https://orcid.org/0000-0002-1786-8530
Figures
Abstract
Background
Narrative descriptions of HIV and Trypanosoma cruzi, the causative agent of Chagas disease, co-infection exist in the literature but the breadth and depth of the data underlying these descriptions has not been previously thoroughly scrutinised and reactivation is poorly understood. The aim of this systematic review was to identify, synthesise and analyse the published literature on the epidemiology and clinical features of T. cruzi and HIV co-infection.
Methods
A systematic review of published literature on HIV and T. cruzi co-infection was conducted. Six international databases were searched: Medline, Embase, Global Health, Global Index Medicus (including LILACS, AIM, IMEMR, IMSEAR & WPRIM), Web of Science and Scopus. Articles reporting on HIV and T. cruzi co-infection, as defined by the authors, with no restrictions on study type, language or date of publication or reporting were included.
Results
152 articles (62% case reports or series) were included, of which 110 reported individual patient data on 352 individuals with HIV and T. cruzi co-infection. Reported prevalence of co-infection varied by region and setting of screening, ranging from 0.2% to 5%. 86% of reactivations were reported in individuals with CD4 < 200 cells/mm3. CNS reactivation, typically presenting with meningoencephalitis and/or central nervous system (CNS) lesions, accounted for 85% of all published cases of reactivation. Myocarditis (accounting for 10% published reactivation cases) was less well characterised. Mortality of all reactivation cases was 67% (79% in those with CNS reactivation).
Conclusion
T. cruzi reactivation mainly affects those with untreated HIV and lower CD4 counts. CNS reactivation is the most common clinical picture and confers high mortality. Prompt recognition of reactivation and immediate initiation of trypanocidal therapy (with benznidazole or nifurtimox) is recommended. Increased education and better awareness of the risks of co-infection are needed, as is systematic screening of individuals at-risk.
Author summary
The consequences of infection with both HIV and Trypanosoma cruzi (the parasite which causes Chagas disease) have been written about in the literature since the 1990s. In this review article, the evidence on co-infection is systematically identified, summarized and critiqued. Most evidence comes from small case reports or series of individual patients and is not of high quality. The main risk of co-infection is reactivation in the central nervous system, when the T. cruzi parasite replicates, causing meningoencephalitis. This usually occurs when HIV is not well-controlled and is associated with a high risk of death. Prompt recognition of co-infection, and antiparasitic treatment of T. cruzi can mitigate this risk.
Citation: Elkheir N, Carter J, Dominic C, Lok P, Fisayo T, Michelen M, et al. (2026) The epidemiology and clinical features of HIV and Trypanosoma cruzi (Chagas disease) co-infection: A systematic review and individual patient data analysis. PLoS Negl Trop Dis 20(1): e0012808. https://doi.org/10.1371/journal.pntd.0012808
Editor: Claudia Ida Brodskyn, Centro de Pesquisa Gonçalo Moniz-FIOCRUZ/BA, BRAZIL
Received: December 23, 2024; Accepted: January 9, 2026; Published: January 22, 2026
Copyright: © 2026 Elkheir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data is deposited in an open-access data repository hosted by the London School of Hygiene & Tropical Medicine, Data Compass, available at http://doi.org/10.17037/DATA.00004916.
Funding: NE was supported by a Medical Research Council Clinical Research Training Fellowship (Grant reference MR/W016028/1). https://www.ukri.org/councils/mrc/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Chagas disease is one of the most important zoonotic infectious diseases in Latin America and is increasingly being recognised as a public health problem in non-endemic settings within migrants from Latin America [1–3]. It is caused by the protozoan parasite Trypanosoma cruzi and is endemic in the 21 countries of Central America, South America and Mexico. About 7 million people worldwide are estimated to be infected with T. cruzi and approximately 12,000 people die each year from clinical manifestations of Chagas disease [4]. Infection is believed to be lifelong without treatment. The consequences of this chronic infection include progression to determinate cardiac or gastrointestinal end-organ disease, which affects approximately one third of individuals with T. cruzi. Chronic infection also poses an additional risk of parasite reactivation and replication in the context of immunocompromise such as immunosuppressant medication or HIV.
The first recognised description of T. cruzi reactivation in people living with HIV (PLHIV) was reported in Argentina in 1990, in a patient with central nervous system reactivation [5]. Since then, many articles have reported high mortality rates associated with HIV/T. cruzi co-infection [6–8]. A systematic review including articles published until 2010 identified 291 cases of co-infection published in the literature, and 100% mortality in untreated cases of reactivation [9]. A narrative review published in 2021 described the epidemiology of co-infection, the clinical presentations most commonly associated with T. cruzi reactivation in PLHIV and highlighted the many gaps in knowledge [10]. This systematic review will complement these earlier papers, through drawing together all international literature and publicly available data to provide an analysis of the current state of knowledge.
Methods
A systematic review was conducted according to PRISMA guidelines [11], and registered with the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42020216125).
Eligibility criteria
- Inclusion criteria: This review includes articles reporting on HIV and T. cruzi co-infection, as defined by the authors, with no restrictions on study type, language or date of publication or reporting.
- Exclusion criteria: Editorials and opinion papers were excluded, along with any articles not presenting primary data. Studies that included people with HIV and T. cruzi as a sub-group but did not present disaggregated data for any of the outcome measures of interest were excluded, unless corresponding authors were able to provide the required information (following two email attempts to contact authors). Articles where HIV and T. cruzi prevalence were reported separately (mainly with reference to blood bank screening and with no way to infer co-infection) were excluded. Systematic reviews and reviews were excluded, but citation tracking of any such publications was undertaken to identify additional publications not otherwise identified by the search strategy.
PICO question
- Population: People of any age with T. cruzi infection/Chagas disease
- Exposure: HIV co-infection, as defined by authors
- Comparison: N/A
- Outcomes:
- Prevalence of co-infection
- Characteristics of patients and co-infection, including but not limited to:
- Age
- Sex
- Country of birth/residence
- CD4 count and HIV viral load
- Clinical presentation
- Presence of other opportunistic infections
- Setting of diagnosis and method of diagnosis (e.g., clinical, serological, parasitological)
- Clinical investigations (including bloodwork, imaging and cerebrospinal fluid examination)
- Treatment (antiretroviral, antiparasitic therapy and other)
- Clinical outcomes: measures of morbidity and mortality
- Prevalence of co-infection
Information sources
The following six databases were searched on 1st July 2022: Ovid Medline, Ovid Embase, Ovid Global Health, Global Index Medicus (including LILACS, AIM, IMEMR, IMSEAR & WPRIM), Web of Science and Scopus. For any review articles identified, the listed references were screened, and citations of the articles were reviewed to identify any additional papers not captured by the original search strategy. Authors were contacted to request additional data where data was missing.
Search strategy
Controlled subject headings and keywords of the following concepts were searched:
- 1). HIV
And
- 2). Chagas disease or Trypanosoma cruzi infection
There were no limits on language or date of publication.
Selection process
Title and abstract screening of all records identified by the search strategy was carried out independently by two reviewers (NE and JC). Subsequent full-text screening of selected articles against the inclusion criteria was carried out independently by the same two reviewers, with all discrepant assessments resolved by consensus discussion. The Rayyan systematic review data automation tool was used to organize articles and record screening decisions.
Data collection process
Data were managed using Endnote for de-duplication of articles, Rayyan for screening, Microsoft Excel for data extraction and STATA version 18 for data analysis. The data extraction tool was developed in Microsoft Excel and piloted with input from the study team. Following this pilot assessment, the data extraction tool was split into two: one for articles that presented only aggregate-level data (e.g., prevalence studies) and one for articles with individual-level data (predominantly case reports and case series). Data extraction was performed independently by two reviewers (NE and either CD, PL, TF, MM, BdB, JWG, MB, AP or AM), who were fluent or native in the language of the article. Data extraction was checked by a third reviewer (JC), using the DeepL Pro (Cologne, Germany) online translation tool if necessary. Disagreements on interpretation of data to extract were resolved, and consensus reached, through discussion. Where important data was missing, the corresponding authors of the articles were contacted (twice via email) to request it.
Data items
The following data (where available) was extracted from all articles: study design, aim, country of study, setting and context, inclusion and exclusion criteria, study population size (including prevalence of co-infection where reported) and characteristics, diagnostic criteria for HIV and T. cruzi infection, CD4 count, HIV viral load, clinical syndromes (signs and symptoms), other opportunistic infections reported, investigations (including laboratory and radiological findings), treatments (antiretroviral, antiparasitic and others) and clinical outcomes (measures of morbidity and mortality).
Study risk of bias assessment
The Joanne Briggs Institute Critical Appraisal Checklists [12] were used to assess for risk of bias in the studies included in the review. Two reviewers (NE and JC) assessed for risk of bias independently and reached consensus through discussion where disagreements arose. No formal measures to assess reporting bias or certainty in the body of evidence were taken, although these are qualitatively described.
Effect measures
Prevalence of co-infection in the study population was extracted where available (for both HIV amongst subjects with T. cruzi infection and for T. cruzi infection amongst subjects with HIV), and the range of estimates were presented according to study setting. For studies reporting individual-level patient data, mortality was calculated as an overall proportion.
Synthesis methods
Articles were analysed in three groups: those that presented prevalence data, those that presented aggregate-level data of selected populations, and those that presented any individual patient-level data. The inclusion criteria for prevalence studies (based on Joanna Briggs Institute guidance [13]) were as follows: cross-sectional study design, population samples of more than 50 individuals (of any age, sex, geographical location or sociodemographic characteristics), studies in unselected populations (or populations recruited based on either known HIV or T. cruzi infection), and prevalence of co-infection reported. The exclusion criteria for prevalence studies were: hospitalised patients, populations selected based on characteristics other than HIV or T. cruzi status, such as study samples drawn from populations with known comorbidities or undergoing interventions that put them at increased risk of co-infection. Articles that met these prevalence study criteria were summarised in Table 1 according to the setting (and context) of presentation. A meta-analysis of prevalence estimates was not performed due to the substantial heterogeneity among the different contexts.
Articles that presented aggregate data on co-infection in selected populations that did not meet the above prevalence study criteria were summarised thematically, according to study design and setting, in Table 2.
Articles with individual-level data (summarised in Table 3) were assessed for duplication (i.e., the same cases being published more than once) by checking the epidemiological and clinical details of age- and sex- matched cases. Duplicate cases are still presented in Table 3 but are excluded from the analysis (and the estimate of number of total cases published in the literature). Once duplicate cases were excluded, due to heterogeneity in reporting of reactivation, the study team classified clinical presentations reported in articles into phenotypic groups (according to T. cruzi laboratory findings and clinical presentation, described further below and in Fig 3) by consensus. The individual patient analysis focussed on individuals meeting the criteria for reactivation.
Continuous data for all patients were presented as the mean and standard deviation (if normally distributed) or median and interquartile range (if not), and comparisons between different clinical presentations of reactivation were assessed using the Student’s t-test or Wilcoxon rank-sum test respectively. The categorical data for all patients are presented as counts and frequencies, and comparisons were performed using the Chi-squared or Fisher’s exact test, as appropriate. All analyses were conducted using STATA version 18 and a P value of less than 0.05 was considered statistically significant.
Results
Study selection
Ovid Medline, Ovid Embase, Ovid Global Health, Global Index Medicus (including LILACS, AIM, IMEMR, IMSEAR & WPRIM), Web of Science and Scopus were searched (as per methods section) on 1st July 2022. Fig 1 outlines the process from article identification to inclusion.
Database searches were performed up to 1st July 2022.
Study characteristics
152 articles were included in this systematic review, of which 131 (86%) were journal articles, 20 (13%) were conference abstracts or posters and one (1%) an online report. These articles consist of case reports (n = 68, 45%), case series (n = 26, 17%), cross-sectional studies (n = 51, 34%), cohort studies (n = 5, 3%) and case-control studies (n = 2, 1%).
Of these 152 studies included, 110 reported individual patient data on 352 individuals with HIV and T. cruzi co-infection (once duplicate cases were identified based on demographic and clinical features, and were excluded from the analysis).
121 studies were performed in endemic countries (Fig 2): Brazil (n = 60, 39% of all included articles), Argentina (n = 39, 26%), Colombia (n = 7) Bolivia (n = 6), Chile (n = 5), Uruguay (n = 1), Venezuela (n = 2) and Mexico (n = 1). Thirty studies were performed in non-endemic countries: Spain (n = 14, 9%), US (n = 13, 9%), Italy (n = 3) and the UK (n = 1).
Table 1 outlines the characteristics of included articles that presented any prevalence data for HIV/T. cruzi co-infection, either T. cruzi infection amongst subjects with HIV or HIV infection amongst individuals with T. cruzi infection or both.
Table 2 outlines the characteristics of included articles that presented aggregate data of selected populations only (i.e., did not meet the criteria of a prevalence study and/or presented no individual-level patient data).
Table 3 outlines the characteristics of included articles that had any individual-level data which could be extracted (and therefore include in our individual patient data analysis).
Risk of bias in studies
The majority of articles were case reports or case series (94 articles, 62%), which are particularly susceptible to selection bias and publication bias. Additionally, the analysis of individual patient data may have unknowingly counted patients twice where authors have published multiple series, further contributing to risk of bias.
All 152 papers were critically appraised using the design-appropriate Joanna Briggs Institute (JBI) critical appraisal tool. Seven articles (5%) were assessed as high quality (a score above 90%), 83 articles (55%) medium quality (score of 75–90%), and the remaining 62 articles (41%) as low quality (score <75%). The majority of the cases reports and case series were of low quality. The mean JBI score for all included articles was of low quality, at 67%.
Results of individual studies
Prevalence of co-infection.
Table 1 outlines study characteristics of four articles that presented prevalence of co-infection (and met the aforementioned criteria for prevalence studies). First-time blood donors in Mato Gross do Sul State of Brazil had a reported prevalence of T. cruzi HIV co-infection of 0.2% (Aguiar 1999) [14].
In the three studies of representative (outpatient) populations with HIV tested for T. cruzi infection, the prevalence of co-infection ranged from 1.3% in a study of 716 subjects in Sao Paulo, Brazil (Almeida 2010) [15] to 5% in a study of 200 subjects in Rio Grande do Sul State (Stauffert 2017) [16].
Proportion of selected study populations with co-infection.
In the four studies reporting testing of selected populations not previously known to have either T. cruzi or HIV, the proportion found to have co-infection ranged from 0.1% in emergency department attendees in Argentina (Auger 2002) [17] to 1% in migrants from Chagas-endemic countries in Spain (Bocanegra 2014) [18].
Twenty-three studies (that did not meet the criteria of a prevalence study) reported T. cruzi serological testing amongst people living with HIV (PLHIV). Excluding the nine studies where patients were explicitly selected based upon specific clinical presentations or risk groups (e.g., PLHIV with diarrhoea or neurological disease), the proportion testing positive for T. cruzi ranged from 0.2% in an outpatient setting in Brazil (Dias 2018) [19] to 28.6% in an inpatient setting in Bolivia (Reimer-McAtee 2021) [20].
Three studies, all from Brazil, reported testing for HIV in patients with known T. cruzi infection in hospital settings, amongst whom the proportion of patients with co-infection ranged from 26.4% (Sartori 2002) [21] to 47.9% (Perez-Ramirez 1999) [22].
Martins Melo et al. reported that both Chagas disease and HIV were mentioned on 196 death certificates in Brazil (out of 22,663,092) between 2000 and 2019 [23].
Twelve studies reported on testing of migrants from Chagas-endemic countries living in non-endemic settings. In the eight studies reporting testing for T. cruzi infection in PLHIV the proportion ranged from 1.1% in primary care in the US (Evans 2018) [24] to 10.5% in Spain (Rodriguez-Guardado 2009) [25].
Clinical features of co-infection.
One cross-sectional retrospective multicentre study of co-infection (Shikanai-Yasuda, 2021) [69] reported on 241 patients with co-infection (87% from Brazil), of whom 60 were cases of reactivation. In these 60 patients with reactivation, 35 (58%) presented with meningoencephalitis, 10 (17%) with myocarditis and eight (13%) with both. 31 (52%) had CD4 counts below 200 cells/mm3 at presentation. Mortality overall was 67%, higher in those with meningoencephalitis (77%), who on average had lower CD4 counts compared to myocarditis (in whom mortality was 50%). Although this article did not report individual-level patient data (and is therefore not included in our analysis), individual level data is available in an online repository and most of the individuals with reactivation referred to in this article have been published in a separate case series so are captured in our individual patient analysis.
This study did not report individual-level patient data so is not included in our analysis below, however most of the individuals with reactivation referred to in this article have been published in separate case series so are captured in our individual patient analysis.
110 studies reported individual-level patient data on clinical features or outcomes for a total of 352 patients with HIV and T. cruzi co-infection (once duplicate patients reported across multiple articles were excluded). Study characteristics are summarised in Table 3. Demographics of patients with HIV/T. cruzi co-infection are summarised in Table 4.
Definition of co-infection and reactivation.
All 352 patients had laboratory-confirmed T. cruzi and HIV co-infection. There was a lack of an internationally standardised definition of T. cruzi reactivation in PLHIV and significant heterogeneity in the reporting of co-infection, with different clinical and laboratory parameters adopted historically and geographically. Therefore, for the purposes of this systematic review, individual cases were assigned one of three clinical phenotypes (co-infection with reactivation, co-infection without reactivation, and congenital co-infection. Fig 3).
Individual patient analysis of T. cruzi reactivation
From here onwards, only the data from the 185 individuals who met our aforementioned ‘Co-infection with T. cruzi reactivation’ criteria (Group 1 of Fig 3) are reported. The 185 subjects determined as having reactivation had a median age of 36 (IQR 29–42). 95(51%) were male, 37(20%) female, and sex was not reported in 53 (29%) cases. 170 (92%) cases presented in endemic settings (39% of whom in Brazil), and 15 (8%) in non-endemic settings.
HIV and Trypanosoma cruzi status.
125 (68%) cases were known to have HIV prior to presentation, HIV was unknown at the point of presentation in 53 (29%) patients and was not recorded in 7 (4%) cases. 15 (8%) cases of reactivation occurred in patients on antiretroviral therapy (ART) (none of whom were HIV virally suppressed in the five cases where viral load was reported), 82 (44%) in ART-naïve cases and this data was missing in 88 (48%) cases. HIV viral load was reported in 31 cases of reactivation (median 143,000, IQR 26,168 –375,000, range 4,700 – 1,800,000 copies/mL), none of whom were virally suppressed. 45 (24%) cases of reactivation were known to have T. cruzi infection prior to presentation, this was unknown in 102 (55%) patients and not recorded in 38 (21%) cases. No cases of reactivation were noted to have previously received trypanocidal treatment with benznidazole or nifurtimox, but one case had received ketoconazole (published in 1999) [139].
Clinical presentation of reactivation.
Table 5 summarises the HIV and T. cruzi investigation findings of all cases of reactivation and Table 6 the presenting features.
39 (32%) individuals with reactivation were reported as acutely unwell (clinical shock – as defined by authors or systolic blood pressure <90 mmHg, altered consciousness or requiring critical care).
Central nervous system reactivation
Meningoencephalitis and/or central nervous system (CNS) space-occupying lesions accounted for 85% of the cases of reactivation, with presentation with focal neurological deficit, headache or seizures most commonly reported, in 38%, 30% and 22% respectively.
Median CD4 counts in reactivation with CNS involvement were lower than those without CNS involvement (46 versus 102 cells/mm3, Wilcoxon rank-sum z statistic 2.12, p < 0.05).
92% of CNS reactivation cases had a CD4 count under 200 cells/mm3; 75% were under 100 cells/mm3.
This is a visual representation of the distribution of the data. The box represents the middle 50% of the data, from the first quartile to third quartile. The line inside the box represents the media and the x the mean. The whiskers extending from the box show the range of the data, extending to the smallest and largest values within 1.5 times the interquartile range from the box. Data points that fall outside the whiskers are considered outliers and are shown as individual points.
Cerebrospinal fluid examination.
104 (56%) patients with reactivation had a lumbar puncture (LP), of whom 98 had neurological symptoms and/or abnormal neuroimaging findings reported suggestive of CNS pathology. The cerebrospinal fluid (CSF) was reported as normal in five cases (one of whom had reported symptoms or neuroimaging suggestive of CNS reactivation) and abnormal in 97 cases (95 of whom had neurological symptoms and/or abnormal neuroimaging findings reported suggestive of CNS reactivation and two of whom did not). T. cruzi was detectable by microscopy in the CSF in 80 cases (83% of presumed CNS reactivation cases with CSF findings reported, Table 4). In three cases, T. cruzi was not detectable by CSF microscopy, but CSF PCR was positive. Fig 4 displays the distribution of CSF white cell counts, protein and glucose, for patients with CNS reactivation. Data on CSF findings pertaining to other OIs was not systematically extracted.
Of 41 reported CSF cell counts, the cell count was greater than five white blood cells/µL in 61% of cases (greater than 10 in 54%, greater than 20 in 32%, greater than 50 in 15% cases) and, when reported, was predominantly lymphocytic.
According to a normal protein CSF reference range of 15–60 mg/dL, of 44 reported protein values: 26 (59%) were raised (48% greater than 80, 34% greater than 100, 10% greater than 200).
According to a normal glucose CSF reference range of 50–80 mg/dL, of 37 reported values, 23 (62%) reported low glucose and 14 (38%) reported normal glucose.
Neuroimaging.
122 patients had neuroimaging: 104 patients (56%) had a CT brain, 47 (25%) an MRI and 29 (16%) had both. In six symptomatic patients, neuroimaging was reported as normal (all six patients had an LP, five of which were reported – all abnormal, including three which had T. cruzi detectable by microscopy in the CSF and one with PCR positive CSF). 53 (43% of those with neuroimaging) patients had a single lesion, and 61 (50%) patients had multiple (2 or more) lesions. 47 (39%) lesions were reported as ring-enhancing (and it should be noted that use of contrast was often not reported), eight (7%) reported as located in white matter, three (2%) in grey matter (and location not stated in the majority of reports). Cerebral oedema was present in 53 (43%), with a mass effect in 37 (30%).
Cardiac reactivation
Myocarditis was reported in 18 cases (10% of all reactivation reports) and was a common finding on autopsy (12 out of 35 cases, 34%). The median CD4 count of the 11 cases for whom CD4 count was reported was higher (median 157, [IQR 104–264]) than for those with CNS reactivation (Wilcoxon rank-sum z = -3.13 p < 0.01).
Cardiorespiratory investigations.
In the absence of prior data on cardiac function, attribution of reported cardiac abnormalities to T. cruzi reactivation cannot be substantiated, nevertheless the reported findings (for all patients with presumed reactivation) were as follows: ECG was reported as abnormal in 28 (15%) cases (supraventricular tachycardia = 3, ventricular tachycardia = 1, right bundle branch block = 7, left bundle branch block = 1, atrioventricular block = 8, ventricular ectopics = 1, ST changes = 1, prolonged QT = 1). Chest x-ray was reported as abnormal in 17 (9%) cases (cardiomegaly = 7, pneumonia = 5, infiltrates = 5, effusion = 4). Echocardiography was reported as abnormal in 16 (9%) cases (systolic dysfunction = 9, thrombus = 1, valve disease = 2, pericardial effusion = 5, dilatation = 4).
Other clinical presentations
Other clinical presentations of T. cruzi reactivation in PLHIV were less frequently reported, and included, but were not limited to, erythema nodosum in two cases [60,75,152], and pleuritis [140], peritonitis [124], cervicitis [159] and panniculitis [75] in one case each.
Opportunistic infections
Concurrent additional opportunistic infections were commonly reported (n = 67, 36%). Herpes simplex virus in four cases (2%), cryptococcosis in six cases (3%), tuberculosis in 11 cases (6%), cytomegalovirus in 13 cases (7%), candidiasis in 14 cases (8%), pneumocystis pneumonia in 13 cases (7%), and toxoplasmosis in 34 cases (18%). In the cases of concurrent cryptococcosis, cytomegalovirus and toxoplasmosis, CNS involvement (of these other OIs) was usually inferred but rarely well described.
Management
Anti-retroviral treatment (ART) was poorly reported. ART was initiated in 43 (23%) patients at some point (43/185, 111 had missing data). Delaying initiation of ART was explicitly noted in 15 (8%) cases. 124 patients (67%) were treated for reactivation disease with trypanocidal drugs (107 with benznidazole and 17 with nifurtimox). Adverse effects from trypanocidal drugs were reported in 22 patients (18% of those treated), with 11 of those 22 patients having to stop trypanocidal treatment because of this. The mean trypanocidal treatment duration was 60 days (standard deviation 104, range 1 – 730). 55 (30%) patients were treated for toxoplasmosis. Steroid therapy was given in 34 (18%) cases. Data on ART choice and timing, as well as secondary (trypanocidal) chemoprophylaxis were lacking. Immune reconstitution inflammatory syndrome (IRIS) was reported (as probable, rather than confirmed) in two cases [74,144], both of whom died.
Outcomes
Overall mortality was 67% (124 patients died out of 185 with reactivation). Seven (4%) survived with morbidity (of which five had neurological sequelae, one had congestive cardiac failure and one not described). Thirty-four patients (18%) fully recovered whilst outcome data was missing for 20 (11%) patients.
Overall mortality in patients with CNS reactivation (79%) was higher than those without (54%) CNS reactivation (χ2 = 7.5, p < 0.01)
Amongst those with data available on both ART at presentation and clinical outcome, there were 7 deaths in 15 people reported to be on ART at presentation (47% mortality), compared to 54 deaths in 77 people known to not be taking ART at presentation (70% mortality).
Time to death was reported in 71 cases, amongst whom it occurred at a median of 21 days after presentation (IQR 8–60 days, range 0–1,950). Median time to death in cases of CNS reactivation was shorter (21 days, IQR 8–57) than for those without CNS reactivation (41 days, IQR 14–75), but this was not statistically significant.
In univariate analyses, age, sex and CD4 count were not statistically significant predictors of death, but neurological presentation was (χ2 = 7.5, p < 0.01).
Autopsies
38 autopsies were reported in people known to have HIV/T. cruzi co-infection (35 in cases of reactivation). The macro- and microscopic patterns of necrosis, haemorrhage and inflammation of cerebral lesions, and direct observation of T. cruzi parasites, were described in 15 articles [32,60,78,89,92,93,100,103,139,142,144,148,155,157,162]. Carditis (mostly myocarditis with amastigotes in muscle cells with infiltrates) was reported in 12 articles [84,89,92,100,107,108,118,125,139,152,154,155]. Nests of T. cruzi amastigotes with inflammation, necrosis and haemorrhage in the adrenal glands were reported in one article [79]. Myositis of the extra-ocular muscles was reported in one article [142].
Maternal and congenital co-infection
Eight articles reported maternal and/or congenital co-infection [51,62,90,105,111,147,150,154]. Scapellato [62] assessed T. cruzi vertical transmission rates in 94 T. cruzi seropositive mothers (three of whom were co-infected with HIV). All three neonates born to co-infected mothers had congenitally acquired T. cruzi (versus 10 out of 91, 10.9%, of those born to HIV negative mothers). Similarly Nisida [154] reported T. cruzi vertical transmission rates in 58 T. cruzi seropositive mothers: congenital T. cruzi transmission occurred in both infants born to the two HIV co-infected mothers compared to two out of 56 (4%) born to HIV negative mothers.
The outcomes of eight cases of co-infection in pregnant women (of which three were reactivation, all survived) were reported [26,60,150,154]. This included four cases published by Sartori et. al in which three resulted in congenital transmission. All three neonates were symptomatic with CNS disease (and two out of three neonates died) [60]. One case report of T. cruzi CNS reactivation in a pregnant woman with co-infection reported the use of benznidazole at 32 weeks in successfully treating the woman; congenital infection did not occur [150].
Eleven congenital cases of co-infection were reported in six articles [51,90,105,111,147,154], of whom nine were symptomatic, with meningoencephalitis (n = 5), anaemia (n = 3) and/or hepatosplenomegaly (n = 3), and six died (of which three had neurological involvement and two with sepsis).
Discussion
This systematic review provides the most comprehensive collation and overview of published evidence on the epidemiology and clinical manifestations of HIV and Trypanosoma cruzi co-infection and reactivation. Although this review includes a large body of evidence (152 articles published over 34 years, reporting on 352 co-infected patients with individual data from 12 countries), the granularity of data in the majority of published articles was low and missing data on key variables was common. As outlined by Clark et al. in a 2021 narrative review on Chagas disease in people with HIV [10], we found significant heterogeneity in the way T. cruzi reactivation is reported across articles. The lack of any internationally recognised and standardised definition of reactivation hindered the interpretation of our results. To aid future research and guideline development, we recommend clearer reporting of clinical and diagnostic (parasitological and molecular) criteria for T. cruzi reactivation. Expert guidelines are clear that microscopic detection of T. cruzi is diagnostic of reactivation, [164,165] however there is no clear consensus on a threshold for parasite load as detected by molecular methods (and development of such consensus is hindered by the lack of standardised PCR procedures for T. cruzi).
Despite advances in access to, and efficacy of, antiretroviral therapy [166,167] reported in the literature and downward trending incidence of T. cruzi infection, the proportion of co-infection reported in hospitalised populations remained high in the more recent publications, for example 24% and 38% of hospitalised patients with known HIV screened for T. cruzi in two different hospitals in Bolivia, published in 2015 and 2021 respectively [20,39]. As no cases of reactivation identified in this review occurred in individuals on ART who were virally suppressed, reactivation cases in modern times are more likely due to access to ART issues rather than their lack of efficacy in preventing reactivation. In one study from Argentina published in 2016, other HIV risk groups with high T. cruzi seroprevalence were men who have sex with men, STI clinic attendees and intravenous drug users, with an overall co-infection prevalence of 3% [40]. Our findings support the recommendation for universal co-infection screening for those known to have either HIV or T. cruzi in endemic settings, ideally at the first point of contact with healthcare providers.
The proportion of co-infection reported in studies performed in non-endemic settings varied more widely, from 1-2% when screening Latin American migrants with HIV for T. cruzi infection in Italy, the US and the UK [24,45,46], to 3–11% in Spain [25,26,44]. Some study authors attributed lower than expected proportions to poor uptake of testing, especially amongst groups born in higher-endemicity countries. Low awareness of Chagas disease amongst at-risk migrants, as well as healthcare professionals in non-endemic countries, has been reported in the literature as a potential barrier to screening uptake [168–171]. We recommend educational interventions, which have successfully been implemented, to improve uptake of screening in these settings [172], whilst acknowledging that the demographic profile of migrant communities from Latin America at highest risk of T. cruzi infection may not overlap substantially with that of migrant populations at highest risk of HIV infection.
This review identified very little evidence on maternal and congenital HIV-T. cruzi co-infection, and this is recommended as a priority area for future research. The eight published articles on this topic suggest high rates of congenital T. cruzi infection amongst neonates born to mothers with co-infection (compared to mothers with T. cruzi alone). The articles also suggest very high neonatal mortality associated with co-infection.
Risk of T. cruzi reactivation in immunosuppression was assessed in another recent systematic review by Antequera et al. [173], which included three prospective studies of HIV/T. cruzi co-infection.[20,40,60] The incidence of reactivation ranged from 11% to 26%, with a pooled cumulative incidence of reactivation of 17% (95% CI 8–29%) in PLHIV, which was lower than other contexts of acquired immunosuppression such as transplant recipients. In our review, we felt the level of heterogeneity between both study contexts and populations, as well as the different interpretations of what constitutes reactivation, plus the limited follow-up time in any prospective studies (which were lacking altogether) impeded a potential meta-analysis of risk of reactivation. More research is needed to understand the true risk of reactivation (including the effect of trypanocidal drugs), with a clearly defined study population and definition of reactivation, prospective outcome measurement, and sufficient sample size and follow-up duration.
This systematic review’s individual-patient analysis focused on 186 cases of co-infection with T. cruzi reactivation. The majority of these patients were born in and presented to healthcare systems in Brazil, with a small representation of patients additionally from Argentina and Bolivia, and a small number of migrants from Bolivia, El Salvador or Honduras presenting in the US or Spain.
Reactivation was mostly reported in patients with a CD4 count below 200 cells/mm3 (87% of patients), 68% were lower than 100. In our review, we found that CNS reactivation accounts for 85% of the total cases of reactivation and is associated with lower CD4 counts (only one case occurred in those with CD4 counts over 500 cells/mm3). Our findings on the clinical features of T. cruzi CNS reactivation are similar to those of a recently published review on this topic which found most (but not all) cases of CNS reactivation to occur in individuals with CD4 counts below 200 cells/mm3, a similar proportion of patients presenting with seizures and motor deficits, and a similar mortality overall (74%) [174]. Our systematic review is more comprehensive, in that a more exhaustive search strategy was utilised, thus identifying more cases of reactivation. HIV viral load was underreported (only 31 cases reported this), nonetheless all 31 cases showed detectable viral loads. As has been previously reported [10], this review found CNS lesions from T. cruzi reactivation to be mainly (but not exclusively) ring-enhancing, and cerebral oedema was commonly reported. Expert groups with significant clinical experience in this area have reported that T. cruzi lesions tend to occur in white or subcortical matter, by contrast with Toxoplasma which may preferentially affect the thalamus and basal ganglia [175], however this was not clearly substantiated from our systematic review. As there are reports (n = 6) of normal neuroimaging in T. cruzi CNS reactivation, CSF examination (ideally including T. cruzi PCR as per expert guidance [165,175]) is recommended in cases of sufficient clinical suspicion, even if imaging is reported as unremarkable.
Neuroimaging can be normal in T. cruzi CNS reactivation. If T. cruzi reactivation is suspected, direct microscopic examination of the CSF is recommended. Where available the use of PCR in CSF to enhance sensitivity has been recommended in expert guidelines [165,175]. Further research to assess the extent to which PCR enhances sensitivity over microscopy is recommended, given that access to PCR remains limited in low-resource settings. Alongside the other main differential diagnoses for PLHIV presenting with neurological features (toxoplasmosis, primary CNS lymphoma, progressive multifocal leukoencephalopathy, tuberculosis and cryptococcosis for example), we recommend that T. cruzi should be considered in anyone who has spent time in any of the 21 Chagas-endemic countries of South America, Central America or Mexico (and people born to mother from endemic countries).
We found a smaller proportion of cardiac reactivation (namely myocarditis) –10% of published cases of reactivation, than expert review articles have suggested (30–40%) [175]. As has previously been postulated, the burden of Chagasic cardiac reactivation is difficult to quantify as it may go unrecognised if not severe, that is, it could be attributed to chronic determinate disease. Additionally non-fatal cases are less likely to be published.
Robust data on management and outcomes of T. cruzi reactivation was lacking, although the lack of published reports of immune reconstitution inflammatory syndrome (IRIS) suggest this is not a common feature. However, it is possible that IRIS is not well described in these cases due to patients dying before IRIS manifested. Expert guidelines suggest waiting until at least three weeks of treatment with benznidazole (or nifurtimox) has been received prior to starting ART [175]. Although the evidence-base is lacking, expert guidelines also recommend secondary chemoprophylaxis for patients who have experienced reactivation due to T. cruzi/HIV co-infection when CD4 level is below 200 cells/mm3 (but do not recommend primary prophylaxis) [175].
The main limitation of the body of evidence presented in this systematic review stems from the biases (namely selection bias and publication bias) to which case series are susceptible. Severe and fatal cases are more likely to be published, and the proportion of reactivation presenting with neurological symptoms may be overrepresented as they are more likely to be attributed to T. cruzi reactivation. Although we were able to estimate the number of cases of co-infection and reactivation (with individual level data) ever published in the literature, it is a limitation of this paper that there was no feasible way to calculate the total cases from aggregate data. One retrospective multicentre study of co-infection was identified, which reported on 241 patients with co-infection, mainly from Brazil, and it is a further limitation of our review that we could not extract individual level patient data from this study to include in our analysis (however it is thought most of the cases of reactivation were published elsewhere so have been captured in our search).
Conclusion
Most evidence on HIV/T. cruzi co-infection and reactivation comes from case series, which are susceptible to selection and publication biases and therefore mainly of low quality. Evidence on maternal and congenital co-infection is particularly lacking. From the published literature, T. cruzi reactivation mainly affects those with untreated HIV and lower CD4 counts. CNS reactivation is the most common clinical picture, typically causing meningoencephalitis and cerebral lesions, and confers high mortality. Prompt recognition of reactivation and immediate initiation of trypanocidal therapy (with benznidazole or nifurtimox) is recommended. Screening for co-infection should be implemented in endemic settings (for T. cruzi in those with HIV and vice versa) and for migrants from at-risk areas (and those born to mothers from endemic countries) in non-endemic settings. Educational initiatives are needed to increase healthcare professionals’ awareness of Chagas disease, in particular of the risk of reactivation in HIV and other forms of immunosuppression.
Supporting information
S1 Checklist. PRISMA Checklist.
Legend: This article was reported according to PRISMA guidelines, as outlined in this checklist (available at: https://www.prisma-statement.org/prisma-2020-checklist).
https://doi.org/10.1371/journal.pntd.0012808.s001
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Acknowledgments
The authors wish to thank Russell Burke and the London School of Hygiene & Tropical Medicine (LSHTM) Library team for their support in building a robust search strategy for this systematic review, and Debbie Nolder (LSHTM) for advice on classification of molecular diagnostics.
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