Dichotomy in Fatal Outcomes in a Large Cohort of People Living with HTLV-1 in São Paulo, Brazil

Abstract

Background: Despite its relatively low incidence of associated diseases, Human T-cell Leukemia Virus-1 (HTLV-1) infection was reported to carry a significant risk of mortality in several endemic areas. HTLV-1-associated diseases, adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraperesis (HAM/TSP), as well as frequent coinfections with human immunodeficiency virus (HIV), hepatitis C virus (HCV), and Strongyloides stercoralis were associated to increased morbidity and mortality of HTLV-1 infection. Objective: To determine the mortality rate and its associated variables from an open cohort started in July 1997 at the HTLV Clinic, Emilio Ribas Institute (IIER), a major infectious disease hospital in São Paulo, Brazil. Methods: Since inception up to September 2018, we admitted 727 HTLV-1-infected individuals, with a rate of 30–50 new admissions per year. All patient data, including clinical and laboratory data, were regularly updated throughout the 21-year period, using a dedicated REDCap database. The Ethical Board of IIER approved the protocol. Results: During 21 years of clinical care to people living with HTLV-1 in the São Paulo region, we recruited 479 asymptomatic HTLV-1-infected individuals and 248 HAM/TSP patients, of which 632 remained under active follow-up. During a total of 3800 person-years of follow-up (maximum follow-up 21.5 years, mean follow-up 6.0 years), 27 individuals died (median age of 51.5 years), of which 12 were asymptomatic, one ATLL patient and 14 HAM/TSP patients. HAM/TSP diagnosis (but neither age nor gender) was a significant predictor of increased mortality by univariate and multivariate (hazard ratio (HR) 5.03, 95% CI [1.96–12.91], p = 0.001) Cox regression models. Coinfection with HIV/HCV was an independent predictor of increased mortality (HR 15.08; 95% CI [5.50–41.32]; p < 0.001), with AIDS-related infections as a more frequent cause of death in asymptomatics (6/13; p = 0.033). HIV/HCV-negative fatal HAM/TSP cases were all female, with urinary tract infection and decubitus ulcer-associated sepsis as the main cause of death (8/14, p = 0.002). Conclusions: All-cause mortality among people living with HTLV-1 in São Paulo differs between asymptomatic (2.9%) and HAM/TSP patients (7.3%), independent of age and gender. We observe a dichotomy in fatal cases, with HAM/TSP and HIV/HCV coinfection as independent risk factors for death. Our findings reveal an urgent need for public health actions, as the major causes of death, infections secondary to decubitus ulcers, and immune deficiency syndrome (AIDS)-related infections, can be targeted by preventive measures.

Systemic cytokines and GlycA discriminate inflammaging, disease progression and corticosteroid response in HTLV-1-associated neuroinflammation

“…Lifelong chronic infection with other latent viruses (CMV and HIV) causes long-term activation of the immune system over time, contributing to inflammaging [12]. To our knowledge, this study is the first demonstration of inflammaging in PLwHTLV-1, which also corroborates the increased mortality rate we observed in the same cohort [7]. Of interest, none of the cytokines nor GlycA were significantly correlated to proviral load (Fig.…”

“…Currently, no disease-modifying therapy is available for HAM/TSP but corticosteroids and other immunomodulators (IFN-α, cyclosporin) provide some clinical benefit [5,6]. Moreover, we recently demonstrated HAM/TSP is an independent predictor for early mortality among PLwHTLV-1 [7] . As such, biomarkers to predict and/or monitor disease progression for PLwHTLV-1 and therapeutic outcome in HAM/TSP patients are direly needed.…”

Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1–associated myelopathy/tropical spastic paraparesis

“…Based on the metaanalysis by Manouchehrinia et al (30), the SMR for multiple sclerosis, a similarly debilitating but a neurological disorder perhaps better known than HAM/TSP, was 2.80 (95% CI, 2.74 to 2.87), which was much the same to the SMR of HAM/TSP. Of note, the poor prognosis of patients with HAM/TSP has been reported from Brazil as well (31).…”

Blocking HTLV-1/2 silent transmission in Brazil: Current public health policies and proposal for additional strategies

“…In Brazil, the risk of HAM and other neurological diseases is reported to be higher than usual at 5% [ 7 – 9 ]. In addition to the high morbidity, HAM was also identified as a significant predictor of increased mortality in PLHTLV from Brazil (hazard ratio (HR) 5.03, 95% CI 1.96 to 12.91) [ 10 ]. Adult T-cell leukaemia (ATL) is an aggressive neoplasm caused by HTLV-1 with a median survival of 8 months and affects about 4% of carriers [ 11 ].…”