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Collaborative Public Health Field Course January 2010

Collaborative Public Health Field Course January 2010. Lecture # 6 HTLV prevention and comprehensive care of people living with HTLV: challenges for the Brazilian healthcare system Aluisio Segurado Department of Infectious Diseases School of Medicine, University of São Paulo.

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Collaborative Public Health Field Course January 2010

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  1. Collaborative Public Health Field Course January 2010 Lecture # 6 HTLV prevention and comprehensive care of people living with HTLV: challenges for the Brazilian healthcare system AluisioSegurado Department of Infectious Diseases School of Medicine, University of São Paulo

  2. HTLV isolation and identification • HTLV-1 – cell line from ex vivo PBMC and lymphonode cells from patient with T-cell cutaneous lymphoma(Poeisz, 1980) • HTLV-2 – spleen cells from patient with hairy cell leukemia (Kalyanaraman, 1982)

  3. Retroviruses

  4. HTLV INFECTION Clinical and epidemiologic relevance • HTLV-1 – 15 - 20 million carriers worldwide lifetime risk of progression to disease  1- 5% • HTLV-2 – high prevalence in certain population groups low risk of progression to disease Mahieux, 1997; Salemi, 1999; Proietti, 2005

  5. GEOGRAPHICAL DISTRIBUTION HTLV - 1

  6. PREVALENCE OF HTLV-1 INFECTION

  7. GEOGRAPHICAL DISTRIBUTION HTLV - 1 37% (Mueller, 1996)

  8. GEOGRAPHICAL DISTRIBUTION HTLV - 1 <5% (Manns, 1999)

  9. GEOGRAPHICAL DISTRIBUTION HTLV - 1 <5% (Manns, 1999)

  10. GEOGRAPHICAL DISTRIBUTION HTLV - 1 <5% (Gessain, 1996, Sarkodie, 2001)

  11. GEOGRAPHICAL DISTRIBUTION HTLV - 1 <6% (Murphy, 1991)

  12. GEOGRAPHICAL DISTRIBUTION HTLV - 1 <2% (Leon, 2003)

  13. HTLV-1 INFECTION IN BRAZIL Serological screening in blood donors is mandatory since 1993 ESTIMATE: 2,500,000 HTLV-1 carriers Source: Proietti, 2005

  14. HTLV INFECTION SOROPREVALENCE AMONG BRAZILIAN BLOOD DONORS Proietti, 2002

  15. HTLV INFECTIONSOROPREVALENCE STUDIES IN BRAZIL HIV ASYMPTOMATIC CARRIERS 1% Caterino-Araújo, 94 AIDS PATIENTS, SP 10% Casseb, 94 HIV/AIDS PATIENTS, Santos 13.4% Etzel, 2001 MSM, RJ 4% Cortes, 93 COMERCIAL SEX WORKERS, RJ/MG 9% Cortes, 93 Santos 2.3% Bellei, 96 IDU, BA 35.2% Dourado, 98 BLOOD DONORS, SP 0.15% Ferreira Jr, 95 RJ 0.42-0.78% Carvalho, 97 PE 0.6% Loureiro, 96 BA 1.35% Galvão-Castro, 97 PREGNANT WOMEN, BA 0.84% Bittencourt, 2001 POPULATION-BASED SURVEY – Salvador, BA 1.76% Dourado, 2003

  16. HTLV INFECTIONSOROPREVALENCE STUDIES IN BRAZIL Nationwide sentinel study pregnant women

  17. GEOGRAPHICAL DISTRIBUTION HTLV - 1 0.84 – 1.76% (Bittencourt, 2001; Dourado, 2003)

  18. GEOGRAPHICAL DISTRIBUTION HTLV - 2

  19. HTLV- 1 andHTLV- 2 • GENETIC SIMILARITY = 65 % • GENOTYPIC VARIANTS

  20. HTLV TRANSMISSION ROUTES • SEXUAL • BLOOD-BORNE – cellular components, IDU • MOTHER-TO-CHILD– breast feeding Kinoshita, 1984; Hino, 1997; Manns, 1992 and 1999; Etzel, 2001

  21. SEXUAL TRANSMISSION • Miyazaki cohort • more efficient from infected males to female susceptible partner • associated with long-term sexual partnerships • associated with age of susceptible female partner • postmenopausal women – more vulnerable • depends on local factors – female genital tract Mueller, 1996

  22. SEXUAL TRANSMISSION • HOST cohort, blood donors, USA • 85 donors: follow-up every 2 years for 10 y (30 HTLV-1+ and 55 HTLV-2+) - steady sexual partnerships • 4 soroconversions  incidence = 0.6 / 100 PYFU (95%CI 0.2 – 1.6) • 2 HTLV-1 / 219 PYFU  0.9 / 100 PYFU (0.1 – 3.3) • 2 HTLV-2 / 411 PYFU  0.4 / 100 PYFU (0.05 – 1.6) • 2 cases M  F and 2 cases F  M Roucoux, 2005

  23. MTCT • Jamaican cohort • associated with anti-HTLV antibody titres (RR = 2.2/quartile) • associated with HTLV proviral load in blood (RR = 1.9/quartile) and breast milk (RR = 2.34/quartile) • dose-response relationship between risk of MTCT by breastfeeding and HLA class I concordance between mother and child • longer survival of maternal cells ? • independent from maternal proviral load, antibody titres and income Hisada, 2002; Li, 2004; Biggar, 2006

  24. HTLV TRANSMISSION Unanswered questions • few quantitative data on incident infections • frequencies vary among populations • frequencies vary in time • impact evaluation of preventive measures • Challenge for prevention low adherence to long-term condom use in steady sexual partnerships

  25. HTLV-1 infection - Natural history - Acute infection Integration to genome Viral persistence – life-long infection Asymptomatic carrier HTLV-1-associated diseases 100% 100% >95% <5%

  26. HTLV-1- RELATED DISEASES • ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL/L) • HTLV-1-ASSOCIATED MYELOPATHY / TROPICAL SPASTIC PARAPARESIS / (HAM/TSP) • INFLAMMATORY SYNDROMES: UVEITIS, ARTHRITIS, POLYMIOSITIS, SJÖGREN SYNDROME, INFECTIVE DERMATITIS, PNEUMONITIS

  27. HTLV-1-RELATED DISEASE IN BRAZIL • ATL/L – Oliveira, 1990 • HAM/TSP – Castro, 1989 Spina-França, 1990

  28. PROGNOSTIC MARKERS – HTLV DISEASE DEVELOPMENT – • Proviral load (Taylor, 99) • Monoclonal expansion of infected CD4+ T cells (Takemoto, 94) • Genetic susceptibility (Jeffery, 99)

  29. PROGNOSTIC FACTORS • Methodological limitations • low prevalence of HTLV infection in many areas • HTLV-related diseases are rare • natural history – long time interval to disease development • few cohorts of asymptomatic carriers

  30. PROGNOSTIC FACTORS • ATL • HLA genetic polymorphisms • Ethnic and family clusters not related to HAM/TSP • ATL-associated (vs. HAM/TSP and asymptomatic carriers) • HLA-A*26, -B*4002, -B*4006 and -B*4801 • less intense CD8+ anti-Tax response Yashiki, 2001

  31. PROGNOSTIC FACTORS • HAM/TSP • HLA genetic polymorphism - Kagoshima cohort • protective haplotypes – HLA-A*02, HLA-CW*08 • associated with lower proviral load • risk-associated haplotypes – HLA-DRB-1, HLA-B54 Saito, 2005

  32. PROGNOSTIC FACTORS • Clinical markers (infective dermatitis) • Mode of exposure to HTLV infection

  33. PROGNOSTIC FACTORS • Risk of ATL = higher for men infected at early ages • varies according to age when infected • Japan > Caribbean • Risk of HAM/TSP = higher for women infected after weaning • Caribbean > Japan

  34. HTLV-2-RELATED DISEASES • CHRONIC MYELOPATHY - HAM/TSP-like • SENSITIVE POLYNEUROPATHIES • INFLAMMATORY MYOPATHIES

  35. SURVIVAL • HOST STUDY • prospective cohort study – blood donors, 5 centers, USA • 152 HTLV-1+, 387 HTLV-2+, and 799 uninfected donors • follow-up visits every 2 years since 1992 • Survival • median follow-up of 8.6 years 45 deaths • HTLV-1 infection - unadjusted HR 1.9 (95%CI 0.8-4.4); adjusted HR 1.9 (95%CI 0.8-4.6) • HTLV-2 infection - unadjusted HR 2.8 (95%CI 1.5-5.5); adjusted HR 2.3 (95%CI 1.1-4.9) Orland, 2004

  36. SURVIVAL • HOST STUDY Orland, 2004

  37. DISEASE OUTCOMES • HOST STUDY • HTLV-2+ donors  acute bronchitis (incidence ratio [IR] = 1.68), bladder or kidney infection (IR = 1.55), arthritis (IR = 2.66), and asthma (IR = 3.28); pneumonia (IR = 1.82, 95% confidence interval [CI] 0.98 to 3.38) • HTLV-1+ participants bladder or kidney infection (IR = 1.82), and arthritis (IR = 2.84) Murphy, 2004

  38. CARE OF PEOPLE LIVING WITH HTLV

  39. CUIDADO/CARE • Diligência, desvelo, zelo – Close attention Sempretevecuidado com seuslivros. He painted the window frames with care. • Encargo, responsabilidade – Watchful oversight, charge/supervision Deixei a encomenda dos livros sob seuscuidados. They left the child in the care of a neighbour. Sources: Aurélio Buarque de Holanda, Portuguese Dictionary www. Thefreedictionary.com

  40. HTLV CARE • Involvement of members of the Brazilian scientific and healthcare communities

  41. HTLV CARE • Involvement of members of the Brazilian scientific and healthcare communities • Governmental initiative

  42. HTLV CARE • Involvement of members of the Brazilian scientific and healthcare communities • Governmental initiative National guidelines, 2004

  43. HTLV CARE • Involvement of members of the Brazilian scientific and healthcare communities • Governmental initiative National guidelines, 2004 available @ <http//www.aids.gov.br

  44. HTLV CARE • How successful have we been so far in providing care to people living with HTLV with the ultimate goal of improving their quality of life?

  45. Challenges • Information about the epidemiology and natural history of HTLV infection is still limited • Access to serodiagnostic tools is not available in many areas (confirmatory tests) • Performance of diagnostic tests • significant proportion of indeterminate results when applied in screening • low sensitivity to detect HTLV-2 infection

  46. Diagnostic algorithm for HTLV-1 and HTLV-2 infections Brazil, Ministry of Health, 2004

  47. Challenges • Alternative algorithms for diagnostic confirmation  molecular biology methods • not available for routine use • not widely available for research • not standardized and lack quality control • operational barriers – nested PCR protocols, detection using radioisotopic probes

  48. INFECTIOUS DISEASES OUTPATIENT CLINICHospital das Clínicas - FMUSP HTLV Clinic • Opened in August 1991 • Clients include • HTLV asymptomatic carriers • HTLV-related diseases

  49. Challenges • Unavailability of a national program to address HTLV prevention and care • Department of HIV/STD/Hepatitis – Ministry of Health • Primary care level

  50. Challenges • Unavailability of a healthcare referral system • prevents patients from accessing standard of care technologies • distresses both patients and healthcare professionals

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