202

Albendazole in Human Loiasis: Results of a Double-Blind, Placebo-Controlled

Trial
Amy D. Klion, Achille Massougbodji, John Horton,
Serge Ekoue, Toussaint Lanmasso,
N arcisse-Leon Ahouissou, and Thomas B. N utman
Laboratory ofParasitic Diseases, National Institutes ofHealth, Bethesda.
Maryland; Faculte des Sciences de la Sante, Universite Nationale du
Benin, Cotonou, and Societe de Recherches sur Ie Palmier a l'Huile. Pobe,
Republic of Benin; SmithKline Beecham Pharmaceuticals.
Welltyn Garden City, United Kingdom

To assess the filaricidal activity and clinical safety of albendazole in human loiasis, a double-
blind, placebo-controlled study was conducted in an endemic area in Benin, Africa. Twenty-three
men with microfilaremia (100-30,OOOjmL) were randomly assigned to receive albendazole (200
mg; n = 11) or placebo (n = 12) twice daily for 21 days; 1 patient from each group withdrew from
the study. There were no clinical adverse effects and no observed hepatotoxicity, renal toxicity, or
hematologic abnormalities attributable to the drug. In the albendazole group, microfilarial levels

Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 6, 2015

began to decrease at day 14 after treatment and by 6 months had fallen to a geometric mean of
20% of pretreatment levels (vs. 84.8% in the placebo group). Blood eosinophil levels and anti-fi-
larial IgG and IgG4 also fell significantly in response to albendazole. Taken together, these data
suggest that albendazole has a primary (possibly embryotoxic) effect on the adult parasite, result-
ing in a slow decrease in microfilaremia.

Loiasis, infection with the filarial parasite Loa loa, affects
between 3 and 13 million people in Central and West Africa
[1]. As is true of the other filarial diseases of humans, the
clinical spectrum of loiasis is quite broad and includes rare
but severe complications, such as encephalopathy [2], ne-
phropathy [3, 4], and cardiomyopathy [5]. While the charac-
teristic manifestations of loiasis are Calabar swellings (tran-
sient localized angioedema) and eyeworm (subconjunctival
migration of the adult worm). a majority of infected individ-
uals from endemic areas have no symptoms despite very high
numbers of microfilariae (rnf) in the blood [6].
The current drug of choice for the treatment of loiasis is
the piperazine derivative. diethylcarbamazine (DEC). Al-
though the drug is active against both mf and adult worms,
multiple courses of therapy may be necessary to eradicate the
infection [4]. Complications of therapy. which include fatal
posttherapeutic encephalitis [7. 8], are thought to be due to
the rapid release of antigens by dying mf and are thus more
common in patients with high microfilarial loads. Cytaphere-
Received 23 December 1992; revised 26 February 1993.
Presented in part: annual meeting of the American Society for Tropical
Medicine and Hygiene, Boston, November 1991 (abstract 414).
Written informed consent (in French) was obtained from subjects; if the
individual was unable to read or spoke only a tribal language, the study
protocol, risks, and benefits, were explained verbally. Guidelines for human
experimentation of the US Department of Health and Human Services were
followed. The project was approved by the Institutional Review Boards of
the Universite Nationale du Benin, Cotonou, and the National Institutes of
Health, Bethesda.
Reprints or correspondence: Dr. Amy Klion, University of Iowa Hospi-
tals and Clinics, SW 54 GH, Iowa City, IA 52242.
The Journal of Infectious Diseases 1993;168:202-6
© 1993 by The University of Chicago. All rights reserved.
0022-1899/93/6801-0030$01.00
sis to decrease the parasite burden has been used in combina-
tion with steroids and antihistamines to prevent these com-
plications [9]; however, this approach is impractical in the
developing world. Finally, diethylcarbamazine treatment of
patients with loiasis who have concomitant Onchocerca vol-
vulus infection may lead inadvertently to a worsening of ocu-
lar pathology [10].
Other pharmacologic agents have been tried in L. loa in-
fection, including ivermectin, the microfilaricidal drug of
choice in onchocerciasis. and mebendazole, an anthelmintic
used primarily in the treatment of intestinal nematode infec-
tions [11-14]. Although single-dose ivermectin has been
shown to reduce the numbers of L. loa mf in the blood [11,
12], in a recent study of ivermectin treatment of 49 patients
with high levels of L. loa mf in the blood (>2500 mf/ml.),
30% of patients had mild to moderate side effects, including
urticaria, arthralgias, and fever [15]. This may be particularly
important as the Widespread use of ivermectin to treat on-
chocerciasis expands into areas of Africa endemic for loiasis.
Several studies with mebendazole have shown efficacy in de-
creasing the mf levels in loiasis and, in high doses, mebenda-
zole may also kill the adult parasites [13, 14]. However, its
poor and variable absorption and the high incidence of side
effects when high doses are used has limited its usefulness in
loiasis.
Albendazole is a benzimidazole derivative related to me-
bendazole but has the advantages of greater absorption after
oral administration and a wider spectrum of activity [16].
Effective in eradicating experimental filarial infections in sev-
eral animal models [17, 18], albendazole has recently been
shown to decrease blood mflevels in human filarial infection
[19-21]. To define the kinetics and filaricidal activity of al-
bendazole in loiasis and to assess the clinical safety and toler-
JID 1993; 168 (July) Albendazole in Human Loiasis 203

Table 1. Baseline characteristics of the study population of men those who had received placebo were offered a 2 l-day course of
with microfilaremia. albendazole (200 mg, orally, twice a day).
Study design. Study drug was administered and signs and
Treatment group
symptoms were recorded twice daily for 21 days. Acetamino-
Albendazole Placebo
phen for pain or fever and antihistamines for pruritus or urti-
Characteristic (n = 10) (n = II) caria were administered when clinically indicated. Blood and
urine were collected on days 0 (before treatment), I, 3, 6, 10,
Median age, years 42 (25-54) 44 (25-55) 14, 21, and 28 and at 3 and 6 months after the beginning of
Geometric mean treatment. Mf counts, white blood cell counts with differentials,
microfilariae/rnl, 2369 (385-20,200) 3119 (236-27,500) and urinalyses were done on the day of collection at each time
Geometric mean point, and serum was frozen in liquid nitrogen for drug and
eosinophils/rnm' 1681 (320-3465) 1426 (750-3312) anti-filarial antibody levels. Liver function tests (alanine amino-
Geometric mean transferase [AL T] and aspartate aminotransferase [AST]), he-
antifilarial IgG,
matocrit determinations, and stool examinations were done on
units/rnl. 358 (84-2271) 308 ( I 19-1321)
days 0 and 21 by the laboratories at the Centre National Hospi-
Geometric mean
antifilarial IgG4, talier et Universitaire, Cotonou.

Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 6, 2015

ng/ml. 16,963 (415-61.350) 13,754 (595-376,500) Blood filtrations for assessment ofmfwere made with 1 mL of
Intestinal nematode anticoagulated blood using a 3-~m filtration technique (Nucleo-
infection* 4 5 pore, Pleasanton, CA) [22]. Filaria-specific IgG and IgG4 were
measured by ELISA as described previously [23,24]. Units were
NOTE. Ranges shown in parentheses. defined on the basis of a reference serum to which all other
* Ascaris lumbricoides. Strongyloides stercoralis. or hookworm.
samples were compared.
Statistical analysis. Geometric means were compared using
Student's t test and relative frequencies by Fisher's exact test.
ance of albendazole treatment in patients with high blood
levels of mf, we conducted a double-blind, placebo-con-
trolled, randomized trial in an endemic area in Benin, West Results
Africa. Neither the albendazole nor the placebo group experi-
enced serious adverse effects during the course of the study
(table 2). Although more than one-third of patients experi-
Patients and Methods enced myalgias and arthralgias, the incidence of these symp-
toms did not differ between groups. Interestingly, 3 patients
Patients. The study site in Pobe, Benin, and the general
characteristics of the population from which the study patients in the albendazole group and only I in the placebo group
were drawn have been described [6]. Of note, epidemiologic noted increased appetite. This trend is likely related to the
surveys have found no evidence of human filarial parasites other effect of albendazole on intestinal helminths [25] and, in
than L. loa in the region. Apparently healthy men and nonpreg- fact, the 5 patients in the albendazole group with docu-
nant women aged 18-65 were considered for the study. Each mented intestinal helminth infection on pretreatment stool
was given a general medical evaluation, including history, physi- examination had no ova or parasites detectable at day 21. No
cal examination, complete blood count, liver function tests, uri- patient in either group developed hematuria, as has been
nalysis, and stool and urine examination for ova and parasites.
In addition, a l-rnl, sample of blood obtained between 11:30
A.M. and 2:30 P.M. was filtered for mf. Persons with a history of
Table 2. Adverse effects observed in the study population of men
benzimidazole allergy or concomitant medication likely to in-
with microfilaremia.
terfere with the interpretation of treatment (rnebendazole,
diethylcarbamazine, or ivermectin) and those with anemia (he- Treatment group
moglobin < 10) or evidence (clinical or laboratory) of renal, cen-
tral nervous system, or hepatic disease, were excluded. Albendazole Placebo
Twenty-three patients (all men) with microfilaremia (range, Symptom (n = 10) (n = II)
100-30,000 mf/rnl, of blood) were enrolled and randomized to
receive either albendazole (200 mg) or identically packaged pla- Fever o o
Myalgia 4 (40) 4 (36)
cebo twice daily. The two patient groups were similar with re-
Arthralgia 5 (50) 4 (36)
spect to age, mf and eosinophil counts and anti-filarial antibody
Pruritus 2 (20) 4 (36)
levels and for the incidence of intestinal nematode infection Calabar swelling o
2 (20)
(table I). Two patients (I in each group) withdrew from the Increased appetite 3 (30) I (9)
study during the first week of treatment because of the frequent Dizziness I (10) o
venipunctures and are excluded from analysis. At the conclu-
sion of the study, participants were informed of the results, and NOTE. Data are no. (%).
204 Klion et al.
200
~
~ 150
~ f-<
~100
~
~ 50
~
0 0
10 100
DAYS
Figure 1. Kinetics of microfilarial clearance. Geometric mean
microfilariae (MF) levels, expressed as percentage of pretreatment
values are shown for placebo (6) and albendazole (.A.) treatment
groups as function of time. *, time points for which difference be-
tween two groups was significant (P < .05; Student's t test).
described with diethylcarbamazine therapy [4], or a fall in
hematocrit. Two patients, both in the placebo group. had
mild transient elevations of AL T and AST. One individual in
the placebo group died of acute renal insufficiency 3 months
after entering the study.
The kinetics of mf clearance with albendazole treatment
are shown in figure I. The geometric mean mf/ml, of blood,
expressed as a percentage of pretreatment levels, is plotted as
a function of the number of days after the administration of
the first dose of albendazole or placebo. Mean mf levels in
\
the placebo group varied between 37.2% and 192% of pre-
treatment values but showed no consistent trend. Interest-
ingly, mf levels in the albendazole group did not begin to
decrease with respect to levels in the placebo group until 14
days into therapy and were significantly lower at 21 days (P
= .04). After a slight rise at 28 days (I week after the end of
treatment), the decline resumed, reaching 20% of pretreat-
ment levels at 6 months, in contrast to 84.8% in the placebo
group (P = .0 I).
Peripheral blood eosinophilia is a commonly used indica-
tor of tissue invasive helminth infection and was common in
patients in both groups before administration of the study
drug (see table I). Figure 2 shows the geometric mean eosin-
ophil levels, expressed as a percentage of pretreatment levels,
for the two groups for each of the study time points. With the
exception of an unexplained dip at day 28, eosinophil levels
in the placebo group remained stable throughout the study.
In contrast, levels in the albendazole group showed a tran-
sient increase at day 21 followed by a decrease to 25% of
pretreatment levels at 6 months (P < .01 vs. placebo group).
A more specific marker of filarial infection, anti-filarial
antibodies, were measured before and at 6 months after ad-
ministration of the first dose of albendazole or placebo. Fig-
JID 1993; 168 (July)
200
l@
en 150
Z *
~
f-<
100
PLACEBO
-<
~
50
~~
ALBENDAZOLE
10 1{)(}
DAYS
Figure 2. Kinetics of eosinophilia. Geometric mean eosinophil
Downloaded from http://jid.oxfordjournals.org/ at East Carolina University on July 6, 2015
levels, expressed as percentage of pretreatment levels. are shown
for placebo (6) and albendazole (.A.) treatment groups as function
of time. *, time points for which difference between two groups was
significant (P < .05; Student's I test).
ure 3 (left) shows the anti-filarial IgG levels at 6 months,
expressed as a percentage of pretreatment levels, for individ-
ual patients in the two study groups. Levels in the albenda-
zole group were significantly lower than in the placebo
group, with geometric mean values of 66% and 118%, respec-
tively (P < .0 I). Similarly, geometric mean levels of anti-fi-
larial IgG4 (an isotype thought to reflect active infection
[26]) at 6 months, expressed as percentage of pretreatment
levels, were 69% in the albendazole group and 112% in the
placebo group (figure 3, right; P = .016).
Discussion
In view of the relative paucity of symptoms in L. loa-in-
fected individuals from endemic areas and the potential se-
Placebo Albendazole Placebo Albendazole
Figure 3. Anti-filarial antibody levels. Anti-filarial IgG (left)
and IgG4 (right) levels at 6 months after treatment are expressed as
percentage of pretreatment values. Each symbol represents individ-
ual patient treated with either albendazole or placebo. Patient in
placebo group who died is omitted from both IgG and IgG4 analy-
sis as no 6-month values were available. Another placebo patient
had no detectable IgG4 before or at 6 months after treatment and
was omitted from IgG4 analysis. Horizontal bars, geometric means.
JID 1993; 168 (July) Albendazole in Human Loiasis
verity of posttreatment reactions, therapy must be safe, well
tolerated, and effective. While diethylcarbamazine fulfills
these criteria in the treatment of individuals with undetect-
able levels of bloodborne mf, serious side effects, including
fatal encephalitis and hypotension, limit its use in microfilar-
ernie subjects (especially in those with high levels of microfi-
laremia). Although precise estimates of the incidence of such
complications in endemic populations are unavailable, in
one study of 60 patients, 14 of whom were microfilarernic,
Mazzotti-like posttreatment reactions occurred in 17 pa-
tients after a single dose of diethylcarbamazine [27]. Milder
adverse effects of the drug, including pruritus, urticaria, and
nausea are nearly universal in this population [28].
Albendazole, initially developed as an intestinal anthel-
mintic, is effective against a variety of systemic helminth in-
fections. Reported adverse effects have been few but include
elevation of liver function tests and leukopenia in patients
given high doses (twice the dose used in this study) for pro-
longed periods [29]. The mechanism of action of albenda-
zole is incompletely understood but is thought to be similar
to that of the other benzimidazoles in which microtubular
function and glucose uptake by the parasite are im-
paired [30].
Albendazole was well tolerated by the study population:
Only 2 patients dropped out of the study, both because of the
frequency of venipuncture. More importantly, despite mi-
crofilarial levels> 5000/mL of blood in 5 of 10 patients in
the albendazole group, side effects attributable to the drug
were not observed. A similar absence of adverse effects has
been documented in a recent double-blind trial of albenda-
zole (400 mg/day) for the treatment of onchocerciasis [20]
and is likely related to the slow rate of mf clearance with
albendazole, which is in marked contrast to the rapid de-
crease seen after diethylcarbamazine or ivermectin treatment
[II, 31].
One of the difficulties in following mf levels as a measure
of drug efficacy in loiasis is their diurnal periodicity. Conse-
quently, despite strict efforts to confine blood drawing to a
3-h period between II :30 A.M. and 2:30 P.M., the mflevels
showed considerable variation. This variation should have
been the same, however, in both the placebo and albenda-
zole groups and, in fact, mf levels remained comparable in
the two groups until day 14 of therapy, when levels in the
albendazole group began to decrease. This delayed effect of
benzimidazoles on microfilarial clearance has been de-
scribed previously in experimental filarial infections [18] and
more recently in human onchocercal infection [20, 21] and
is consistent with either a slow microfilaricidal effect or more
likely a primary effect on adult parasites. Histopathologic
examination of subcutaneous nodules from patients with on-
chocerciasis after albendazole treatment showed disruption
of all intrauterine stages but no reduction in viable adult
worms [21]. Although an exclusively embryotoxic effect of
albendazole could explain our results, adult L. loa are rela-
205
tively more susceptible to chemotherapeutic agents than are
adult O. volvulus, as evidenced by the macrofilaricidal activ-
ity of diethylcarbamazine in loiasis but not in onchocerci-
asis [32].
Determination of drug efficacy in loiasis ideally would in-
clude direct measures of both microfilaricidal and macrofi-
laricidal activity. Direct quantification of adult parasites,
which reside in the subcutaneous tissues, is impossible; thus,
persistently decreased mf levels as well as eosinophil and
anti-filarial antibody levels at 6 months after treatment were
used as an indicator of adult parasite death. Reinfections
with significant production ofmfare unlikely to occur within
this period and residual microfilaricidal effects of albenda-
zole would be expected to have ceased. Although total elimi-
nation of detectable mf at 6 months was achieved in only 1
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patient in the albendazole treatment group, levels were de-
creased in all but 2 patients. The normal life span of L. loa mf
in humans is unknown, however, and longer follow-up may
be necessary.
A transient posttreatment rise in eosinophilia has been de-
scribed in patients with filarial infections and is thought to be
a response to the liberation of parasite antigens from dying
mf [33, 34]. The significant increase in eosinophil levels in
the albendazole treatment group on day 21, 1 week after a
decrease in microfilarial counts was noted, is consistent with
this hypothesis. While the subsequent decrease may reflect
to some degree the temporary eradication of intestinal hel-
minths by albendazole, the sustained decrease observed at 6
months (when reinfection with intestinal nematodes would
be common) is more likely related to the anti-filarial activity
of the drug.
Anti-filarial antibody levels have been shown to decrease
with effective treatment of loiasis [4] and, while cross-reac-
tive with other filarial pathogens, are not elevated in intes-
tinal nematode infections [23]. As a result, they constitute a
good marker of therapeutic response. Levels of both anti-fi-
larial IgG and IgG4 (an isotype believed to reflect active
infection [26]) were significantly decreased in the albenda-
zole group at 6 months and provide additional evidence for
the efficacy of albendazole treatment in loiasis. Attempts to
correlate anti-filarial antibody levels in loiasis with numbers
of circulating mf in the blood have been unsuccessful [6]
and, similarly, we observed no correlation either before or
after treatment. While circulating phosphocholine antigen
levels have been shown to reflect adult worm burden in lym-
phatic filariasis [35] and could be used to indirectly assess
macrofilaricidal efficacy, an equivalent antigen has not been
identified in loiasis.
In summary, albendazole treatment was well tolerated and
without serious adverse effects, even in patients with high
blood levels of L. loa mf, and filaricidal activity of albenda-
zole in human loiasis was confirmed. The observed kinetics
of microfilarial clearance with albendazole are consistent
with a macrofilaricidal effect on the adult parasite, although
206 Klion et al.
an embryotoxic effect on the developing mf, as observed in
onchocerciasis [21], must also be considered. A larger trial
and longer follow-up will be necessary to more completely
assess the efficacy of albendazole in eradicating L. loa infec-
tion and its potential use in mass treatment of infected indi-
viduals in endemic areas. Should albendazole prove to have
an embryotoxic rather than macrofilaricidal effect on L. loa,
the utility of eliminating microfilaremia (and presumably ad-
verse effects) with a short course ofalbendazole before dieth-
ylcarbamazine therapy will merit investigation.
Acknowledgments
We thank the administrative staff of the Center for Palm Oil
Research, Pobe, for access to the study population, and Robert
Poindexter for help with the antifilarial antibody assays.
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