Pérez-Molina, José A.
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, which is endemic in the American continent from the south of the United States to the north of Chile and Argentina. In 2005, it was estimated that 8–10 million people were infected . Carriage of infectious diseases by mobile populations has made Chagas disease a public health problem in many nonendemic countries. Most patients are immigrants who acquired the infection in their countries of origin. An estimated 300 000 persons with chronic T. cruzi infection currently live in the United States, and 63–315 congenital infections are estimated to occur each year . In Europe, 68 000–123 000 people are believed to have chronic T. cruzi infection, and 20–183 babies with congenital Chagas disease are born annually. Nevertheless, most patients remain undiagnosed (94–96%) .
Vector transmission only occurs in endemic areas, where infection can be also transmitted orally (contaminated food or drink). Additionally, T. cruzi infection can be transmitted in both endemic and nonendemic countries through blood transfusion, organ transplant, congenital disease, and, rarely, laboratory accidents . After a mostly asymptomatic acute phase, the infection progresses to the chronic phase if not treated. An estimated 20–40% of chronically infected individuals progress over 20–30 years to cardiac and/or gastrointestinal disease. Reactivation of the disease is rare except in immunosuppressed persons .
Although T. cruzi infection and HIV infection are well documented, the interaction between these pathogens has received less attention, and most information on clinical course, treatment, and prognosis comes either from isolated case reports and series published before the extensive use of combined antiretroviral therapy (cART) or from patients not taking antiretrovirals. This review focuses on the management of patients coinfected with HIV and T. cruzi, with particular emphasis on areas to be improved.
EPIDEMIOLOGY OF T. CRUZI–HIV COINFECTION
Although T. cruzi infection is mostly restricted to endemic areas, HIV infection is a worldwide pandemic . Migrants can be infected with HIV both in their country of origin and in their host countries. Thus, co-occurrence is mainly expected in areas with a high number of Latin American migrants. In Western Europe, 20–40% of newly diagnosed HIV infections occur among migrants . In Spain, up to 40.9% of newly diagnosed HIV infections during 2007–2012 were among migrants, mainly those of Latin American origin (21.2%) .
In endemic countries, the coinfection rate ranges from 1.3 to 7.1% [8–10] and is slightly higher in intravenous drug users (8.9%). Spain is the only nonendemic country with published data on the prevalence of coinfection to date. Figures range from 1.9 to 3.9% for larger studies [11▪,12], and almost all coinfected persons are Bolivian males with chronic T. cruzi infection. HIV care guidelines increasingly reflect that awareness of this infection is growing [13–16]. T. cruzi infection should be ruled out in patients from endemic areas, children of mothers born in an endemic area, and recipients of potentially contaminated blood and organs. Although rare, acute cases should be suspected in travelers returning from endemic areas.
T. cruzi is a genetically heterogeneous species, and the six near-clades identified (discrete typing units TcI to TcVI) seem to be associated with a specific geographical distribution or a specific clinical presentation [17▪▪]. Discrete typing units in the blood of HIV-infected patients are similar to those found in the general population, although mixtures of lineages and differential tissue tropism have been described . In this regard, TcI seems to have a preferential tropism for the central nervous system (CNS) in cases of reactivation .
DIAGNOSIS OF T. CRUZI INFECTION IN HIV-INFECTED PATIENTS
Most coinfected patients in nonendemic areas are in the chronic phase of the disease; in addition, they are asymptomatic and therefore unaware of their infection. Consequently, in HIV-infected patients, deterioration of immunity secondary to HIV infection enables T. cruzi infection to reactivate and lead to severe symptoms.
Diagnosis of chronic T. cruzi infection
After acute infection, it is very difficult to detect the parasite, and diagnosis is based largely on the detection of anti-T. cruzi antibodies using serology. No single standard reference test is currently available, and, for a patient to be considered infected, positive results must be obtained in two separate serology tests with different antigens or based on different techniques [20,21▪,22].
However, equivocal or false-positive results are a recurrent problem when serological titers are near the cut-off point, and even the results of a third assay may not always clarify infection status. Furthermore, serology results in HIV-infected individuals may be negative more frequently owing to immunosuppression [23,24]. Techniques such as western blotting have proven useful, specially in areas where Leishmania is endemic and, therefore, the probability of cross reactivity is higher [25▪]. Polymerase chain reaction (PCR) can be helpful in diagnosing chronic HIV infection, although it is generally not a sensitive diagnostic test for chronic T. cruzi infection (<70%) [26–28]. Test performance is highly variable and depends on methods and patient characteristics . Thus, for HIV-infected patients with suspected seronegative T. cruzi infection, close follow up may be recommended, especially in the case of severe immunosuppression and after the initiation of cART. The main objectives of this strategy are early detection of reactivations, immune restoration Chagas disease, and conversion to positive T. cruzi serology.
Detection should be complemented by an evaluation on the degree of visceral involvement (mainly cardiac and gastrointestinal), which should be guided by clinical symptoms in the case of gastrointestinal and neurological conditions; for cardiac evaluation, electrocardiography and echocardiography are routinely indicated [30–32].
Diagnosis of T. cruzi reactivation
Detection of T. cruzi in blood using direct methods (microscopy) in the chronic phase of Chagas disease is exceptional (even in coinfected individuals); therefore, the presence of the parasite is indicative of reactivation. Up to 70–80% of diagnoses are confirmed by detection of the parasite in blood, cerebrospinal fluid (positive in >80% of cases of CNS involvement), and other body fluids (ascitic and pericardial), although in some cases it is only made through histopathology testing [23,24,33–36]. Cerebrospinal fluid generally presents lymphocytic pleocytosis, with moderately increased protein levels and normal or reduced glucose levels [24,37,38].
Detection using PCR or blood culture should not be considered evidence of reactivation, as the results can be positive during the chronic phase, even in immunocompetent patients. Real-time PCR can detect rising parasite numbers in serial determinations, and could thus be used as an indicator of reactivation long before the onset of clinical symptoms [39,40].
Chronic Chagas disease is asymptomatic for most patients, although 20–40% develop organ involvement, mainly dilated cardiomyopathy, enlarged viscera, and, more rarely, polyneuropathy. Gastrointestinal involvement is less common than heart disease and is seen mainly in patients from the Southern Cone [4,41]. Furthermore, Chagas disease is increasingly recognized as an independent risk factor for stroke [42,43]. This observation must be borne in mind in a population such as HIV-infected patients, whose cardiovascular risk is greater than in age-matched noninfected individuals .
Chronic T. cruzi infection behaves as an opportunistic infection in HIV-infected patients and is considered an AIDS-defining illness in endemic areas [45,46]. Immunosuppression may lead to reactivation characterized by patent parasitemia, which is associated with increased intracellular parasite replication and lack of immunological control of the infection [23,24,33,38]. Reactivation is typically observed in patients with less than 200 CD4+ cells/μl (mostly with <100 CD4+ cells/μl), prior opportunistic infections, or both. Administration of immunosuppressants, such as corticosteroids for Pneumocystis jiroveci pneumonia, could also trigger a reactivation .
Reactivations appear in 15–35% of coinfected patients [8,38,47] without cART and typically affect the CNS (75–90%) in the form of single or multiple space-occupying lesions or as severe necrohemorrhagic meningoencephalitis. The most common clinical manifestations are fever, headache, vomiting, altered consciousness that could progress to coma, focal neurological deficits, and convulsions. Meningeal signs, however, are uncommon [8,23,24,48,49]. Cardiac involvement is the second most common clinical presentation (10–55%) and accompanies CNS involvement in up to 10% of cases. Patients may present rapid progression of existing chronic cardiomyopathy, new arrhythmias, pericardial effusion, or acute myocarditis [23,24,33,38,47,50]. Much less frequent manifestations of reactivation include cervicitis, spontaneous peritonitis, chronic diarrhea, ocular myositis, skin lesions, or erythema nodosum [38,51–54].
Reactivation of Chagas disease should be included in the differential diagnosis of space-occupying lesions in the CNS, especially in cases of suspected toxoplasmic encephalitis. Similarly, in coinfected individuals with cardiac involvement, it is very important to distinguish between a reactivation and the natural course of heart disease, because treatment differs for each : antiparasitic and cART for reactivations and aggressive management of cardiac failure in chronic heart disease.
In a study performed in Brazil, T. cruzi–HIV coinfection was more associated with early mortality than infection with T. cruzi alone . Most deaths were attributable to AIDS (77%), although Chagas disease was identified in 17% of cases, with a predominance of chronic cardiac forms (77%). Nevertheless, reactivation played an important role (15%) in coinfection-associated deaths. In general, mortality related to reactivations is very high (>70%) [23,24,38]; in fatal cases, the CNS is the most commonly involved site (89%), followed by the heart (19%). Early antiparasitic therapy for more than 30 days reduces mortality to 20% and significantly improves prognosis [23,24,34,38]. The use of cART has increased survival after reactivation from nearly 1 month to 3–5 years, although greater awareness of coinfection is still needed to prevent late diagnosis [24,49,57–59].
TREATMENT OF T. CRUZI INFECTION IN HIV-INFECTED PATIENTS
Antiparasitic treatment of Chagas disease has proven efficacious in acute, congenital, and early chronic forms. As for late chronic infection, symptomatic forms, or infection with advanced organ involvement, efficacy of therapy is much more uncertain. The indications for therapy in coinfected patients with chronic infection would be the same as in the general population, with the potential additional benefit that therapy could prevent reactivations [20,30,60–63,64]. Early initiation of parasiticidal therapy and cART seems to improve prognosis [8,24,33,34,59,65].
The two drugs used for the treatment of T. cruzi infection are benznidazole and nifurtimox. Although no standardized therapeutic schedules for HIV-infected patients have been developed, therapy could be longer than in non-HIV-infected individuals. Benznidazole (5–8 mg/kg/day in 2 or 3 doses for 60–90 days) is preferred over nifurtimox (8–10 mg/kg/day in 2 or 3 doses for 60–120 days) [13,15,66]. Neither drug is well tolerated in the general population [26,67–68]. The most common adverse reactions with benznidazole are cutaneous hypersensitivity reactions, followed by gastrointestinal complaints, and, more rarely, peripheral neuropathy, fever, leukopenia, dizziness, and insomnia. These adverse reactions do not seem to be related to drug levels in blood [69▪]. Nifurtimox is less well tolerated than benznidazole; the most common adverse reactions are gastrointestinal manifestations, weight loss, headache, skin rash, and myalgia. More severe reactions include drug reaction with eosinophilia and systemic symptoms syndrome, Quincke's edema, acute myocarditis, and anaphylaxis. Although data on tolerability in HIV-infected patients are scarce, up to 50% can present adverse reactions  similar to those observed in non-HIV-infected patients. Nifurtimox can be used as second-line therapy in non-HIV-infected patients – and almost certainly in HIV-infected patients – who have experienced benznidazole hypersensitivity reactions [70▪].
Antiparasitic therapy should be restarted if a relapse occurs after initially effective therapy. Nevertheless, no data are available on whether the same drug, a different drug, or a combination of drugs should be used. Data on alternatives to benzimidazoles in coinfected patients are rare. Itraconazole, fluconazole, and ketoconazole have been used, although information is too scarce to make solid recommendations. Although posaconazole initially seemed a useful alternative , it has recently been called into question. The results of a clinical trial in the general population with chronic T. cruzi infection revealed therapeutic failure rates of 80%, even when the drug was administered at full doses . A recent pilot study analyzing combined therapy with benznidazole and allopurinol demonstrated induction of T-cell and B-cell responses indicative of a reduction in parasite burden .
As with other opportunistic infections affecting the brain, there is a theoretical risk of immune restoration syndrome and worsening clinical condition after initiation of cART. Nevertheless, no cases of this complication have been reported to date in T. cruzi (with the exception of a possible case of erythema nodosum ); therefore, initiating or optimizing cART is not contraindicated. As no studies have been performed on pharmacokinetic interactions between benznidazole or nifurtimox and antiretrovirals, close monitoring is recommended. Precautions should be taken for additive toxicities [74▪]. Given its low potential for pharmacologic interactions, raltegravir seems to be well tolerated .
PREVENTION OF EXPOSURE, PREVENTION OF DISEASE, AND SECONDARY PROPHYLAXIS
Transmission in endemic regions by the triatomine vector commonly takes place in rural areas with poor-quality buildings that facilitate colonization (adobe walls and palm or straw roofs). Thus, people living in or visiting those areas should not sleep in such dwellings or outdoors. A mosquito insecticide-impregnated bed net should be used if necessary.
Chagas disease can also be transmitted orally through contaminated cane or fruit juices [76,77]; therefore, noncommercial products should be avoided. Although most blood products are screened for T. cruzi in the United States, Europe, and Latin America, screening is not universal; consequently, transfusion with blood or blood products remains a risk practice for T. cruzi infection [78–81].
As for non-HIV-infected individuals, treatment of chronic T. cruzi infection aims to prevent long-term complications [41,82,83], and can thus be considered for all patients except those with advanced heart failure. An additional benefit would be the prevention of reactivations. Nevertheless, treated patients are still considered at risk for reactivations, given that the efficacy of trypanocidal drugs in the chronic phase is poor and there is no early confirmatory test for cure. Besides parasiticidal treatment, early diagnosis and treatment of HIV infection are fundamental for preventing severe immunosuppression. No cases of reactivation have been described in nonseverely immunosuppressed HIV-infected individuals on stable cART.
Once a reactivation has occurred, there is a theoretical risk of relapse, especially during CD4 lymphocyte recovery, if HIV viral load is not controlled, or both. Information on secondary prophylaxis is too scarce to make firm recommendations. Therapeutic schedules with benznidazole (200 mg/day or 5 mg/kg/day three times a week) [24,57] or ketoconazole (400 mg/day)  have been used to treat reactivation. A tentative approach could involve benznidazole until the CD4 lymphocyte count reaches 200–250 cells/μl and viral load is undetectable for at least 6 months in a patient on stable cART.
CARE OF COINFECTED PREGNANT WOMEN
The prevalence of T. cruzi infection in women of childbearing potential in endemic areas can be very high (≤30%) [85,86]. In nonendemic areas, figures range from 0.4 to 4.8%, although they have reached 17–27% in Bolivian women [87,88,89▪,90]. Rates of mother-to-child transmission range from 1 to 13.8% [85,86,88,89▪], reaching as high as 31% for women with positive T. cruzi PCR [89▪]. As for HIV-infected women with frank parasitemia or parasitemia that can be detected by PCR, the frequency of T. cruzi transmission can reach above 75%. Coinfected newborns could have severe symptoms, especially neurologic symptoms, and a poor prognosis [38,91–95,96].
The teratogenic potential of benznidazole and nifurtimox is unknown; however, use of these drugs in pregnancy is contraindicated owing to their mechanism of action (they cross the placenta to bind with fetal proteins in animal models) and the detection of chromosomal diseases in children treated with them [69▪,97–99]. Treatment of chronic infection should be considered after delivery. A possible additional advantage of the treatment of women is that it can reduce the rate of mother-to-child transmission in future pregnancies [18,89▪,95]. In the case of a reactivation, clinicians should evaluate the risk–benefit ratio of drugs that are potentially toxic for the fetus but that could save the mother's life . cART should be initiated/optimized as early as possible in order to maximize the immune response and reduce transmission of HIV to the fetus.
In severely immunodepressed HIV-infected patients, chronic infection by T. cruzi can behave as an opportunistic disease, affecting mainly the CNS and heart and causing high morbidity and mortality. Thus, screening for this parasite is essential in HIV-infected individuals from endemic areas and in the children of infected mothers. There are no reliable methods to predict reactivations, and diagnosis is based on direct parasitological methods and/or histopathology. Late initiation of parasiticidal therapy worsens prognosis; however, ideal therapeutic schedules are not well established. The many remaining areas of uncertainty include the epidemiology of coinfection in nonendemic countries, natural history in the era of cART, the ideal therapeutic regimen, interaction between benzimidazoles and antiretrovirals, and dosing and duration of secondary prophylaxis. Until new data covering current gaps in knowledge become available, early diagnosis of coinfection and prompt cART seems to be the optimal approach for preventing reactivations and relapses and improving prognosis.
This work was supported by the VI PN de I+D+I 2008–2011, ISCIII – Subdirección General de Redes y Centros de Investigación Cooperativa, expediente RD12/0018/0019.
Conflicts of interest
There are no conflicts of interest.
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