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Title: HTLV-I-associated myelopathy : natural history and interventions
Author: Aghakhani Zandjani-Martin, Fabiola
ISNI:       0000 0004 2683 9373
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Background: The human T-lymphotropic virus type 1 (HTLV-1) is associated with HTLV-1-associated myelopathy (HAM)/Tropical Spastic Paraparesis (TSP) and inflammation at other sites. Objectives: of the thesis were to prospectively describe the clinical progression of HAM, document the incidence of all new inflammatory events (IE) in HTLV-1 asymptomatic carriers (AC) and in patients already diagnosed with an HTLV-1 associated inflammatory disease (HAID), explore the clinical and laboratory effects of two therapeutic approaches (anti-inflammatory and HTLV-1 reverse transcription inhibitor) and to detect and quantify extrachromosomal (EC) HTLV-1 DNA circles as markers of HTLV-1 reverse transcriptase (RT) activity in vitro and in vivo. Methods: Prospective clinical study of a cohort of patients with HAID and initially asymptomatic carriers. Treatment of patients with HAM with tenofovir and with intermittent, high dose, intravenous methylpredinosolone. Detection of EC HTLV-1 DNA in peripheral blood mononuclear cells (PBMCs) and MT-2 cell lines through polymerase chain reaction. Treatment of MT-2 cells with tenofovir and the peptide entry inhibitor Pcr-400. Results: The incidence of IE historically associated with HTLV-1 infection was 3.4/100 person years (py) for ACs and 5.9/100 py for patients with HAID (Relative Risk: AC/HAID= 0.58). Idiopathic uveitis was most common but hepatic transaminitis was also commonly observed and described for the first time in association with HAM. Tax expression in conjunction with serum soluble TNF-α-receptor I predicted 97% of patients without IE correctly. Median time from onset of HAM to unilateral walking stick use was 11 years and to wheelchair dependence 18 years. During a median follow up of 3.8 years timed walk (tw) deteriorated in 77% at a mean rate of 2sec/10m/year and 33% of patients needed additional aid. HTLV-1 viral load was stable but higher in those who deteriorated. Age of onset <50 years predicted progression. Treatment with tenofovir was not associated with clinical improvement nor change in viral load. Methylprednisolone improved pain considerably and has been incorporated in routine management of chronic pain in patients with HAM. EC 1LTR DNA circles were detected but did not correlate with HTLV-1 disease status or viral load and levels did not change significantly with in vivo or in vitro treatment. Conclusion: The progression of HAM, even in patients with chronic disease, the increased incidence of other IE and the response to pulsed methylprednisolone implies persistent inflammation that may respond to longterm anti-inflammatory therapy. The low concentration of, and lack of TDF effect in vivo and RT and entry inhibition in vitro on, EC 1 LTR DNA circles argues against a significant role of viral replication in HTLV-1 infection.
Supervisor: Weber, Jonathan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral