Timed walk as primary outcome measure of treatment response in clinical trials for HTLV-1-associated myelopathy: a feasibility study.

BACKGROUND: To advance the treatment of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), randomised controlled therapeutic studies with appropriate and sensitive outcomes are reuired. One candidate outcome is the 10-metre walk test (10MWT), a patient-centred, simple and functional measure. To calculate sample size based on 10MWT as the primary outcome, variability within and between subjects must be known. METHODS: Data on 10MWT from 76 patients with HAM/TSP were prospectively collected from four specialist centres in Brazil, Japan, USA and UK. Data, collected at two time points, 6 months apart, were log transformed and subjected to analysis of covariance. RESULTS: Baseline mean (standard deviation = SD), median 10MWT were 23.5 (18.9), 16.3 s/10 m and at 6 months 24.9 (23.9), 16.4 s/10 m. The mean (SD) % increase in walk time was 5.74 % (28.2 %). After logarithmic transformation, the linear correlation between baseline and 24 weeks 10MWT was r = 0.938. Using these data, it was determined that a randomised controlled trial with 30 participants per group would have 90 % power to detect a 19 % decrease or a 23 % increase in 10MWT. CONCLUSIONS: The intra-patient variability of 10MWT is relatively small in HAM/TSP over 6 months. 10MWT is a feasible outcome measure for a clinical trial in HAM/TSP. To our knowledge, this is the first ever recommendation for the sample size required for trials in HAM/TSP patients.

Ascorbic acid has superior ex vivo antiproliferative, cell death-inducing and immunomodulatory effects over IFN-α in HTLV-1-associated myelopathy.

BACKGROUND: Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP. PRINCIPAL FINDINGS: Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes. CONCLUSIONS: In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.

Keratoconjunctivitis sicca of human T cell lymphotropic virus type 1 (HTLV-1) infected individuals is associated with high levels of HTLV-1 proviral load.

BACKGROUND: A high HTLV-1 proviral load is found in HTLV-1-associated diseases, mainly HAM/TSP. However, the association between proviral load and keratoconjunctivitis sicca (KCS) has not been well established. AIM: To verify the association between KCS and HTLV-1 proviral load. STUDY DESIGN: 104 HTLV-1 infected patients (51 asymptomatic and 52 with HAM/TSP) from the HTLV reference center in Salvador, Brazil were followed from June 2008 to May 2010. Evaluation of tear secretion was performed by BUT (break-up time), Rose Bengal and Schirmer I tests. The diagnosis of KCS was based upon the presence of symptoms and when at least two of three tests were positive. HTLV-1 proviral load was determined using real-time PCR. RESULTS: The prevalence of KCS was 44.2%. KCS was more frequent among HAM/TSP patients (p = 0.022). Patients with KCS had higher proviral load (mean 134,672 ± 150,393copies/10(6) PBMC) than patients without the disease (mean 66,880 ± 109,525copies/10(6) PBMC) (p = 0.001). HTLV-1 proviral load>100,000copies/10(6) PBMC increased significantly the risk of developing KCS (OR = 4.05 and 95% CI = 1.40-11.76). After age>45 years and HAM/TSP status were excluded in stepway reward analysis, the variables PVL>100,000 (OR = 4.77 and 95% CI = 1.83-12.44) still remained statistically significant. CONCLUSION: HTLV-1 proviral loads are higher in patients with KCS and may represent a relevant biological marker of disease.