Chagas disease: Antitrypanosomal drug therapy

INTRODUCTION — Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi [1]. Issues related to antitrypanosomal drugs will be reviewed here.

The approach to management of Chagas disease varies by phase and form of disease and is discussed in detail separately. (See "Chagas disease: Acute and congenital Trypanosoma cruzi infection" and "Chagas disease: Chronic Trypanosoma cruzi infection".)

ANTITRYPANOSOMAL DRUGS — The only drugs with proven efficacy against Chagas disease in human trials are benznidazole and nifurtimox [2-4]. In general, benznidazole is better tolerated and so is favored by most experts as the first-line treatment for Chagas disease [5]. In addition, compared with nifurtimox, there are more recent clinical trial data for the use of benznidazole, which was used in both pediatric trials in the 1990s [6,7] and in several drug trials [8-10]. However, some patients tolerate nifurtimox better than benznidazole; when treatment with one drug must be discontinued, the other can be used as an alternative. Limited human data, supported by findings in animal models, suggest that T. cruzi strains may vary in their drug susceptibility [11-14].

Both benznidazole and nifurtimox are contraindicated in pregnancy, so effective contraception should be assured. In addition, both drugs demonstrate in vitro mutagenicity and have been associated with increased risk of lymphomas in experimental animals [15-18]. No increase in incidence of lymphoma has been observed among immunocompetent humans, although no long-term studies examining this issue have been conducted [19]. An increased incidence of neoplasm was reported in a small series of heart transplantation recipients for Chagas disease [20].

Antitrypanosomal agents are contraindicated in patients with severe renal or hepatic dysfunction.

Benznidazole was approved by the US Food and Drug Administration (FDA) in August 2017 and became commercially available in the United States in May 2018. The FDA approval is for treatment of Chagas disease in children ages 2 to 12 years [21]; use for other age groups is off-label. Prescriptions require submission of a completed order form, available at http://www.benznidazoletablets.com/ or by contacting Foundation Care (tel 877-303-7181; fax 877-620-2849; email [email protected]). Urgent requests for benznidazole should be made by telephone.

Nifurtimox was approved by the FDA in August 2020 for treatment of Chagas disease in children up to 17 years of age [22]; use for other age groups is off-label. The approved dosing schedule differs from the dosing schedule approved under the United States Centers for Disease Control and Prevention (CDC) investigational protocol (which has been in place for the last 30 years) with lower daily dosing and a shorter course (table 1) [23]. As of January 2021, nifurtimox is available from Bayer distribution centers through commercial pharmacy requests.

The CDC provides diagnostic and clinical consultations via the Division of Parasitic Diseases Public Inquiries line (404-718-4745; email [email protected]) and for emergencies after business hours, on weekends, and on federal holidays, through the CDC Emergency Operations Center (770-488-7100).

Benznidazole — Benznidazole is a nitroimidazole derivative with activity against T. cruzi trypomastigotes and amastigotes; it was introduced in 1971. The drug is rapidly absorbed from the gastrointestinal tract, and the average half-life is 12 hours. Elimination is predominantly renal; about 22 percent of excretion is fecal. The weight-corrected clearance rate (CL/F) is significantly higher, and the same dosing regimen leads to lower plasma levels in younger than older children and adults [24].

Dosing is outlined in the table (table 1). The duration of therapy is usually 60 days. A phase II trial suggests that a course as short as two weeks may have similar efficacy but changes in recommended regimens will require additional data [10]. Children have fewer side effects than adults and tolerate higher doses. Laboratory testing, including complete blood count (CBC), hepatic enzymes, bilirubin, serum creatinine, and blood urea nitrogen, should be performed before beginning treatment, and the CBC should be repeated every 2 to 3 weeks during treatment.

Adverse effects include dermatitis, peripheral neuropathy, angioedema, and bone marrow suppression [25]:

●Dermatologic side effects are frequent and consist of rash due to photosensitization with rare progression to exfoliative dermatitis (table 2) [26,27]. The dermatitis reflects a delayed hypersensitivity reaction and is usually manageable with topical or low-dose systemic corticosteroids. Severe dermatitis, exfoliative dermatitis, or dermatitis associated with fever and lymphadenopathy should prompt immediate cessation of the drug. Patients should be monitored weekly for dermatologic side effects beginning about 10 days after initiation of treatment. In one cohort study, the median onset of dermatitis was in the second week of treatment, but nearly 20 percent had onset at four weeks or later [28].

●Peripheral neuropathy is dose dependent and usually occurs after four weeks or more of therapy [28]. Onset of peripheral neuropathy should prompt immediate cessation of treatment. It is nearly always reversible but may take months to resolve.

●Bone marrow suppression is rare; it should prompt immediate interruption of drug treatment. Blood counts should be monitored every two to three weeks during the treatment.

Concurrent alcohol use can lead to disulfiram-like effects (abdominal cramps, nausea, vomiting, flushing, or headache) and should be avoided [29].

Evidence for efficacy of benznidazole and the approach to its use varies by phase and form of disease. (See "Chagas disease: Acute and congenital Trypanosoma cruzi infection" and "Chagas disease: Chronic Trypanosoma cruzi infection".)

Nifurtimox — Nifurtimox is a nitrofuran compound with activity against T. cruzi trypomastigotes and amastigotes; it was introduced in 1965 [2,30,31]. The drug is rapidly absorbed from the gastrointestinal tract and metabolized in the liver, where nitroreduction occurs through the cytochrome P450 reductase. Elimination of metabolites is predominantly renal. After a single oral dose in humans, plasma levels peak at one hour and have an elimination half-life of three hours.

Dosing is outlined in the table (table 1). Historically, the duration of therapy was usually at least 90 days [32], but recommendations have decreased the recommended regimen to 60 days [33,34]. Nifurtimox is better tolerated by children than adults [32,35,36]; the approach to dosing depends on patient age.

Adverse effects are frequent but usually resolve when treatment is discontinued (table 2). They include gastrointestinal complaints and central nervous system toxicity [32].

●Gastrointestinal complaints occur in 30 to 70 percent of patients and include anorexia leading to weight loss, nausea, vomiting, and abdominal discomfort [32,37].

●Central nervous system toxicity is also common, including irritability, insomnia, and disorientation. Less common side effects include tremors, paresthesias, polyneuropathy, and peripheral neuropathy. Peripheral neuropathy is dose dependent, appears late in the course of therapy, and should prompt interruption of treatment.

Laboratory testing (CBC, hepatic enzymes, bilirubin, serum creatinine, and blood urea nitrogen) should be performed before beginning treatment, every four to six weeks during the course, and at the end of treatment. Patients should be weighed and monitored for symptoms and signs of peripheral neuropathy every two weeks, especially during the second and third months of treatment.

Alcohol use may increase the risk of side effects and should be avoided during nifurtimox treatment [38].

Evidence for efficacy of nifurtimox and the approach to its use varies by phase and form of disease. (See "Chagas disease: Acute and congenital Trypanosoma cruzi infection" and "Chagas disease: Chronic Trypanosoma cruzi infection".)

NEW DRUGS — New, more effective drugs with fewer side effects are needed, although progress in developing and testing drug candidates has been slow [39].

Triazoles that inhibit ergosterol synthesis, including posaconazole and ravuconazole, have in vitro activity against T. cruzi [40,41]. However, thus far posaconazole does not appear to be effective for clinical treatment of Chagas disease:

●A randomized trial including 120 asymptomatic T. cruzi–infected adults compared the combination of posaconazole and benznidazole with posaconazole monotherapy, benznidazole monotherapy, and placebo [9]. Treatment failure (defined by positive results by quantitative polymerase chain reaction (PCR) during six months of follow-up) was observed among 13 percent of patients who received benznidazole monotherapy, 20 percent of patients who received posaconazole plus benznidazole, 86 percent of patients who received posaconazole monotherapy, and 90 percent of patients who received placebo. There was no statistically significant difference in efficacy between benznidazole monotherapy and the combination of benznidazole plus posaconazole; however, the trial was inadequately powered to detect such a difference. Among patients who received benznidazole, 32 percent discontinued early due to adverse effects.

●In a randomized trial including 78 adults with chronic T. cruzi infection, treatment failure occurred among most patients who received posaconazole (80 percent in the high-dose arm; 90 percent in the low-dose arm), compared with 6 percent of patients who completed the 60-day course of benznidazole (per protocol analysis) [8]. In the intention-to-treat analysis, the failure rate in the benznidazole arm was 38 percent.

Other drug candidates with in vitro (and in some cases in vivo) activity include other nitroimidazoles (eg, fexinidazole), cruzipain inhibitors, bisphosphonates, and trypanothione synthesis inhibitors [42,43].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chagas disease".)

SUMMARY

●Approach – The approach to management of Chagas disease varies by phase and form of disease and is discussed in detail separately. (See "Chagas disease: Acute and congenital Trypanosoma cruzi infection".)

●Drugs – Benznidazole and nifurtimox are the only drugs with proven efficacy against Chagas disease in humans. In general, we favor benznidazole as first-line treatment for Chagas disease, since in general it is better tolerated than nifurtimox and there are more recent efficacy data available of benznidazole. (See 'Antitrypanosomal drugs' above.)

●Administration – Dosing and duration for benznidazole and nifurtimox are outlined in the table (table 1). Adverse effects are outlined in the table (table 2). (See 'Benznidazole' above and 'Nifurtimox' above.)