Chagas Disease: An Opportunistic Infection in AIDS

Abstract

Purpose of review

The purpose of this review is to provide a comprehensive overview of Chagas disease as an opportunistic infection in AIDS, elucidate critical gaps in the literature, and outline priorities for future clinical research.

Recent findings

New promising tools for diagnosis include T. cruzi loop-mediated isothermal amplification, a non-invasive Chunap urine antigen test, and rRNA sequencing. People living with AIDS may benefit from sequential quantitative PCR testing for early detection of reactivation. This method is also a promising tool for treatment response monitoring. Prompt antitrypanosomal treatment and antiretrovirals are crucial for reducing morbidity and mortality. Several novel compounds and repurposed agents have shown preliminary activity against T. cruzi. Secondary prophylaxis may not be necessary, as relapse rarely occurs in patients on antiretrovirals.

Summary

Although primarily endemic to South America, increasing global migration has increased the prevalence of HIV/T. cruzi coinfection in non-endemic regions. Early recognition, timely treatment, and prevention strategies are crucial to reducing associated morbidity and mortality.

Introduction

The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic constitutes one of the most formidable public health challenges, with an estimated 39.9 million people with HIV in 2023 [1]. Among patients with AIDS, opportunistic infections account for a substantial proportion of morbidity and mortality. Chagas disease, also known as American trypanosomiasis, is an anthropozoonosis caused by the protozoan parasite Trypanosoma cruzi that can manifest as an opportunistic infection in patients with AIDS. It is endemic in 21 Latin American countries, affects over 7 million people globally, and claims over 10,000 deaths annually [2–4].

Chagas disease progresses through two phases: an acute phase that is often asymptomatic, or, when symptomatic resembles an influenza-like illness, and a lifelong chronic phase. During the chronic phase, some individuals remain clinically asymptomatic with no detectable end-organ involvement on standardized diagnostic assessment (i.e., the indeterminate form), whereas others develop symptomatic disease with corresponding structural or functional abnormalities identified by testing (i.e., the determinate form). In addition, reactivation, characterized by a surge in the level of parasitemia and clinical relapse, can occur in chronically infected individuals during periods of immunosuppression [5]. Reactivation was first reported in 1969 in a patient treated for chronic lymphocytic leukemia [6]. In 1990, the first reported case of reactivation was reported in a patient with AIDS [7]. Chagas disease reactivation is considered an AIDS-defining illness in Brazil since 2004 [8, 9••], typically manifesting as central nervous system (CNS) involvement or acute myocarditis [10].

The purpose of this review is to provide a comprehensive overview of Chagas disease as an opportunistic infection in the context of AIDS, to elucidate critical gaps in the literature, and to outline priorities for future clinical research.

Epidemiology

The prevalence of T. cruzi among people with HIV parallels its prevalence in the corresponding general population [11]. Reported HIV/T. cruzi coinfection rates in endemic countries, such as Brazil, Argentina, and Bolivia, range from 1.2% to 27.6% [11–13–14–15, 16•], while in non-endemic countries, including the United States (US) and Spain, rates range from 0% to 10.5% [17, 18–19–20]. A systematic review of retrospective studies reported a reactivation rate of 41% [21], a figure that may be inflated due to the tendency for coinfection to be identified primarily in individuals with reactivation. By contrast, two prospective longitudinal studies found reactivation rates of 15–20.8% among coinfected individuals not receiving antiretroviral therapy [11, 22]. A separate prospective study with prolonged follow-up, reported a similar reactivation rate of 20%, which fell to 9.8% when surveillance was limited to only several months [23].

The clinical severity and case-fatality rate associated with Chagas disease reactivation in individuals with AIDS are determined by several factors, including the degree of immunosuppression, the timing, adherence, and effectiveness of antiretroviral therapy, the promptness of diagnosis, and the opportune initiation of specific antiparasitic treatment [24]. Coinfected patients who experience delayed diagnosis and late initiation of therapy face the highest case fatality rates [24]. The prognosis has nonetheless significantly improved since the advent of highly active antiretroviral therapy, with median survival extending to three to five years [24]. In Brazil, the estimated mean annual mortality rate attributable to HIV/T. cruzi coinfection is 0.05 deaths per 1,000,000 inhabitants; a figure that is considered to underestimate the true disease burden [25].

Pathophysiology

Transmission of T. cruzi occurs predominantly through vector-mediated inoculation by triatomine insects, transfusion of contaminated blood products [26], organ transplantation [27], or orally via the ingestion of contaminated foods and beverages (for example, açaí pulp or sugar-cane juice) [10, 28–31]. Vertical transmission is also well documented, with maternal coinfection with HIV/T. cruzi conferring a transmission risk of approximately 75%, compared to 1–5% among immunocompetent women with T. cruzi infection [32–34].

High HIV viral loads and low CD4 + T lymphocyte counts, particularly < 200 cells/mm³, are associated with an increased risk of T. cruzi reactivation [12, 24]. Studies using quantitative polymerase chain reaction (qPCR) have demonstrated a direct correlation between T. cruzi parasitemia and HIV viral load, as well as a statistically significant inverse correlation between the parasite load and CD4 + cell count on a logarithmic scale [16•]. Although polyclonal T. cruzi infections can occur in people with HIV, the genetic diversity and clonality of T. cruzi are similar to those in people without HIV [35]. Furthermore, no particular T. cruzi discrete typing unit has been associated with an increased risk of reactivation or clinical phenotype among people living with HIV [35].

The specific immunologic mechanism that triggers reactivation remains unclear. Prolonged administration of corticosteroids (prednisone ≥ 20 mg daily or an equivalent for 21 or more days) has been implicated as a potential precipitant, highlighting the need to carefully weigh their use when treating other opportunistic infections in the context of AIDS, such as Pneumocystis jirovecii pneumonia [36]. Experimental studies further suggest that oxidative imbalance within the CNS, characterized by increased reactive oxygen species, promotes parasite proliferation within astrocytes [37].

The pathophysiology of T. cruzi infection is governed by the dynamic interplay between Th1 and Th2-mediated immune responses. Th1-mediated immunity, marked by elevated interferon [IFN-γ] and interleukin [IL]−2 production, is critical for protective host defense against parasitic infections, including T. cruzi. In contrast, Th2-mediated immunity, characterized by increased levels of IL-4, IL-5, IL-10, IL-13, and transforming growth factor-β, attenuates Th1 effector functions, leading to impaired IL-2-mediated CD8 + T-cell differentiation, reduced IFN-γ-mediated macrophage activation, and diminished reactive nitrogen species production, all of which are necessary for parasite clearance [38–40]. In individuals with HIV, a Th2-skewed cytokine profile and suppressed Th1 responses contribute to higher baseline T. cruzi parasitemia levels and a heightened T. cruzi reactivation risk [41]. Paradoxically, this Th2 predominance may mitigate the development of certain complications of chronic Chagas disease. Clinical observations from a Brazilian cohort indicate that patients with HIV/T. cruzi coinfection, may experience a slower progression of Chagas cardiomyopathy [42]. This observation is consistent with the hypothesis that CD8 + T-cells, principal mediators of cardiac tissue damage, are less activated under Th2 dominance [38]. The role of Th1 and Th2-mediated immunity in HIV/T. cruzi coinfection is extrapolated from studies of HIV and T. cruzi monoinfection. Targeted investigations in coinfected human cohorts and relevant experimental models are therefore needed to validate these inferred relationships and should be prioritized in future research. Moreover, murine models have demonstrated the protective effect of CD40 ligand signaling in T. cruzi infections, providing mechanistic insight into the increased disease risk susceptibility observed in cohorts of people living with HIV [43].

A case report described a patient with an asymptomatic T. cruzi reactivation accompanied by an unexplained rise in the HIV viral load that resolved with antitrypanosomal therapy, suggesting parasite-mediated upregulation of HIV replication [44]. Conversely, in vitro studies have shown that T. cruzi can inhibit HIV replication at several stages within macrophages; however, the clinical significance of this inhibitory effect remains to be defined [45]. Further research is thus needed to better understand the interplay between T. cruzi infection and HIV pathogenesis, particularly the immunologic mechanisms that trigger Chagas reactivation.

Clinical manifestations

Most individuals coinfected with HIV and T. cruzi remain asymptomatic; however, in the setting of profound immunosuppression, the clinical course diverges from that of immunocompetent hosts by exhibiting a markedly increased risk of parasitic reactivation. T. cruzi reactivation in individuals with AIDS occurs almost exclusively with CD4 + counts < 200 cells/mm³. Reactivation most commonly involves the CNS (approximately 75 to 90% of patients), presenting as meningoencephalitis or space-occupying lesions (i.e., chagomas) [3, 21, 36].

Central nervous system reactivation represents the most severe and fatal form of T. cruzi reactivation. Fever, headache, seizures, altered mental status, and focal neurological deficits are critical clinical clues. Increased intracranial pressure can progress rapidly and contribute to irreversible neurologic damage. The clinical presentation can be confused with other opportunistic infections that affect the CNS, such as toxoplasmosis, cryptococcosis, tuberculosis, nocardiosis, and primary CNS lymphoma, among others. A retrospective study showed that patients with CNS involvement exhibit markedly lower CD4 + counts (median 29 cells/mm³) compared with those experiencing milder forms of reactivation (median 241 cells/mm³) [46].

Cardiac involvement is observed in approximately 44% of coinfected patients, and may range from clinically silent to rapidly progressive myocarditis presenting with acute decompensated heart failure [36]. Reactivation has also been documented in the pericardium [47], peritoneum [48], skin [49], intestine [47, 50], and cervix [51].

A distinct subgroup of HIV/T. cruzi coinfection is characterized by mild, oligosymptomatic reactivation. A retrospective multicenter study found that these patients generally have higher CD4 + counts and achieve better outcomes after antiparasitic therapy than those with CNS reactivation, thus highlighting the importance of recognizing T. cruzi reactivation [46].

Offspring born to mothers coinfected with HIV/T. cruzi face an elevated risk of developing more severe manifestations of Chagas disease, including neurologic or cardiac involvement [33, 52]. There is also an increased proportion of spontaneous abortions, stillbirths, and low birth weight [53].

Diagnosis

Current guidelines for the diagnosis of chronic Chagas disease recommend the same approach for people with and without HIV. Laboratory confirmation requires at least two positive results from different serologic methodologies targeting distinct antigens [54]. Available serologic techniques include ELISA (mean sensitivity 95.2%, mean specificity 96.4%), chemiluminescence (mean sensitivity 91.2%, mean specificity 99.9%), immunochromatographic rapid diagnostic tests (mean sensitivity 94.7%, mean specificity 91.8%), indirect hemagglutination (mean sensitivity 95.5%, mean specificity 91.3%), and indirect immunofluorescence, for which standardized test-performance data are not available) [54, 55]. Western blot has both a mean sensitivity and specificity of 100%; however, it is generally limited to reference laboratories and research settings due to cost and complexity [55]. Because profound immunosuppression may lead to false-negative serologic results in coinfected individuals, further diagnostic evaluation is warranted in those with a high index of suspicion – particularly when epidemiologic risk factors are present [21, 56].

The approach to the diagnosis of T. cruzi reactivation mirrors that used for acute Chagas disease. Direct parasitological methods are instrumental in settings with a high degree of parasitemia, particularly in acute and congenital infections, as well as in cases of reactivation. Microscopic visualization of the parasite after concentration techniques, such as the Strout method or microhematocrit, improves sensitivity. However, these methods are operator dependent and exhibit variable sensitivity [24]. Although culture techniques and xenodiagnosis offer superior sensitivity, their laborious protocols and prolonged turnaround times (ranging from 30 to 120 days) render them impractical for routine diagnosis [57–59].

Conventional PCR has limited diagnostic value for T. cruzi reactivation, as it frequently yields positive results in chronic infections, including immunocompetent patients. In one series, PCR was positive in 42% of patients with chronic Chagas disease [24, 60]. By contrast, qPCR can detect a rising parasitemia before the development of clinical manifestations and before other diagnostic methodologies become positive [61]. Because the sensitivity of qPCR relies on parasite burden, this method is beneficial for people with poorly controlled HIV, who typically have higher levels of parasitemia [16, 39, 62]. It also has clear utility in solid organ transplant recipients with chronic Chagas disease, for both routine monitoring and for assessment when symptomatic reactivation is suspected. Rising parasite loads on successive assays are considered evidence of reactivation and constitutes an indication for antitrypanosomal treatment [63, 64]. Additionally, qPCR can distinguish between HIV/T. cruzi coinfected patients with active reactivation from those without, supporting its potential role as a criterion for preemptive therapy in this population [59]. Quantitative PCR has also demonstrated utility in confirming parasitological clearance following benznidazole therapy in individuals with HIV/T. cruzi coinfection [65, 66]. In addition, digital droplet PCR has emerged as a novel approach that enables the absolute quantification of genetic material by partitioning samples into discrete droplets. This method offers high sensitivity and specificity; its disadvantages include cost, lack of validation, and signal saturation at moderate levels of parasitemia [67].

Furthermore, the Chagas urine nanoparticle test (Chunap), which measures T. cruzi antigenuria, is particularly promising because urine antigen levels correlate with parasitemia, exhibits less variability than direct quantification of parasitemia, it is non-invasive, and it does not require expensive equipment [58]. A complementary molecular approach—sequencing of the internal transcribed spacer 2 and D2 regions of the 28S ribosomal RNA gene—can confirm CNS reactivation in patients with HIV presenting with neurologic symptoms and a cerebral mass. In well-resourced settings, this method provides a rapid and sensitive diagnostic option when microscopy and serology are inconclusive [68]. However, because ribosomal RNA may also be detectable in chronic infection, sequencing should be interpreted cautiously and only within the appropriate clinical context. Further studies are thus needed to assess its ability to distinguish chronic infection from early reactivation.

T. cruzi loop-mediated isothermal amplification (Tc-LAMP) represents a new diagnostic approach that has shown a 63% sensitivity and 100% specificity while enabling rapid detection without the specialized instrumentation required for PCR. [57]. Nevertheless, intermittent parasitemia in chronic Chagas disease may limit the ability of Tc-LAMP to discriminate chronic infection and reactivation. Its most promising application may be as a tool for monitoring parasitological response to antiparasitic therapy [60, 69].

Central nervous system reactivation of T. cruzi should be suspected in patients with AIDS who present with new neurologic manifestations, particularly when risk factors for T. cruzi infection are present [39]. These risk factors include residence in or origin from endemic areas or a history of blood transfusions or intravenous drug use in endemic settings [3]. Focal neurological findings warrant neuroimaging, with magnetic resonance imaging (MRI) being the modality of choice [3]. MRI typically reveals a single, tumor-like, rim-enhancing hypodense lesion accompanied by mass effect and surrounding edema. Differentiation from other opportunistic intracranial processes in patients with AIDS can be difficult, most notably from toxoplasmosis, but also from primary CNS lymphoma, progressive multi-focal leukoencephalopathy, tuberculomas, cryptococcomas, and pyogenic abscess [70]. Lesions due to T. cruzi are most often localized in the supratentorial white matter, whereas Toxoplasma gondii preferentially involves the cerebral cortex and basal ganglia [36, 71]. Moreover, coinfection with T. gondii and T. cruzi may coincide [70, 72].

Normal neuroimaging does not exclude CNS involve ment, as up to 17% of patients with T. cruzi reactivation have unremarkable imaging studies [36]. A definitive diagnosis requires direct demonstration of the parasite; therefore, a lumbar puncture should be performed in all patients without contraindications [36]. In reactivation involving the CNS, trypomastigotes are detected in the cerebrospinal fluid (CSF) in over 80% of cases [36]. CSF fluid analysis generally shows low-to-moderate lymphocytic pleocytosis, proteinorachia, and normal-to-low glucose levels [24, 36]. PCR testing of CSF may also be performed, and when initially positive, serial PCR testing can be used to monitor treatment response [73]. CNS reactivation is associated with the presence of T. cruzi in the peripheral blood, and parasitemia should be evaluated whenever possible [9••]. If non-invasive diagnostic approaches remain inconclusive, brain biopsy should be pursued [3]. Histopathological examination in Chagas meningoencephalitis reveals hemorrhagic necrosis with obliterative angiitis and an abundance of parasites within glial cells, macrophages, and endothelial cells [24, 70].

Cardiac reactivation can be difficult to differentiate from chronic Chagas cardiomyopathy because both present with similar clinical features [24, 74]. The differential diagnoses include HIV-associated myocarditis, myocardial involvement by toxoplasmosis, cytomegalovirus, and other viral etiologies [9••]. Electrocardiographic findings may include arrhythmias or conduction abnormalities, while echocardiography often reveals dilated cardiomyopathy, a reduced ejection fraction, and valvular abnormalities [74]. Cardiac reactivation should be suspected in immunosuppressed individuals who develop sudden-onset cardiac decompensation and have positive results on direct parasitological methods [74]. Histopathology of reactivation shows diffuse or focal myocarditis with a predominantly mononuclear infiltrate, interstitial edema, and intramyocytic and interstitial amastigotes, in contrast to chronic Chagas cardiomyopathy, which is characterized by fibrosing myocarditis [74, 75].

Treatment

Chagas reactivation in patients with AIDS warrants prompt initiation of antitrypanosomal treatment and optimization of antiretroviral therapy [10].

Benznidazole and nifurtimox are the only approved antitrypanosomal agents [76]. Benznidazole constitutes first-line therapy for both chronic and disease reactivation (Table 1) [24, 39]. However, standard dosing may be suboptimal in treating CNS reactivation. An Argentinian case series found that only half of treated patients had detectable CSF benznidazole levels, all of which were below the putative therapeutic threshold of < 2 μg/mL, implying that higher doses may be necessary for adequate CNS penetration [77]. These concerns are compounded by a high incidence of adverse events – affecting up to 50% of individuals with HIV [36] – and by a contraindication to use in pregnancy. Benznidazole is contraindicated in pregnancy due to placental transfer and binding to fetal proteins in animal models [78], as well as reports of cytogenic damage in exposed children [79]. Nonetheless, isolated case reports describe the successful use of benznidazole at 32 weeks of gestation for T. cruzi CNS reactivation, underscoring the need for individualized risk–benefit assessment in this setting [80].

Table 1.

Antitrypanosomal Medications for the Treatment of T. cruzi [24, 93–9,7]

Antitrypanosomal Agent	Dose	Duration	Side Effects	Contraindications
Benznidazole	5–7.5 mg/kg daily in two to three divided doses	60 days	Gastrointestinal: abdominal pain, nausea, vomiting, anorexia Cutaneous: pruritus, rash, DRESS** syndrome, Stevens-Johnson syndrome Hematologic: leukopenia, thrombocytopenia Neurologic: peripheral neuropathy, dysgeusia, insomnia Hepatic: elevated transaminases Arthritis	Hypersensitivity Pregnancy * Use with caution in severe renal and hepatic impairment
Nifurtimox	8–10 mg/kg daily in two to three divided doses	60–90 days	Gastrointestinal: abdominal pain, nausea, vomiting, anorexia Neurologic: headache, amnesia, somnolence, peripheral neuropathy Arthralgia, myalgia Hematologic: leukopenia Dermatologic: pruritic, rash Less well tolerated than benznidazole	Hypersensitivity Pregnancy * Alcohol consumption during use Use with caution in severe renal and hepatic impairment, neurologic and psychiatric conditions, porphyria

^*Risk–benefit should be evaluated given that CNS Chagas reactivation is life-threatening;

^**DRESS - Drug Reaction with Eosinophilia and Systemic Symptoms

Nifurtimox serves as a second-line therapy [24, 39], but is often less well tolerated than benznidazole, primarily because of gastrointestinal side effects [24]. Irrespective of the agent used, prompt initiation of antitrypanosomal therapy is critical. A retrospective study demonstrated that all patients with meningoencephalitis who did not receive anti-parasitic treatment died within 36 h of reactivation diagnosis, underscoring the importance of immediate intervention upon diagnosis [46]. In the event of reactivation following treatment, a repeat course of antitrypanosomal medication is advised [39, 81••], although no consensus exists regarding the use of the same drug versus an alternative.

Several novel compounds and repurposed agents have demonstrated preliminary activity against T. cruzi. There have been reported cases of parasitological cure with azole antifungals itraconazole [82–84], fluconazole, ketoconazole [83], and posaconazole [85], with one case being with adjunctive use of allopurinol [84]. Among these, posaconazole showed promising results in preliminary studies but had only a limited curative effect, both as monotherapy and in combination with benznidazole [86, 87]. Ravuconazole also had suboptimal results in a clinical trial [88]. Another potential direction is the development of newer, more efficient, and better-tolerated nitro-compounds. Fexinidazole outperformed benznidazole and nifurtimox in preliminary studies; however, a recent clinical trial demonstrated poor tolerability [89, 90••]. In vitro studies suggest that protease inhibitors, such as lopinavir and nelfinavir, may have a direct parasiticidal effect against T. cruzi [91]. Phosphodiesterase inhibitors have demonstrated promising activity against T. cruzi both in vitro and in vivo [92]. Additional investigational targets include parasite cysteine proteases, methionyl-tRNA synthetase, and enzymes involved in glycoconjugate biosynthesis [90••]. Rigorous clinical studies are needed to establish the efficacy and safety of these emerging therapies in the management of AIDS-associated Chagas reactivation.

Because uncontrolled HIV is a known risk factor for T. cruzi reactivation, antiretroviral therapy should be started promptly in the setting of reactivation. Only two instances of potential Chagas-related immune reconstitution inflammatory syndrome have been reported; however, the evidence in both cases is inadequate or not conclusively supported by the authors: one manifested as a cerebral chagoma after initiation of antiretroviral therapy [98] and another presented with erythema nodosum [49]. Most published studies and US guidelines recommend immediate initiation of antiretroviral therapy, as rapid initiation has been shown to reduce the risk of reactivation [24, 81, 97, 98]. Conversely, Brazilian guidelines recommend completing at least three weeks of benznidazole due to the small risk of immune reconstitution inflammatory syndrome [9, 97]. Further research is needed to define the optimal timing of antiretroviral therapy initiation.

Both benznidazole and nifurtimox are metabolized by the cytochrome P450 system, creating potentially important pharmacokinetic interactions with certain antiretrovirals [99]. Protease inhibitors inhibit the cytochrome P450 system, while non-nucleoside reverse transcriptase inhibitors (NNRTI) have variable effects (some are inhibitors and some are inducers of the P450 system). Such interactions can alter the levels of antitrypanosomal drugs, potentially increasing toxicity or reducing efficacy. Additionally, co-administration may result in additive toxicities, including 1) cutaneous reactions with NNRTIs, fosamprenavir, and abacavir, 2) leukopenia with nucleoside reverse transcriptase inhibitors, particularly zidovudine, 3) peripheral neuropathy with didanosine or stavudine, and 4) CNS toxicity with efavirenz [100].

Brazilian guidelines recommend systematic parasitological monitoring during and after treatment of reactivation, with 1) weekly direct parasitological tests during treatment, until negative results, 2) following conversion to negative results, perform monthly direct parasitological tests for six months, then at six-month intervals thereafter, and 3) direct parasitological testing whenever an acute sign of infection arises [9, 97]. Argentinian, US, and Spanish guidelines do not provide recommendations for follow-up during treatment [24, 81, 95]. The Brazilian monitoring guidelines offer a practical framework for parasitological surveillance during and after treatment. They can be applied as a monitoring guide for people with HIV and Chagas reactivation, including in non-endemic settings.

Prevention

The World Health Organization endorses a series of measures to prevent T. cruzi infection that are equally applicable to individuals coinfected with HIV and T. cruzi. These strategies include enhanced community education, structural improvements to housing and sanitation, the use of bed-nets, and strict food-handling hygiene protocols [2]. Because intravenous drug use represents a common route of transmission for both HIV and T. cruzi, implementation of needle exchange programs and behavior-modification interventions is essential [3]. Finally, to forestall T. cruzi reactivation in coinfected individuals, prompt initiation and adherence to antiretroviral therapy are critical [39].

Routine screening for chronic T. cruzi infection is recommended for people living with HIV in endemic settings and for immigrant populations originating from T. cruzi endemic countries residing in non-endemic regions [17, 101, 102]. National guidelines in several South American countries, such as Argentina and Brazil, advocate for screening with routine serologic testing for T. cruzi at the time of HIV diagnosis or entry to HIV care [76, 101]. Screening for T. cruzi infection in the US is recommended for individuals who were born in or have lived in Mexico, Central, or South America for at least six months, for those with a first-degree relative diagnosed with Chagas disease, and for individuals who report exposure to triatomine bugs [103]. In the US, it is recommended that screening for T. cruzi infection be incorporated into the standard laboratory panel performed at the initiation of HIV care for individuals born in continental Latin America or to mothers from that region [102]. Patients with a positive screening serologic result may benefit from treatment with benznidazole or nifurtimox [3]. This is supported by a study that demonstrated parasite clearance by qPCR following benznidazole treatment in individuals with HIV without clinical reactivation, indicating that such patients are likely to benefit from preemptive treatment [65••]. Treatment recommendations for acute and chronic T. cruzi infection should be individualized and based on local guidelines.

The efficacy of secondary prophylaxis – employed here as a tertiary prevention strategy to avert T. cruzi reactivation in HIV/T. cruzi coinfected individuals with low CD4 + T-lymphocyte counts—remains uncertain. Evidence is sparse regarding both its benefit and the appropriate timing for discontinuation following immune reconstitution, and existing practices are largely extrapolated from management protocols for other AIDS-related opportunistic infections. In one reported case, benznidazole was discontinued after the patient sustained a CD4 + count consistently above 200 cells/mm³ alongside persistently undetectable HIV viral loads, with no reactivations observed over three years of follow-up [3].

In Argentina, secondary prophylaxis is indicated in patients with CD4 + count < 200 cells/mm³ with either benznidazole or nifurtimox at the standard daily dose given three times weekly, until CD4 + count is above 200 cells/mm³ [95]. Brazilian guidelines also recommend secondary prophylaxis in patients with a CD4 + count of less than 200 cells/mm³. The recommended regimen is benznidazole 2.5 mg/kg/day divided into three doses, three times weekly. However this approach requires validation given the low relapse rate observed among patients receiving highly active antiretroviral treatment [9••]. US guidelines likewise state that the need for secondary prophylaxis remains uncertain [81••]. Prospective research is therefore necessary to determine the true benefit of secondary prophylaxis, optimal duration, and evidence-based criteria for discontinuation following antiretroviral-mediated immune reconstitution.

Conclusion

Chagas disease reactivation in the context of HIV presents substantial diagnostic and therapeutic challenges, including overlapping clinical syndromes with chronic cardiomyopathy, limited CNS drug penetration, high rates of adverse effects, and uncertain benefits and optimal duration of secondary prophylaxis. Current guideline recommendations vary by region, and evidence supporting monitoring strategies and treatment timing remains limited. Priorities for future research include a deeper understanding of the pathophysiological mechanisms underlying T. cruzi reactivation, establishing pharmacokinetic and safety profiles of antitrypanosomal agents in immunosuppressed patients, defining evidence-based protocols for parasitological surveillance and secondary prophylaxis, and determining the optimal timing of antiretroviral initiation to minimize reactivation risk while avoiding immune reconstitution complications. Addressing these gaps—both within and outside endemic regions—is critical to improving outcomes for people with HIV/T. cruzi coinfection.

Abbreviations

AIDS

Acquired immunodeficiency syndrome

CNS

Central nervous system

CSF

Cerebrospinal fluid

HIV

Human immunodeficiency virus

IFN

Interferon

IL

Interleukin

MRI

Magnetic resonance imaging

NNRTI

Non-nucleoside reverse transcriptase inhibitors

US

United States

qPCR

Quantitative polymerase chain reaction

Data Availability

No datasets were generated or analysed during the current study.