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THE RESULTS OF THE STUDY OF IMPORTANT CLINICAL ASPECTS OF TTV INFECTION: SPECTRUM OF MANIFESTATIONS, ASSOCIATION WITH MINOR IMMUNODEFICIENCIES, EFFICACY OF ARTESUNATE

Background. TT, or Torque teno virus, is a widespread population of DNA-containing simple virus from the Anelloviridae family that can cause both chronic hepatitis and extrahepatic lesions, but is still an under-studied pathogen that lacks effective antiviral drugs. 
Aim of the study: to study the spectrum of clinical phenotype, immune status and efficacy of artesunate in chronic reactivated TTV infection in humans. 
Materials and methods. In this retrospective clinical case study, we examined the results of case histories of 67 patients aged 19 to 52 years (36 men, 31 women) with reactivated TTV infection (PCR data from blood cells) who received artesunate therapy. 38 additional patients with reactivated TTV infection with similar age, gender distribution, and clinical picture who did not receive artesunate constituted the control group. 
Immunological study included the study of indicators of total blood count, subpopulation composition of lymphocytes using laser flow cytofluorimetry (cytofluorometer Epics Xl, USA) and indirect immunofluorescence method with monoclonal antibodies to CD  (CD3+, CD3+ CD4+, CD3+CD8+, CD3-CD19+, CD3-CD16+CD56 +, CD3+CD16+ CD56+) (Beckman Coulter reagents, USA). Phagocytosis was evaluated according to a latex test to determine the index of phagocytosis, the number of active phagocytes and phagocytic blood capacity. Serum immunoglobulin concentrations of the major classes (M, G, A) were determined by Mancini simple radial immunodiffusion. Concentration of IgE, IgD and IgG subclasses (IgG1, IgG2, IgG3, IgG4) in serum was measured by enzyme-linked immunosorbent assay (VectorBEST, RF). Serum mannose binding lectin concentration and myeloperoxidase activity were determined by enzyme immunoassay. 
Within 1 month of therapy, artesunate was administered at a dose of 50 mg twice a day 1 time for 12 hours orally after meals, and for 2-3 months with insufficient effectiveness of the previous course - at a dose of 50 mg three times a day 1 time for 8 hours orally after food. 
Statistical analysis of information was performed using structural and comparative analyzes. Methods of variational statistics were applied with the calculation of the  parametric index of the Student’s T-test with the index of confidence probability p and the nonparametric criterion of the number of signs Z by Urbach Yu.V. 
Results of the study and discussion. Hepatic lesions were reported in only 34%, while non-hepatic forms of the disease - in 66% of cases. Extrahepatic manifestations were determined by chronic fatigue syndrome (34%), neuropsychiatric symptoms associated with temporal mesial sclerosis (32%), mononucleosis-like syndrome (16%), vasculopathy of small cerebral vessels (14%), encephalitis (5% of cases) . All patients were immunocompromised individuals. Only one case was diagnosed with HIV infection, and all other patients suffered from minor immunodeficiencies, including deficiency of natural killer T-lymphocytes (49%), natural killer cells (30%), cytotoxic T-lymphocytes (24%), IgE and/or IgD, mannose-binding lectin (15%), myeloperoxidase (12%), IgA (4%), and idiopathic CD4+ T-cell lymphopenia (3% of cases). Artesunate therapy was effective in 62% of cases (p<0.05; Z<Z0.05), providing removal of virus DNA from blood cells according to PCR for 1-3 months. In 21% of cases there was a partial and 17% - complete resistance of the virus to artesunate. This is 10-15% more effective than previously reported in alpha interferon preparations, with better tolerability and ease of use for artesunate. According to PCR, the mean number of viral particles in blood cells during therapy decreased from 97 to 11 thousand in the sample (p<0.05; Z<Z0.05). 
Conclusions. TTV is not exclusively hepatotropic, but a multitropic opportunistic virus that is reactivated in an immunosuppressed organism, including primary minor immunodeficiencies with damage to various branches of the immune system. Artesunate, given a three-month course of 100-150 mg/day orally, provides the elimination of viral DNA from blood cells in 62% of cases with satisfactory tolerability, so it can be considered as a new promising drug for the treatment of this infection.