Tolerance of Benznidazole in a United States Chagas Disease Clinic
Tolerance of Benznidazole in a United States Chagas Disease Clinic
David A. Miller 1 2 3
Salvador Hernandez 0 2
Lissette Rodriguez De Armas 0 2
Samantha J. Eells 1 2 3
Mahmoud M. Traina 0 2
Loren G. Miller 1 2 3
Sheba K. Meymandi 0 2
0 Center of Excellence for Chagas Disease, Olive View-UCLA Medical Center , Sylmar, California
1 Division of Infectious Diseases, Harbor- UCLA Medical Center , Torrance
2 Received 31 August 2014; accepted 17 December 2014; electronically published 18 January 2015. Medical Center , 1000 W Carson St, Box 466, Torrance, CA 90509
3 Los Angeles Biomedical Research
The US-based Center of Excellence for Chagas Disease performed an observational study on the safety and tolerance of benznidazole 5 mg/kg/day for 60 days in 30 adults with chronic Chagas disease. The side-effect profile was suboptimal, including 5 cases of debilitating neuropathy and an unusually high angioedema rate.
Chagas disease; trypanosomiasis; benznidazole; United States; drug tolerance
Chagas disease, primarily endemic to Latin America, afflicts
8–10 million people worldwide . The often untreated acute
protozoan illness evolves to a chronic clinically silent
(indeterminate) phase; 20%–30% of cases will progress to cardiac or
gastrointestinal disease after years to decades . Through
immigration, the United States has become the seventh largest
chagasic population in the world, with >300 000 affected persons
. Ten percent to 15% have cardiomyopathy , and the
remainder carry a substantial risk of disease progression ,
contributing to an annual economic burden of >$100 million .
Treatment of adults in the chronic phase has been evidenced
to acutely eliminate polymerase chain reaction positivity, reduce
long-term seropositivity, slow the progression of
cardiomyopathy, and possibly decrease maternal-to-child and blood donor–
related transmission [6–9]. However, the significant side-effect
profile of the recommended chemotherapeutics will continue to
obscure the risk-benefit ratio of treatment until large prospective
trials that are under way can further refine the utility of therapy
. The 2007 US guidelines  recommend offering treatment
to all chronic chagasic patients aged 19–50 in the absence of
pregnancy, hepatic or renal failure, or advanced cardiomyopathy, and
favor benznidazole (over the less well-tolerated nifurtimox) at
5–7 mg/kg/day in 2 divided doses for 60 days , although
there remain inadequate data to guide optimal dosing.
The Center of Excellence for Chagas Disease (CECD) at the
Olive View–UCLA Medical Center is the first dedicated Chagas
disease clinic in the United States to systematically review and
treat Chagas disease. This study aimed to evaluate the tolerance
of benznidazole in an adult US cohort to better understand the
barriers to completing therapy and to refine our treatment
standards in this population.
MATERIALS AND METHODS
Study Design, Setting, and Population
CECD is a public university–affiliated clinic that provides care to
patients regardless of insurance status or ability to pay. There
were 2 446 000 foreign-born Hispanics  in Los Angeles
County during the study period. A panel of nearly 300 patients
had been acquired through in-hospital and community outreach
screening, routine blood bank referrals, and solicitation of
chagasic patient family members. This retrospective observational
study reviews the initial 30 consecutive chagasic patients treated
with benznidazole (February 2011 through July 2013) since it last
became available from the Centers for Disease Control and
Prevention (CDC) through a Food and Drug Administration
protocol. Nifurtimox had previously been the single available agent.
Diagnosis was confirmed by 2 CDC serological tests, using an
immunofluorescent antibody titer ≥1:32, an enzyme
immunoassay, and, as a tiebreaker, a trypomastigote excreted-secreted
antigens Western blot. Patients aged ≥18 years were invited
to undergo clinical evaluation including disease staging and
elicitation of contraindications to medical therapy.
Cardiomyopathy was characterized by electrocardiography,
echocardiography, and cardiac magnetic resonance imaging. Patients were
excluded from receiving benznidazole for Kuschnir grade III
cardiomyopathy (Chagas-associated congestive heart failure)
, pregnancy, severe hepatic or renal insufficiency, or
inability to state commitment to follow-up appointments. Patients
aged >50 years were factored on a case-by-case basis. Patients
eligible for benznidazole therapy received risk-benefit
consultation and signed informed consent prior to treatment.
Dosing of benznidazole (manufactured by Laboratório
Farmacêutico de Pernambuco [LAFEPE]) consisted of 5 mg/kg/day in
2 divided doses for 60 days, initiated at half-dose and
uptitrated to the full dose over the first 4 days. Clinical evaluation
included systematized history, symptom surveillance, physical
examination, and serum analysis (chemistries, liver function tests,
and complete blood count) at 2, 4, 6, and 8 weeks, 1 month after
therapy completion, and at 1 year. Treatment terminations were
determined by the patient and/or the CECD program director.
A standardized medical records abstraction instrument was
used to gather adverse event (AE) data that had been
prospectively recorded in a format adherent to the National Institutes of
Health Common Terminology Criteria for Adverse Events,
version 4.0 . Institutional review board exemption for medical
records review was obtained through the Olive View–UCLA
Education and Research Institute.
Statistical analysis was performed using SAS version 9.3.1 (Cary,
North Carolina). Bivariate analyses were conducted using the
Mann–Whitney U test, Student t test, and Fisher exact test, as
appropriate, to calculate P values. Variables were considered
significant at the α = .05 level.
Thirty patients received benznidazole: mean age was 42 years
(range, 17–67 years), 18 (60%) were female, 10 (33%) had
cardiomyopathy, and 2 (7%) had indigestion issues too minor to alter
clinical management. Twelve patents (40%) were from each
Mexico and El Salvador, 1 (3%) was from Colombia, another from
Nicaragua, and 2 (7%) were born in the United States without
clear epidemiological exposure. Four patients eligible to receive
benznidazole refused therapy. No patients were lost to follow-up.
All 30 patients had AEs: 28/30 (93%) experienced >1 AE; 12
had severe AEs, none life threatening (Table 1). Rash principally
involved the classically described maculopapular eruption
occurring within the first 2 weeks and resolving spontaneously within
2 weeks. There was a trend toward an association between rash
and higher mean weight (81 kg vs 72 kg; P = .054), body mass
index (29.8 kg/m2 vs 27.4 kg/m2; P = .24), and, therefore,
benznidazole total dose. There were no cases of Stevens–Johnson
syndrome. Facial angioedema generally developed within the first 2
weeks of therapy, always in the setting of dermal hypersensitivity
(24% [4/17]), progressing invariably over hours with symmetrical
swelling of the eyelids and lips (Figure 1). Two cases categorized
as angioedema were limited to peripherally localized swelling—1
case involving the hand, and another the shoulder. All cases of
angioedema were observed by providers, yet reported by the
No. of Patients
With Moderate or
Twenty-one patients (70%) completed therapy. Six patients (20%) discontinued
as a direct result of treatment-related AEs: 4 (13%) due to facial angioedema, 1
(3%) due to rash without angioedema, and 1 (3%) due to mild transaminitis near
the end of therapy (peak alanine aminotransferase level, 4 IU/L). Treatment
interruption was elected in 1 patient for 1 week, which was prompted by rash
and transient angioedema of the hand; these symptoms did not return after
resuming therapy and extending treatment duration to complete the 60-day
course. Non-therapy-related treatment discontinuations included 1 patient with
a urinary tract infection at 4 weeks, 1 patient with incidental development of
lichenoid keratosis on his chest wall at 7 weeks, and 1 patient who became
overwhelmed by concurrent dental caries at 7 weeks. All occurrences of
transaminitis (4/30 [13%]) remained <5 times the upper limit of normal. One
patient developed leukopenia with neutropenia after 2 weeks of therapy,
which improved after angioedema prompted therapy discontinuation.
Abbreviation: AE, adverse event.
a Common Terminology Criteria for AEs. b Severe by definition.
patients to be spontaneously improving by the time of clinical
contact. No dyspnea or wheezing was observed. There was a
trend toward an association with angioedema and higher mean
weight (83 kg and 75 kg, respectively; P = .22). No association
could be attributed to either of the 2 benznidazole lot numbers
(L09070538, L11121421) in use.
Peripheral sensory neuropathy occurred only in those
patients who completed the 60-day regimen, occurring within
the last 2 weeks of therapy. Neuropathies were clinically
diagnosed and were typically mild with symptoms of formication,
numbness, pain, and dysgeusia. However, painful neuropathy
limited instrumental activities of daily living in 3 cases and
activities of daily living in 2 others. Neuropathy resolved except in
3 patients exhibiting only slow, progressive improvement
(lasting up to 3.5 years at the time of manuscript submission).
Our observation of a relatively high AE-related discontinuation
rate  was notable for an unusual frequency of angioedema,
an otherwise rare AE . The abrupt onset of localized edema
represents a distinct clinical entity from the rash-associated
edema conventionally described . The root cause remains
speculative and cannot be readily attributed to differences in
lot number, dosing regimen, genetic predisposition, or diet.
Although LAFEPE produces benznidazole consumed in select
Latin American nations without similar reported angioedema
frequency, monitoring of the aforementioned lot numbers is
Our cohort is clinically distinct from other studies in
nonendemic countries, in that European cohorts are principally
comprised of Bolivian immigrants  treated with benznidazole
from a different manufacturer , and the clinical
manifestations and drug susceptibility of Trypanosoma cruzi vary
We observed that rash and angioedema may have correlated
with higher doses. Notably, children are successfully treated with
comparable (mg/kg) dosing strategies and experience minimal
AEs , suggesting that adults have a decreased
weightcorrected clearance of benznidazole and, therefore, a higher
serum half-life. As pharmacokinetic studies to better understand
AE and clinical outcome profiles are lacking , avoidance of
high doses of benznidazole may be wise. We adopted a strategy
widely utilized in Latin America; the total daily benznidazole
dose is capped at 300 mg/day with extension of therapy past 60
days to complete the equivalent cumulative dose .
Rash is common and typically the principal provocation for
treatment interruption, yet, apart from cases of concomitant facial
angioedema, severe rash did not necessarily entail therapy
interruption, and could be temporized with antihistamines or steroids.
Neuropathy was commonly observed and, in 2 cases, limited
ambulation and manual dexterity, resulting in prolonged
unemployment. Importantly, a 30-day course of therapy has been
evidenced to decrease the progression of cardiomyopathy and
possibly decrease mortality while evading the cumulative toxic
neuropathy found typically at the end of a 60-day regimen .
Until the benefit of a more prolonged therapy is demonstrated,
we believe that symptoms of neuropathy should prompt
immediate treatment interruption.
This study demonstrates a significant yet non-life-threatening
side-effect profile of benznidazole in an adult US population.
The suboptimal drug tolerance of benznidazole and nifurtimox
in adults needs to be carefully considered in the decision to treat
chronic Chagas disease while awaiting results of the large
prospective multicenter Benznidazole Evaluation for Interrupting
Trypanosomiasis trial, which is expected to provide more clarity
on the merits of universal treatment . Pharmacokinetic
profiling and optimization of dosing strategies while limiting
hypersensitivity-mediated and neuropathic AEs will be critical
to provide safe clinical management to patients with this
infection that is increasingly recognized in nonendemic nations.
Financial support. Research was supported by Olive View–UCLA
Medical Center and from Center of Excellence for Chagas Disease
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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