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Overview

Overview. Background HIV and tuberculosis syndemic Pathophysiology, clinical manifestations Epidemiology Diagnosis Management What drugs to use When to start ART IRIS and drug interactions Prevention of TB & HIV Advances IPT ART Infection Control Unmet Needs & Recommendations.

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Overview

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  1. Overview • Background • HIV and tuberculosis syndemic • Pathophysiology, clinical manifestations • Epidemiology • Diagnosis • Management • What drugs to use • When to start ART • IRIS and drug interactions • Prevention of TB & HIV Advances • IPT • ART • Infection Control • Unmet Needs & Recommendations

  2. What is a Syndemic? “A set of linked health problems involving two or more afflictions, interacting synergistically, contributing to excess burden of disease in a population.” • Linked epidemics, interacting epidemics, connected epidemics, co-occurring epidemics, co-morbidities, and clusters of health-related crises http://www.medterms.com/script/main/art.asp?articlekey=22591

  3. TB Pathophysiology & Clinical Manifestations

  4. TB Pathophysiology Etiology: Mycobacterium tuberculosis complex Airborne droplets (1-5 μ) ~10% lifetime risk ~36-50% lifetime risk Small PM, Fujiwara PI. N Engl J Med 2001;345:189-200

  5. Clinical Sites of TB 78.7% TB Cases by Site, 2012* • Pulmonary (PTB) 68.5 • Both PTB and EPTB 10.2 • Extrapulmorary (EPTB) 21.1 • Miliary 3.5 * CDC. Reported Tuberculosis in the United States, 2012. Atlanta, GA. Dept HHS Oct 2013

  6. Individual benefits Prevent morbidity and mortality Kill bacilli rapidly (rifamycins play key role) Prevent drug resistance (multidrug therapy) Eliminate persistent bacilli  relapse Public health benefits Prevent transmission (identify contacts in need of treatment for LTBI or active TB) Protect effective drug regimens Goals of Anti-TB Chemotherapy

  7. Epidemiology (TB and HIV-associated associated TB) in U.S. and Globe

  8. Reported TB Cases United States, 1982–2013* 2013 Data 9,588 Cases Rate 3.0/100,000 No. of Cases • 1985-1992 Resurgence • HIV • MDR TB • Immigration • Institutional transmission • Weak infrastructure Year * MMWR 2013;63:229-33

  9. HIV-Associated MDR TB Outbreaks,1988-1995 and 2006 Evidence of institutional MDR TB transmission Hospital KZN, South Africa, 2006 53 100 98 2 Wells CD, et al. J Infect Dis 2007;196:S86-S107; Gandhi NR et al. Lancet 2006;368:1575-80

  10. Reporting of HIV Test Results in Persons with TB by Age Group,United States, 1993 – 2012* % with Test Results *Updated as of June 10, 2013. Note: Includes persons with positive, negative, or indeterminate HIV test results and persons from California with co-diagnosis of TB and AIDS. Rhode Island did not report HIV test results for years 1993–1997. HIV test results for Vermont are not included for years 2007–2010. HIV test results for California are not included for years 2005 - 2010

  11. Estimated HIV Coinfection in Persons Reported with TB, U.S., 1993 – 2012* % Coinfection Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group CDC. Reported Tuberculosis in the United States, 2012. Atlanta, GA. Dept HHS Oct 2013

  12. TB Case Rates by Race/Ethnicity,* United States, 2003–2012** Cases per 100,000 *All races are non-Hispanic. **Updated as of June 10, 2013.

  13. TB Case Rates in U.S.-born vs. Foreign-born Persons, United States,* 1993 – 2012** Cases per 100,000 * TB case-rates presented on a logarithmic scale. **Updated as of June 10, 2013.

  14. HIV Prevalence and IncidenceUnited States, 1980-2010 Number of people living with HIV has grown because incidence is relatively stable and survival has increased Hall HI et al. JAMA 2008 Aug 6;300(5):520-9; Prejean J et al PLoS One 2011;6(8):e17502; MMWR 2012 Mar 2;61(8):133-8.

  15. Estimated Number of Adults and Adolescents Living with HIV Infection and Percent Undiagnosed, U.S., 1985-2008

  16. Estimated HIV prevalence among new TB cases, 2012

  17. Adults and children estimated to be living with HIV, 2012 Eastern Europe & Central Asia 1.3 million [1.0 million – 1.7 million] Western & Central Europe 860 000 [800 000 – 930 000] North America 1.3 million [980 000 – 1.9 million] East Asia 880 000 [650 000 – 1.2 million] Middle East & North Africa 260 000 [200 000 – 380 000] Caribbean 250 000 [220 000 – 280 000] South & South-East Asia 3.9 million [2.9 million – 5.2 million] Sub-Saharan Africa 25.0 million [23.5 million – 26.6 million] Latin America 1.5 million [1.2 million – 1.9 million] Oceania 51 000 [43 000 – 59 000] Total: 35.3 million [32.2 million – 38.8 million]

  18. Estimated HIV-associated TB incidence and mortality globally, 1990-2012 • In 2012: 8.6 million TB cases (1.3 million deaths ) • 1.3 million (13%) with HIV – 75% in AFRO • 450,000 with MDR TB (170,000 deaths)

  19. Diagnosis & Management/ Rx Needs

  20. Clinical Signs & Symptoms - Pulmonary TB Pulmonary Symptoms: Productive, prolonged cough of over 3 weeks duration Chest pain Hemoptysis Systemic Symptoms: Fever Chills Night sweats Appetite loss Weight loss Easy fatigability Armitige LY. U Texas HSC Tyler

  21. Frequency and broad spectrum of lung disease among patients with HIV/AIDS Rapid progression of HIV-related TB and possibility of transmission to others – need for quick diagnosis Effects of immunodeficiency on clinical symptoms and signs of TB Challenges of Diagnosing HIV-related TB Burman WJ. 2008

  22. Challenges in HIV-associated TB Diagnosis • Paucibacillary • Atypical CXR • Extrapulmonary* Treatment • Drug-drug interactions between rifamycins and ARV • Inmune reconstitution inflammatory syndrome * Lymphatic, meningeal, milliary, disseminated (mycobacteremia)

  23. CD4 > 200 Upper lobe, fibronodular Cavitation CD4 < 200 Upper or lower lung field involvement Absence of scarring and cavitation Miliary or nodular infiltrates Intrathoracic adenopathy, with necrosis Pleural and pericardial involvement Effect of HIV-induced Immunosuppression on CXR Presentation of TB

  24. Extrapulmonary manifestations of TB, by CD4+ T-lymphocyte count range Jones BE et al. Am Rev Respir Dis 1993;148:1292-7

  25. Nodal peripheral nodes: cervical > axillary > inguinal central nodes: mediastinal > hilar, intra-abdominal Disseminated disease Serosal - pleural, pericardial > ascites Central nervous system - meningitis, tuberculoma Soft tissue abscesses Common Forms of Extrapulmonary TB in HIV-infected Persons (Burman WJ. 2008) http://generalsurgeryclinics.blogspot.com/2013/02/clinical-pleomorphism-tuberculosis.html

  26. Influenced mostly by degree of immunity HIV-positive patients are more likely to have: Isolated extrapulmonary localization (53-63% in some studies) Primary infection Pulmonary basilar involvement Tuberculous pneumonia Hilar or mediastinal lymphadenopathies Miliary or disseminated TB Normal CXR (8-20% in some studies) Clinical PresentationHIV-positive vs HIV-negative patients Aaron L et al. Clinical Microbiology and Infection 2004;10 (5): 388-98

  27. Options: 1. At time of TB treatment initiation 2. 2-8 weeks after TB medications are started 3. After TB treatment is completed 4. Not at all When Should You Start ART in a Patient with Active TB?

  28. N Engl J Med 2010;365:1471-81

  29. N Engl J Med 2011;362:697-706

  30. PRO: High mortality without ART Beneficial effect of HAART on other OIs ART decreases risk of TB relapse CON: Large pill burden for TB and HIV regimens Drug-drug interactions and toxicity IRIS risk increased Early Timing of ART Therapy in TB-HIV

  31. Ruling Out TB in HIV-infectedBefore Isoniazid Preventive Therapy 151 (61%) of 249 TB cases had two negative AFB smears • Symptoms % Sensitivity • Cough <3wks 33 • Cough or fever or 3wkNS 93 • NPV 97% Cain KP, et al. N Eng J Med 2010;362:707-16

  32. 12–dose Isoniazid and Rifapentine Regimen for LTBI in PLWH Sterling T, et al. CROI 2014. Abstract 817

  33. 1. Start TB therapy: deal with initial side effects 2. Help patient deal with 2 new diagnoses 3. Begin PCP prophylaxis if CD4 < 200 4. Coordinate start of ART: usually 2 weeks after TB treatment start 5. Use DOT visits to  adherence with ART 6. Anticipate and manage IRIS events Starting ART During TB Treatment – Steps Required

  34. Approach to building a regimen: Use a rifamycin Use efavirenz and rifampin as preferred regimen Alternative: Use rifabutin with PI ART and TB Therapy

  35. Modest reduction in EFV levels does not appear to reduce EFV activity EFV-based ART (600 mg) with RIF-based TB therapy is regimen of choice EFV-based ART with RIF-based TB therapy

  36. Rifabutin is as active as rifampin No dose adjustments of ART needed for commonly-used drugs (ATZ, lopinavir/R) Decrease RBT from 300 mg daily to 150 mg thrice-weekly for boosted PIs *Caution– RBT dose would be inadequate if patient stopped PI Rifabutin and TB Therapy

  37. How long should TB treatment be given? 6-9 months* Can intermittent therapy be used in someone with advanced HIV disease? Daily preferred After the intensive phase, can use thrice-weekly Avoid highly-intermittent Rx if CD4 low * Extend treatment to 9 months if culture-positive at 2 months or extensive bilateral cavitary pulmonary disease Summary – Treatment of HIV TB

  38. Should antiretroviral therapy be used during TB treatment? Yes What regimens can be used for co-treatment of HIV and TB? Preferred: efavirenz-based ART + rifampin-based TB treatment Alternative: PI-based ART + rifabutin-based TB treatment When should HAART be started? 2 weeks to 2 months after starting TB treatment Summary-Treatment of HIV TB

  39. Side Effects & Drug-to Drug Interaction

  40. Overlapping Side Effect Profiles of First-line TB drugs and Antiretroviral (ART) Drugs Possible causes Side effect TB drugs ART drugs PZA, RIF, INH PZA, RIF, RBT, INH PZA, RIF, RBT, INH RBT, RIF NVP, EFV, ABC AZT, PIs NVP, PIs, IRIS AZT Skin rash Nausea, vomiting Hepatitis Leukopenia, Anemia, platelet decrease

  41. Immune Reconstitution Inflammatory Syndrome (IRIS) Paradoxical Worsening of TB following ARTHow Common?

  42. Immune Reconstitution Inflammatory Syndrome (IRIS)Possible Risk Factors Manosuthi W et al. Journal of Infection 2006;53:357-363

  43. Diagnosing IRIS Meintjes et al. Lancet Infect Dis 2008;8:516-23.

  44. IRIS Management Exclude treatment failure or new OI Continue anti-TB and ART NSAIDS For severe symptoms: steroids (40 to 80 mg/d) for 5 to 14 weeks Furrer, Am J Med, 1999.

  45. Mansouthi W

  46. Mansouthi W

  47. Mansouthi W

  48. Mansouthi W

  49. Prevention and Treatment Advances

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