Tuberculosis and HIV in Children

  • Mark F. CottonEmail author
  • Samantha Fry
  • Shaun Barnabas


Tuberculosis (TB) is a leading cause of morbidity and mortality in both adults and children across the globe. The causative agent, Mycobacterium tuberculosis (M.tb), causes more deaths than any other infectious agent. Human Immunodeficiency Virus (HIV) coinfection contributes greatly to the global burden of TB, particularly in sub-Saharan Africa with increased mortality and morbidity. In the HIV/TB co-infected child, the risk of infection and disease is increased, diagnosis is challenging, and treatment involves high medication burden and complex drug interactions. However, national TB programs, highlighting early identification of childhood case contacts, adequate and appropriate preventative therapy, novel strategies and advancements in TB diagnostics and drug therapy, and early initiation of antiretroviral therapy, are all positive steps toward achieving this goal.

Although a microbiological diagnosis of TB is extremely important for directing anti-TB therapy, it should not be a barrier to either preventing TB infection or treating TB disease where the diagnosis can be supported by contact history, suggestive symptoms and signs and radiological evidence. TB prevention therapy should be implemented whenever a source case is identified and for all HIV-infected individuals over a year of age. Although infection can be identified through skin tests or interferon gamma release assays, the non-availability of these tests should not preclude prevention therapy, once active TB has been excluded. Isoniazid for 6 months is a reasonable option for HIV-infected children as they are in regular follow-up for antiretroviral therapy. Prevention therapy after exposure to a source case with resistant TB must also be implemented.

A microbiological diagnosis for TB remains the gold standard because of increasing drug resistance. Antiretroviral therapy for rifampicin co-treatment requires adaptation for those on lopinavir-ritonavir, which requires super-boosting with additional ritonavir. For those on integrase inhibitors such as raltegravir or dolutegravir, adpatations ae also necessary. For those with drug resistant TB, the main problems are identification and overlapping toxicity between antiretroviral and anti-TB therapy. In spite of renewed focus and better interventions, infants are still vulnerable to TB.

Human Immunodeficiency Virus (HIV) coinfection contributes greatly to the global burden of TB, particularly in sub-Saharan Africa with increased mortality and morbidity. In the HIV/TB co-infected child, the risk of infection and disease is increased, diagnosis is challenging, and treatment involves high medication burden and complex drug interactions. However, national TB programs, highlighting early identification of childhood case contacts, adequate and appropriate preventative therapy, novel strategies and advancements in TB diagnostics and drug therapy, and early initiation of antiretroviral therapy, are all positive steps toward achieving this goal.


HIV Childhood TB Coinfection Rifampicin Drug-drug interactions Microbiological diagnosis 


  1. 1.
    Daniel TM. The history of tuberculosis. Respir Med. 2006;100(11):1862–70. Scholar
  2. 2.
    Centers For Disease Control and Prevention. Pneumocystis carinii pneumonia in Los Angeles. Morb Mortal Wkly Rep. 1981;30:250–2.Google Scholar
  3. 3.
    Centers For Disease Control and Prevention. Unexplained immunodeficiency and opportunistic infections in infants - New York, New Jersey, California. Morb Mortal Wkly Rep. 1982;31:665–7.Google Scholar
  4. 4.
    Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983;220(4599):868–71.CrossRefGoogle Scholar
  5. 5.
    Mann JM, Francis H, Quinn T, et al. Surveillance for AIDS in a central African city. Kinshasa, Zaire. JAMA. 1986;255(23):3255–9.CrossRefGoogle Scholar
  6. 6.
    World Health Organization. Global tuberculosis report. Geneva: World Health Organization; 2018.Google Scholar
  7. 7.
    Chretien J. Tuberculosis and HIV. Bull Int Union Tuberc Lung Dis. 1990;65(1):25–8.PubMedGoogle Scholar
  8. 8.
    Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med. 1995;151(1):129–35. Scholar
  9. 9.
    Fry SH-L, Barnabas SL, Cotton MF. Tuberculosis and HIV—an update on the “cursed duet” in children. Front Pediatr. 2019;7:159. Scholar
  10. 10.
    Martin DJ, Sim JG, Sole GJ, et al. CD4+ lymphocyte count in African patients co-infected with HIV and tuberculosis. J Acquir Immune Defic Syndr Hum Retrovirol. 1995;8:386–91.CrossRefGoogle Scholar
  11. 11.
    Geldmacher C, Ngwenyama N, Schuetz A, et al. Preferential infection and depletion of Mycobacterium tuberculosis-specific CD4 T cells after HIV-1 infection. J Exp Med. 2010;207(13):2869–81. Scholar
  12. 12.
    Daniel OJ, Adejumo OA, Gidado M, Abdur-Razzaq HA, Jaiyesimi EO. HIV-TB co-infection in children: associated factors and access to HIV services in Lagos, Nigeria. Public Health Action. 2015;5(3):165–9. Scholar
  13. 13.
    Madhi SA, Huebner RE, Doedens L, Aduc T, Wesley D, Cooper PA. HIV-1 co-infection in children hospitalised with tuberculosis in South Africa. Int J Tuberc Lung Dis. 2000;4(5):448–54.PubMedGoogle Scholar
  14. 14.
    Jeena PM, Pillay P, Pillay T, Coovadia HM. Impact of HIV-1 co-infection on presentation and hospital-related mortality in children with culture proven pulmonary tuberculosis in Durban. Int J Tuberc Lung Dis. 2002;6(8):672–8.PubMedGoogle Scholar
  15. 15.
    Wiseman CA, Gie RP, Starke JR, et al. A proposed comprehensive classification of tuberculosis disease severity in children. Pediatr Infect Dis J. 2012;31(4):347–52. Scholar
  16. 16.
    Centers For Disease Control and Prevention. Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Morb Mortal Wkly Rep. 1994;43:1–10.Google Scholar
  17. 17.
    World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification for HIV-related disease in adults and children. Geneva: World Health Organization; 2006.Google Scholar
  18. 18.
    Goga A, Chirinda W, Ngoma K, et al. Closing the gaps to eliminate mother-to-child transmission of HIV (MTCT) in South Africa: understanding MTCT case rates, factors that hinder the monitoring and attainment of targets, and potential game changers. S Afr Med J. 2018;108(3 Suppl):S17–24. Scholar
  19. 19.
    King CC, Kourtis AP, Persaud D, et al. Delayed HIV detection among infants exposed to postnatal antiretroviral prophylaxis during breastfeeding. AIDS. 2015;29(15):1953–61. Scholar
  20. 20.
    Kourtis AP, King CC, Nelson J, Jamieson DJ, van der Horst C. Time of HIV diagnosis in infants after weaning from breast milk. AIDS. 2015;29(14):1897–8. Scholar
  21. 21.
    Slogrove AL, Becquet R, Chadwick EG, et al. Surviving and thriving—shifting the public health response to HIV-Exposed Uninfected Children: Report of the 3rd HIV-Exposed Uninfected Child Workshop. Front Pediatr. 2018;6:157. Scholar
  22. 22.
    Afran L, Garcia Knight M, Nduati E, Urban BC, Heyderman RS, Rowland-Jones SL. HIV-exposed uninfected children: a growing population with a vulnerable immune system? Clin Exp Immunol. 2014;176(1):11–22. Scholar
  23. 23.
    Marquez C, Chamie G, Achan J, et al. Tuberculosis infection in early childhood and the association with HIV-exposure in HIV-uninfected children in rural Uganda. Pediatr Infect Dis J. 2016;35(5):524–9. Scholar
  24. 24.
    Bekker A, Preez KD, Schaaf HS, Cotton MF, Hesseling AC. High tuberculosis exposure among neonates in a high tuberculosis and human immunodeficiency virus burden setting. Int J Tuberc Lung Dis. 2012;16(8):1040–6. Scholar
  25. 25.
    Hesseling AC, Westra AE, Werschkull H, et al. Outcome of HIV infected children with culture confirmed tuberculosis. Arch Dis Child. 2005;90(11):1171–4. Scholar
  26. 26.
    Walters E, Cotton MF, Rabie H, Schaaf HS, Walters LO, Marais BJ. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on antiretroviral therapy. BMC Pediatr. 2008;8:1.CrossRefGoogle Scholar
  27. 27.
    Martinson NA, Moultrie H, van Niekerk R, et al. HAART and risk of tuberculosis in HIV-infected South African children: a multi-site retrospective cohort. Int J Tuberc Lung Dis. 2009;13(7):862–7.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359(21):2233–44.CrossRefGoogle Scholar
  29. 29.
    Mangtani P, Abubakar I, Ariti C, et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin Infect Dis. 2014;58(4):470–80. Scholar
  30. 30.
    mondiale de la Santé, Organisation, World Health Organization. BCG vaccines: WHO position paper – February 2018. Wkly Epidemiol Rec. 2018;93(8):73–96.Google Scholar
  31. 31.
    Hesseling AC, Jaspan HB, Black GF, Nene N, Walzl G. Immunogenicity of BCG in HIV-exposed and non-exposed infants following routine birth or delayed vaccination. Int J Tuberc Lung Dis. 2015;19(4):454–62. Scholar
  32. 32.
    Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis. 2004;8(4):392–402.PubMedGoogle Scholar
  33. 33.
    World Health Organization. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018.Google Scholar
  34. 34.
    Marais BJ, Gie RP, Hesseling AC, et al. A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics. 2006;118(5):e1350–9.CrossRefGoogle Scholar
  35. 35.
    World Health Organization, International Union against Tuberculosis and Lung Disease. Guidance for national tuberculosis and HIV programmes on the management of tuberculosis in HIV-infected children: Recommendations for a public health approach. Paris: International Union against Tuberculosis and Lung Disease; 2010.Google Scholar
  36. 36.
    Cobelens FG, Egwaga SM, van Ginkel T, Muwinge H, Matee MI, Borgdorff MW. Tuberculin skin testing in patients with HIV infection: limited benefit of reduced cutoff values. Clin Infect Dis. 2006;43(5):634–9. Scholar
  37. 37.
    Mandalakas AM, Kirchner HL, Walzl G, et al. Optimizing the detection of recent tuberculosis infection in children in a high tuberculosis-HIV burden setting. Am J Respir Crit Care Med. 2015;191(7):820–30. Scholar
  38. 38.
    Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007;334(7585):136.CrossRefGoogle Scholar
  39. 39.
    Madhi SA, Nachman S, Violari A, et al. Effect of primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011;365(1):21–31.CrossRefGoogle Scholar
  40. 40.
    Schaaf HS, Marais BJ, Whitelaw A, et al. Culture-confirmed childhood tuberculosis in Cape Town, South Africa: a review of 596 cases. BMC Infect Dis. 2007;7:140. Scholar
  41. 41.
    Maritz ER, Montepiedra G, Liu L, et al. Source case identification in HIV-exposed infants and tuberculosis diagnosis in an isoniazid prevention study. Int J Tuberc Lung Dis. 2016;20(8):1060–4. Scholar
  42. 42.
    Marais BJ, Hesseling AC, Gie RP, Schaaf HS, Enarson DA, Beyers N. The bacteriologic yield in children with intrathoracic tuberculosis. Clin Infect Dis. 2006;42(8):e69–71.CrossRefGoogle Scholar
  43. 43.
    Chakravorty S, Roh SS, Glass J, et al. Detection of isoniazid-, fluoroquinolone-, amikacin-, and kanamycin-resistant tuberculosis in an automated, multiplexed 10-color assay suitable for point-of-care use. J Clin Microbiol. 2017;55(1):183–98. Scholar
  44. 44.
    Friedrich SO, Venter A, Kayigire XA, Dawson R, Donald PR, Diacon AH. Suitability of Xpert MTB/RIF and genotype MTBDRplus for patient selection for a tuberculosis clinical trial. J Clin Microbiol. 2011;49(8):2827–31. Scholar
  45. 45.
    Nicol MP, Workman L, Isaacs W, et al. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: a descriptive study. Lancet Infect Dis. 2011;11(11):819–24. Scholar
  46. 46.
    Nicol MP, Workman L, Prins M, et al. Accuracy of Xpert Mtb/Rif Ultra for the diagnosis of pulmonary tuberculosis in children. Pediatr Infect Dis J. 2018;37(10):e261–3. Scholar
  47. 47.
    Detjen AK, DiNardo AR, Leyden J, et al. Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in children: a systematic review and meta-analysis. Lancet Respir Med. 2015;3(6):451–61. Scholar
  48. 48.
    Theron G, Venter R, Smith L, et al. False-Positive Xpert MTB/RIF results in retested patients with previous tuberculosis: frequency, profile, and prospective clinical outcomes. J Clin Microbiol. 2018;56(3):e10696–17. Scholar
  49. 49.
    Graham SM, Cuevas LE, Jean-Philippe P, et al. Clinical case definitions for classification of intrathoracic tuberculosis in children: an update. Clin Infect Dis. 2015;61(Suppl 3):S179–87. Scholar
  50. 50.
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67. Scholar
  51. 51.
    Crom WR, Relling MV, Christensen ML, Rivera GK, Evans WE. Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine. Clin Pharmacol Ther. 1991;50(2):132–40.CrossRefGoogle Scholar
  52. 52.
    World Health Organization. Rapid advice. In: Treatment of Tuberculosis in children. Geneva: World Health Organization; 2010.Google Scholar
  53. 53.
    World Health Organization. Technical step process to switch to new paediatric tuberculosis formulations. Geneva: World Health Organization; 2016.Google Scholar
  54. 54.
    World Health Organization. Fixed-dose combinations for the treatment of TB in children. Geneva: World Health Organization; 2018.Google Scholar
  55. 55.
    Daskapan A, Idrus LR, Postma MJ, et al. A systematic review on the effect of HIV infection on the pharmacokinetics of first-line tuberculosis drugs. Clin Pharmacokinet. 2018;58:747. Scholar
  56. 56.
    Wallis RS, Maeurer M, Mwaba P, et al. Tuberculosis—advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers. Lancet Infect Dis. 2016;16(4):e34–46. Scholar
  57. 57.
    World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care. Geneva: World Health Organization; 2017.Google Scholar
  58. 58.
    Chabala C, Turkova A, Thomason MJ, et al. Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial. Trials. 2018;19(1):237. Scholar
  59. 59.
    Willamson B, Dooley KE, Zhang Y, Back DJ, Owen A. Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin, rifabutin and rifapentine. Antimicrob Agents Chemother. 2013;57(12):6366–9. Scholar
  60. 60.
    Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet. 2001;40:327–31.CrossRefGoogle Scholar
  61. 61.
    Oudijk JM, McIlleron H, Mulenga V, et al. Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based antituberculosis treatment. AIDS. 2012;26:1523. Scholar
  62. 62.
    Ramachandran G, Hemanthkumar AK, Rajasekaran S, et al. Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin coadministration. J Acquir Immune Defic Syndr. 2006;42(1):36–41. Scholar
  63. 63.
    Ren Y, Nuttall JJ, Egbers C, et al. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr. 2008;47(5):566–9.CrossRefGoogle Scholar
  64. 64.
    Rabie H, Denti P, Lee J, et al. Lopinavir–ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir–ritonavir without rifampicin: a pharmacokinetic modelling and clinical study. Lancet HIV. 2019;6(1):e32–42. Scholar
  65. 65.
    la Porte CJ, Colbers EP, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother. 2004;48(5):1553–60.CrossRefGoogle Scholar
  66. 66.
    McIlleron H, Ren Y, Nuttall J, et al. Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis. Antivir Ther. 2011;16(3):417–21. Scholar
  67. 67.
    Arrow Trial Team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet. 2013;381(9875):1391–403. Scholar
  68. 68.
    Maartens G, Boffito M, Flexner CW. Compatibility of next-generation first-line antiretrovirals with rifampicin-based antituberculosis therapy in resource limited settings. Curr Opin HIV AIDS. 2017;12(4):355–8. Scholar
  69. 69.
    Grinsztejn B, De Castro N, Arnold V, et al. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014;14(6):459–67. Scholar
  70. 70.
    Dooley KE, Kaplan R, Mwelase N et al. Dolutegravir-Based Antiretroviral Therapy for Patients Co-Infected with Tuberculosis and HIV: A Multicenter, Noncomparative, Open-Label, Randomized Trial Clin Infect Dis 2019 (epub)
  71. 71.
    Krogstad P, Samson P, Meyers T, et al. P1101: phase I/II study of raltegravir containing regimen in HIV-and TB co-treated children aged 6-<12 years. In: 10th International workshop on HIV Pediatrics. Virology Education, Amsterdam; 2018.Google Scholar
  72. 72.
    Dodd PJ, Seddon JA. Global burden of drug-resistant tuberculosis in children: a mathematical modelling study. Lancet Infect Dis. 2016;16:1193. Scholar
  73. 73.
    Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(6):449–56. Scholar
  74. 74.
    Harausz EP, Garcia-Prats AJ, Law S, et al. Treatment and outcomes in children with multidrug-resistant tuberculosis: a systematic review and individual patient data meta-analysis. PLoS Med. 2018;15(7):e1002591. Scholar
  75. 75.
    World Health Organization. WHO treatment guidelines for drug resistant tuberculosis. Geneva: World Health Organization; 2016.Google Scholar
  76. 76.
    Cruz AT, Garcia-Prats AJ, Furin J, Seddon JA. Treatment of multidrug-resistant tuberculosis infection in children. Pediatr Infect Dis J. 2018;37(10):1061–4. Scholar
  77. 77.
    Haddow LJ, Easterbrook PJ, Mosam A, et al. Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort. Clin Infect Dis. 2009;49(9):1424–32. Scholar
  78. 78.
    Smith K, Kuhn L, Coovadia A, et al. Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy. AIDS. 2009;23(9):1097–107. Scholar
  79. 79.
    Rabie H, Lomp A, Goussard P, Nel E, Cotton M. Paradoxical tuberculosis associated immune reconstitution inflammatory syndrome presenting with chylous ascites and chylothorax in a HIV-1 infected child. J Trop Pediatr. 2010;56:355. Scholar
  80. 80.
    Zampoli M, Kilborn T, Eley B. Tuberculosis during early antiretroviral-induced immune reconstitution in HIV-infected children. Int J Tuberc Lung Dis. 2007;11(4):417–23.PubMedGoogle Scholar
  81. 81.
    Rabie H, Violari A, Duong T, et al. BCG immune reconstitution adenitis in HIV-infected infants randomised to early or deferred antiretroviral therapy. Int J Tuberc Lung Dis. 2011;15: 1194–1200.CrossRefGoogle Scholar
  82. 82.
    Meintjies G, Rabie H, Wilkinson RJ, Cotton MF. Tuberculosis associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. In: Clinics in chest medicine, vol. 30. Philadelphia: Saunders; 2009. p. 797–810.Google Scholar
  83. 83.
    Meintjes G, Stek C, Blumenthal L, et al. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS. N Engl J Med. 2018;379(20):1915–25. Scholar
  84. 84.
    van Toorn R, Schaaf HS, Laubscher JA, van Elsland SL, Donald PR, Schoeman JF. Short intensified treatment in children with drug-susceptible tuberculous meningitis. Pediatr Infect Dis J. 2014;33(3):248–52. Scholar
  85. 85.
    Rabie H, Marais BJ, Van Toorn R, Nel ED, Cotton MF. Common opportunistic infections in HIV infected infants and children Part 2 non-respiratory infections. S Afr Fam Pract. 2014;49(2):40–5. Scholar
  86. 86.
    Hesseling AC, Rabie H. Tuberculosis and HIV remain major causes of death in African children. Int J Tuberc Lung Dis. 2016;20(8):996–7. Scholar
  87. 87.
    Rabie H, Frigati L, Hesseling AC, Garcia-Prats AJ. Tuberculosis: opportunities and challenges for the 90-90-90 targets in HIV-infected children. J Int AIDS Soc. 2015;18(7 (Suppl 6)):20236. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.FAM-CRU, Department of Paediatrics and Child Health, Faculty of Medicine and Health SciencesStellenbosch UniversityStellenboschSouth Africa

Personalised recommendations