Sergio Sosa Estani, Elsa Leonor
Segura
Centro Nacional de Diagnóstico e Investigación de
Endemoepidemias, Administración Nacional de Laboratorios e
Institutos de Salud "Dr. Carlos G. Malbrán", Casilla Postal
1063, Buenos Aires, Argentina
Received 9 June 1999
Accepted 9 August 1999
Code Number:OC99201
Key words: Trypanosoma cruzi - undetermined phase -
treatment - Argentina
The goals of specific treatment against Trypanosoma cruzi
infection, at an individual level, are to eliminate the parasite,
to diminish the probability of developing illness (Chagas disease),
and to hinder the chain of T. cruzi transmission as actions
for the control of vectorial and non vectorial transmission (Sosa
Estani 1993). Around 1930, investigations began in Argentina to
obtain an effective drug against T. cruzi. Of all the
substances evaluated, only nifurtimox (1972) and benznidazol (1974)
have been accepted by the Ministry of Health as anti-T.
cruzi drugs. Both drugs began to be assessed on the acute
phase, and later, on the chronic phase of the disease.
The experiences
In patients treated with nifurtimox following recommended
guidelines, xenodiagnoses turned negative for 88 to 100% of the
cases evaluated up to 123 months after treatment, although in the
chronic patients, serology rarely became negative. Some researches
found negativization to occur between 28 and 38% of the cases
(Cerisola 1969, Boca Tourres 1969, Cançado 1969, Cichero et
al. 1969).
Until 1983, in Argentina, it was recommended to treat
exclusively patients in the acute phase of Chagas disease, because
in the undetermined and chronic phases, conventional serology
persisted reactive, in spite of negative xenodiagnoses. However,
different authors (Cichero et al. 1969, Cançado 1969, Rubio
& Donoso 1969, Schenone et al. 1969, Ferreira 1969, 1990,
Cerisola 1977), concluded that these drugs were also effective in
the undetermined phase. This was inferred based on the evaluation
of parasitemia through xenodiagnoses, which became undetectable or
decreased. It must be stressed that in most cases serology
persisted reactive (Rubio & Donoso 1969, Schenone et al. 1969,
Cerisola 1977). Some of these authors indicated a decrease of
serologic titers (Ferreira 1969, Viotti et al. 1994, de Andrade et
al. 1996, Sosa Estani et al. 1998). Some authors suggested the
possibility that lack of parasitic clearance was the cause of
reactive serology. It was also suggested that the difference of
antibodies (Abs) involved in the conventional serology and those
Abs that unite to the circulating forms of the parasite would
influence the serological evaluation of the specific treatment
(Krettli & Brener 1982, Krettli et al. 1984).
In 1994, Viotti et al. in an eight year follow-up of adult and
young patients non treated or treated with benznidazol, showed that
23% of the controls had unfavorable changes in their
electrocardiograms (ECGs). Those alterations were seen in 5% of the
treated patients (p <0.05). However among those that maintained
a reactive serology, the alterations of the ECGs were observed in
29% of the control patients and 2% of the patients treated with
benznidazol. The authors concluded that specific treatment has a
protective effect during the chronic phase of the infection.
Between 1991 and 1995 a controlled clinical trial was carried
out to evaluate the effectiveness of treatment with benznidazol in
children during the undetermined phase of Chagas disease (Sosa
Estani et al. 1998). After a four year follow-up, this study
demonstrated a significant decrease on the titers of Abs in
patients that received benznidazol, while changes were not observed
in those that received placebo. In patients that showed reactivity
against the recombinant antigen (Ag) F29 (Porcel et al. 1996),
negativization of serology at the end of the follow-up was 62.1%
among children treated with benznidazol and 0% among those that
received placebo. After seven years of follow-up, the
negativization in children treated with benznidazol was around 69%
(manuscript in preparation). Other authors found similar results
using Ags not currently used in conventional serology
(Galvão et al. 1993, Gazzinelli et al. 1993, Krautz et al.
1995, de Andrade et al. 1996). Xenodiagnoses at the end of the
follow-up was positive in 4.7% of patients treated with benznidazol
and 51.2% among control children (p<0.05). Our study concluded
that the effectiveness was over 60%, and that children infected
with T. cruzi that inhabited rural areas may be successfully
treated with benznidazol in an outpatient modality. There are good
opportunities of administering specific treatment, and obtaining
the cure of the infection in the first decade of life (Cichero et
al. 1969, de Andrade et al. 1996, Cançado 1997). The cure of
infection will also eliminate the risk of developing visceral
alterations due to Chagas disease (Viotti et al. 1994) and will
contribute to the interruption of T. cruzi transmission in
areas under vector surveillance. Moreover, our study provided a new
serological marker of cure after treatment, implemented as a quick
and simple serological procedure. In a preliminary observation in
this same population, we also found that at the end of treatment,
the plasmatic concentration of p-Selectin (molecule of adhesion)
was significantly lower in patients treated with benznidazol
compared with the controls, evaluated through an enzymatic immune
assay (Laucella et al. manusc. in prep.). These studies are being
completed. Other clinical trials that reproduce the results
previously mentioned have been documented in the last years in
Argentina, although they were not performed under controlled
conditions (del Barco et al. 1993, Blanco et al. 1997, Fabro et al.
1997).
Side effects
Different authors refer that side effects appear among 4%
and 30% of cases (Barclay et al. 1978, Lugones 1978, Castro &
Diaz de Toanzo 1988, Blanco et al. 1997, Sosa Estani et al. 1998).
These could include dermal (cutaneous maculopapular rush), or
gastrointestinal (colic, nausea, vomits) manifestations, central
neurotoxicity (nervous irritability, insomnia, headache, anorexia),
and peripheral neurotoxicity (paresthesia, hiperesthesia),
mioartralgias. Laboratory tests showed normal bilirrubin values,
while elevation of transaminases could sometimes be observed
(Lugones et al. 1969, Castro & Diaz de Toanzo 1988); leucopenia
or plaquetopenias are exceptionally observed (Cançado 1997).
Side effects are directly related with the dose and the patient's
age, being more tolerated in children and babies than in
adolescents and adults (Bocca Tourres 1969, Cerisola 1977, Moya et
al. 1985). In our experience, in all cases, side effects disappear
when the dose is diminished or the treatment suspended. The
treatment always demands direct medical supervision (Coura 1996).
Evaluation of treatment
To evaluate the response to specific chemotherapy, it is
advisable to use clinical, immu-noserological and parasitological
methods. For the last years in Argentina and other countries like
Brazil, the response to specific treatment has also been performed
using new tools, such as recombinants Ags, tripomastigote Ags, the
polimerase chain reaction or adhesion molecules, that complete
those already in existence. Presently, to evaluate the
effectiveness of treatment, it is necessary to consider the absence
of parasites and a significant decrease of Ab concentration, or
until negativization of serology.
Current situation
Since 1994, the Control Program of Chagas in Argentina
included the subprogram "Detection and treatment in children
between 0 to 14 years old infected by T. cruzi", detecting
children inhabiting the households under surveillance for
triatomine populations. This is a necessary condition for the
administration of specific treatment (OPAS 1998). In 1997, the
guidelines for treatment of the chagasic patient in Argentina were
revised and the current criteria has been elaborated based on
results obtained through scientific investigations on medical care,
and health system support. At the moment, treatment is recommended
for (a) all patients undergoing the acute phase of Chagas disease;
(b) children and young people undergoing the undetermined phase of
Chagas disease; (c) adults undergoing the undetermined phase or
with incipient heart lesions; and (d) transplant recipients or
donors.
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