tuberculosis hiv : the deadly intersection mi

1. Tuberculosis & HIV :

3. Tuberculosis & HIV Impact of declining Tb cases on Tb control and prevention: “increasing difficulty in assuring proficiency among health care providers in diagnosing and treating Tb disease ..” “ diagnosis of infectious cases may be delayed….resulting in unnecessary transmission..” - CDC Division of Tb Elimination

4. Tuberculosis & HIV HIV: Prevalence in the Caribbean is second only to Sub- Saharan Africa

5. Tuberculosis & HIV Region Adults & Children Adult living with HIV/AIDS Prevalence Rate Sub-Saharan 23.3 million 8.0 % Latin America 1.3 million 0.57 % Caribbean 360,000 1.96% Western Europe 520,000 0.25% North America 920,000 0.56% World HIV/AIDS Statistics by Region, December 1999

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11. Tuberculosis & HIV Implications: two-fold One epidemic ( i.e. HIV ) can potentially drive a second epidemic ( i.e. Tuberculosis ), if one examines the Sub-Saharan model Intersection of both epidemics (i.e. HIV + Tb ) could potentially spawn a third: i.e. Multiple Drug Resistant Tuberculosis ( MDRTb )

12. Tuberculosis & HIV MDRTb : Tb resistant to conventional therapy: specifically Isoniazid ( INH ) and Rifampicin Treatment regimen is six-seven drugs Mortality remains in excess of 80 % Has the potential to infect both HIV and non- HIV populations

13. Tuberculosis & HIV Interaction: HIV interferes with ability to fight Tb, because the virus is lymphotrophic Tuberculosis is felt to impair viral immunity by suppression of alpha-interferon production by T-lymphocytes

14. Tuberculosis & HIV Conversion ( to active Tb disease after infection ) : Non-HIV: following infection, conversion is 5-10% over a lifetime HIV: conversion is 5-10 % per year

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18. Tuberculosis & HIV Epidemiology: The link between HIV and Tb remains a substantial worldwide health problem Tb is the most common lung complication of HIV in developing countries one-third of the new cases of Tb in the last 5 years attributable to HIV

19. Tuberculosis & HIV One -third ( 1/3 ) of the 34.3 million HIV cases worldwide are co-infected with Tuberculosis ( 10.7 million or 0.18% of the world population -1997 ) 70% of these persons are in Sub-Saharan Africa. Tb- leading killer of HIV-infected persons worldwide ( 1/3 of AIDS deaths worldwide ) In most of the developing world, Tb is the most common opportunistic infection in persons living with HIV

20. Tuberculosis & HIV Potential Threat ( Sub - Saharan Model ) : currently 1 - 2 % population in Jamaica is HIV infected i.e. at least 25,000 persons assuming 1/3 to be Tb infected : 8,000 (approx.) conversion to active Tb ( in this population ) is approx. 10% per year i.e. 800 new cases of tuberculosis per year.

21. Tuberculosis & HIV Compared to the general population, HIV infected persons have higher rates of active Tb and higher rates of reactivating inactive Tb due to being immunocompromised

22. Tuberculosis & HIV From the International classification it becomes obvious that : exposure is not synonymous with infection infection is not synonymous with active disease.

24. Tuberculosis & HIV Exposure suggests coming into contact with the organism M.tuberculosis Infection implies having the organism enter your body and then being sequestered / contained / ingested. Active disease implies that the organism can no longer be effectively “contained” by the immune system

25. Tuberculosis & HIV Conversion ( to active Tb disease after infection ) : Non-HIV: following infection, conversion is 5-10% over a lifetime HIV: conversion is 5-10 % per year

26. Tuberculosis & HIV “ CDC calls for Tuberculous Screening and Treatment for All Patients with HIV Infection “ - American Family Physician, March 15, 1999

27. Tuberculosis & HIV Screening : Mantoux testing : used to screen for presence of infection Mantoux testing can be of limited value positive test > / = 5 mm suggests infection However, a negative test has no predictive value ( function of absolute lymphocyte count )

28. Tuberculosis & HIV Screening: Mantoux Testing - Confusion and Controversy Purpose: to identify persons who have been infected - nothing else Confounding factors: immune status, BCG vaccination, previous mantoux testing, cross reactivity with other mycobacterial species.

29. Tuberculosis & HIV Positive results: >/= 5mm HIV positive persons at high risk for HIV close contacts of persons with pulmonary/ laryngeal tuberculosis radiographic evidence of old tuberculosis

30. Tuberculosis & HIV Screening : Mantoux testing can be of limited value positive test > / = 5 mm suggests infection However, a negative test has no predictive value ( function of absolute lymphocyte count )

31. Tuberculosis & HIV Screening: The results of delayed-type hypersensitivity ( DTH ) skin testing should not be used to make decisions on diagnosis and treatment of most HIV-infected patients with suspected tuberculosis. Problems exist with standardization and reproducibility of anergy skin testing methods

32. Tuberculosis & HIV Screening: a DTH ( anergy panel testing ) response in the presence of a negative PPD/ mantoux does not indicate the absence of infection with M tuberculosis Nash DR et al. Anergy in active pulmonary tuberculosis. Chest 1980; 77:32-37 CDC. Anergy skin testing and preventive therapy for HIV-infected persons, revised MMWR 1997; 46 ( RR15): 1-5 Chi etal. Reliability of anergy skin testing in persons with HIV infection. Am J. Respir Crit Care Med 1996; 153: 1982-84

33. Tuberculosis & HIV Screening : sputum smears : used to screen for active disease ( in patients who are infectious ) sputum smear microscopy is the most cost-effective method of screening pulmonary Tb suspects. identifies highly infectious Tb cases WHO Tuberculosis Strategy and Operations

34. Tuberculosis & HIV Acid-fast smears of sputum and mycobacterial blood cultures are more frequently positive in patients with advanced immunocompromise, as the ability to control the extent of mycobacterial involvement wanes.

36. Tuberculosis - Diagnosis AFB smear - most rapid diagnostic test available, simple and economical relatively low sensitivity - > 10,000 bacilli/per ml. required for average technician to detect a “ positive result “ smear negative, culture positive results may frequently be encountered in patients with minimal disease

37. Tuberculosis & HIV Chest X-ray: used to screen for presence of disease Appearance of Tb by CXR is not definable ( diffuse / lobar infiltrates, lung abscess,hilar lymphadenopathy, pleural effusion are all admissible )

38. Tuberculosis & HIV Approaches to Diagnosis: history physical exam radiographic findings mantoux testing recovery of M. tuberculosis

39. Tuberculosis & HIV Approaches to Diagnosis: history: HIV proven or suspected exposure : h/o contact with tuberculosis travel to a high prevalence area significant weight loss, fever of unknown origin, haemoptysis, etc.

40. Tuberculosis & HIV Diagnosis : Pitfalls in Diagnosis of active Tuberculosis: Symptoms / signs are non-specific ( weight loss, fever, night sweats etc. ) Chest X-ray findings not definitive ( may be normal )

41. Tuberculosis & HIV Preliminary Investigations: Chest X-ray, sputum - AFB x 3, mantoux testing

42. Tuberculosis & HIV Chest X-ray: In HIV persons Appearance of Tb by CXR is not definable ( diffuse, lobar infiltrates, lung abscess,hilar lymphadenopathy, pleural effusion are all admissible )

43. Tuberculosis & HIV Mediastinal lymphadenopathy is noted with increasing frequency in HIV-infected persons with Tb as the CD4+ count falls. Mediastinal nodes were present in 34 pts. with CD4 counts < 200/nm prevalence was only 14% in those with CD4 counts > 200/nm Disseminated Tb in the acquired immunodeficiency syndrome era; Am Rev Respir Dis 1991; 144; Hill et al Relationship of the manifestations of tuberculosis to CD4 cell counts in pts with HIV infection Am Rev Respir Dis 1993;148

44. Tuberculosis & HIV Lymphadenopathy ( mediastinal and / or supraclavicular / cervical ) is the most common extrapulmonary manifestation of Tb Its presence should raise the suspicion of Tb and HIV co-infection, especially if the presentation consists of fever and X-ray evidence of mediastinal lymphadenopathy - without parenchymal infiltrates - and pulmonary symptoms are absent

45. Tuberculosis & HIV Less typical: lobar infiltrates, pleural effusions, no abnormality ( primary infection )

46. Tuberculosis & HIV Lymphocytic exudative pleural effusions due to Tb is less commonly observed in pts. With CD4+ counts < 200/nm presumably a committed “pool” of CD4+ cells is essential for the development of the effusion.

48. Centarl bronchiectasis and LULobe cavity

49. RULobe abscess

50. LULobe pneumonia with air bronchograms

51. Tuberculosis & HIV With decreasing CD4+ counts, upper lobe fibrocavitary infiltrates are noted less frequently mid- and lower-zone interstitial and/ or alveolar infiltrates often accompany mediastinal lymphadenopathy, although isolated lymphadenopathy is well recognised Disseminated Tb in the acquired immunodeficiency syndrome era; Am Rev Respir Dis 1991; 144; Hill et al Relationship of the manifestations of tuberculosis to CD4 cell counts in pts with HIV infection Am Rev Respir Dis 1993;148

52. Tuberculosis & HIV Previously thought that reactivation of disease acquired remotely was the major cause of infection. However, restriction-fragment-length-polymorphism analysis of mycobacterial isolates indicates that new infection is responsible for approximately half of all Tb infections in HIV-positive individuals Shulger et al. Issues in the treatment of active Tb in human immunodeficiency infected patients Clin Infect Dis 1999; 28:130-135

53. ARV therapy significantly reduces the subsequent incidence of active TB. Rio de Janeiro 80% reduction (Clin Inf Dis. 2002, 34. 541-6) South Africa CD4 cell count 200- risk ratio 0.18 per 100 PY CD4 cell count 200-350 RR 0.12 per 100 PY

54. Tuberculosis & HIV CD4 count of questionable value - HIV patients at increased risk of Tb, regardless of count Diagnosis of Tb, essentially is established by recovery of viable organisms - acid fast bacilli in sputum smears, gastric washings, bronchial l’avage etc. or finding of caseating granulomas by biopsy

55. Tuberculosis & HIV Systemic dissemination of Tb occurs in direct relationship to the degree of reduction in CD4 + in one large series, extrapulmonary disease was found in more than 70% of pts. with CD4+ counts below 100/nm * * Disseminated Tb in the acquired immunodeficiency syndrome era; Am Rev Respir Dis 1991; 144; Hill et al

56. Tuberculosis & HIV Recovery of M. Tuberculosis: Active disease can only be documented by recovery of viable organisms smears, cultures for acid-fast bacilli collected from sputum samples, preferably on 3 consecutive days

58. Tuberculosis & HIV Other techniques: PCR ( polymerase chain reaction ) TMA (transcription-mediated amplification) both use amplification of nucleic acids directly to avoid delays of culturing - require 5-6 hrs of processing

59. Tuberculosis & HIV Sensitivity of these assays for smear negative specimens is only about 70% non viable organisms may produce positive results

60. Tuberculosis & HIV Prophylaxis vs. Treatment: Prophylaxis indicated for HIV positive persons with Mantoux >/= 5mm, but no evidence of active disease ( i.e. potentially infected persons ) Prophylaxis requires single or dual drug therapy ( INH +/- Rifampicin ) for 6 - 9 months

61. Tuberculosis & HIV Although some studies suggest that anergic pts. with HIV infection are at increased risk of developing active tuberculosis, the effectiveness of isoniazid preventive therapy has not been established in this population and there is no good data to recommend its use CDC. Anergy skin testing and preventive therapy for HIV-infected persons, revised MMWR 1997; 46 ( RR15): 1-5 Whalen et al.Preventive therapy for Tb in HIV-infected Ugandans. N. Engl. J Med 1997; 337: 801-808 Gordin et al. A controlled trial if isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. N. Engl.. J Med 1997: 337: 315-320

62. Tuberculosis & HIV To begin treating or not to begin treating empirically: - delays in establishing diagnosis - difficulty in differentiating from other lung conditions - brief exposure to anti-tuberculosis drugs can foster resistance - empiric treatment probably indicated if patient on steroids

63. Tuberculosis & HIV Treatment indicated for patients with active disease treatment constitutes 6 months of therapy: intensive phase: 4-7 drugs X >2 months (INH, Rifamycin, Ethambutal, Pyrazinamide, Streptomycin, Ciprofloxacin etc) continuation phase: 2-4 drugs X > 4 months ( INH, Rifamycin etc. )

64. Tuberculosis & HIV A 2cm tuberculous cavity typically harbours 100 million bacilli, it usually contains mutants resistant to all antituberculous agents. The probability that a mutant organism is resistant to two antibiotics is the product of the individual frequencies

65. Tuberculosis & HIV Probability of resistances occurring naturally: isoniazid : 1 in 1 million organisms streptomycin : 1 in 1 million organisms rifampin: 1 in 100 million organisms ethambutol: 1 in 100,000 organisms cycloserine: 1 in 10,000 organisms

66. Tuberculosis & HIV Core principle of antituberculous chemotherapy : treatment with multiple drugs curtails the development of resistant organisms If monotherapy is used in a sequential manner, a process of resistance takes place that leads to the development of multi-drug resistant tuberculosis

67. ARV therapy and TB ARV therapy significantly reduces the subsequent incidence of active TB. Rio de Janeiro 80% reduction (Clin Inf Dis. 2002, 34. 541-6) South Africa CD4 cell count 200- risk ratio 0.18 per 100 PY CD4 cell count 200-350 RR 0.12 per 100 PY

68. Tuberculosis & HIV anti- retroviral therapy and anti-tuberculous therapy: drug interactions complicate Tb treatment. Interaction is largely with Rifampicin ( rifamycins ) Regimens with rifampin are shorter, have faster conversion and lower relapse rates than those without HIV-infected Tb patients treated without rifampin may have a higher risk of dying

69. Tuberculosis & HIV Rifamycins: Rifampicin Rifabutin Rifapentin

70. Tuberculosis Four populations of tubercle bacilli in the diseased host: extracellular - cavity wall intracellular - macrophage semidormant -caesum dormant

71. Tuberculosis & HIV Extracellular -high metabolic activity bactericidal drugs, especially isoniazid quickly kills all extracellular bacilli. Which comprise over 90% of bacterial burden

72. Tuberculosis & HIV Intracellular ( macrophage ) - lower metabolic activity Pyrazinamide is highly effective against intracellular organisms

73. Tuberculosis & HIV Semidormant - metabolic activity occurs in spurts Dormant - very low metabolic activity organisms with low metabolic activity are more difficult to destroy therefore treatment must continue for an extended period to kill these organisms, hence the “ continuation phase “

74. Tuberculosis & HIV Rifampicin becomes the star player in this effort since since it is active against all extracellular, intracellular and semidormant bacteria No medication is active against dormant organisms, which are largely kept in check by the immune system

75. Tuberculosis & HIV Rifamycins induce p450, decreasing serum levels of the protease inhibitors Protease inhibitors inhibit p450 system, increasing serum rifamycins levels to possibly toxic levels Net effect is that protease inhibitors may lose their efficacy and rifamycin toxicity may be increased.

76. Tuberculosis & HIV Rifabutin does not induce p450 system as strongly as Rifamycin Protease inhibitors that can be concurrently administered are indinavir and nelfinavir More recently: Ritonavir, Lopinavir, Amprenavir can be given, but with adjusted doses of Rifabutin: 150mg

77. Tuberculosis & HIV NNRTI’s - may inhibit or induce p450 . Efavirenz use supported, but rifabutin dosage must be increased. Nevirapine can be used without dosage adjustment

78. Tuberculosis & HIV Rifampicin is the most potent inducer Rifabutin is the least potent inducer ( CYP450 ) and may be substituted for rifampicin clinical trials have demonstrated comparable safety and efficiency the dose of rifabutin should be reduced from 300 to 150 mg daily in pts. on Protease Inhibitors. CDC. Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR 1998; 48 ( No. RR-5): 1 -63

79. Tuberculosis & HIV Rifampicin becomes the star player in this effort since since it is active against all extracellular, intracellular and semidormant bacteria No medication is active against dormant organisms, which are largely kept in check by the immune system

80. Tuberculosis Intermittent regimens have been found to save time and resources while decreasing some side effects ( e.g. aminoglycosides ) These are administered two or three times a week as Direct Observed Therapy ( DOT )

81. Tuberculosis & HIV Up to 1/3 of patients of co-infected patients on anti-Tb meds will experience paradoxical worsening when antiretroviral therapy is introduced – “ immune reconstitution “ The clinical manifestation is usually fever, intrathoracic and cervical lymphadenopathy, pleural effusions and / or skin lesions usually occurs within 15 days of initiation of therapy Paradoxical worsening of Tb following antiretroviral therapy in pts with AIDS Am. J Respir Crit Care Med 1998; Nariita M et al Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J. Infect Dis 1987; 15: 1-3

82. Tuberculosis & HIV This appears to be associated with a marked drop in HIV viral load even though the peripheral CD4+ remains abnormally reduced Paradoxical reactions have been attributed to strengthening of the host’s delayed hypersensitivity response, a decrease in suppressor mechanisms and / or an increased exposure to mycobacterial antigens following bactericidal Tb chemotherapy

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