Pharmacological treatment of
CD
Both NF and BZN are
nitroheteroerocyclic drugs developed over four decades ago by Bayer and
Roche, respectively. Their mechanism of action is believed to rely on
intracellular activation, that generates intermediates affecting the
parasite’s vital biological functions 26,27. Both
drugs are highly liposoluble, with very low water solubility. The
parasite‘s mechanisms against these drugs relies on detoxifying
molecules such as trypanothione 28 a vital part of the
free radical scavenging cycle that is recycled by the enzyme
trypanothione disulfide reductase.
Treatment with BZN and NF is contraindicated during pregnancy in most
guidelines, due to limited evidence on safety, yet there is evidence of
low concentration of BZN or NF in breastmilk with no risk to infants
during lactation 29–31.
These drugs are usually not recommended in patients with renal or
hepatic impairment, mostly on the basis of lack of safety data. However,
given that there are almost completely metabolized, renal elimination
only plays a marginal role in their clearance and use in kidney failure
would be possible with appropriate monitoring for adverse events.
Similarly, in cases requiring emergency treatment (e.g. CD
meningoencephalitis), hepatic impairment should not be an obstacle for
treatment assuming that strict monitoring can be implemented32.
Although BZN is more commonly used than NF, both drugs seem to have
similar efficacy and safety profiles. Reported treatment responses in
the chronic indeterminate phase in children (mostly based on measuring
serologic titers) are near 90% after NF treatment 33and 94% for BNZ 34,35. In adults NF has treatment
response rate of 7-8% 36,37 and BZN between 2 and
40% 13,38, with more studies carried for BZN than NF
in this area (see table 1 ). There are no current data formally
comparing both drugs, but some clinical studies are currently ongoing
attempting to address this issue, such as TESEO (NCT03981523) and
CHICAMOCHA 339.
Unfortunately, given the natural history of CD and heterogeneity of
response follow-up techniques, it is logistically challenging to treat
this disease during the earlier asymptomatic chronic phase and follow
that patient cohort to determine clinical outcomes, which can take
decades to appear, with sufficient statistical power to differentiate
potential effects in treated versus control patients. About 30 years ago
two controlled placebo clinical trials assessed the efficacy of
treatment in CD chronic phase in pediatric patients with good
results35,40, and other studies followed those,
leaving no doubt that the earlier children are treated, the better the
response achieved8,40,41. Women in fertile age should
also be treated to prevent congenital CD
transmission9,40–42.
Unlike treatment for children or women of reproductive age,
controversies regarding treatment of adult patients still abound; in
2016 the first prospective multi-centric and randomized CD cohort study
in older adults with advanced CD, the ‘Benznidazole Evaluation for
Interrupting Trypanosomiasis’ (BENEFIT), was published, describing the
outcomes of 2854 patients with established Chagas heart disease that
received BZN or placebo and where followed for 5.4
years13. This study concluded that no significant
morbidity or mortality reduction was achieved with anti-parasitic
treatment in patients with advanced cardiac stage. On the other side,
the evidence from cohort and historical controlled trials has supported
treating most chronic patients at early stages, with the available
drugs16,43–47.
Monitoring treatment is recommended for either drug, with complete blood
counts, hepatic, and renal function testing. Frequency varies through
different guidelines between every two and five weeks, always with a
pre-treatment laboratory evaluation to compare later
findings34,48.