Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected patients

Gary Maartens, MBChB, MMed
Section Editor
C Fordham von Reyn, MD
Deputy Editor
Elinor L Baron, MD, DTMH


The intersection of the HIV and tuberculosis (TB) epidemics resulted in a dramatic upsurge in global TB incidence, which peaked around 2005. The greatest burden of HIV-associated TB is borne by sub-Saharan Africa [1].

In high income countries, all forms of TB are regarded as AIDS-defining conditions [2]. In contrast, the World Health Organization (WHO) staging system, used in most low-middle income countries, separates pulmonary TB (stage 3) from extrapulmonary TB (stage 4 or AIDS) [3]. Since TB commonly occurs in immunocompetent people, it is not surprising that TB occurs with a wide range of CD4 counts. The CD4 count determines the incidence as well as the clinical and radiographic presentations of TB [4,5].

The epidemiology, clinical features, and diagnosis of TB in HIV-infected patients will be reviewed here. Prophylaxis and treatment of this disorder are discussed separately. (See "Treatment of latent tuberculosis infection in HIV-infected adults" and "Treatment of pulmonary tuberculosis in HIV-infected adults".)


The World Health Organization (WHO) estimated 9 million new tuberculosis (TB) cases in 2013, 1.1 million of whom were HIV infected with 360,000 deaths [6]. Among people with HIV, the global incidence of new TB cases has declined marginally since 2005, while deaths have declined from a peak of just over 500,000 in 2004 to 320,000 in 2012, largely due to increasing access to antiretroviral therapy (ART). The 2013 estimated incidence of TB by country and the prevalence of HIV in TB cases by country are summarized in the Figures (figure 1 and figure 2). A large proportion of the global burden of HIV-associated TB occurs in sub-Saharan Africa, with 79 percent of new cases of TB and 83 percent of deaths. The burden is particularly high in southern Africa, where some countries have annual TB incidence rates exceeding 1000 per 100,000 population.

Interactions between HIV and tuberculosis — Dual infection with HIV and TB leads to reciprocal interactions that have significant clinical impact.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Aug 26, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Chaisson RE, Martinson NA. Tuberculosis in Africa--combating an HIV-driven crisis. N Engl J Med 2008; 358:1089.
  2. From the Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. JAMA 1993; 269:729.
  3. World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. WHO Press, Geneva, Switzerland 2006.
  4. Jones BE, Young SM, Antoniskis D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993; 148:1292.
  5. Greenberg SD, Frager D, Suster B, et al. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994; 193:115.
  6. World Health Organization. Global Tuberculosis Report 2014. http://www.who.int/tb/publications/global_report/en/ (Accessed on July 07, 2015).
  7. Sonnenberg P, Glynn JR, Fielding K, et al. How soon after infection with HIV does the risk of tuberculosis start to increase? A retrospective cohort study in South African gold miners. J Infect Dis 2005; 191:150.
  8. Geldmacher C, Schuetz A, Ngwenyama N, et al. Early depletion of Mycobacterium tuberculosis-specific T helper 1 cell responses after HIV-1 infection. J Infect Dis 2008; 198:1590.
  9. Wood R, Maartens G, Lombard CJ. Risk factors for developing tuberculosis in HIV-1-infected adults from communities with a low or very high incidence of tuberculosis. J Acquir Immune Defic Syndr 2000; 23:75.
  10. Holmes CB, Wood R, Badri M, et al. CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment. J Acquir Immune Defic Syndr 2006; 42:464.
  11. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989; 320:545.
  12. Corbett EL, Charalambous S, Moloi VM, et al. Human immunodeficiency virus and the prevalence of undiagnosed tuberculosis in African gold miners. Am J Respir Crit Care Med 2004; 170:673.
  13. Shuchman M. Improving global health--Margaret Chan at the WHO. N Engl J Med 2007; 356:653.
  14. Daley CL, Small PM, Schecter GF, et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. N Engl J Med 1992; 326:231.
  15. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575.
  16. Lahey T, Mackenzie T, Arbeit RD, et al. Recurrent tuberculosis risk among HIV-infected adults in Tanzania with prior active tuberculosis. Clin Infect Dis 2013; 56:151.
  17. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999; 353:444.
  18. Huang CC, Tchetgen ET, Becerra MC, et al. The effect of HIV-related immunosuppression on the risk of tuberculosis transmission to household contacts. Clin Infect Dis 2014; 58:765.
  19. López-Gatell H, Cole SR, Hessol NA, et al. Effect of tuberculosis on the survival of women infected with human immunodeficiency virus. Am J Epidemiol 2007; 165:1134.
  20. Badri M, Ehrlich R, Wood R, et al. Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area. Int J Tuberc Lung Dis 2001; 5:225.
  21. Toossi Z, Mayanja-Kizza H, Hirsch CS, et al. Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients. Clin Exp Immunol 2001; 123:233.
  22. Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium tuberculosis on HIV replication. Role of immune activation. J Immunol 1996; 157:1271.
  23. Wolday D, Tegbaru B, Kassu A, et al. Expression of chemokine receptors CCR5 and CXCR4 on CD4+ T cells and plasma chemokine levels during treatment of active tuberculosis in HIV-1-coinfected patients. J Acquir Immune Defic Syndr 2005; 39:265.
  24. Wolday D, Hailu B, Girma M, et al. Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive ethiopians. Int J Tuberc Lung Dis 2003; 7:110.
  25. Vanham G, Edmonds K, Qing L, et al. Generalized immune activation in pulmonary tuberculosis: co-activation with HIV infection. Clin Exp Immunol 1996; 103:30.
  26. Lawn SD, Bekker LG, Wood R. How effectively does HAART restore immune responses to Mycobacterium tuberculosis? Implications for tuberculosis control. AIDS 2005; 19:1113.
  27. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002; 359:2059.
  28. Girardi E, Antonucci G, Vanacore P, et al. Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection. AIDS 2000; 14:1985.
  29. Girardi E, Sabin CA, d'Arminio Monforte A, et al. Incidence of Tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. Clin Infect Dis 2005; 41:1772.
  30. Lawn SD, Badri M, Wood R. Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort. AIDS 2005; 19:2109.
  31. Keiper MD, Beumont M, Elshami A, et al. CD4 T lymphocyte count and the radiographic presentation of pulmonary tuberculosis. A study of the relationship between these factors in patients with human immunodeficiency virus infection. Chest 1995; 107:74.
  32. Gupta A, Wood R, Kaplan R, et al. Tuberculosis incidence rates during 8 years of follow-up of an antiretroviral treatment cohort in South Africa: comparison with rates in the community. PLoS One 2012; 7:e34156.
  33. del Amo J, Moreno S, Bucher HC, et al. Impact of antiretroviral therapy on tuberculosis incidence among HIV-positive patients in high-income countries. Clin Infect Dis 2012; 54:1364.
  34. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 2010; 363:257.
  35. Lawn SD, Wood R, De Cock KM, et al. Antiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in settings with limited health-care resources. Lancet Infect Dis 2010; 10:489.
  36. McIlleron H, Meintjes G, Burman WJ, Maartens G. Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution inflammatory syndrome. J Infect Dis 2007; 196 Suppl 1:S63.
  37. Barnes PF, Bloch AB, Davidson PT, Snider DE Jr. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324:1644.
  38. Yang Z, Kong Y, Wilson F, et al. Identification of risk factors for extrapulmonary tuberculosis. Clin Infect Dis 2004; 38:199.
  39. Leeds IL, Magee MJ, Kurbatova EV, et al. Site of extrapulmonary tuberculosis is associated with HIV infection. Clin Infect Dis 2012; 55:75.
  40. Naing C, Mak JW, Maung M, et al. Meta-analysis: the association between HIV infection and extrapulmonary tuberculosis. Lung 2013; 191:27.
  41. Shafer RW, Kim DS, Weiss JP, Quale JM. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine (Baltimore) 1991; 70:384.
  42. Hudson CP, Wood R, Maartens G. Diagnosing HIV-associated tuberculosis: reducing costs and diagnostic delay. Int J Tuberc Lung Dis 2000; 4:240.
  43. Frye MD, Pozsik CJ, Sahn SA. Tuberculous pleurisy is more common in AIDS than in non-AIDS patients with tuberculosis. Chest 1997; 112:393.
  44. Ansari NA, Kombe AH, Kenyon TA, et al. Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana, 1997-1998. Int J Tuberc Lung Dis 2002; 6:55.
  45. von Reyn CF, Kimambo S, Mtei L, et al. Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality. Int J Tuberc Lung Dis 2011; 15:1087.
  46. Mtei L, Matee M, Herfort O, et al. High rates of clinical and subclinical tuberculosis among HIV-infected ambulatory subjects in Tanzania. Clin Infect Dis 2005; 40:1500.
  47. Rangaka MX, Wilkinson RJ, Glynn JR, et al. Effect of antiretroviral therapy on the diagnostic accuracy of symptom screening for intensified tuberculosis case finding in a South African HIV clinic. Clin Infect Dis 2012; 55:1698.
  48. Sterling TR, Pham PA, Chaisson RE. HIV infection-related tuberculosis: clinical manifestations and treatment. Clin Infect Dis 2010; 50 Suppl 3:S223.
  49. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med 2000; 161:1376.
  50. Lessnau KD, Gorla M, Talavera W. Radiographic findings in HIV-positive patients with sensitive and resistant tuberculosis. Chest 1994; 106:687.
  51. Perlman DC, el-Sadr WM, Nelson ET, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG). Clin Infect Dis 1997; 25:242.
  52. Pastores SM, Naidich DP, Aranda CP, et al. Intrathoracic adenopathy associated with pulmonary tuberculosis in patients with human immunodeficiency virus infection. Chest 1993; 103:1433.
  53. Koh DM, Burn PR, Mathews G, et al. Abdominal computed tomographic findings of Mycobacterium tuberculosis and Mycobacterium avium intracellulare infection in HIV seropositive patients. Can Assoc Radiol J 2003; 54:45.
  54. Sinkala E, Gray S, Zulu I, et al. Clinical and ultrasonographic features of abdominal tuberculosis in HIV positive adults in Zambia. BMC Infect Dis 2009; 9:44.
  55. Santín M, Podzamczer D, Ricart I, et al. Utility of the gallium-67 citrate scan for the early diagnosis of tuberculosis in patients infected with the human immunodeficiency virus. Clin Infect Dis 1995; 20:652.
  56. Cohen T, Murray M, Wallengren K, et al. The prevalence and drug sensitivity of tuberculosis among patients dying in hospital in KwaZulu-Natal, South Africa: a postmortem study. PLoS Med 2010; 7:e1000296.
  57. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed on September 21, 2016).
  58. Monkongdee P, McCarthy KD, Cain KP, et al. Yield of acid-fast smear and mycobacterial culture for tuberculosis diagnosis in people with human immunodeficiency virus. Am J Respir Crit Care Med 2009; 180:903.
  59. Kerkhoff AD, Gupta A, Samandari T, Lawn SD. The proportions of people living with HIV in low and middle-income countries who test tuberculin skin test positive using either a 5 mm or a 10 mm cut-off: a systematic review. BMC Infect Dis 2013; 13:307.
  60. Kerkhoff AD, Kranzer K, Samandari T, et al. Systematic review of TST responses in people living with HIV in under-resourced settings: implications for isoniazid preventive therapy. PLoS One 2012; 7:e49928.
  61. Wilson D, Nachega J, Morroni C, et al. Diagnosing smear-negative tuberculosis using case definitions and treatment response in HIV-infected adults. Int J Tuberc Lung Dis 2006; 10:31.
  62. Conde MB, Soares SL, Mello FC, et al. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis: experience at an acquired immune deficiency syndrome reference center in Rio de Janeiro, Brazil. Am J Respir Crit Care Med 2000; 162:2238.
  63. Conde MB, Loivos AC, Rezende VM, et al. Yield of sputum induction in the diagnosis of pleural tuberculosis. Am J Respir Crit Care Med 2003; 167:723.
  64. Salzman SH, Schindel ML, Aranda CP, et al. The role of bronchoscopy in the diagnosis of pulmonary tuberculosis in patients at risk for HIV infection. Chest 1992; 102:143.
  65. Relkin F, Aranda CP, Garay SM, et al. Pleural tuberculosis and HIV infection. Chest 1994; 105:1338.
  66. Luzze H, Elliott AM, Joloba ML, et al. Evaluation of suspected tuberculous pleurisy: clinical and diagnostic findings in HIV-1-positive and HIV-negative adults in Uganda. Int J Tuberc Lung Dis 2001; 5:746.
  67. Bem C, Patil PS, Elliott AM, et al. The value of wide-needle aspiration in the diagnosis of tuberculous lymphadenitis in Africa. AIDS 1993; 7:1221.
  68. Pithie AD, Chicksen B. Fine-needle extrathoracic lymph-node aspiration in HIV-associated sputum-negative tuberculosis. Lancet 1992; 340:1504.
  69. Bem C. Human immunodeficiency virus-positive tuberculous lymphadenitis in Central Africa: clinical presentation of 157 cases. Int J Tuberc Lung Dis 1997; 1:215.
  70. Munseri PJ, Talbot EA, Bakari M, et al. The bacteraemia of disseminated tuberculosis among HIV-infected patients with prolonged fever in Tanzania. Scand J Infect Dis 2011; 43:696.
  71. Archibald LK, den Dulk MO, Pallangyo KJ, Reller LB. Fatal Mycobacterium tuberculosis bloodstream infections in febrile hospitalized adults in Dar es Salaam, Tanzania. Clin Infect Dis 1998; 26:290.
  72. Reid MJ, Shah NS. Approaches to tuberculosis screening and diagnosis in people with HIV in resource-limited settings. Lancet Infect Dis 2009; 9:173.
  73. Harries AD. Tuberculosis and human immunodeficiency virus infection in developing countries. Lancet 1990; 335:387.
  74. Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 2006; 6:664.
  75. Hassim S, Shaw PA, Sangweni P, et al. Detection of a substantial rate of multidrug-resistant tuberculosis in an HIV-infected population in South Africa by active monitoring of sputum samples. Clin Infect Dis 2010; 50:1053.
  76. Bakari M, Arbeit RD, Mtei L, et al. Basis for treatment of tuberculosis among HIV-infected patients in Tanzania: the role of chest x-ray and sputum culture. BMC Infect Dis 2008; 8:32.
  77. Garay SM. Tuberculosis and HIV infection. Semin Respir Crit Care Med 1995; 16:187.
  78. Yajko DM, Nassos PS, Sanders CA, et al. High predictive value of the acid-fast smear for Mycobacterium tuberculosis despite the high prevalence of Mycobacterium avium complex in respiratory specimens. Clin Infect Dis 1994; 19:334.
  79. Kivihya-Ndugga LE, van Cleeff MR, Githui WA, et al. A comprehensive comparison of Ziehl-Neelsen and fluorescence microscopy for the diagnosis of tuberculosis in a resource-poor urban setting. Int J Tuberc Lung Dis 2003; 7:1163.
  80. Shea YR, Davis JL, Huang L, et al. High sensitivity and specificity of acid-fast microscopy for diagnosis of pulmonary tuberculosis in an African population with a high prevalence of human immunodeficiency virus. J Clin Microbiol 2009; 47:1553.
  81. Schluger NW, Rom WN. The polymerase chain reaction in the diagnosis and evaluation of pulmonary infections. Am J Respir Crit Care Med 1995; 152:11.
  82. Aceti A, Zanetti S, Mura MS, et al. Identification of HIV patients with active pulmonary tuberculosis using urine based polymerase chain reaction assay. Thorax 1999; 54:145.
  83. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999; 340:367.
  84. O'Grady J, Bates M, Chilukutu L, et al. Evaluation of the Xpert MTB/RIF assay at a tertiary care referral hospital in a setting where tuberculosis and HIV infection are highly endemic. Clin Infect Dis 2012; 55:1171.
  85. Boehme CC, Nicol MP, Nabeta P, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet 2011; 377:1495.
  86. Steingart KR, Schiller I, Horne DJ, et al. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2014; :CD009593.
  87. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. Lancet 2014; 383:424.
  88. Cox HS, Mbhele S, Mohess N, et al. Impact of Xpert MTB/RIF for TB diagnosis in a primary care clinic with high TB and HIV prevalence in South Africa: a pragmatic randomised trial. PLoS Med 2014; 11:e1001760.
  89. Small PM, Pai M. Tuberculosis diagnosis--time for a game change. N Engl J Med 2010; 363:1070.
  90. Theron G, Pinto L, Peter J, et al. The use of an automated quantitative polymerase chain reaction (Xpert MTB/RIF) to predict the sputum smear status of tuberculosis patients. Clin Infect Dis 2012; 54:384.
  91. Friedrich SO, Rachow A, Saathoff E, et al. Assessment of the sensitivity and specificity of Xpert MTB/RIF assay as an early sputum biomarker of response to tuberculosis treatment. Lancet Respir Med 2013; 1:462.
  92. Boyles TH, Hughes J, Cox V, et al. False-positive Xpert® MTB/RIF assays in previously treated patients: need for caution in interpreting results. Int J Tuberc Lung Dis 2014; 18:876.
  93. Shah M, Martinson NA, Chaisson RE, et al. Quantitative analysis of a urine-based assay for detection of lipoarabinomannan in patients with tuberculosis. J Clin Microbiol 2010; 48:2972.
  94. Talbot E, Munseri P, Teixeira P, et al. Test characteristics of urinary lipoarabinomannan and predictors of mortality among hospitalized HIV-infected tuberculosis suspects in Tanzania. PLoS One 2012; 7:e32876.
  95. Nakiyingi L, Moodley VM, Manabe YC, et al. Diagnostic accuracy of a rapid urine lipoarabinomannan test for tuberculosis in HIV-infected adults. J Acquir Immune Defic Syndr 2014; 66:270.
  96. Peter JG, Theron G, van Zyl-Smit R, et al. Diagnostic accuracy of a urine lipoarabinomannan strip-test for TB detection in HIV-infected hospitalised patients. Eur Respir J 2012; 40:1211.
  97. Peter JG, Zijenah LS, Chanda D, et al. Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. Lancet 2016; 387:1187.
  98. Lawn SD, Gupta-Wright A. Detection of lipoarabinomannan (LAM) in urine is indicative of disseminated TB with renal involvement in patients living with HIV and advanced immunodeficiency: evidence and implications. Trans R Soc Trop Med Hyg 2016; 110:180.
  99. Minion J, Leung E, Talbot E, et al. Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis. Eur Respir J 2011; 38:1398.
  100. Lawn SD, Kerkhoff AD, Nicol MP, Meintjes G. Underestimation of the True Specificity of the Urine Lipoarabinomannan Point-of-Care Diagnostic Assay for HIV-Associated Tuberculosis. J Acquir Immune Defic Syndr 2015; 69:e144.
  101. Shah M, Hanrahan C, Wang ZY, et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults. Cochrane Database Syst Rev 2016; :CD011420.
  102. http://www.who.int/tb/publications/use-of-lf-lam-tb-hiv/en/ (Accessed on March 16, 2016).