6|
|6 months|| || ||150.0||29.8|
|12 months|| || ||124.9||59.4|
|% Change 6 months|| || ||80.4||96.3‡|
|% Change 12 months|| || ||83.6||92.7‡|
Table 3. Microfilarial density for albendazole vs. placebo, vs. DEC, and in combination with DEC (months of follow-up)
| ||Unit|| ||Placebo||Albendazole||DEC||Albendazole + DEC|
|India 2002 (Pani et al. 2002)||Mf/100 μl||n|| ||19||17||18|
|Baseline|| ||77.6 (range: from 22 to 606)||81.3 (range: from 22 to 542)||79.4 (range: from 22 to 223)|
|% Change day 3|| ||8.7||26.2||35.7|
|% Change day 7|| ||14.1||36.7||45.1|
|% Change day 360|| ||94.7||89.6||95.4|
|Haiti 2004 (Fox et al. 2005)||Mf/20 μl||n||243||256||246||245|
|Baseline||17.3 (95% CI: from 14.5 to 20.6)||12.1 (95% CI: from 10.3 to 14.2)||12.9 (95% CI: from 11.0 to 15.2)||13.4 (95% CI: from 11.4 to 15.8)|
|3 months||8.7 (95% CI: from 7.4 to 10.2)||4.7 (95% CI: from 3.9 to 5.7)||2.9 (range: from 2.5 to 3.4)||2.3 (95% CI: from 2.0 to 2.7)|
|6 months||11.2 (95% CI: from 9.2 to 13.7)||4.4 (95% CI: from 3.7 to 5.3)||2.8 (95% CI: from 2.3 to 3.4)||0.76 (range: from 0.7 to 0.9)|
|% Change 3 months||8.2||22.0||31.3||37.3|
|% Change 6 months||10.3||34.7†||50.4||80.4‡|
Albendazole co-administered with ivermectin
In three trials reporting on participants who were mf positive at baseline, albendazole was co-administered with ivermectin and compared with ivermectin alone (Addiss et al. 1997; Beach et al. 1999; Dunyo et al. 2000). One study from Haiti reported a 73% reduction in mf prevalence for the combination compared with ivermectin alone at 4 months (RR 0.27, 95% CI 0.11 to 0.70, n = 52) (Addiss et al. 1997; Beach et al. 1999) (Figure 1). A second study from Ghana found no difference after 1 year (RR 1.04, 95% CI 0.87 to 1.25, n = 145) (Simonsen et al. 2004). The third study from Tanzania found a statistically significant reduction in mf prevalence after 6 months (RR = 0.74, 95% CI 0.62 to 0.87, n = 203), but after 1 year there was no difference (RR = 0.96, 95% CI 0.81 to 1.13, n = 203) (Simonsen et al. 2004). Meta-analysis of the two trials reporting outcomes at 4–6 months (Addiss et al. 1997; Beach et al. 1999; Simonsen et al. 2004), gave a reduction in mf prevalence of 51% with combination treatment, but this was not significant (RR = 0.49, 95% CI 0.18 to 1.39, n = 255). The two trials reporting at 1 year showed no difference between the treatment arms (RR = 1.0, 95% CI 0.88 to 1.13, n = 348) (Dunyo et al. 2000; Simonsen et al. 2004). The Haiti 1999 trial also reported on mf prevalence for individuals who were mf positive or negative at baseline; results are similar to those presented above (Figure 2).
All three trials reported on mf density (Table 2). One (Ghana) did not find a statistically significant difference between the two groups (Dunyo et al. 2000). The 1999 Haiti study found a significantly greater reduction in geometric mean microfilarial density in the combination group (from 13.7 to 0.3, 98.9%), compared with the ivermectin group (from 15.5 to 1.5, 76.1%) at 4 months (P < 0.05) (Addiss et al. 1997; Beach et al. 1999). As mf density was very low in both groups, the importance of this difference is uncertain. The Tanzania study also found a greater reduction at 6 months in the combination group (from 812.6 to 29.8, 96.3%, compared with 763.5 to 150.0, 80.4%, in the group receiving ivermectin alone, P < 0.001 for both groups compared with baseline) (Simonsen et al. 2004). Similar results were found at 12 months, although the difference between the two groups had narrowed (92.7% reduction in combination group, compared with 83.6% in the ivermectin group) (Simonsen et al. 2004).
Albendazole co-administered with diethylcarbamazine
Three trials compared albendazole co-administered with DEC vs. DEC alone (Pani et al. 2002; Kshirisagar et al. 2004; Fox et al. 2005). The first small study from India randomised only hospital patients who were mf positive at baseline. This study found no significant difference in mf prevalence at 360 days (RR = 0.88, 95% CI 0.61 to 1.26, n = 35) (Pani et al. 2002) (Figure 1). The second community trial from India found no significant differences in mf prevalence at any of the time points assessed (3, 6 and 12 months), but only a small proportion of the study population were included in this assessment (Kshirisagar et al. 2004) (Figure 1). The third, larger study from Haiti enrolled children who were mf positive or negative at baseline (Fox et al. 2005). It found no difference in mf prevalence at 3 months in the treatment arm receiving DEC alone compared with that receiving DEC and albendazole co-administered (at 3 months RR = 0.96, 95% CI = 0.56 to 1.66, n = 491). A non-significant 38% reduction was observed in the group receiving combination therapy at 6 months (RR = 0.62, 95% CI 0.32 to 1.21, n = 491), but the 95% confidence intervals are wide and the estimate is therefore imprecise (Figure 2).
The small hospital trial from India showed no difference in mf density between the treatment arms (Table 3) (Pani et al. 2002). In the 2004 Haiti study, there was no difference in mf density at 3 months, but a statistically significant difference was found at 6 months in favour of combination treatment (2.8 mf/20 μl in the DEC arm compared with 0.76 in the combination arm, P < 0.05) (Fox et al. 2005). The community trial from India did not report on mf density (Kshirisagar et al. 2004).
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This review was designed to assess the effects of albendazole alone or in combination with antifilarial drugs currently recommended by GPELF. Albendazole alone did not appear to reduce mf prevalence when compared with placebo, and only one trial found any significant reduction in mf density.
Both ivermectin and DEC are known to kill microfilaria. It has been suggested that combination treatment of albendazole with ivermectin may be more effective than ivermectin alone in the short term, implying that the drug combination will have a greater impact on transmission. However, these findings are based on just three trials, which reported outcomes between 4 and 12 months only; further evidence is clearly required. Doses of ivermectin also differed between the trials; they were highest in the 1999 Haiti study, which showed the greatest relative reduction in mf for the combination treatment compared with ivermectin alone (see Table 1). Three trials compared albendazole co-administered with DEC to DEC alone (Pani et al. 2002; Kshirisagar et al. 2004; Fox et al. 2005). These also had mixed findings (Figures 1 and 2). Most trials had significant losses to follow-up which may influence their results.
A recently published review concluded that co-administration of albendazole was more effective in reducing mf prevalence than one antifilarial drug alone (Gyapong et al. 2005). This review had different inclusion criteria (it included observational data, and did not assess the quality of the studies). Most importantly, it incorporated data from several studies twice (by counting results at 6 and 12 months and combining them in the same meta-analysis) which artificially narrows 95% CI, resulting in the authors erroneously concluding that overall the effect was ‘statistically significant’ (Gyapong et al. 2005).
This review does not consider the positive effects of administering albendazole to people with filariasis, many of whom are incidentally infected with intestinal helminths (Dickson et al. 2003). It is possible other health benefits from albendazole may improve the adherence to mass drug administration for filariasis, if communities perceive them to be valuable. The inclusion criteria do not include non-randomised data, comprehensively assessed by Ottesen et al. (1999), which may well be relevant to programme decisions.
With only six trials of albendazole plus either DEC or ivermectin, statistical power was limited for some of the combinations. Further, all include only a single treatment cycle, and not the annual treatment over at least 5 years recommended to eliminate the disease in a community. Several trials are under way which may provide further data (Kshirisagar et al. 2004). Other outcomes reported in the trials (including antigen prevalence and density, safety, and effects on clinical disease) were not qualitatively different from those described here (International Filariasis Review Group 2005). Ideally, studies should assess the effect of albendazole-containing regimens on adult worms but only two trials attempted this in a sub-group of patients (Pani et al. 2002; Kshirisagar et al. 2004) . Further large well-designed studies and monitoring of on-going programmes are clearly required to assess the effectiveness of albendazole in combination with DEC or ivermectin on transmission of lymphatic filariasis.