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Antitrypanosomal Therapy for Chronic Chagas' Disease

Caryn Bern, M.D., M.P.H.

N Engl J Med 2011; 364:June 30, 2011

Article

References

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author's clinical recommendations.

A 42-year-old woman presents to her physician with a letter stating that after she made a recent blood donation, a serologic test of her donated blood was positive for Chagas' disease. The patient was born in El Salvador and moved to the United States when she was 18 years of age. Her three children are 8, 13, and 16 years of age. Her medical history is remarkable only for a cholecystectomy 2 years earlier; she reports no cardiac or gastrointestinal symptoms. Her physical examination is unremarkable. Electrocardiography (ECG) shows sinus rhythm at a rate of 72 beats per minute and a complete right bundle-branch block. An echocardiogram shows mild left ventricular segmental wall-motion abnormalities, but a normal ejection fraction and left ventricular diameter. The patient is referred to an infectious-disease consultant, who recommends antitrypanosomal therapy.

THE CLINICAL PROBLEM

Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi.1 An estimated 8 million to 10 million people are infected with this parasite, primarily in the Americas.1-3 An estimated 300,000 infected persons live in the United States, most of whom are immigrants from areas of Latin America where the infection is endemic.4 Enzootic T. cruzi transmission has been reported across the southern half of the United States, but locally acquired cases in humans are rare.

Clinical Chagas' disease is classified into acute and chronic phases. During the acute phase of infection, most patients have mild, self-limited symptoms such as fever that do not come to medical attention. If inoculation of the parasite occurred through the conjunctiva, the patient may present with nonpainful unilateral edema of the upper and lower eyelids that lasts for several weeks; this is known as Romaña's sign. Severe acute infection with myocarditis, meningoencephalitis, or both is life-threatening; the acute-phase case fatality rate is estimated to be 0.25 to 0.50%.1

The acute phase lasts 4 to 8 weeks. The infection then enters the chronic phase, and without successful treatment, it is lifelong. Persons with chronic T. cruzi infection, but without signs or symptoms of Chagas' disease, are considered to have the “indeterminate” form of infection. An estimated 20 to 30% of people who initially have the indeterminate form have progression to clinically evident cardiac disease, gastrointestinal disease, or both over a period of years to decades.1

The earliest cardiac manifestations are usually conduction-system abnormalities and segmental left ventricular wall-motion abnormalities.1,5, Later manifestations include high-degree heart block, sustained and nonsustained ventricular tachycardia, sinus-node dysfunction leading to severe bradycardia, apical aneurysm (usually in the left ventricle), embolic phenomena due to thrombus formation in the dilated left ventricle or aneurysm, and progressive dilated cardiomyopathy with congestive heart failure. 5 These abnormalities are associated with palpitations, syncope, and a high risk of sudden death.6,7

Gastrointestinal Chagas' disease usually affects the esophagus, colon, or both.8,9 Advanced disease results in megaesophagus, megacolon, or both. Gastrointestinal involvement is much less common than Chagas' heart disease. This clinical form is seen predominantly in patients who are infected in the countries of the Southern Cone (Argentina, Bolivia, Chile, Paraguay, Uruguay, and parts of Brazil) and is rare in northern South America, Central America, and Mexico.8

PATHOPHYSIOLOGY AND EFFECT OF THERAPY

T. cruzi is carried in the gut of hematophagous triatomine bugs. Transmission most often occurs when the feces of an infected bug are inoculated through a bite wound or through intact mucous membranes (Figure 1FIGURE 1The Life Cycle ofTrypanosoma cruzi.). Thus, the great majority of cases of Chagas' disease occur in the zones of distribution of these vectors.

T. cruzi can also be transmitted through transfusion, through organ or tissue transplantation, and congenitally.1 Because of the risk of transmission through transfusion, most blood banks in the United States screen donated units of blood; however, such screening is voluntary and is not required by the Food and Drug Administration (FDA).

The incubation period after exposure to vectorborne T. cruzi is 1 to 2 weeks.1The acute phase of infection is characterized by active parasite replication and microscopically detectable parasitemia (Figure 2FIGURE 2Phases and Forms ofTrypanosoma cruziInfection.). After 4 to 8 weeks in the acute phase, replication is controlled by the host immune response, and parasitemia decreases to levels that are undetectable by means of microscopy. However, intracellular T. cruzi amastigotes remain in infected tissues, especially in cardiac and skeletal muscle.

Chagas' cardiomyopathy is characterized by a chronic inflammatory process causing damage to the myocardium of all four chambers of the heart as well as the conduction system.10 The pathogenesis may involve several mechanisms, including immunologically mediated tissue damage, cardiac autonomic dysfunction, and coronary microvascular disease.10 In the past, it was hypothesized that the chronic cardiomyopathy was solely attributable to cross-reacting autoantibodies to cardiac tissue and that the presence of the parasite was unnecessary for pathogenesis.11 This belief led to skepticism about the usefulness of antiparasitic treatment in chronic T. cruzi infection, which persisted until the late 1990s.12 More recently, a consensus has emerged that parasite persistence is essential to the development and progression of Chagas' cardiomyopathy.13-15 Experimental data from animal models also provide support for the hypothesis that elimination of the parasite reduces the risk of progression of cardiac disease.16 In contrast, gastrointestinal manifestations are thought to result from damage to intramural neurons that occurs primarily during the acute phase of the disease and is unmasked by neural attrition later in life.8,9

The only currently available drugs with proven efficacy against T. cruzi are nifurtimox and benznidazole,1,17-19,– which were developed empirically in the late 1960s and early 1970s, respectively.20 Benznidazole, a nitroimidazole derivative, is thought to act through covalent binding of nitroreduction intermediates to parasite molecules. 18,21 Nifurtimox, a nitrofuran compound, acts through production of reduced oxygen metabolites (e.g., superoxide and hydrogen peroxide), for which the parasites have lower detoxification capacity, as compared with vertebrate cells.12,19,22

CLINICAL EVIDENCE

In acute T. cruzi infection, treatment with either benznidazole or nifurtimox reduces the severity of symptoms and shortens the clinical course and duration of detectable parasitemia.1,23,24Parasitologic cure is reported in 60 to 85% of patients treated in the acute phase.1,17,23,24

Clinical trial data for the treatment of chronic T. cruzi infection are sparse. Uncertainty remains regarding the degree of efficacy because of the lack of a reliable test of cure.17,25-27 The diagnosis of chronic infection relies on serologic methods to detect IgG antibodies to T. cruzi. No single assay has sufficient sensitivity and specificity to be relied on alone; two tests based on different antigens, techniques (e.g., enzyme-linked immunosorbent assay [ELISA], immunofluorescence antibody assay, and immunoblot assay), or both are used in parallel to increase the accuracy of the diagnosis.28 Patients with discordant results from two serologic assays require further testing. In a small proportion of cases, the infection status remains difficult to resolve even after a third test because there is no accepted reference assay for the detection of chronic T. cruzi infection.27 Most clinical trials have therefore required that participants have positive results on three separate serologic tests at baseline.29,30

Early trials of nifurtimox for chronic infection used a technique called “xenodiagnosis,” in which laboratory-reared triatomine vectors were allowed to feed either directly on the patient's arm or leg or indirectly on blood from the patient, kept for 30 to 60 days, and examined for T. cruzi in the contents of the gut.31 However, only 30 to 60% of untreated patients with chronic T. cruzi infection have positive results of xenodiagnosis.32,33 Similar considerations affect the use of polymerase-chain-reaction (PCR) assays for the assessment of treatment response. Because the circulating parasite load is low in the chronic phase, PCR sensitivity in untreated patients is not high and varies depending on the gene target, methods, and population tested.34-36

These test limitations likewise have implications for assessing the outcome of therapy. The results of conventional serologic assays remain positive for years or even decades after successful treatment; the length of time for serologic assays to become negative is reported to be proportionate to the duration of the infection.37 Since they lack sensitivity for detecting chronic infection, xenodiagnosis and PCR are not reliable indicators of cure if the results are negative after treatment.

In the 1990s, two double-blind, randomized, placebo-controlled trials evaluated the efficacy of a 60-day course of benznidazole treatment in children with chronic T. cruzi infection.29,33 Each trial used a different, nonconventional serologic assay to document the response. In one of these trials, which enrolled 130 children, 58% of those who received benznidazole, as compared with 5% of those who received placebo, had seroconversion to negative titers with the nonconventional assay at 3 years.29In the second trial, which involved 106 children, negative seroconversion rates at 48 months with another nonconventional assay were 62% with benznidazole as compared with 0% with placebo, whereas rates of positive xenodiagnosis were 4.7% and 51.2%, respectively.33

Another small, randomized, placebo-controlled clinical trial compared the efficacy of 30 days of treatment with either nifurtimox or benznidazole with placebo in 77 adults with chronic T. cruziinfection.38 At the end of the 12-month follow-up period, all patients continued to have positive results on conventional serologic assays, but patients who had received benznidazole and nifurtimox were significantly less likely to have a positive xenodiagnosis than the placebo group (1.8% and 9.6%, respectively, vs. 34.3%).38

More recently, a nonrandomized, nonblinded cohort study compared 283 adults who received benznidazole with 283 untreated patients over a median follow-up period of 9.8 years.30 The analysis showed a significant decrease in the proportion of patients with progression of cardiomyopathy (4.2% of treated patients vs. 14.1% of untreated patients; adjusted hazard ratio, 0.24; P=0.002) and a trend toward decreased mortality (1.1% vs. 4.2%; adjusted hazard ratio, 0.2; P=0.09) in treated as compared with untreated patients.30 Conversion to negative serologic results occurred in 14.7% of treated and 5.7% of untreated patients (adjusted hazard ratio, 0.55; P<0.001); however, the median time to negative seroconversion was 11.7 years. Progression of cardiac disease was more frequent among patients with persistently positive results on serologic testing than among those with negative seroconversion (10.7% vs. 2.4%; adjusted hazard ratio, 4.88; P=0.009).

The Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT; ClinicalTrials.gov number, NCT00123916), a large, multicenter, double-blind, randomized, placebo-controlled trial of benznidazole for patients with mild-to-moderate Chagas' cardiomyopathy, is under way.25,39

CLINICAL USE

Before therapy for presumed Chagas' disease is initiated, it is necessary to confirm the diagnosis with the use of appropriate testing. As noted above, the diagnosis of chronic infection requires two separate serologic tests; if the results are discordant, further testing should be performed. Options for T. cruzi serologic testing in the United States are relatively limited; several ELISA kits based on parasite lysate or recombinant antigens have been cleared by the FDA for diagnostic application. The Centers for Disease Control and Prevention (CDC) offers consultation to health care providers concerning diagnostic testing for Chagas' disease and acts as a reference laboratory for serologic testing and PCR assays to detect Chagas' disease; contact information is provided below.

On the basis of the pediatric trials reviewed above, antitrypanosomal drug treatment in children with chronic T. cruzi infection was accepted as the standard of care throughout Latin America by the late 1990s, followed in recent years by a growing movement to offer treatment to older patients.3,15,28,30,39 Most experts now believe that the majority of patients up to 50 years of age who have chronic T. cruzi infection, including those without symptoms and those with early manifestations of cardiomyopathy, should be offered antitrypanosomal treatment.1,3,15 Because treatment is expected to reduce the probability of congenital transmission, stronger consideration may be warranted for women of reproductive age. 40

In patients older than 50 years of age, treatment decisions should take into account the current lack of certainty about the benefit of such treatment, the need for a prolonged course, and the frequent side effects. 1,3 Patients with advanced Chagas' cardiomyopathy, especially those with poorly compensated congestive heart failure, are not considered to be candidates for antitrypanosomal treatment. Such treatment would not be expected to reverse the cardiac structural abnormalities, and the drugs are likely to be poorly tolerated.1,3,39

There is no evidence that antitrypanosomal treatment affects the progression of gastrointestinal Chagas' disease.1,3 In patients with such disease, treatment decisions should be based on the potential to decrease the progression of heart disease. In patients with megaesophagus, absorption may be impaired, and treatment should be delayed until after corrective surgery has been performed.

Neither benznidazole nor nifurtimox is approved by the FDA, but both can be obtained free of charge from the CDC and used under investigational protocols. Consultations and requests for drugs should be addressed to the Parasitic Diseases Public Inquiries Line (            770-488-7775 begin_of_the_skype_highlighting            770-488-7775      end_of_the_skype_highlighting      ;parasites@cdc.gov; www.cdc.gov/parasites/chagas), the CDC Drug Service (            404-639-3670 begin_of_the_skype_highlighting            404-639-3670      end_of_the_skype_highlighting      ) or, in emergencies after business hours, on weekends, and on federal holidays, to the CDC Emergency Operations Center (            770-488-7100 begin_of_the_skype_highlighting            770-488-7100      end_of_the_skype_highlighting      ). Questions about access to drugs outside the United States can be addressed to the World Health Organization (www.who.int/neglected_diseases/diseases/chagas/en/index.html).

Because benznidazole is usually better tolerated, this drug is viewed by most experts as the first-line treatment.1,3 Nevertheless, some patients tolerate nifurtimox better than benznidazole. Both agents are administered orally on an outpatient basis. Both drugs are contraindicated in pregnant women and in patients with severe renal or hepatic dysfunction. Alcohol use should be avoided during treatment with either agent, since it has been suggested that a disulfiram-like effect may occur, although the data are limited.19,22

The treatment regimen for benznidazole in adults consists of 5 to 7.5 mg per kilogram of body weight per day, administered orally in two divided doses for 60 days. In children younger than 12 years of age, the recommended dose is higher (10 mg per kilogram per day).41 A complete blood count and levels of hepatic enzymes, bilirubin, serum creatinine, and blood urea nitrogen should be obtained before the start of treatment, and the complete blood count should be repeated every 2 to 3 weeks during treatment. Patients should be monitored weekly for dermatologic side effects (described below), beginning 9 to 10 days after the initiation of treatment.

The treatment regimen for nifurtimox in adults is 8 to 10 mg per kilogram per day, administered orally in three or four divided doses for 90 days. In children 11 to 16 years of age, the recommended dose is 12.5 to 15 mg per kilogram per day, and in children 10 years of age or younger, the recommended dose is 15 to 20 mg per kilogram per day.41 Laboratory testing (a complete blood count and levels of hepatic enzymes, bilirubin, serum creatinine, and blood urea nitrogen) should be carried out before the start of treatment, 4 to 6 weeks into the course of treatment, and at the end of treatment. Patients should be weighed and monitored for symptoms and signs of peripheral neuropathy (described below) every 2 weeks, especially during the second and third months of treatment.

ADVERSE EFFECTS

Both benznidazole and nifurtimox have frequent side effects, especially in adults38,42-45 (Table 1TABLE 1Frequency of Adverse Effects Associated with Benznidazole and Nifurtimox in Adults.). Benznidazole causes dermatitis and photosensitization in one third to one half of patients.30,38,44,45 Mild rashes may respond to antihistamines, and moderate dermatitis can be managed with topical or low-dose oral glucocorticoids.46 Severe or exfoliative dermatitis or dermatitis associated with fever and lymphadenopathy should prompt immediate discontinuation of treatment. Benznidazole can also cause peripheral neuropathy (in up to 30% of patients), which is also an indication for discontinuation of treatment. The neuropathy is nearly always reversible, but it may take months to resolve. Bone marrow suppression is a rare side effect (in <1% of patients) that should prompt immediate discontinuation. In the two placebo-controlled trials of benznidazole in children, adverse effects were less frequent than in adults (12% of the children had rash and <5% had gastrointestinal symptoms in one study; <10% had moderate reversible side effects in the other).29,33

Nifurtimox causes gastrointestinal side effects in 50 to 75% of patients.31,38,43 These side effects include anorexia leading to weight loss, nausea, vomiting, and abdominal discomfort. Patients' weight should be monitored at regular intervals. Neurologic toxicity is common (occurring in up to 50% of patients), including irritability, insomnia, disorientation, mood changes, paresthesias, and, less often, tremors. Peripheral neuropathy is a rare, dose-dependent side effect that may appear late in the course of drug treatment and should prompt discontinuation. The condition is reversible, but complete resolution may require months.

AREAS OF UNCERTAINTY

The assessment of drug efficacy has been hampered by the lack of a sensitive, timely test of cure, the slowly progressive natural history of the disease, and the inability to predict which patients will have cardiomyopathy and which patients will remain asymptomatic. The trend toward offering treatment to adults with long-standing T. cruzi infection rests largely on the observation that treated patients are less likely than untreated patients to have progression of cardiomyopathy.1,3,30 Current data are insufficient to determine whether this effect is due to parasitologic cure or a reduced parasite burden.15

Physicians are often reluctant to treat patients with chronic T. cruzi infection because of both the frequency of side effects with the drugs that are currently available and the inability to confirm cure conclusively.43,47 New drugs with better safety profiles and proven efficacy would alter the risk–benefit balance considerably and lead to wider treatment. Data from in vitro studies and studies in animals suggest that several triazoles that inhibit ergosterol synthesis, including posaconazole and ravuconazole, have curative activity against T. cruzi.47,48 In a single case report, a patient with chronic T. cruzi infection and prior failure of benznidazole treatment had a good response to posaconazole according to PCR monitoring.49 A phase II trial of posaconazole (Clinical Trial for the Treatment of Chronic Chagas Disease with Posaconazole and Benznidazole; NCT01162967) is under way. Additional trials of the ravuconazole prodrug E1224 are planned.50

GUIDELINES

Consensus documents from the World Health Organization, the United States, and Brazil3,28,51strongly recommend antitrypanosomal treatment for acute, congenital, and reactivated T. cruziinfection, and for children (up to 12 or up to 18 years of age, depending on the publication) with chronic infection. Recommendations for adults with long-standing infection carry a lower evidence grade and strength because of the lack of data from randomized clinical trials; nevertheless, most recommendations published since 2000 include provisions to offer treatment for this group of patients.3,28,51,52

RECOMMENDATIONS

For the patient described in the clinical vignette, the diagnosis of Chagas' disease should be confirmed on the basis of positive results of at least two serologic tests. She should receive counseling, including the advice not to donate blood in the future. Assuming that the diagnosis is established, antitrypanosomal treatment should be offered, accompanied by a careful discussion of uncertainty regarding benefits and potential side effects. The patient has characteristic ECG signs of early Chagas' cardiomyopathy, indicating a higher risk of subsequent progression as compared with the risk among infected patients with normal ECG findings.30,53 Our best current understanding suggests that treatment will decrease the risk of further progression.25,30 Treatment may also decrease the risk of congenital transmission in subsequent pregnancies. The patient's children should undergo serologic testing for congenital Chagas' disease. Regular cardiologic follow-up should be scheduled to monitor the patient for disease progression and to optimize her cardiac care.

The findings and conclusions in this article are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

I thank Susan Montgomery for helpful comments.

SOURCE INFORMATION

From the Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta.

Address reprint requests to Dr. Bern at the Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333, or at cxb9@cdc.gov.

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