Toxoplasmic encephalitis (TE), caused by the intracellular protozoan parasite Toxoplasma gondii, is the most common central nervous system (CNS) opportunistic infection (OI) of people living with the human immunodeficiency virus (PLHIV) (1–3). If left untreated, it is a life-threatening condition that may cause different cognitive, psychological, and physical sequelae (4, 5). In Brazil, where clinical management of HIV/AIDS is provided free of charge (6), and despite the fact that the advent of highly active antiretroviral therapy (ART) has significantly decreased the morbidity and mortality of HIV/AIDS (7–9) in the past years, the prevalence of TE is a major cause of hospitalization in PLHIV and still represents a challenge for the healthcare system (10, 11). The treatment of patients with HIV and acute neurological infections (ANI) is challenging and the optimal timing to initiate ART remains a topic of major discussion (12–14).

The Brazilian Ministry of Health recommends the early initiation of ART in all PLHIV, regardless of symptoms and CD4⁺ T cell count, except for those with active meningeal tuberculosis and cryptococcal meningoencephalitis. In these patients, ART should be postponed 4 and 6 weeks after the initiation of tuberculous and fungal treatment, respectively (6). Similar approaches to the initiation of ART in PLHIV can be found in recommendations provided by international panels of experts (15, 16). Studies and data on when to start ART for PLHIV with TE and its impact are scarce. In this study, we aimed to compare major clinical outcomes of early vs. delayed ART initiation time in ART-naïve patients with HIV-associated TE who were admitted to an infectious disease referral center in the Amazonas state, Western Brazilian Amazon.

Opportunistic infections (OIs) are the leading cause of mortality in the HIV population (22). Currently, the evidence to guide ART initiation time in PLHIV in low- and middle-income countries co-infected with OIs is limited and based on studies with different socioeconomic and demographic characteristics (23, 24), as also documented in this study. In these countries, scientific research is limited (25, 26) and management of infectious diseases is challenging (27, 28). To our knowledge, not many studies investigate the association between timing of ART initiation and mortality and prevalence of sequelae in hospitalized patients with HIV and TE, regardless of the potential for CNS infections to cause cognitive and/or motor sequelae (5, 29). Our findings indicate that mortality was similar in both groups, but the prevalence of sequelae was lower in those who started ART after 4 weeks, which suggests an association with a better clinical sequelae profile when starting ART in a delayed manner in this population.

The population in our study has three notable characteristics (i) ART-naïve HIV individuals, (ii) the occurrence of TE as an influential factor on the decision to start ART early or administer treatment for the coinfections first, and (iii) a large proportion of patients who at the time of inclusion in the study already had advanced HIV/AIDS disease, with low CD4⁺ lymphocyte count and CD4⁺/CD8⁺ ratio, and a high viral load. The presence of an ANI in ART-naive patients will always bring major therapeutic challenges associated with the possibility of developing immune reconstitution inflammatory syndrome (IRIS) (30, 31) and complex pharmacokinetic interactions and pharmacological co-toxicities (32, 33), which not only occur between ART and coinfections' treatment but also with drugs used chronically to treat other comorbidities (34, 35).

In several decades of the epidemics, Brazilian health authorities have been concerned with the quality of care offered to people with HIV/AIDS (36, 37). Of note, TE remains a persistent problem in the Amazon (38). Furthermore, the morbimortality due to AIDS continues to exceed the national rate (Amazonas: 6.4%, Brazil: 4.1%) (8). Until 2013, the Brazilian Ministry of Health recommended initiation of ART in symptomatic or asymptomatic individuals with CD4⁺ cells below 350 cells/mm³ (21). At the end of that year, treatment guidelines were updated to recommend ART in all symptomatic PLHIV regardless of the CD4⁺ count, and asymptomatic individuals with CD4⁺ <500 cells/mm³ (20). Currently, Brazilian HIV treatment guidelines recommends the start of ART in all PLHIV, despite clinical presentation and CD4⁺ counts (6). This Brazilian guidelines changes might have influenced the decision of when to start the ART in seven (2012–2018) out of the 9 years of this study period, as well as interfere in which antiretroviral drugs to use, since, as showed in the results, the combination of NRTI plus NNRTI was the most common choice in both groups.

Although the initiation of ART is associated with a lower mortality rate, HIV-infected individuals continue to present late for treatment and care, and consequently initiate ART with low CD4⁺ count and have a significantly higher risk of mortality (39, 40). The mortality rate in our series was 4.9%, which is lower than in a 20-year population based cohort study (31.0%) conducted in Denmark (5), where all TE patients had advanced HIV-disease and approximately 40% knew their serological status. Zolopa et al. (12), in a multicenter randomized trial with PLHIV and OIs, showed a decrease in mortality when ART was initiated within the first 2 weeks after diagnosis, compared to after 4 weeks. However, the study had a higher prevalence of patients with lung infections, not ART-naïve, and the whole population had CD4⁺ counts lower than 200 cells/mm³ and only 13 patients with HIV/TE were included. Similar findings were reported in a Spanish cohort study (13) involving ART-naïve patients with AIDS-defining diseases (with pulmonary infections being the most frequent), where late initiation of ART was associated with faster progression to death. In our study, the data reflect similar findings, in which patients with neurological infections due to T. gondii, who had ART introduced earlier, showed a trend toward lower mortality rates, although not statistically significant differences were demonstrated.

Sequelae can range from impairment of cranial nerves and headache to motor deficits and cognitive disorders (5, 29), occurring in up to 38% of patients (41). Here, sequelae at discharge were significantly more prevalent in the EIT group, indicating that the early start of ART in this population could be detrimental for this population. This could be due to the nature of the TE itself, because although, to our knowledge, no other study has directly addressed the relationship between the onset of ART and the incidence of sequelae, other studies have shown that patients coinfected with HIV-TE present more severe and persistent cognitive and motor deficits when compared with other ANI (23, 42, 43). It seems that early initiation of ART is always beneficial or does not interfere (44, 45), however the number of subjects in several of these studies is reduced in comparison to the present study. We show an elevated prevalence of sequelae, higher than the reported by Erdem et al. (46) (18.5%) regarding a multicenter study of CNS infections, with neurocryptococcosis and neurotuberculosis becoming the most prevalent diseases among 84 patients with HIV (41.6 and 18.5%, respectively). The same scenario is in agreement with the findings of an 11-year French study by Sonneville et al. (4) with PLHIV with TE admitted to the ICU, showing a lower prevalence of sequelae in their population (37.0%).

Our study has several limitations. Its retrospective nature accounts for incomplete data availability on patients' medical charts, mostly due to the absence of detailed targeted investigation, including proper registration of imaging and laboratory studies. The decision to admit patients and clinical management approaches were made at the physician's discretion, and may have resulted in classification bias for some of the outcomes here reported, which were minimized by the choice of hard clinical outcomes. Finally, our study could not fully characterize IRIS, associated with ART introduction, which has been shown to be associated with neurological sequelae and high mortality rates, especially in patients with cerebral tuberculosis and neurocryptococcosis (47, 48). Notwithstanding this, we do not believe that this is a major limitation, since several studies have reported a low incidence of IRIS in HIV-TE coinfection (49, 50), and the early or late introduction of ART does not seem to influence its onset (51, 52).

This is the largest series of cases presenting data on mortality, prevalence of sequelae and secondary neurologic complications in people with HIV and TE. The analyzed data show that early ART initiation in this population might have a detrimental influence on the occurrence of sequelae in these patients. These findings have not been previously reported, as ART initiation in this population has been based on limited availability of clinical evidence (17), routinely within the first 2 weeks after diagnosis and TE treatment. Neurological infections remain a major challenge in Brazil, especially in increasing HIV prevalence scenarios and decreasing government interest in this population's health status. Further studies under controlled conditions to generate evidence are needed to corroborate these findings. Future research also needs to address the chronic complications of those who manage to survive ANI secondary to HIV/AIDS and OIs and provide insights into cognitive and physical disabilities and rehabilitation (53).

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by FMT-HVD Ethics Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

NC-V, ML, WM, and FV: study concept and design. NC-V and PL: acquisition of the data. NC-V, VS, DB-d-S, and FV: analysis of the data. NC-V, DB-d-S, ML, and FV: drafting of the manuscript. NC-V, PL, DB-d-S, VS, BJ, MS, LF, IS, MA, ML, WM, and FV: critical revision of the manuscript and approval of final manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES) and the Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM) RESOLUÇÃO No. 002/2008, 007/2018 e 005/2019—Pró-Estado and RESOLUÇÃO No. 006/2020. WM and ML are CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) fellows. The funders had no role in study design, data collection, manuscript preparation, or decision to publish.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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