Skip Navigation LinksHome > February 2014 - Volume 27 - Issue 1 > Management of Trypanosoma cruzi coinfection in HIV-positive...
Current Opinion in Infectious Diseases:
doi: 10.1097/QCO.0000000000000023
HIV INFECTIONS AND AIDS: Edited by David Dockrell

Management of Trypanosoma cruzi coinfection in HIV-positive individuals outside endemic areas

Pérez-Molina, José A.

Free Access
Article Outline
Collapse Box

Author Information

Correspondence to José A. Pérez-Molina, Tropical Medicine Unit, Infectious Diseases Department, Hospital Ramón y Cajal – IRYCIS, Carretera de Colmenar Km 9,1, Madrid 28034, Spain. Tel: +34 913368108; e-mail: jose.perezmolina@gmail.com

Collapse Box

Abstract

Purpose of the review: Chagas disease has spread beyond the geographical barriers of the American continent in the past decade. Consequently, physicians treating HIV-infected patients in nonendemic countries have to face an opportunistic infection they have little experience with. This review examines the literature on Chagas disease in HIV-infected patients, with special emphasis on recent findings.

Recent findings: Although infection by Trypanosoma cruzi is a severe opportunistic infection in HIV-infected patients, awareness of this parasitosis in nonendemic countries remains low. Deeply immunosuppressed patients with chronic infection can develop reactivations, which can be very severe and are associated with high mortality. Reactivations mostly affect the central nervous system, followed by the heart, and diagnosis is based on the direct detection of the parasite or histology. There is no reliable method of predicting reactivations. Treatment is based on benzimidazoles, although neither the appropriate treatment schedule nor the need for secondary prophylaxis has been clearly established. Antiretroviral therapy seems to play a fundamental role in the prevention of reactivations and control of relapses; however, more information is needed.

Summary: Many aspects of T. cruzi–HIV coinfection remain uncertain. Until new data covering the current gaps become available, early diagnosis and prompt antiretroviral therapy seem to be fundamental for avoiding reactivations and improving late visceral involvement.

Back to Top | Article Outline

INTRODUCTION

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 [1]. 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 [2]. 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%) [3].

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 [4]. 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 [4].

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.

Box 1
Box 1
Image Tools
Back to Top | Article Outline

EPIDEMIOLOGY OF T. CRUZI–HIV COINFECTION

Although T. cruzi infection is mostly restricted to endemic areas, HIV infection is a worldwide pandemic [5]. 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 [6]. 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%) [7].

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 [18]. In this regard, TcI seems to have a preferential tropism for the central nervous system (CNS) in cases of reactivation [19].

Back to Top | Article Outline

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.

Back to Top | Article Outline
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 [29]. 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].

Back to Top | Article Outline
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].

Back to Top | Article Outline

CLINICAL MANIFESTATIONS

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 [44].

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 [24].

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 [55]: antiparasitic and cART for reactivations and aggressive management of cardiac failure in chronic heart disease.

Back to Top | Article Outline
Mortality

In a study performed in Brazil, T. cruzi–HIV coinfection was more associated with early mortality than infection with T. cruzi alone [56]. 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].

Back to Top | Article Outline

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 [24] 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 [71], 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 [72]. 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 [73].

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 [51]); 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 [75].

Back to Top | Article Outline

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) [84] 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.

Back to Top | Article Outline

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 [100]. cART should be initiated/optimized as early as possible in order to maximize the immune response and reduce transmission of HIV to the fetus.

Back to Top | Article Outline

CONCLUSION

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.

Back to Top | Article Outline

Acknowledgements

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.

Back to Top | Article Outline
Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Back to Top | Article Outline

REFERENCES

1. Organización Panamericana de la salud (OPS/OMS)Quantitative estimation of Chagas disease in the Americas [in Spanish]. OPS/HDM/CD/425-06. Montevideo, Uruguay:Organización Panamericana de la salud (OPS/OMS); 2006.

2. Bern C, Kjos S, Yabsley MJ, Montgomery SP. Trypanosoma cruzi and Chagas’ disease in the United States. Clin Microbiol Rev 2011; 24:655–681.

3. Basile L, Jansa J, Carlier Y, et al. Chagas disease in European countries: the challenge of a surveillance system. Euro Surveill 2011; 16:14–23.

4. Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet 2010; 375:1388–1402.

5. Global report: UNAIDS report on the global AIDS epidemic 2012. UNAIDS /JC2417E; 2012. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/20121120_UNAIDS_Global_Report_2012_en.pdf. [Accessed 23 June 2013]

6. European Centre for Disease Prevention and Control Technical Report. Migrant health: epidemiology of HIV and AIDS in migrant communities and ethnic minorities in EU/EEA countries. http://www.ecdc.europa.eu/en/publications/publications/0907_ter_migrant_health_hiv_epidemiology_review.pdf [Accessed 23 June 2013], 2009.

7. Epidemiological surveillance of HIV/AIDS in Spain. Updated 30 June 2012. http://www.msc.es/ciudadanos/enfLesiones/enfTransmisibles/sida/vigilancia/InformeVIHsida_Junio2012.pdf. [Accessed 23 June 2013]

8. Almeida EA, Lima JN, Lages-Silva E, et al. Chagas’ disease and HIV co-infection in patients without effective antiretroviral therapy: prevalence, clinical presentation and natural history. Trans R Soc Trop Med Hyg 2010; 104:447–452.

9. Dolcini G, Ambrosioni J, Andreani G, et al. Prevalence of human immunodeficiency virus (HIV)-Trypanosoma cruzi co-infection and injectable-drugs abuse in a Buenos Aires health center. Rev Argent Microbiol 2008; 40:164–166.

10. Diez MS, Nocito I, de Frade AR, et al. Serological evidence of cytomegalovirus, hepatitis B and C, Epstein-Barr virus, Toxoplasma gondii, Trypanosoma cruzi and Treponema pallidum in HIV infected patients. Medicina (B Aires) 2001; 61:378–380.

11▪. Llenas-Garcia J, Hernando A, Fiorante S, et al. Chagas disease screening among HIV-positive Latin American immigrants: an emerging problem. Eur J Clin Microbiol Infect Dis 2012; 31:1991–1997.

The authors apply a standardized diagnostic protocol for all HIV-infected immigrants at their institution. The number of Latin American patients studied (n = 155) makes estimates of T. cruzi prevalence (1.9%) reliable.

12. Salvador F, Molina I, Sulleiro E, et al. Tropical diseases screening in immigrant patients with human immunodeficiency virus infection in Spain. Am J Trop Med Hyg 2013; 88:1196–1202.

13. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America; 2013. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. [Accessed 29 June 2013]

14. Expert Panel from GESIDA. 2008 prevention of opportunistic infections in HIV-infected adolescents and adults guidelines. Recommendations of GESIDA/National AIDS Plan AIDS Study Group (GESIDA) and National AIDS Plan. Enferm Infecc Microbiol Clin 2008; 26:437–464.

15. Perez-Molina JA, Rodriguez-Guardado A, Soriano A, et al. Guidelines on the treatment of chronic coinfection by Trypanosoma cruzi and HIV outside endemic areas. HIV Clin Trials 2011; 12:287–298.

16. Nelson M, Dockrell D, Edwards S, et al. British HIV Association and British Infection Association guidelines for the treatment of opportunistic infection in HIV-seropositive individuals 2011. HIV Med 2011; 12 (Suppl 2):1–140.

17▪▪. Zingales B, Miles MA, Campbell DA, et al. The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications. Infect Genet Evol 2012; 12:240–253.

An excellent review of the different discrete typing units, their origin, geographical distribution, and potential clinical and epidemiological impact.

18. Bisio M, Cura C, Duffy T, et al. Trypanosoma cruzi discrete typing units in Chagas disease patients with HIV co-infection. Rev Biomed 2009; 20:166–178.

19. Burgos JM, Begher S, Silva HM, et al. Molecular identification of Trypanosoma cruzi I tropism for central nervous system in Chagas reactivation due to AIDS. Am J Trop Med Hyg 2008; 78:294–297.

20. WHO Technical Report Series No. 905. Control of Chagas Disease. Second report of the WHO Expert Committee. Geneva: World Health Organization; 2002.

21▪. Afonso AM, Ebell MH, Tarleton RL. A systematic review of high quality diagnostic tests for Chagas disease. PLoS Negl Trop Dis 2012; 6:e1881.

A comprenhensive and methodologically solid reference on the accuracy of serological test for the diagnosis of T. cruzi infection. The results highlight that sensitivity and specificity of serological assays appear less accurate than previously thought. The authors made suggestions to improve future studies in this field.

22. Flores-Chavez M, Cruz I, Rodriguez M, et al. Comparison of conventional and nonconventional serological tests for the diagnosis of imported Chagas disease in Spain. Enferm Infecc Microbiol Clin 2010; 28:284–293.

23. Almeida EA, Ramos Junior AN, Correia D, Shikanai-Yasuda MA. Co-infection Trypanosoma cruzi/HIV: systematic review (1980–2010). Rev Soc Bras Med Trop 2011; 44:762–770.

24. Cordova E, Boschi A, Ambrosioni J, et al. Reactivation of Chagas disease with central nervous system involvement in HIV-infected patients in Argentina, 1992–2007. Int J Infect Dis 2008; 12:587–592.

25▪. Riera C, Verges M, Iniesta L, et al. Identification of a Western blot pattern for the specific diagnosis of Trypanosoma cruzi infection in human sera. Am J Trop Med Hyg 2012; 86:412–416.

The authors describe an efficient alternative diagnostic method that could be used to confirm chronic T. cruzi infection and detect cross-reactivity with Leishmania species.

26. Perez-Ayala A, Perez-Molina JA, Norman F, et al. Chagas disease in Latin American migrants: a Spanish challenge. Clin Microbiol Infect 2011; 17:1108–1113.

27. Murcia L, Carrilero B, Munoz MJ, et al. Usefulness of PCR for monitoring benznidazole response in patients with chronic Chagas’ disease: a prospective study in a nondisease-endemic country. J Antimicrob Chemother 2010; 65:1759–1764.

28. Brasil PE, De Castro L, Hasslocher-Moreno AM, et al. ELISA versus PCR for diagnosis of chronic Chagas disease: systematic review and meta-analysis. BMC Infect Dis 2010; 10:337.

29. Schijman AG, Bisio M, Orellana L, et al. International study to evaluate PCR methods for detection of Trypanosoma cruzi DNA in blood samples from Chagas disease patients. PLoS Negl Trop Dis 2011; 5:e931.

30. Bern C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of Chagas disease in the United States: a systematic review. JAMA 2007; 298:2171–2181.

31. Gascon J, Albajar P, Canas E, et al. Diagnosis, management and treatment of chronic Chagas’ heart disease in areas where Trypanosoma cruzi infection is not endemic. Enferm Infecc Microbiol Clin 2008; 26:99–106.

32. Perez-Ayala A, Perez-Molina JA, Norman F, et al. Gastro-intestinal Chagas disease in migrants to Spain: prevalence and methods for early diagnosis. Ann Trop Med Parasitol 2011; 105:25–29.

33. Ferreira MS, Nishioka Sde A, Silvestre MT, et al. Reactivation of Chagas’ disease in patients with AIDS: report of three new cases and review of the literature. Clin Infect Dis 1997; 25:1397–1400.

34. Solari A, Saavedra H, Sepulveda C, et al. Successful treatment of Trypanosoma cruzi encephalitis in a patient with hemophilia and AIDS. Clin Infect Dis 1993; 16:255–259.

35. Ferreira MS, Nishioka Sde A, Rocha A, et al. Acute fatal Trypanosoma cruzi meningoencephalitis in a human immunodeficiency virus-positive hemophiliac patient. Am J Trop Med Hyg 1991; 45:723–727.

36. Verdu J, De Paz F, Castano V, et al. Reactivation of Chagas disease with central nervous system involvement: peripheral blood smear evidence. Int J Infect Dis 2009; 13:e527–e528.

37. Lages-Silva E, Ramirez LE, Silva-Vergara ML, Chiari E. Chagasic meningoencephalitis in a patient with acquired immunodeficiency syndrome: diagnosis, follow-up, and genetic characterization of Trypanosoma cruzi. Clin Infect Dis 2002; 34:118–123.

38. Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101:31–50.

39. Duffy T, Bisio M, Altcheh J, et al. Accurate real-time PCR strategy for monitoring bloodstream parasitic loads in Chagas disease patients. PLoS Negl Trop Dis 2009; 3:e419.

40. de Freitas VL, da Silva SC, Sartori AM, et al. Real-time PCR in HIV/Trypanosoma cruzi coinfection with and without Chagas disease reactivation: association with HIV viral load and CD4 level. PLoS Negl Trop Dis 2011; 5:e1277.

41. Lescure FX, Le Loup G, Freilij H, et al. Chagas disease: changes in knowledge and management. Lancet Infect Dis 2010; 10:556–570.

42. Carod-Artal FJ, Vargas AP, Falcao T. Stroke in asymptomatic Trypanosoma cruzi-infected patients. Cerebrovasc Dis 2010; 31:24–28.

43. Lima-Costa MF, Matos DL, Ribeiro AL. Chagas disease predicts 10-year stroke mortality in community-dwelling elderly: the Bambui cohort study of aging. Stroke 2010; 41:2477–2482.

44. Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med 2012; 13:453–468.

45. Almeida EA, Ramos Junior AN, Correia D, Shikanai-Yasuda MA. Brazilian Network of Attention and Studies on Trypanosoma cruzi/HIV Co-infection and others immunossupression conditions. Rev Soc Bras Med Trop 2009; 42:605–608.

46. Panamerican Health Organization. WHO definition of HIV infection for purposes of surveillance and for the review of clinical staging and immunological classification of HIV-related diseases in adults and children [in Spanish]. OPS/FCH/HI/04-09.E; 2009.

47. Sartori AM, Shikanai-Yasuda MA, Amato Neto V, Lopes MH. Follow-up of 18 patients with human immunodeficiency virus infection and chronic Chagas’ disease, with reactivation of Chagas’ disease causing cardiac disease in three patients. Clin Infect Dis 1998; 26:177–179.

48. Pagano MA, Segura MJ, Di Lorenzo GA, et al. Cerebral tumor-like American trypanosomiasis in acquired immunodeficiency syndrome. Ann Neurol 1999; 45:403–406.

49. Sica RE, Gargiullo G, Papayanis C. Tumour-like chagasic encephalitis in AIDS patients: an atypical presentation in one of them and outcome in a small series of cases. Arq Neuropsiquiatr 2008; 66:881–884.

50. Sartori AM, Lopes MH, Benvenuti LA, et al. Reactivation of Chagas’ disease in a human immunodeficiency virus-infected patient leading to severe heart disease with a late positive direct microscopic examination of the blood. Am J Trop Med Hyg 1998; 59:784–786.

51. Sartori AM, Sotto MN, Braz LM, et al. Reactivation of Chagas disease manifested by skin lesions in a patient with AIDS. Trans R Soc Trop Med Hyg 1999; 93:631–632.

52. Iliovich E, Lopez R, Kum M, Uzandizaga G. Spontaneous chagasic peritonitis in a patient with AIDS. Medicina (B Aires) 1998; 58:507–508.

53. dos Santos Sde S, Almeida GM, Monteiro ML, et al. Ocular myositis and diffuse meningoencephalitis from Trypanosoma cruzi in an AIDS patient. Trans R Soc Trop Med Hyg 1999; 93:535–536.

54. Concetti H, Retegui M, Perez G, Perez H. Chagas’ disease of the cervix uteri in a patient with acquired immunodeficiency syndrome. Hum Pathol 2000; 31:120–122.

55. Almeida EA, Silva EL, Guariento ME, et al. Fatal evolution of Chagas’ disease/AIDS co-infection: diagnostic difficulties between myocarditis reactivation and chronic chagasic myocardiopathy. Rev Soc Bras Med Trop 2009; 42:199–202.

56. Martins-Melo FR, Ramos AN Jr, Alencar CH, Heukelbach J. Mortality related to Chagas disease and HIV/AIDS coinfection in Brazil. J Trop Med 2012; 2012:534649.

57. Diazgranados CA, Saavedra-Trujillo CH, Mantilla M, et al. Chagasic encephalitis in HIV patients: common presentation of an evolving epidemiological and clinical association. Lancet Infect Dis 2009; 9:324–330.

58. Lopez MO. Three-year survival of a patient with HIV and chagasic meningoencephalitis: case report. Rev Chilena Infectol 2010; 27:160–164.

59. Corti M, Yampolsky C. Prolonged survival and immune reconstitution after chagasic meningoencephalitis in a patient with acquired immunodeficiency syndrome. Rev Soc Bras Med Trop 2006; 39:85–88.

60. de Andrade AL, Zicker F, de Oliveira RM, et al. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet 1996; 348:1407–1413.

61. Sosa Estani S, Segura EL, Ruiz AM, et al. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas’ disease. Am J Trop Med Hyg 1998; 59:526–529.

62. Andrade JP, Marin-Neto JA, Paola AA, et al. I Latin American guidelines for the diagnosis and treatment of Chagas cardiomyopathy. Arq Bras Cardiol 2011; 97:1–48.

63. Perez-Molina JA, Perez-Ayala A, Moreno S, et al. Use of benznidazole to treat chronic Chagas’ disease: a systematic review with a meta-analysis. J Antimicrob Chemother 2009; 64:1139–1147.

64. Jackson Y, Chatelain E, Mauris A, et al. Serological and parasitological response in chronic Chagas patients 3 years after nifurtimox treatment. BMC Infect Dis 2013; 13:85.

65. Del Castillo M, Mendoza G, Oviedo J, et al. AIDS and Chagas’ disease with central nervous system tumor-like lesion. Am J Med 1990; 88:693–694.

66. Brazilian Consensus on Chagas disease. Rev Soc Bras Med Trop 2005; 38 (Suppl 3):7–29.

67. Pinazo MJ, Munoz J, Posada E, et al. Tolerance of benznidazole in treatment of Chagas’ disease in adults. Antimicrob Agents Chemother 2010; 54:4896–4899.

68. Jackson Y, Alirol E, Getaz L, et al. Tolerance and safety of nifurtimox in patients with chronic Chagas disease. Clin Infect Dis 2010; 51:e69–e75.

69▪. Pinazo MJ, Guerrero L, Posada E, et al. Benznidazole-related adverse drug reactions and their relationship to serum drug concentrations in patients with chronic Chagas disease. Antimicrob Agents Chemother 2013; 57:390–395.

This study demonstrates that benznidazole serum concentrations do not appear to be related to the appearance of severe adverse reactions.

70▪. Perez-Molina JA, Sojo-Dorado J, Norman F, et al. Nifurtimox therapy for Chagas disease does not cause hypersensitivity reactions in patients with such previous adverse reactions during benznidazole treatment. Acta Trop 2013; 127:101–104.

This is the first report on the use of nifurtimox in patients with previous hypersensitivity reactions to benznidazole. Nifurtimox appears to be well tolerated as second-line therapy in patients who discontinued benznidazole specifically because of hypersensitivity reactions.

71. Pinazo MJ, Espinosa G, Gallego M, et al. Successful treatment with posaconazole of a patient with chronic Chagas disease and systemic lupus erythematosus. Am J Trop Med Hyg 2010; 82:583–587.

72. Molina I, Gomez J, Salvador F, et al.Clinical trial of posaconazole and benznidazole for the treatment of chronic Chagas disease [abstract, in Spanish]. In: XVII Congress of the Spanish Society of Infectious Diseases and Clinical Microbiology, Zaragoza 29–31 May: 2013. 328.

73. Perez-Mazliah DE, Alvarez MG, Cooley G, et al. Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study. J Antimicrob Chemother 2013; 68:424–437.

74▪. Seden K, Khoo S, Back D, et al. Drug–drug interactions between antiretrovirals and drugs used in the management of neglected tropical diseases: important considerations in the WHO 2020 Roadmap and London Declaration on Neglected Tropical Diseases. AIDS 2013; 27:675–686.

This article provides a comprehensive review of drug interactions between antiretrovirals and drugs used for the treatment of neglected tropical diseases. The authors highlight the lack of data in this field.

75. Rodriguez-Guardado A, Tuset M, Asensi V, Miro JM. Human immunodeficiency virus and Chagas disease coinfection treated successfully with benznidazole and a raltegravir-based antiretroviral regimen: a case report. Med Clin (Barc) 2010; 137:278–279.

76. Shikanai-Yasuda MA, Carvalho NB. Oral transmission of Chagas disease. Clin Infect Dis 2012; 54:845–852.

77. Alarcon de Noya B, Diaz-Bello Z, Colmenares C, et al. Large urban outbreak of orally acquired acute Chagas disease at a school in Caracas, Venezuela. J Infect Dis 2010; 201:1308–1315.

78. Control and prevention of Chagas disease in Europe. Report of a WHO Informal Consultation (jointly organized by WHO headquarters and the WHO Regional Office for Europe). Geneva, Switzerland, 17–18 December 2009. WHO/HTM/NTD/IDM/2010.1; 2010.

79. ROYAL DECREE 1088/2005, dated September 16. Technical requirements and minimal conditions for blood donation and for transfusion services and centers [in Spanish]. Ministry of Health. Edited by the Official State Gazette, number 225; 2005.

80. Agapova M, Busch MP, Custer B. Cost-effectiveness of screening the US blood supply for Trypanosoma cruzi. Transfusion 2010; 50:2220–2232.

81. Schmunis GA, Cruz JR. Safety of the blood supply in Latin America. Clin Microbiol Rev 2005; 18:12–29.

82. Coura JR, Borges-Pereira J. Chronic phase of Chagas disease: why should it be treated? A comprehensive review. Mem Inst Oswaldo Cruz 2011; 106:641–645.

83. Perez-Molina JA, Norman F, Lopez-Velez R. Chagas disease in nonendemic countries: epidemiology, clinical presentation and treatment. Curr Infect Dis Rep 2012; 14:263–274.

84. Galhardo MC, Martins IA, Hasslocher-Moreno A, et al. Reactivation of Trypanosoma cruzi infection in patients with acquired immunodeficiency syndrome. Rev Soc Bras Med Trop 1999; 32:291–294.

85. Torrico F, Alonso-Vega C, Suarez E, et al. Maternal Trypanosoma cruzi infection, pregnancy outcome, morbidity, and mortality of congenitally infected and noninfected newborns in Bolivia. Am J Trop Med Hyg 2004; 70:201–209.

86. Bern C, Verastegui M, Gilman RH, et al. Congenital Trypanosoma cruzi transmission in Santa Cruz, Bolivia. Clin Infect Dis 2009; 49:1667–1674.

87. Di Pentima MC, Hwang LY, Skeeter CM, Edwards MS. Prevalence of antibody to Trypanosoma cruzi in pregnant Hispanic women in Houston. Clin Infect Dis 1999; 28:1281–1285.

88. Munoz J, Coll O, Juncosa T, et al. Prevalence and vertical transmission of Trypanosoma cruzi infection among pregnant Latin American women attending 2 maternity clinics in Barcelona, Spain. Clin Infect Dis 2009; 48:1736–1740.

89▪. Murcia L, Carrilero B, Munoz-Davila J, et al. Risk factors and primary prevention of congenital Chagas Disease in a nonendemic country. Clin Infect Dis 2013; 56:496–502.

This is a longitudinal study evaluating the congenital transmision of T. cruzi infection in a nonendemic country and the role of T. cruzi PCR in predicting mother-to-child transmission. Of note is that among PCR+ women, the mother-to-child transmission rate of transmission was 31% whereas it was 0% for those PCR−. Neither women treated with benznidazole before becoming pregnant transmitted T. cruzi to their offspring (all were PCR−).

90. Soriano Arandes A, Munoz Gutierrez J, Verges Navarro M, et al. Prevalence of Chagas disease in the Latin American immigrant population in a primary health centre in Barcelona (Spain). Acta Trop 2009; 112:228–230.

91. Agosti MR, Ercoli P, Dolcini G, et al. Two cases of mother-to-child transmission of HIV and Trypanosoma cruzi in Argentina. Braz J Infect Dis 2012; 16:398–399.

92. Scapellato PG, Bottaro EG, Rodriguez-Brieschke MT. Mother-child transmission of Chagas disease: could coinfection with human immunodeficiency virus increase the risk? Rev Soc Bras Med Trop 2009; 42:107–109.

93. Freilij H, Altcheh J, Muchinik G. Perinatal human immunodeficiency virus infection and congenital Chagas’ disease. Pediatr Infect Dis J 1995; 14:161–162.

94. Brutus L, Castillo H, Bernal C, et al. Detectable Trypanosoma cruzi parasitemia during pregnancy and delivery as a risk factor for congenital Chagas disease. Am J Trop Med Hyg 2010; 83:1044–1047.

95. Sosa-Estani S, Cura E, Velazquez E, et al. Etiological treatment of young women infected with Trypanosoma cruzi, and prevention of congenital transmission. Rev Soc Bras Med Trop 2009; 42:484–487.

96. Nisida IV, Amato Neto V, Braz LM, et al. A survey of congenital Chagas’ disease, carried out at three health institutions in Sao Paulo City, Brazil. Rev Inst Med Trop Sao Paulo 1999; 41:305–311.

97. de Toranzo EG, Masana M, Castro JA. Administration of benznidazole, a chemotherapeutic agent against Chagas disease, to pregnant rats. Covalent binding of reactive metabolites to fetal and maternal proteins. Arch Int Pharmacodyn Ther 1984; 272:17–23.

98. Gorla NB, Ledesma OS, Barbieri GP, Larripa IB. Assessment of cytogenetic damage in chagasic children treated with benznidazole. Mutat Res 1988; 206:217–220.

99. Gorla NB, Ledesma OS, Barbieri GP, Larripa IB. Thirteenfold increase of chromosomal aberrations nonrandomly distributed in chagasic children treated with nifurtimox. Mutat Res 1989; 224:263–267.

100. Bisio M, Altcheh J, Lattner J, et al. Benznidazole treatment of Chagasic encephalitis in pregnant woman with AIDS. Emerg Infect Dis 2013; 19:1490–1492.

Keywords:

Chagas disease; HIV; immunosuppression; neglected tropical diseases; opportunistic infections; Trypanosoma cruzi

© 2014 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.