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.